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THIRD EDITION
BRAD W. NEVILLE,
DDS
DOUGLAS D. DAMM,
DDS
Professor
Division of Oral and Maxillofacial Pathology
College of Dentistry
University of Kentucky
Lexington, Kentucky
CARL M. ALLEN,
DDS, MSD
Professor
Department of Pathology
College of Medicine and Public Health
The Ohio State University
Columbus, Ohio
JERRY E. BOUQUOT,
Professor and Chair
Department of Diagnostic Sciences
University of Texas
Dental Branch at Houston
Houston, Texas
Consultant in Pediatric Oral Pathology
Division of Dentistry
Pittsburgh Childrens Hospital
Pittsburgh, Pennsylvania
DDS, MSD
Consultant in Oral Pathology
Department of Pathology
New York Eye and Ear Inrmary
New York, New York
Adjunct Professor
Department of Rural Health and Community
Dentistry
School of Dentistry
West Virginia University
Morgantown, West Virginia
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Contributors
ANGELA C. CHI, DMD
Assistant Professor
Division of Oral and Maxillofacial Pathology
Department of Stomatology
College of Dental Medicine
Medical University of South Carolina
Charleston, South Carolina
Professor
Department of Biomedical Sciences
University of NevadaLas Vegas
School of Dental Medicine
Las Vegas, Nevada
Professor Emeritus
Department of Stomatology
College of Dental Medicine
Medical University of South Carolina
Charleston, South Carolina
vii
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Preface
Oral and maxillofacial pathology is the specialty of
dentistry and the discipline of pathology that addresses
the nature, identication, and management of diseases
affecting the oral and maxillofacial regions. As such, it
occupies a unique position in the health care community for both the dental and medical professions. Naturally, members of the dental profession (including
general practitioners, specialists, and dental hygienists)
must have a good knowledge of the pathogenesis, clinical features, treatment, and prognosis for oral and
paraoral diseases. Likewise, such knowledge is important for those in the medical profession, especially for
physicians who specialize in such areas as otolaryngology, dermatology, and pathology.
ORGANIZATION
The purpose of the third edition of this text remains
the same: to provide the reader with a comprehensive
discussion of the wide variety of diseases that may
affect the oral and maxillofacial region. Oral and Maxillofacial Pathology has been organized to serve as a
primary teaching text, although it should also be a
valuable reference source for the practicing clinician.
Chapters have been created that include disease processes of a similar source (e.g., Bacterial Infections,
Salivary Gland Pathology, Bone Pathology, Dermatologic Diseases), because the basic understanding
of pathology is facilitated by discussing diseases of a
similar nature at the same time. Only after attaining
this basic understanding can the clinician tackle the
difcult task of clinical diagnosis and treatment. With
this in mind, a comprehensive appendix is included
at the end of the book to help the clinician with the
differential diagnosis of oral and maxillofacial disease
processes.
It is impossible to write a book that perfectly matches
the requirements of every reader. Because all the
authors are involved in teaching, the subjects selected
for inclusion in this text primarily reect what is taught
in courses on oral and maxillofacial pathology. Although dental caries is undeniably a common and
important disease affecting the oral cavity, it is usually
not taught in an oral and maxillofacial pathology course;
rather, it is taught elsewhere in most dental schools
curricula. Therefore, we have not included a chapter
on dental caries. Similarly, our discussion on common
gingivitis and periodontitis is limited in scope, although
a more in-depth discussion is provided for other conditions that affect the periodontium. In other areas, the
text offers greater detail than necessary for some
primary courses in oral and maxillofacial pathology.
However, because this book is also intended as a reference source for the practicing clinician, this additional
material has been included.
ACKNOWLEDGMENTS
Obviously, this book could not have been accomplished
without the help of many individuals. We wish to thank
Dr. Edward E. Herschaft, who thoroughly updated his
excellent chapter on forensic dentistry. For this third
edition, we are deeply indebted to Dr. Angela C. Chi,
who revised the chapters on Epithelial Pathology and
Bone Pathology. We are also grateful to Dr. Theresa S.
Gonzales, who updated the chapter on Facial Pain and
Neuromuscular Diseases. We must thank our many
colleagues who shared cases with us, and they have
been credited in the legends of the illustrations.
Although these individuals are too numerous to cite
here, one person in particular, Dr. George Blozis,
deserves special recognition for his generosity in
sharing his excellent teaching collection. We have
attempted to be as thorough as possible in listing credit
ix
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Preface
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BRAD W. NEVILLE
DOUGLAS D. DAMM
CARL M. ALLEN
JERRY E. BOUQUOT
Contents
CHAPTER
CHAPTER
Abnormalities of Teeth,
54
120
Pulpitis, 120
Secondary and Tertiary Dentin, 123
Pulpal Calcications, 126
Periapical Granuloma, 127
Periapical Cyst, 130
Periapical Abscess, 135
Cellulitis, 138
Osteomyelitis, 141
Diffuse Sclerosing Osteomyelitis, 144
Condensing Osteitis, 147
Osteomyelitis with Proliferative Periostitis, 148
Alveolar Osteitis, 150
Developmental Cysts, 25
Palatal Cysts of the Newborn, 26
Nasolabial Cyst, 27
Globulomaxillary Cyst, 28
Nasopalatine Duct Cyst, 28
Median Palatal (Palatine) Cyst, 31
Median Mandibular Cyst, 32
Follicular Cysts of the Skin, 32
Dermoid Cyst, 33
Thyroglossal Duct Cyst, 35
Branchial Cleft Cyst, 36
Oral Lymphoepithelial Cyst, 37
CHAPTER
Periodontal Diseases,
154
Gingivitis, 154
Necrotizing Ulcerative Gingivitis, 157
Plasma Cell Gingivitis, 159
Granulomatous Gingivitis, 160
Desquamative Gingivitis, 162
Drug-Related Gingival Hyperplasia, 163
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Contents
CHAPTER
CHAPTER
181
Impetigo, 181
Erysipelas, 182
Streptococcal Tonsillitis and Pharyngitis, 183
Scarlet Fever, 184
Tonsillar Concretions and Tonsillolithiasis, 185
Diphtheria, 186
Syphilis, 188
Gonorrhea, 193
Tuberculosis, 195
Leprosy, 198
Noma, 201
Actinomycosis, 203
Cat-Scratch Disease, 205
Sinusitis, 207
CHAPTER
CHAPTER
Viral Infections,
213
CHAPTER
Candidiasis, 213
Histoplasmosis, 224
Blastomycosis, 226
Paracoccidioidomycosis, 229
Coccidioidomycosis, 230
Cryptococcosis, 231
Zygomycosis, 232
Aspergillosis, 234
Toxoplasmosis, 235
285
Bacterial Infections,
240
330
10
Epithelial Pathology,
362
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XIII
CHAPTER
11
453
Oncocytoma, 480
Oncocytosis, 481
Warthin Tumor, 482
Monomorphic Adenoma, 483
Canalicular Adenoma, 484
Basal Cell Adenoma, 484
Ductal Papillomas, 485
Mucoepidermoid Carcinoma, 487
Intraosseous Mucoepidermoid Carcinoma, 490
Acinic Cell Adenocarcinoma, 491
Malignant Mixed Tumors, 492
Adenoid Cystic Carcinoma, 495
Polymorphous Low-Grade Adenocarcinoma, 497
Salivary Adenocarcinoma, Not Otherwise Specied, 498
CHAPTER
12
507
Fibroma, 507
Giant Cell Fibroma, 509
Epulis Fissuratum, 510
Inammatory Papillary Hyperplasia, 512
Fibrous Histiocytoma, 514
Fibromatosis, 515
Myobroma, 515
Oral Focal Mucinosis, 516
Pyogenic Granuloma, 517
Peripheral Giant Cell Granuloma, 520
Peripheral Ossifying Fibroma, 521
Lipoma, 523
Traumatic Neuroma, 524
Palisaded Encapsulated Neuroma, 525
Neurilemoma, 526
Neurobroma, 528
Neurobromatosis Type I, 529
Multiple Endocrine Neoplasia Type 2B, 532
Melanotic Neuroectodermal Tumor of Infancy, 533
Paraganglioma, 535
Granular Cell Tumor, 536
Congenital Epulis, 537
Hemangioma and Vascular Malformations, 538
Sturge-Weber Angiomatosis, 543
Nasopharyngeal Angiobroma, 544
HemangiopericytomaSolitary Fibrous Tumor, 546
Lymphangioma, 547
Leiomyoma, 549
Rhabdomyoma, 550
Osseous and Cartilaginous Choristomas, 552
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Contents
CHAPTER
13
Hematologic Disorders,
571
CHAPTER
CHAPTER
15
678
14
Bone Pathology,
613
Ameloblastoma, 702
Malignant Ameloblastoma and Ameloblastic Carcinoma, 711
Clear Cell Odontogenic Carcinoma, 712
Adenomatoid Odontogenic Tumor, 713
Calcifying Epithelial Odontogenic Tumor, 716
Squamous Odontogenic Tumor, 718
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xv
CHAPTER
16
Dermatologic Diseases,
741
18
17
CHAPTER
Pemphigus, 765
Paraneoplastic Pemphigus, 769
Mucous Membrane Pemphigoid, 771
Bullous Pemphigoid, 775
Erythema Multiforme, 776
Erythema Migrans, 779
Reactive Arthritis, 781
Lichen Planus, 782
Chronic Ulcerative Stomatitis, 788
Graft-versus-Host Disease, 790
Psoriasis, 793
Lupus Erythematosus, 794
Systemic Sclerosis, 798
CREST Syndrome, 801
Acanthosis Nigricans, 803
CHAPTER
CHAPTER
19
Forensic Dentistry,
EDWARD E. HERSCHAFT
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xvi
Contents
Part 3: Mucosal and Soft Tissue Pathology: Masses or
Enlargements, 926
Part 4: Radiographic Pathology, 929
Part 5: Pathology of Teeth, 934
Index,
937
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1
Developmental Defects of the Oral
and Maxillofacial Region
CHAPTER OUTLINE
Orofacial Clefts
Commissural Lip Pits
Paramedian Lip Pits
Double Lip
Fordyce Granules
Leukoedema
Microglossia
Macroglossia
Ankyloglossia
Lingual Thyroid
Fissured Tongue
Hairy Tongue
Varicosities
Caliber-Persistent Artery
Lateral Soft Palate Fistulas
Coronoid Hyperplasia
Condylar Hyperplasia
Condylar Hypoplasia
Bid Condyle
Exostoses
Torus Palatinus
Torus Mandibularis
Eagle Syndrome
Stafne Defect
DEVELOPMENTAL CYSTS
Palatal Cysts of the Newborn
Nasolabial Cyst
Globulomaxillary Cyst
Nasopalatine Duct Cyst
Median Palatal Cyst
Median Mandibular Cyst
Follicular Cysts of the Skin
Dermoid Cyst
Thyroglossal Duct Cyst
Branchial Cleft Cyst
Oral Lymphoepithelial Cyst
OTHER RARE DEVELOPMENTAL ANOMALIES
Hemihyperplasia
Progressive Hemifacial Atrophy
Segmental Odontomaxillary Dysplasia
Crouzon Syndrome
Apert Syndrome
Mandibulofacial Dysostosis
OROFACIAL CLEFTS
The formation of the face and oral cavity is complex in
nature and involves the development of multiple tissue
processes that must merge and fuse in a highly orchestrated fashion. Disturbances in the growth of these
tissue processes or their fusion may result in the formation of orofacial clefts.
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ORAL
AND
MAXILLOFACIAL PATHOLOGY
Box 1-1
Locus
SKI/MTHFR
TGFB2
TGFA
MSX1
PVRL1
TGFB3
GABRB3
RARA
BCL3
1p36
1q41
2p13
4p16, 4q31, 6p23
11q23
14q24
15q11
17q21
19q13
ENVIRONMENTAL FACTORS
Maternal alcohol consumption
Maternal cigarette smoking
Folic acid deciency
Corticosteroid use
Anticonvulsant therapy
Adapted from Murray JC: Gene/environment causes of cleft lip and/or
palate, Clin Genet 61:248-256, 2002; Eppley BL, van Aalst JA, Robey A
et al: The spectrum of orofacial clefting, Plast Reconstr Surg 115:101e114e, 2005.
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Chapter 1
DEVELOPMENTAL DEFECTS
OF THE
ORAL
AND
MAXILLOFACIAL REGION
Fig. 1-1 Cleft lip (CL). Infant with bilateral cleft of the
upper lip. (Courtesy of Dr. William Bruce.)
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ORAL
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MAXILLOFACIAL PATHOLOGY
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Chapter 1
DEVELOPMENTAL DEFECTS
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ORAL
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MAXILLOFACIAL REGION
improve function and cosmetic appearance. Distraction osteogenesis of the maxilla can prove useful in
patients in whom palatal scarring limits the amount of
advancement possible at the time of osteotomy.
Genetic counseling is important for the patient and
family. In nonsyndromic cases, the risk for cleft development in a sibling or offspring of an affected person
is 3% to 5% if no other rst-degree relatives also are
affected. The risk increases to 10% to 20% if other rstdegree relatives are affected. The risk may be even
higher for those with clefts that are associated with
syndromes, depending on the possible inheritance
pattern.
Fig. 1-6 Commissural lip pit. Depression at the labial
commissure.
CLINICAL FEATURES
Commissural lip pits are usually discovered on routine
examination, and the patient often is unaware of their
presence. These pits may be unilateral or bilateral.
They manifest as blind stulas that may extend to a
depth of 1 to 4 mm (Fig. 1-6). In some cases a small
amount of uid may be expressed from the pit when
the pit is squeezed, presumably representing saliva
from minor salivary glands that drain into the depth of
the invagination.
Unlike paramedian lip pits (described in the following section), commissural lip pits are not associated
with facial or palatal clefts. However, there does appear
to be a signicantly higher prevalence of preauricular
pits (aural sinuses) in these patients.
HISTOPATHOLOGIC FEATURES
Although biopsy rarely is performed for patients with
commissural lip pits, microscopic examination reveals
a narrow invagination lined by stratied squamous epi-
CLINICAL FEATURES
Paramedian lip pits typically appear as bilateral and
symmetric stulas on either side of the midline of the
vermilion of the lower lip (Fig. 1-7). Their appearance
can range from subtle depressions to prominent humps.
These blind sinuses can extend down to a depth of 1.5
cm and may express salivary secretions. Occasionally,
only a single pit is present that may be centrally located
or lateral to the midline.
The greatest signicance of paramedian lip pits is
that they are usually inherited as an autosomal dominant trait in combination with cleft lip (CL) and/or cleft
palate (CP) (van der Woude syndrome). Van der
Woude syndrome is the most common form of syndromic clefting and accounts for 2% of all cases of CL
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ORAL
AND
MAXILLOFACIAL PATHOLOGY
HISTOPATHOLOGIC FEATURES
Microscopic examination of a paramedian lip pit shows
a tract that is lined by stratied squamous epithelium.
Minor salivary glands may communicate with the
sinus. A chronic inammatory cell inltrate often is
noted in the surrounding connective tissue.
DOUBLE LIP
Double lip is a rare oral anomaly characterized by a
redundant fold of tissue on the mucosal side of the lip.
It is most often congenital in nature, but it may be
acquired later in life. Congenital cases are believed to
arise during the second to third month of gestation as
a result of the persistence of the sulcus between the
pars glabrosa and pars villosa of the lip. Acquired
double lip may be a component of Ascher syndrome,
or it may result from trauma or oral habits, such as
sucking on the lip.
CLINICAL FEATURES
In a patient with double lip, the upper lip is affected
much more often than the lower lip; occasionally, both
lips are involved. With the lips at rest, the condition is
usually unnoticeable, but when the patient smiles or
when the lips are tensed, the excess fold of tissue is
visible (Fig. 1-8).
Ascher syndrome is characterized by a triad of
features:
Double lip
Blepharochalasis
Nontoxic thyroid enlargement
In a person with blepharochalasis, recurring edema
of the upper eyelid leads to sagging of the lid at the
outer canthus of the eye (Fig. 1-9). This drooping may
be severe enough to interfere with vision. Both the
double lip and blepharochalasis usually occur abruptly
and simultaneously, but in some cases they develop
more gradually.
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Chapter 1
DEVELOPMENTAL DEFECTS
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HISTOPATHOLOGIC FEATURES
On microscopic examination, double lip shows essentially normal structures. Often there is an abundance
of minor salivary glands. The blepharochalasis of
Ascher syndrome usually shows hyperplasia of the lacrimal glands or prolapse of orbital fat.
Fig. 1-11 Fordyce granules. Lesions at the commissure.
FORDYCE GRANULES
Fordyce granules are sebaceous glands that occur on
the oral mucosa. Similar lesions also have been reported
on the genital mucosa. Because sebaceous glands are
typically considered to be dermal adnexal structures,
those found in the oral cavity often have been considered to be ectopic. However, because Fordyce granules have been reported in more than 80% of the
population, their presence must be considered a normal
anatomic variation.
CLINICAL FEATURES
Fordyce granules appear as multiple yellow or yellowwhite papular lesions that are most common on the
buccal mucosa and the lateral portion of the vermilion
HISTOPATHOLOGIC FEATURES
Except for the absence of associated hair follicles,
Fordyce granules are closely similar to normal sebaceous glands found in the skin. Acinar lobules can be
seen immediately beneath the epithelial surface, often
communicating with the surface through a central duct
(Fig. 1-12). The sebaceous cells in these lobules are
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ORAL
AND
MAXILLOFACIAL PATHOLOGY
LEUKOEDEMA
Leukoedema is a common oral mucosal condition of
unknown cause. It occurs more commonly in blacks
than in whites, supporting the likelihood of an ethnic
predisposition to its development. Leukoedema has
been reported in 70% to 90% of black adults and in 50%
of black children. The prevalence in whites is considerably less, although published reports have ranged from
less than 10% to more than 90%. This variation may
reect differing population groups, examination conditions, and stringency of criteria used to make the diagnosis. At any rate, leukoedema shows a much milder
presentation in whites and often is hardly noticeable.
The difference in racial predilection may be explained
by the presence of background mucosal pigmentation
in blacks that makes the edematous changes more
noticeable.
Because leukoedema is so common, it can reasonably be argued that it represents a variation of normal
rather than a disease. The nding of similar edematous
mucosa in the vagina and larynx further supports
CLINICAL FEATURES
Leukoedema is characterized by a diffuse, gray-white,
milky, opalescent appearance of the mucosa (Fig.
1-13). The surface frequently appears folded, resulting
in wrinkles or whitish streaks. The lesions do not rub
off. Leukoedema typically occurs bilaterally on the
buccal mucosa and may extend forward onto the labial
mucosa. On rare occasions, it can also involve the oor
of the mouth and palatopharyngeal tissues. Leukoedema can be easily diagnosed clinically because the
white appearance greatly diminishes or disappears
when the cheek is everted and stretched (Fig. 1-14).
HISTOPATHOLOGIC FEATURES
Biopsy specimens of leukoedema demonstrate an
increase in thickness of the epithelium, with striking
intracellular edema of the spinous layer (Fig. 1-15).
These vacuolated cells appear large and have pyknotic
nuclei. The epithelial surface is frequently parakeratinized, and the rete ridges are broad and elongated.
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Chapter 1
DEVELOPMENTAL DEFECTS
OF THE
ORAL
AND
MAXILLOFACIAL REGION
MICROGLOSSIA (HYPOGLOSSIA)
CLINICAL FEATURES
Microglossia is an uncommon developmental condition of unknown cause that is characterized by an
abnormally small tongue. In rare instances, virtually
the entire tongue may be missing (aglossia). Isolated
microglossia is known to occur, and mild degrees of
microglossia may be difcult to detect and may go
unnoticed. However, most reported cases have been
associated with one of a group of overlapping conditions known as oromandibular-limb hypogenesis
syndromes. These syndromes feature associated limb
anomalies, such as hypodactylia (i.e., absence of digits)
and hypomelia (i.e., hypoplasia of part or all of a limb).
Other patients have had coexisting anomalies, such
as cleft palate, intraoral bands, and situs inversus. Microglossia frequently is associated with hypoplasia of
the mandible, and the lower incisors may be missing
(Fig. 1-16).
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10
ORAL
AND
MAXILLOFACIAL PATHOLOGY
Box 1-2
Causes of Macroglossia
CONGENITAL AND HEREDITARY
Vascular malformations
Lymphangioma
Hemangioma
Hemihyperplasia
Cretinism
Beckwith-Wiedemann syndrome
Down syndrome
Mucopolysaccharidoses
Neurobromatosis type I
Multiple endocrine neoplasia, type 2B
ACQUIRED
Edentulous patients
Amyloidosis
Myxedema
Acromegaly
Angioedema
Carcinoma and other tumors
MACROGLOSSIA
Macroglossia is an uncommon condition characterized by enlargement of the tongue. The enlargement
may be caused by a wide variety of conditions, including congenital malformations and acquired diseases.
The most frequent causes are vascular malformations
and muscular hypertrophy. Box 1-2 lists the most
common and important causes of macroglossia. Many
of these diseases are discussed in greater detail in subsequent chapters of this book.
CLINICAL FEATURES
Macroglossia most commonly occurs in children and
can range from mild to severe (Fig. 1-17). In infants,
macroglossia may be manifested rst by noisy breathing, drooling, and difculty in eating. The tongue
enlargement may result in a lisping speech. The pressure of the tongue against the mandible and teeth can
produce a crenated lateral border to the tongue (Fig.
1-18), open bite, and mandibular prognathism. If the
tongue constantly protrudes from the mouth, it may
ulcerate and become secondarily infected or may even
undergo necrosis. Severe macroglossia can produce
airway obstruction.
Macroglossia is a characteristic feature of Beckwith-Wiedemann syndrome, a rare hereditary condition that includes many other possible defects, such
as the following:
Omphalocele (i.e., protrusion of part of the intestine through a defect in the abdominal wall at the
umbilicus)
Visceromegaly
Gigantism
Neonatal hypoglycemia
Individuals with Beckwith-Wiedemann syndrome
have an increased risk for several childhood visceral
tumors, including Wilms tumor, adrenal carcinoma,
hepatoblastoma, rhabdomyosarcoma, and neuroblastoma. Facial features may include nevus ammeus of
the forehead and eyelids, linear indentations of the
earlobes, and maxillary hypoplasia (resulting in relative mandibular prognathism). Most examples of Beckwith-Wiedemann syndrome are sporadic, but 10% to
15% of cases show autosomal dominant inheritance
with preferential maternal transmission. The genetic
basis is complex, involving a variety of alterations
within two domains of imprinted growth-regulatory
genes on chromosome 11p15.
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Chapter 1
DEVELOPMENTAL DEFECTS
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11
HISTOPATHOLOGIC FEATURES
CLINICAL FEATURES
ANKYLOGLOSSIA (TONGUE-TIE)
Ankyloglossia is a developmental anomaly of the
tongue characterized by a short, thick lingual frenum
resulting in limitation of tongue movement. It has been
reported to occur in 1.7% to 4.4% of neonates and is
four times more common in boys than in girls. In adults,
mild forms are not unusual, but severe ankyloglossia
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12
ORAL
AND
MAXILLOFACIAL PATHOLOGY
LINGUAL THYROID
During the third to fourth week of fetal life, the thyroid
gland begins as an epithelial proliferation in the oor
of the pharyngeal gut. By the seventh embryonic week,
this thyroid bud normally descends into the neck to its
nal resting position anterior to the trachea and larynx.
The site where this descending bud invaginates later
becomes the foramen cecum, located at the junction of
the anterior two thirds and posterior third of the tongue
in the midline. If the primitive gland does not descend
normally, ectopic thyroid tissue may be found between
the foramen cecum and the epiglottis. Of all ectopic
thyroids, 90% are found in this region.
CLINICAL FEATURES
Based on autopsy studies, small asymptomatic remnants of thyroid tissue can be discovered on the posterior dorsal tongue in about 10% of both men and
women. However, clinically evident or symptomatic
lingual thyroids are much less common and are four
to seven times more frequent in females, presumably
because of hormonal inuences. Symptoms most often
develop during puberty, adolescence, pregnancy, or
menopause. In 70% of cases, this ectopic gland is the
patients only thyroid tissue.
Lingual thyroids may range from small, asymptomatic, nodular lesions to large masses that can block the
airway (Fig. 1-20). The most common clinical symptoms are dysphagia, dysphonia, and dyspnea. The mass
often is vascular, but the physical appearance is variable and there are no reliable features to distinguish it
from other masses that might develop in this area.
Hypothyroidism has been reported in up to 33% of
patients. Many authors say that lingual thyroid enlarge-
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Chapter 1
DEVELOPMENTAL DEFECTS
OF THE
ORAL
AND
FISSURED TONGUE
(SCROTAL TONGUE)
Fissured tongue is a relatively common condition that
is characterized by the presence of numerous grooves,
or ssures, on the dorsal tongue surface. The cause is
uncertain, but heredity appears to play a signicant
role. Evidence indicates that the condition may be
either a polygenic trait or an autosomal dominant
trait with incomplete penetrance. Aging or local
environmental factors also may contribute to its
development.
CLINICAL FEATURES
Patients with ssured tongue exhibit multiple grooves,
or furrows, on the surface of the tongue, ranging from
2 to 6 mm in depth (Fig. 1-21). Considerable variation
can be seen. In the most severe cases, numerous ssures cover the entire dorsal surface and divide the
tongue papillae into multiple separate islands. Some
patients have ssures that are located mostly on the
dorsolateral areas of the tongue. Other patients exhibit
a large central ssure, with smaller ssures branching
outward at right angles. The condition is usually asymptomatic, although some patients may complain of mild
burning or soreness.
Most studies have shown that the prevalence of ssured tongue ranges from 2% to 5% of the overall population. The condition may be seen in children or adults,
but the prevalence and severity appear to increase with
age, with some studies noting the presence of ssured
tongue in as many as 30% of older adults. In some
investigations, a male predilection has been noted.
A strong association has been found between ssured tongue and geographic tongue (see page 779),
with many patients having both conditions. A hereditary basis also has been suggested for geographic
MAXILLOFACIAL REGION
13
HISTOPATHOLOGIC FEATURES
Microscopic examination of ssured tongue reveals
hyperplasia of the rete ridges and loss of the keratin
hairs on the surface of the liform papillae. The papillae vary in size and often are separated by deep grooves.
Polymorphonuclear leukocytes can be seen migrating
into the epithelium, often forming microabscesses in
the upper epithelial layers. A mixed inammatory cell
inltrate is present in the lamina propria.
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14
ORAL
AND
MAXILLOFACIAL PATHOLOGY
CLINICAL FEATURES
Hairy tongue most commonly affects the midline just
anterior to the circumvallate papillae, sparing the
lateral and anterior borders (Fig. 1-22). The elongated
papillae are usually brown, yellow, or black as a result
of growth of pigment-producing bacteria or staining
from tobacco and food. Sometimes most of the dorsal
tongue may be involved, resulting in a thick, matted
appearance (Fig. 1-23). Multiple individual elongated
HISTOPATHOLOGIC FEATURES
On histopathologic examination, hairy tongue is
characterized by marked elongation and hyperparakeratosis of the liform papillae (Fig. 1-25). Usually,
numerous bacteria can be seen growing on the
epithelial surface.
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VARICOSITIES (VARICES)
Varicosities, or varices, are abnormally dilated and
tortuous veins. Age appears to be an important etiologic factor because varices are rare in children but
common in older adults. This suggests that their development may be an age-related degeneration, in which
a loss of connective tissue tone supporting the vessels
occurs. Oral varices have not been associated with systemic hypertension or other cardiopulmonary diseases,
although one study did nd that people with varicose
veins of the legs were more likely to have varicosities
of the tongue.
HISTOPATHOLOGIC FEATURES
CLINICAL FEATURES
The most common type of oral varicosity is the sublingual varix, which occurs in two thirds of people older
than 60 years of age. Sublingual varicosities classically
present as multiple blue-purple, elevated or papular
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CALIBER-PERSISTENT ARTERY
A caliber-persistent artery is a common vascular
anomaly in which a main arterial branch extends up
into the supercial submucosal tissues without a reduction in its diameter. Similar to oral varices, caliberpersistent arteries are seen more frequently in older
adults. This suggests that their development may be an
age-related degenerative phenomenon in which there
is a loss of tone in the surrounding supporting connective tissue.
CLINICAL FEATURES
The caliber-persistent artery occurs almost exclusively
on the lip mucosa. Either lip may be affected, and some
patients have bilateral lesions or lesions on both lips.
The average patient age is 58 years, and the gender
ratio is nearly equal. The lesion presents as a linear,
arcuate, or papular elevation that ranges from pale to
normal to bluish in color (Fig. 1-28). Stretching the lip
usually causes the artery to become inconspicuous. The
unique feature is pulsationnot only vertically but also
in a lateral direction. However, usually it is not possible
HISTOPATHOLOGIC FEATURES
Microscopic examination shows a thick-walled artery
situated close to the mucosal surface (Fig. 1-29).
CLINICAL FEATURES
Lateral soft palate stulas are usually bilateral, but they
may occur only on one side. They are more common on
the anterior tonsillar pillar (Fig. 1-30), but they also may
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Fig. 1-30 Lateral palatal stula. A, Asymptomatic hole in the anterior tonsillar pillar.
B, Periodontal probe has been used to demonstrate the communication of the lesion with the
tonsillar fossa.
involve the posterior pillar. The perforations are typically asymptomatic, ranging from a few millimeters to
more than 1 cm. A few cases have been associated with
other anomalies, such as absence or hypoplasia of the
palatine tonsils, hearing loss, and preauricular stulas.
CORONOID HYPERPLASIA
Hyperplasia of the coronoid process of the mandible
is a rare developmental anomaly that may result
in limitation of mandibular movement. The cause of
coronoid hyperplasia is unknown, but the overall
male-to-female ratio is 5:1. Because most cases have
been seen in pubertal males, an endocrine inuence
has been suggested. Heredity also may play a role,
because cases have been noted in siblings.
Coronoid hyperplasia may be unilateral or bilateral,
although bilateral cases are nearly ve times more
common than unilateral examples. Unilateral enlargement of the coronoid process also can result from a
true tumor, such as an osteoma or osteochondroma,
and such cases should be distinguished from pure coronoid hyperplasia. However, some cases reported as
tumors of the coronoid process actually may have been
hyperplastic processes rather than true neoplasms.
CONDYLAR HYPERPLASIA
Condylar hyperplasia is an uncommon malformation
of the mandible created by excessive growth of one of
the condyles. The cause of this hyperplasia is unknown,
but local circulatory problems, endocrine disturbances,
and trauma have been suggested as possible etiologic
factors.
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CONDYLAR HYPOPLASIA
Condylar hypoplasia, or underdevelopment of the
mandibular condyle, can be either congenital or
acquired. Congenital condylar hypoplasia often is
CLINICAL AND
RADIOGRAPHIC FEATURES
Condylar hyperplasia may manifest itself in a variety
of ways, including facial asymmetry, prognathism,
crossbite, and open bite (Fig. 1-31). Sometimes compensatory maxillary growth and tilting of the occlusal
plane occurs. The condition most commonly is discovered in adolescents and young adults.
The radiographic features are quite variable. Some
patients have an enlargement of the condylar head,
and others show elongation of the condylar neck (Fig.
1-32). Many cases also demonstrate hyperplasia of the
entire ramus, suggesting that the condition sometimes
affects more than just the condyle. Scintigraphy using
99m
Tc-MDP has been advocated as a useful method for
assessing the degree of bone activity in condylar
hyperplasia.
HISTOPATHOLOGIC FEATURES
During active growth, proliferation of the condylar cartilage is noted. Once condylar growth has ceased, the
condyle has a normal histologic appearance.
Fig. 1-32 Condylar hyperplasia. Enlargement of the left mandibular condyle (arrow).
(Courtesy of Dr. Gary Reinhart.)
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CLINICAL AND
RADIOGRAPHIC FEATURES
Condylar hypoplasia can be unilateral or bilateral, producing a small mandible with a Class II malocclusion.
Unilateral hypoplasia results in distortion and depression of the face on the affected side. The mandibular
midline shifts to the involved side when the mouth is
opened, accentuating the deformity. Ankylosis of the
temporomandibular joint (TMJ) can develop in cases
caused by trauma.
The deformity is observed easily on panoramic lms
and can range in severity. In severe cases the condyle
or ramus may be totally absent. Milder types demonstrate a short condylar process, shallow sigmoid notch,
and poorly formed condylar head. A prominent antegonial notch may be present. CT scans may be helpful
in evaluating the condyles.
BIFID CONDYLE
A bid condyle is a rare developmental anomaly
characterized by a double-headed mandibular condyle.
Most bid condyles have a medial and lateral head
divided by an anteroposterior groove. Some condyles
may be divided into an anterior and posterior
head.
The cause of bid condyle is uncertain. Anteroposterior bid condyles may be of traumatic origin, such
as a childhood fracture. Mediolaterally divided condyles may result from trauma, abnormal muscle attach-
CLINICAL AND
RADIOGRAPHIC FEATURES
A bid condyle is usually unilateral, but occasionally
both sides may be affected. The malformation is often
asymptomatic and may be discovered on routine radiographs, although some patients may have a pop or
click of the TMJ when opening their mouths. Panoramic radiographs and CT scans will demonstrate a
bilobed appearance of the condylar head (Fig. 1-33).
EXOSTOSES
Exostoses are localized bony protuberances that arise
from the cortical plate. These benign growths frequently affect the jaws. The best-known oral exostoses,
the torus palatinus and the torus mandibularis, are
described later in the chapter. Other types of exostoses
also may affect the jaws and are considered here.
CLINICAL AND
RADIOGRAPHIC FEATURES
Exostoses are discovered most often in adults. Buccal
exostoses occur as a bilateral row of bony hard nodules
along the facial aspect of the maxillary and/or
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HISTOPATHOLOGIC FEATURES
Microscopic examination reveals a mass of dense,
lamellar, cortical bone with a small amount of bro-
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TORUS PALATINUS
The torus palatinus is a common exostosis that occurs
in the midline of the vault of the hard palate. The
pathogenesis of these tori has long been debated, with
arguments centering on genetic versus environmental
factors, such as masticatory stress. Some authorities
have suggested that the torus palatinus is inherited as
an autosomal dominant trait. However, others believe
that the development of this lesion is multifactorial,
including both genetic and environmental inuences.
In this model, patients are affected by a variety of
hereditary and local environmental factors. If enough
of these factors are present, then a threshold is
surpassed and the trait (torus palatinus) will be
expressed.
MAXILLOFACIAL REGION
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HISTOPATHOLOGIC FEATURES
Microscopic examination of the torus shows a mass of
dense, lamellar, cortical bone. An inner zone of trabecular bone sometimes is seen.
TORUS MANDIBULARIS
The torus mandibularis is a common exostosis that
develops along the lingual aspect of the mandible. As
with torus palatinus, the cause of mandibular tori is
probably multifactorial, including both genetic and
environmental inuences.
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HISTOPATHOLOGIC FEATURES
The histopathologic appearance of the torus mandibularis is similar to that of other exostoses, consisting primarily of a nodular mass of dense, cortical lamellar
bone (Fig. 1-44). An inner zone of trabecular bone with
associated fatty marrow sometimes is visible.
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HISTOPATHOLOGIC FEATURES
Because of the typical radiographic appearance, biopsy
is usually not necessary to establish the diagnosis of
Stafne defects of the posterior mandible. If biopsy is
performed, normal submandibular gland tissue is
usually seen. However, some defects are devoid of
tissue or contain muscle, blood vessels, fat, connective
tissue, or lymphoid tissue. In cases reported to be
devoid of contents, it is possible that the gland was
simply displaced at the time of biopsy.
Developmental Cysts
By denition, a cyst is a pathologic cavity (often uidlled) that is lined by epithelium. A number of different developmental cysts of the head and neck have
been described. Some of these have been considered
historically as ssural cysts because they were thought
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CLINICAL FEATURES
Palatal cysts of the newborn are quite common and
have been reported in as many as 65% to 85% of neonates. The cysts are small, 1- to 3-mm, white or yellowwhite papules that appear most often along the midline
near the junction of the hard and soft palates (Fig.
1-50). Occasionally, they may occur in a more anterior
location along the raphe or on the posterior palate
lateral to the midline. Frequently a cluster of two to
six cysts is observed, although the lesions also can
occur singly.
Fig. 1-49 Stafne defect. A, Ill-dened radiolucency near the angle of the mandible.
B, Appearance of the same defect several years later showing enlargement of the lesion.
C, Computed tomography (CT) image of the same lesion showing a left lingual cortical defect
(arrow). (Courtesy of Dr. Carroll Gallagher.)
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Microscopic examination reveals keratin-lled cysts
that are lined by stratied squamous epithelium. Sometimes these cysts demonstrate a communication with
the mucosal surface.
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HISTOPATHOLOGIC FEATURES
Fig. 1-50 Epsteins pearls. Small keratin-lled cysts at the
junction of the hard and soft palates. (Courtesy of Tristan Neville.)
The nasolabial cyst is characteristically lined by pseudostratied columnar epithelium, often demonstrating goblet cells and cilia (Fig. 1-52). Areas of cuboidal
Fig. 1-51 Nasolabial cyst. A, Enlargement of the left upper lip with elevation of the ala of
the nose. B, Intraoral swelling lls the maxillary labial fold. (Courtesy of Dr. Jim Weir.)
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GLOBULOMAXILLARY CYST
As originally described, the globulomaxillary cyst
was purported to be a ssural cyst that arose from epithelium entrapped during fusion of the globular portion
of the medial nasal process with the maxillary process.
This concept has been questioned, however, because
the globular portion of the medial nasal process is primarily united with the maxillary process and a fusion
does not occur. Therefore, epithelial entrapment should
not occur during embryologic development of this
area.
Virtually all cysts in the globulomaxillary region
(between the lateral incisor and canine teeth) can be
explained on an odontogenic basis. Many are lined by
inamed stratied squamous epithelium and are consistent with periapical cysts (see page 130). Some
exhibit specic histopathologic features of an odontogenic keratocyst (see page 683) or developmental
lateral periodontal cyst (see page 692). Researchers
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Occasionally, two smaller foramina carrying the nasopalatine nervesthe canals of Scarpaare found
within the incisive foramen.
In some mammals the nasopalatine ducts remain
patent and provide communication between the oral
and nasal cavities. On rare occasions, patent or partially patent nasopalatine ducts may be encountered in
humans. In mammals the nasopalatine ducts may communicate with the vomer-nasal organ of Jacobson,
acting as an accessory olfactory organ. However, in
humans, Jacobsons organ usually recedes in uterine
life to become a vestigial structure.
Researchers have suggested that the nasopalatine
duct cyst may arise from the epithelium of Jacobsons
organ, but this appears highly unlikely. Trauma or
infection of the duct and mucous retention of adjacent
minor salivary glands also have been mentioned as
possible etiologic factors, but the role of each has been
questioned. Although the pathogenesis of this lesion is
still uncertain, the lesion most likely represents a spontaneous cystic degeneration of remnants of the nasopalatine duct.
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called cysts of the incisive papilla. These cysts frequently demonstrate bluish discoloration as a result of
the uid contents in the cyst lumen (Fig. 1-56).
HISTOPATHOLOGIC FEATURES
The epithelial lining of nasopalatine duct cysts is highly
variable (Figs. 1-57 and 1-58). It may be composed of
the following:
Stratied squamous epithelium
Pseudostratied columnar epithelium
Simple columnar epithelium
Simple cuboidal epithelium
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HISTOPATHOLOGIC FEATURES
Microscopic examination shows a cyst that is usually
lined by stratied squamous epithelium. Areas of ciliated pseudostratied columnar epithelium have been
reported in some cases. Chronic inammation may be
present in the cyst wall.
CLINICAL FEATURES
Epidermoid (infundibular) cysts account for approximately 80% of follicular cysts of the skin and are most
common in the acne-prone areas of the head, neck, and
back. They are unusual before puberty unless they are
associated with Gardner syndrome (see page 651).
Young adults are more likely to have cysts on the face,
whereas older adults are more likely to have cysts on
the back. Males are affected more frequently than
females.
Epidermoid cysts present as nodular, uctuant subcutaneous lesions that may or may not be associated
with inammation (Figs. 1-61 and 1-62). If a noninamed lesion presents in an area of thin skin, such as
the earlobe, then it may be white or yellow.
Pilar (tricholemmal) cysts comprise approximately
10% to 15% of skin cysts, occurring most frequently on
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Fig. 1-64 Epidermoid cyst. A, Low-power view showing a keratin-lled cystic cavity.
B, High-power view showing stratied squamous epithelial lining with orthokeratin production.
HISTOPATHOLOGIC FEATURES
Epidermoid and pilar cysts are usually treated by conservative surgical excision, and recurrence is uncommon. Malignant transformation has been reported but
is exceedingly rare.
DERMOID CYST
The dermoid cyst is an uncommon developmental
cystic malformation. The cyst is lined by epidermis-like
epithelium and contains dermal adnexal structures in
the cyst wall. It is generally classied as a benign cystic
form of teratoma.
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especially because they are occasionally found in combination with dermoid cysts.
Dermoid cysts are simpler in structure than complex
teratomas or teratoid cysts. Although they do not
contain tissue from all three germ layers, they probably
represent a forme fruste of a teratoma. Similar cysts of
the oral cavity can be seen that are lined by epidermislike epithelium, but they contain no dermal appendages in the cyst wall. These lesions have been called
epidermoid cysts and represent the simplest expression of the teratoma spectrum. These intraoral epidermoid cysts should not be confused with the more
common epidermoid cyst of the skin (see page 32),
a nonteratomatous lesion that arises from the hair
follicle.
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CLINICAL FEATURES
HISTOPATHOLOGIC FEATURES
Dermoid cysts are lined by orthokeratinized stratied
squamous epithelium, with a prominent granular cell
layer. Abundant keratin often is found within the cyst
lumen. On rare occasions, areas of respiratory epithelium can be seen. The cyst wall is composed of brous
connective tissue that contains one or more skin
appendages, such as sebaceous glands, hair follicles, or
sweat glands (Fig. 1-67).
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HISTOPATHOLOGIC FEATURES
Thyroglossal duct cysts are usually lined by columnar
or stratied squamous epithelium, although occasionally, cuboidal or even small intestine epithelium may
be documented (Fig. 1-69). Sometimes a mixture of
epithelial types is present. Thyroid tissue may occur in
the cyst wall, but this is not a constant nding.
CLINICAL FEATURES
The branchial cleft cyst most commonly occurs in the
upper lateral neck along the anterior border of the
sternocleidomastoid muscle (Figs. 1-70 and 1-71). It
most frequently affects young adults between the ages
of 20 and 40. Clinically, the cyst appears as a soft,
uctuant mass that can range from 1 to 10 cm in diameter. Associated tenderness or pain sometimes may
occur with secondary infection. Occasionally, the lesion
becomes evident after an upper respiratory tract infection or trauma. Some lesions appear as sinuses or
stulae that may produce a mucoid discharge onto
the skin. Two thirds of branchial cleft cysts occur on
the left side of the neck, and one third are found on the
right side. In rare instances, bilateral cysts may
develop.
Although one theory suggests that these cysts are
derived from parotid epithelium that becomes
entrapped within lymph node tissue, lymphoepithelial
cysts are uncommon within the parotid gland itself. In
recent years, however, increased numbers of parotid
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Fig. 1-72 Cervical lymphoepithelial cyst. Mediumpowered view showing a cyst lined by stratied squamous
epithelium. Note the lymphoid tissue in the cyst wall.
HISTOPATHOLOGIC FEATURES
More than 90% of branchial cleft cysts are lined by
stratied squamous epithelium that may or may not be
keratinized (Fig. 1-72). Some cysts demonstrate respiratory epithelium. The wall of the cyst typically contains lymphoid tissue, often demonstrating germinal
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HISTOPATHOLOGIC FEATURES
Microscopic examination of the oral lymphoepithelial
cyst demonstrates a cystic cavity that is lined by stratied squamous epithelium without rete ridges (Fig.
1-75). This epithelium is typically parakeratinized,
with desquamated epithelial cells seen lling the cyst
lumen. In rare instances the epithelial lining also may
contain mucous cells. Occasional cysts may communicate with the overlying mucosal surface.
The most striking feature is the presence of lymphoid tissue in the cyst wall. In most instances, this
lymphoid tissue encircles the cyst, but sometimes it
involves only a portion of the cyst wall. Germinal
centers are usually, but not always, present.
Fig. 1-74 Oral lymphoepithelial cyst. Small white nodule
of the posterior lateral border of the tongue.
CLINICAL FEATURES
The oral lymphoepithelial cyst presents as a small submucosal mass that is usually less than 1 cm in diameter;
rarely will the lesion be greater than 1.5 cm (Figs. 1-73
and 1-74). The cyst may feel rm or soft to palpation,
and the overlying mucosa is smooth and nonulcerated.
The lesion is typically white or yellow and often con-
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Fig. 1-75 Oral lymphoepithelial cyst. A, Low-power view showing a keratin-lled cyst
below the mucosal surface. Lymphoid tissue is present in the cyst wall. B, High-power view
showing lymphoid tissue adjacent to the cystic lining.
Box 1-3
Beckwith-Wiedemann syndrome
Neurobromatosis
Klippel-Trnaunay-Weber syndrome
Proteus syndrome
McCune-Albright syndrome
Epidermal nevus syndrome
Triploid/diploid mixoploidy
Langer-Giedion syndrome
Multiple exostoses syndrome
Maffucci syndrome
Ollier syndrome
Segmental odontomaxillary dysplasia
Almost all cases of isolated hemihyperplasia are sporadic. A number of possible etiologic factors have been
suggested, but the cause remains obscure. Various
theories include vascular or lymphatic abnormalities,
central nervous system disturbances, endocrine
dysfunctions, and aberrant twinning mechanisms.
Occasionally, chromosomal anomalies have been
documented.
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Fig. 1-76 Hemihyperplasia. A, Enlargement of the right side of the face. B, Same patient
with associated enlargement of the right half of the tongue. C, Panoramic radiograph of the
same patient showing enlargement of the mandible and teeth on the right side. (Courtesy of
Dr. George Blozis.)
HISTOPATHOLOGIC FEATURES
Microscopic examination shows an increase in thickness of the epithelium, with hyperplasia of the underlying connective tissues.
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SEGMENTAL ODONTOMAXILLARY
DYSPLASIA (HEMIMAXILLOFACIAL
DYSPLASIA)
Segmental odontomaxillary dysplasia is a recently
recognized developmental disorder that affects the jaw
and (sometimes) the overlying facial tissues. The cause
is unknown. Clinically, it is frequently mistaken for
craniofacial brous dysplasia or hemifacial hyperplasia, but it represents a distinct and separate entity.
HISTOPATHOLOGIC FEATURES
Microscopic examination of the affected skin reveals
atrophy of the epidermis and a variable perivascular
inltrate of lymphocytes and monocytes. In cases
showing clinical features of linear scleroderma, dermal
brosis can be seen. Degenerative changes in the vascular endothelium can be identied with electron
microscopy.
HISTOPATHOLOGIC FEATURES
The gingival soft tissues may show nonspecic brosis.
The affected maxillary bone consists of irregular trabeculae with a woven appearance. This bone shows
numerous resting and reversal lines, but it lacks signicant osteoblastic and osteoclastic activity. Deciduous
teeth in the involved area may exhibit irregular dentinal tubules, a focally decient odontoblastic layer,
and external resorption.
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CROUZON SYNDROME
(CRANIOFACIAL DYSOSTOSIS)
Crouzon syndrome is one of a rare group of syndromes characterized by craniosynostosis, or premature closing of the cranial sutures. It is believed to be
caused by one of a variety of mutations of the broblast
growth factor receptor 2 (FGFR2) gene on chromosome 10q26. The condition occurs in about 1 of every
65,000 births and is inherited as an autosomal dominant trait. A signicant number of cases, however, represent new mutations, often apparently related to
increased paternal age.
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Fig. 1-79 Crouzon syndrome. Ocular proptosis and midface hypoplasia. (Courtesy of Dr. Robert
Gorlin.)
APERT SYNDROME
(ACROCEPHALOSYNDACTYLY)
Like Crouzon syndrome, Apert syndrome is a rare
condition that is characterized by craniosynostosis. It
occurs in about 1 of every 65,000 births and is caused
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(TREACHER COLLINS SYNDROME;
FRANCESCHETTI-ZWAHLEN-KLEIN
SYNDROME)
Mandibulofacial dysostosis is a rare syndrome that
is characterized primarily by defects of structures
derived from the rst and second branchial arches. It
MAXILLOFACIAL REGION
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Fig. 1-84 Mandibulofacial dysostosis. Patient exhibits a hypoplastic mandible, downwardslanting palpebral ssures, and ear deformities. (Courtesy of Dr. Tom Brock.)
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BIBLIOGRAPHY
Orofacial Clefts
Avery JK, Chiego DJ Jr: Development of the face and palate.
In Essentials of oral histology and embryology: a clinical approach,
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Berkovitz BK, Holland GR, Moxham BJ: Development of the face
and development of the palate. In Oral anatomy, histology and
embryology, ed 3, pp 269-283, St Louis, 2002, Mosby.
Carinci F, Pezzetti F, Scapoli L et al: Recent developments in
orofacial cleft genetics, J Craniofac Surg 14:130-143, 2003.
Derijcke A, Eerens A, Carels C: The incidence of oral clefts: a
review, Br J Oral Maxillofac Surg 34:488-494, 1996.
Eppley BL, van Aalst JA, Robey A et al: The spectrum of orofacial
clefting, Plast Reconstr Surg 115:101e-114e, 2005.
Evans CA: Orthodontic treatment for patients with clefts, Clin
Plast Surg 31:271-290, 2004.
Gorlin RJ, Cohen MM Jr, Hennekam RCM: Orofacial clefting
syndromes: general aspects. In Syndromes of the head and neck,
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Gosain AK, Conley SF, Marks S et al: Submucous cleft palate:
diagnostic methods and outcomes of surgical treatment, Plast
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Harada K, Sato M, Omura K: Long-term maxillomandibular skeletal and dental changes in children with cleft lip and palate
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Radiol Endod 102:292-299, 2006.
Krapels IP, Vermeij-Keers C, Mller M et al: Nutrition and genes
in the development of orofacial clefting, Nutr Rev 64:280288, 2006.
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Double Lip
Barnett ML, Bosshardt LL, Morgan AF: Double lip and double lip
with blepharochalasis (Aschers syndrome), Oral Surg Oral
Med Oral Pathol 34:727-733, 1972.
Eski M, Nisanci M, Atkas A et al: Congenital double lip: review
of 5 cases, Br J Oral Maxillofac Surg 45:68-70, 2007.
Gomez-Duaso AJ, Seoane J, Vazquez-Garcia J et al: Ascher syndrome: report of two cases, J Oral Maxillofac Surg 55:88-90,
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Kenny KF, Hreha JP, Dent CD: Bilateral redundant mucosal
tissue of the upper lip, J Am Dent Assoc 120:193-194,
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Macroglossia
Cohen MM Jr: Beckwith-Wiedemann syndrome: historical, clinicopathological, and etiopathogenetic perspectives, Pediatr
Dev Pathol 8:287-304, 2005.
Engstrm W, Lindham S, Schoeld P: Wiedemann-Beckwith
syndrome, Eur J Pediatr 147:450-457, 1988.
Maturo SC, Mair EA: Submucosal minimally invasive lingual
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Mukai S, Mukai C, Asaoka K: Ankyloglossia with deviation of the
epiglottis and larynx, Ann Otol Rhinol Laryngol 100:3-20,
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Smith RG, Cherry JE: Traumatic Eagles syndrome: report of a
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Stafne Defect
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Roddi R, Riggio E, Gilbert PM et al: Clinical evaluation of techniques used in the surgical treatment of progressive hemifacial atrophy, J Craniomaxillofac Surg 22:23-32, 1994.
Sommer A, Gambichler T, Bacharach-Buhles M et al: Clinical
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Segmental Odontomaxillary Dysplasia
Armstrong C, Napier SS, Boyd RC et al: Histopathology of the
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Becktor KB, Reibel J, Vedel B et al: Segmental odontomaxillary
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Packota GV, Pharoah MJ, Petrikowski CG: Radiographic features of segmental odontomaxillary dysplasia. A study of 12
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Apert Syndrome
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CHAPTER OUTLINE
ENVIRONMENTAL ALTERATIONS OF TEETH
Environmental Effects on Tooth Structure
Development
Turners Hypoplasia
Molar Incisor Hypomineralization
Hypoplasia Caused by Antineoplastic Therapy
Dental Fluorosis
Syphilitic Hypoplasia
Postdevelopmental Loss of Tooth Structure
Tooth Wear
Attrition
Abrasion
Erosion
Abfraction
Internal and External Resorption
Environmental Discoloration of Teeth
Extrinsic Stains
Intrinsic Stains
Localized Disturbances in Eruption
Impaction
Ankylosis
DEVELOPMENTAL ALTERATIONS OF TEETH
Developmental Alterations in the Number of Teeth
Hypodontia
Hyperdontia
Developmental Alterations in the Size of Teeth
Environmental Alterations
of Teeth
The abnormalities of the teeth can be divided into
those that are inuenced by environmental forces
and those that are idiopathic and appear hereditary
Microdontia
Macrodontia
Developmental Alterations in the Shape of Teeth
Gemination, Fusion, and Concrescence
Accessory Cusps
Cusp of Carabelli
Talon Cusp
Dens Evaginatus
Dens Invaginatus
Ectopic Enamel
Enamel Pearls
Cervical Enamel Extensions
Taurodontism
Hypercementosis
Dilaceration
Supernumerary Roots
Developmental Alterations in the Structure of Teeth
Amelogenesis Imperfecta
Hypoplastic Amelogenesis Imperfecta
Hypomaturation Amelogenesis Imperfecta
Hypocalcied Amelogenesis Imperfecta
Amelogenesis Imperfecta with Taurodontism
Dentinogenesis Imperfecta
Dentin Dysplasia
Dentin Dysplasia Type I
Dentin Dysplasia Type II
Regional Odontodysplasia
in nature. Later parts of this chapter delineate the
idiopathic and hereditary alterations of teeth. Box
2-1 lists the major categories of tooth alteration
that can be affected by environmental inuences.
In many cases the cause and effect are obvious; in
others the primary nature of the problem is less
distinct.
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Box 2-1
Box 2-2
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TURNERS HYPOPLASIA
Another frequent pattern of enamel defects seen in
permanent teeth is caused by periapical inammatory
disease of the overlying deciduous tooth. The altered
tooth is called a Turners tooth (after the clinician
whose publications allowed this problem to be widely
recognized). The appearance of the affected area varies
according to the timing and severity of the insult. The
enamel defects vary from focal areas of white, yellow,
or brown discoloration to extensive hypoplasia, which
can involve the entire crown. The process is noted most
frequently in the permanent bicuspids because of their
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HYPOPLASIA CAUSED BY
ANTINEOPLASTIC THERAPY
DENTAL FLUOROSIS
As modern medicine increases the prevalence of successful therapy against childhood cancer, it has become
evident that a number of developmental alterations
arise secondary to use of therapeutic radiation or chemotherapy. As would be expected, developing teeth
are affected most severely, with these therapies producing clinically obvious alterations most commonly in
patients younger than 12 years and most extensively
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potential sources of uoride for children in their formative years. Infant formulas also used to contain signicant amounts of uoride; however, in 1979, U.S.
manufacturers voluntarily agreed to dramatically limit
uoride in infant formulas. Despite this, some investigators have noted an increased prevalence of uorosis
continuing after 1979 in individuals who consumed
powdered, concentrated formula that was reconstituted with optimally uoridated water. To minimize
the chance of uorosis, the use of ready-to-feed formula
or reconstitution with low-uoride bottled water has
been recommended.
Because of this dissemination of uoride, the need
for supplements in nonuoridated areas is declining.
In patients who use uoride toothpastes, the anticariogenic benet of supplements is very small or nonexistent and the risk of uorosis at the community level
becomes a certainty. Several investigators have recommended strongly that children younger than 7 years of
age apply only a pea-sized amount of uoride toothpaste on the toothbrush and avoid swallowing. Because
young children tend to swallow almost all toothpaste
placed on their brush, parents should be warned to
avoid uoridated toothpaste in children younger than
2 years of age and perform oral hygiene with only a
toothbrush and water. In addition, uoride supplements are recommended only in nonuoridated areas
for children who are at high risk for rampant caries.
Finally, an effort is under way to alter the 1962 recommendation and lower the optimum level of uoride in
the public water supply to 0.7 ppm.
Fluoride appears to create its signicant enamel
defects through retention of the amelogenin proteins
in the enamel structure, leading to the formation of
hypomineralized enamel. These alterations create a
permanent hypomaturation of the enamel in which an
increased surface and subsurface porosity of the enamel
is observed. This enamel structure alters the light
reection and creates the appearance of white, chalky
areas. Most of the problems associated with dental uorosis are aesthetic and concern the appearance of the
anterior teeth. Therefore, the critical period for clinically signicant dental uorosis is during the second
and third years of life, when these teeth are forming.
The severity of dental uorosis is dose dependent,
with higher intakes of uoride during critical periods
of tooth development being associated with more
severe uorosis. The affected teeth are caries resistant,
and the altered tooth structure appears as areas of lusterless white opaque enamel that may have zones of
yellow to dark-brown discoloration (Figs. 2-8 and 2-9).
In the past, areas of moderate-to-severe enamel uorosis were termed mottled enamel. True enamel hypoplasia is uncommon but can occur as deep, irregular,
and brownish pits. Because other factors can result in
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so rare that lengthy discussion is not warranted. Anterior teeth altered by syphilis are termed Hutchinsons
incisors and exhibit crowns that are shaped like
straight-edge screwdrivers, with the greatest circumference present in the middle one third of the crown
and a constricted incisal edge. The middle portion of
the incisal edge often demonstrates a central hypoplastic notch. Altered posterior teeth are termed mulberry
molars and demonstrate constricted occlusal tables
with a disorganized surface anatomy that resembles
the bumpy surface of a mulberry.
a similar pattern of enamel damage, a denitive diagnosis requires that the defects be present in a bilaterally symmetric distribution, and evidence of prior
excessive uoride intake or elevated levels of uoride
in the enamel or other tissues should be found.
Recently, an increased prevalence of dental changes
similar to dental uorosis has been linked to amoxicillin use during early infancy. Commonly affected teeth
include the permanent rst molars and maxillary
central incisors. The number of affected teeth appears
to correlate with the duration of use. Although the
mechanism of this alteration is unclear, the antibiotic
may reduce gene expression of selected matrix proteins or reduce the activity of proteinases that hydrolyze matrix proteins. It also should be noted that one
of the etiologic theories suggested for molar incisor
hypomineralization (see page 58) is prior antibiotic
therapy.
SYPHILITIC HYPOPLASIA
Congenital syphilis (see page 190) results in a pattern
of enamel hypoplasia that is well known but currently
POSTDEVELOPMENTAL LOSS OF
TOOTH STRUCTURE
Tooth structure can be lost after its formation by a
variety of inuences beyond the obvious cases related
to caries or traumatic fractures. Destruction can begin
on the enamel surface of the crown through abrasion,
attrition, erosion, or abfraction. In addition, loss of
tooth structure can begin on the dentin or cemental surfaces of the teeth by external or internal
resorption.
TOOTH WEAR
Tooth wear, also termed tooth surface loss, is a normal
physiologic process that occurs with aging but must be
considered pathologic when the degree of destruction
creates functional, aesthetic, or dental sensitivity problems. Although the four causes of tooth wear (i.e., attrition, abrasion, erosion, abfraction), often are
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CLINICAL FEATURES
ATTRITION
Attrition can occur in both the deciduous and the
permanent dentitions. As would be expected, the surfaces predominantly affected are those that contact the
opposing dentition. Most frequently, the incisal and
occlusal surfaces are involved, in addition to the lingual
of the anterior maxillary teeth and the labial of the
anterior mandibular teeth. Large, at, smooth, and
shiny wear facets are found in a relationship that corresponds to the pattern of occlusion. The interproximal
contact points also are affected from the vertical
movement of the teeth during function. Over time, this
interproximal loss can result in a shortening of the arch
length. Pulp exposure and dentin sensitivity are rare
because of the slow loss of tooth structure and the
apposition of reparative secondary dentin within the
pulp chamber (Fig. 2-10).
ABRASION
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EROSION
In patients with erosion, the tooth loss does not
correlate with functional wear patterns or with those
typically associated with known abrasives. The predominant sites of tooth loss appear to correlate closely
with those areas not protected by the serous secretions
of the parotid and submandibular glands. The facial
and palatal surfaces of the maxillary anterior teeth and
the facial and occlusal surfaces of the mandibular posterior teeth are affected most frequently. Involvement
of the lingual surfaces of the entire mandibular dentition is uncommon, possibly because of the protective
buffering capacity of the submandibular serous saliva.
The classic pattern of dental erosion is the cupped
lesion in which a central depression of dentin is surrounded by elevated enamel. Cupped areas are seen
on the occlusal cusp tips, incisal edges, and marginal
ridges (Fig. 2-14). In contrast to abrasion, erosion commonly affects the facial surfaces of the maxillary anteriors and appears as shallow spoon-shaped depressions
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ABFRACTION
Abfraction appears as wedge-shaped defects limited
to the cervical area of the teeth and may closely resemble cervical abrasion or erosion. Clues to the diagnosis
include defects that are deep, narrow, and V-shaped
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Box 2-3
Internal resorption
External resorption
Cysts
Dental trauma
Excessive mechanical forces (e.g., orthodontic
therapy)
Excessive occlusal forces
Grafting of alveolar clefts
Hormonal imbalances
Intracoronal bleaching of pulpless teeth
Local involvement by herpes zoster
Pagets disease of bone
Periodontal treatment
Periradicular inammation
Pressure from impacted teeth
Reimplantation of teeth
Tumors
Inflammatory
Replacement/
metaplastic
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source of radiation will shift distally). With this technique, the sites of external resorption appear to shift
away from the pulp canal when the radiographs are
compared. In addition, the radiographs can reveal
which side of the root is affected in cases of external
resorption.
HISTOPATHOLOGIC FEATURES
In patients with internal inammatory resorption, the
pulp tissue in the area of destruction is vascular and
exhibits increased cellularity and collagenization.
Immediately adjacent to the dentinal wall are numerous multinucleated dentinoclasts, which are histologically and functionally identical to osteoclasts (Fig.
2-29). An inammatory inltrate characterized by lymphocytes, histiocytes, and polymorphonuclear leukocytes is not uncommon. In replacement resorption, the
normal pulp tissue is replaced by woven bone that
fuses with the adjacent dentin. External resorption is
similar in appearance, with numerous multinucleated
dentinoclasts located in the areas of structure loss.
Areas of resorption often are repaired through deposition of osteodentin. In large defects, external inammatory resorption results in deposition of inamed
granulation tissue, and areas of replacement with
woven bone may also be seen. Extensive bony replacement in areas of external resorption can lead
to ankylosis.
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ENVIRONMENTAL DISCOLORATION
OF TEETH
The color of normal teeth varies and depends on the
shade, translucency, and thickness of the enamel.
Abnormal colorations may be extrinsic or intrinsic.
Extrinsic stains occur from surface accumulation of an
exogenous pigment and typically can be removed with
a surface treatment, whereas intrinsic discolorations
arise from an endogenous material that is incorporated
into the enamel or dentin and cannot be removed by
prophylaxis with toothpaste or pumice. Box 2-4 lists
the most frequently documented causes of tooth
discolorations.
Dental uorosis is discussed in the section on environmental effects on the structural development of the
teeth (see page 58). The alterations associated with
amelogenesis imperfecta (see page 99) and dentinogenesis imperfecta (see page 106) are presented later
Box 2-4
Tooth Discolorations
EXTRINSIC
Bacterial stains
Iron
Tobacco
Foods and beverages
Gingival hemorrhage
Restorative materials
Medications
INTRINSIC
Amelogenesis imperfecta
Dentinogenesis imperfecta
Dental uorosis
Erythropoietic porphyria
Hyperbilirubinemia
Ochronosis
Trauma
Localized red blood cell breakdown
Medications
in this chapter in the text devoted to primary developmental alterations of the teeth.
CLINICAL FEATURES
EXTRINSIC STAINS
Bacterial stains are a common cause of surface staining of exposed enamel, dentin, and cementum. Chromogenic bacteria can produce colorations that vary
from green or black-brown to orange. The discoloration occurs most frequently in children and is usually
seen initially on the labial surface of the maxillary anterior teeth in the gingival one third. In contrast to most
plaque-related discolorations, the black-brown stains
most likely are not primarily of bacterial origin but are
secondary to the formation of ferric sulde from an
interaction between bacterial hydrogen sulde and
iron in the saliva or gingival crevicular uid.
Extensive use of tobacco products, tea, or coffee
often results in signicant brown discoloration of the
surface enamel (Fig. 2-30). The tar within the tobacco
dissolves in the saliva and easily penetrates the pits and
ssures of the enamel. Smokers (of tobacco or marijuana) most frequently exhibit involvement of the
lingual surface of the mandibular incisors; users of
smokeless tobacco often demonstrate involvement of
the enamel in the area of tobacco placement. Stains
from beverages also often involve the lingual surface of
the anterior teeth, but the stains are usually more widespread and less intense. In addition, foods that contain
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INTRINSIC STAINS
Congenital erythropoietic porphyria (Gnther disease) is an autosomal recessive disorder of porphyrin
metabolism that results in the increased synthesis and
excretion of porphyrins and their related precursors.
Signicant diffuse discoloration of the dentition is
noted as a result of the deposition of porphyrin in the
teeth (Fig. 2-31). Affected teeth demonstrate a marked
red-brown coloration that exhibits a red uorescence
when exposed to a Woods ultraviolet (UV) light. The
deciduous teeth demonstrate a more intense coloration
because porphyrin is present in the enamel and the
dentin; in the permanent teeth, only the dentin
is affected. Excess porphyrins also are present in the
urine, which may reveal a similar uorescence when
exposed to a Woods light.
Another autosomal recessive metabolic disorder,
alkaptonuria, is associated with a blue-black discoloration termed ochronosis that occurs in connective tissue,
tendons, and cartilage. On rare occasions, a blue discoloration of the dentition may be seen in patients who
also are affected with Parkinsons disease.
Bilirubin is a breakdown product of red blood cells,
and excess levels can be released into the blood in a
number of conditions. The increased amount of
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produce a similar clinical presentation. A yellow discoloration is indicative of pulpal obliteration, termed
calcic metamorphosis, and is discussed more fully
in Chapter 3 (see page 123). The dark-gray discoloration is long-term and occurs in teeth with signicant
pulpal pathosis in which blood degradation products
have diffused into the dentinal tubules. Endodontic
therapy initiated before or shortly after the total death
of the pulp often prevents the discoloration. The pulpal
necrosis may be aseptic and not associated with signicant tenderness to percussion, mobility, or associated
periapical inammatory disease. A related process secondary to localized red blood cell destruction also
can result in discoloration of the teeth. Occasionally,
during a postmortem examination, a pink discoloration
of teeth is found. The crowns and necks of the teeth are
affected most frequently, and the process is thought to
arise from hemoglobin breakdown within the necrotic
pulp tissue in patients in whom blood has accumulated
in the head.
A similar pink or red discoloration of the maxillary
incisors has been reported in living patients with lepromatous leprosy (see page 198). Although controversial, some investigators believe these teeth are
involved selectively because of the decreased temperature preferred by the causative organism. This process
is thought to be secondary to infection-related necrosis
and the rupture of numerous small blood vessels within
the pulp, with a secondary release of hemoglobin into
the adjacent dentinal tubules.
Dental restorative materials, especially amalgam,
can result in black-gray discolorations of teeth. This
most frequently arises in younger patients who presumably have more open dentinal tubules. Large Class
II proximal restorations of posterior teeth can produce discoloration of the overlying facial surface. In
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LOCALIZED DISTURBANCES
IN ERUPTION
IMPACTION
Eruption is the continuous process of movement of a
tooth from its developmental location to its functional
location. Teeth that cease to erupt before emergence
are impacted. Some authors subdivide these nonerupted teeth into those that are obstructed by a physical barrier (impacted) and those that appear to exhibit
a lack of eruptive force (embedded). In many cases a
tooth may appear to be embedded; however, on
removal a previously undetected overlying odontogenic hamartoma or neoplasm is discovered. Therefore, it appears appropriate to classify all these teeth
as impacted.
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Trismus
Infection
Fracture
Temporomandibular joint (TMJ) injury
Periodontal injury
Injury to adjacent teeth
Dental referral patterns provide a variety of perspectives of different dental practitioners. Many specialists (e.g., oral and maxillofacial surgeons, oral and
maxillofacial pathologists) see a large percentage of
signicant pathologic conditions associated with
impacted teeth compared with the experience of other
clinicians. Although pathology rarely is associated with
impacted teeth in children and young adults, numerous reports have documented an increased prevalence
of problems in the later decades; therefore, any meaningful prospective studies must be lifelong rather than
conned to just a few years. One review of 2646 pericoronal lesions submitted to an active oral pathology
service revealed that 32.9% of cases had pathologically signicant lesions, with strong relationship
between increasing age and the prevalence of pericoronal pathosis. In this 6-year review were six primary
squamous cell carcinomas arising from dentigerous
cysts in addition to numerous odontogenic keratocysts
and odontogenic tumors. Because of the frequent
occurrence of signicant pericoronal pathology, specialists often recommend extraction over close observation of impacted teeth.
The eruption sequestrum requires no therapy
and usually undergoes spontaneous resorption or
exfoliation.
ANKYLOSIS
Eruption continues after the emergence of the teeth
to compensate for masticatory wear and the growth of
the jaws. The cessation of eruption after emergence is
termed ankylosis and occurs from an anatomic fusion
of tooth cementum or dentin with the alveolar bone.
Although the areas of union may be too subtle to be
detected clinically and radiographically, histopathologic examination will demonstrate fusion between the
affected tooth and the adjacent bone in almost all cases.
Other terms for this process within the literature
include infraocclusion, secondary retention, submergence, reimpaction, and reinclusion. Secondary
retention is an acceptable term but may be confused
with retained primary teeth, which maintain their emergence. Submergence, reimpaction, and reinclusion connote
an active depression, and this is not the case.
The pathogenesis of ankylosis is unknown and may
be secondary to one of many factors. Disturbances
from changes in local metabolism, trauma, injury,
chemical or thermal irritation, local failure of bone
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Developmental Alterations
of Teeth
Numerous developmental alterations of teeth can
occur. Box 2-5 delineates the major reported alterations, and the following text pertains to these entities.
These alterations may be primary or arise secondary to
environmental inuences (e.g., concrescence, hypercementosis, dilaceration). For the sake of convenience,
both the primary and the environmental forms will be
discussed together.
Box 2-5
DEVELOPMENTAL ALTERATIONS IN
THE NUMBER OF TEETH
Variations in the number of teeth that develop are
common. Several terms are useful in the discussion of
the numeric variations of teeth. Anodontia refers to a
total lack of tooth development. Hypodontia denotes
the lack of development of one or more teeth; oligodontia (a subdivision of hypodontia) indicates the lack
of development of six or more teeth. Hyperdontia
is the development of an increased number of teeth,
and the additional teeth are termed supernumerary.
Terms such as partial anodontia are oxymorons and
should be avoided. In addition, these terms pertain to
teeth that failed to develop and should not be applied
to teeth that developed but are impacted or have been
removed.
Genetic control appears to exert a strong inuence
on the development of teeth. Hypodontia and hyperdontia have been noted in patients with a variety of
syndromes (Boxes 2-6 and 2-7). In all of these syndromes, an increased prevalence of hypodontia or
hyperdontia exists, but the strength of the association
varies. Furthermore, the actual genetic contribution to
the increased or decreased number of teeth may be
unclear in some of these conditions. In addition to
these syndromes, an increased prevalence of hypodontia is noted in patients with nonsyndromic cleft lip (CL)
or cleft palate (CP).
Genetic inuences still may affect nonsyndromic
numeric alterations of teeth, because more than 200
genes are known to play a role in odontogenesis.
Because of the complexity of the system, variations in
tooth number arise in a wide variety of patterns. A large
percentage of primary hypodontia cases appear to
be inherited in an autosomal dominant fashion, with
incomplete penetrance and variable expressivity,
whereas a minority of examples present an autosomal
recessive or sex-linked pattern. The environment is not
without its inuence, with occasional examples suggesting multifactorial inheritance. Several investigators
have reported variable expression of hypodontia in
monozygotic twins (conrmed by DNA ngerprinting).
This discordance conrms the occasional multifactorial nature of the process. Overall, hypodontia most
likely represents a variety of disorders caused by variable genetic and epigenetic factors.
Research has identied a gene mutation in only a
small percentage of nonsyndromic hypodontia cases.
Although this list will continue to lengthen over time,
the currently implicated genes include the PAX9 gene,
the MSX1 gene, the AXIN2 gene, and He-Zhao deciency, which is associated with an unknown gene
that maps to chromosome 10q11.2. Although variable
expressivity is common, most of these examples
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Box 2-6
Box 2-7
Ankyloglossia superior
Bk
Cockayne
Cofn-Lowry
Cranio-oculo-dental
Crouzon
Down
Ectodermal dysplasia
Ectodermal dysplasia, cleft lip, cleft palate
Ehlers-Danlos
Ellis-van Creveld
Focal dermal hypoplasia
Freire-Maia
Frontometaphyseal dysplasia
Goldenhar
Gorlin
Gorlin-Chaudhry-Moss
Hallermann-Streiff
Hanhart
Hurler
Hypoglossia-hypodactylia
Incontinentia pigmenti
Johanson-Blizzard
Lipoid proteinosis
Marshall-White
Melanoleukoderma
Monilethrix-anodontia
Oral-facial-digital type I
Otodental dysplasia
Palmoplantar keratosis, hypotrichosis, cysts of eyelid
Progeria
Rieger
Robinson
Rothmund-Thomson
Sturge-Weber
Tooth-and-nail
Turner
Apert
Angio-osteohypertrophy
Cleidocranial dysplasia
Craniometaphyseal dysplasia
Crouzon
Curtius
Down
Ehlers-Danlos
Ellis-van Creveld
Fabry-Anderson
Fucosidosis
Gardner
Hallermann-Streiff
Incontinentia pigmenti
Klippel-Trnaunay-Weber
Laband
Leopard
Nance-Horan
Oral-facial-digital types I and III
Sturge-Weber
Tricho-rhino-phalangeal
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CLINICAL FEATURES
HYPODONTIA
Failure of teeth to form is one of the most common
dental developmental abnormalities, with a reported
prevalence of 1.6% to 9.6% in permanent teeth when
absence of third molars is excluded. The prevalence
increases to 20% if third molars are considered.
A female predominance of approximately 1.5:1 is
reported. Anodontia is rare, and most cases occur in
the presence of hereditary hypohidrotic ectodermal
dysplasia (see page 741). Indeed, when the number
of missing teeth is high or involves the most stable
teeth (i.e., maxillary central incisors, rst molars), the
patient should be evaluated for ectodermal dysplasia.
Hypodontia is uncommon in the deciduous dentition,
with a prevalence that ranges from 0.5% to 0.9% and,
when present, most frequently involves the lateral incisors. Absence of a deciduous tooth is associated strongly
with an increased prevalence of a missing successor.
Missing teeth in the permanent dentition are not rare,
with third molars being the most commonly affected.
After the molars, the second premolars and lateral incisors are absent most frequently (Fig. 2-40). Hypodontia
is associated positively with microdontia (see page 83),
reduced alveolar development, increased freeway
space, and retained primary teeth (Fig. 2-41). In whites
with missing teeth, approximately 80% will demonstrate loss of only one or two teeth.
Mutation of the PAX9 gene creates an autosomal
dominant pattern of oligodontia that can involve
various teeth but most commonly affects most of the
permanent molars. In severe cases, loss of the primary
molars, second premolars, and permanent mandibular
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second and third molars, second premolars, lower incisors, and maxillary lateral incisors. The maxillary
central incisors always are present and usually accompanied by the canines, rst premolars, and rst molars.
However, the number and type of missing teeth are
highly variable, a typical nding of inheritable oligodontia. Although the missing teeth can produce a signicant oral problem, the presence of the AXIN2
mutation in these kindreds also has been associated
with development of adenomatous polyps of the colon
and colorectal carcinoma. This suggests that patients
with similar examples of oligodontia should be questioned closely for a family history of colon cancer, with
further medical evaluation recommended for those
possibly at risk.
Even in kindreds with an obviously inherited pattern
of hypodontia or oligodontia, it must be stressed that,
in the majority of the cases, the genes are yet to be discovered. The most common form of inherited hypodontia is an autosomal dominant pattern in which the
average number of missing teeth is slightly more than
two. Excluding the third molars, the most commonly
missing teeth in these cases are the lower second premolars, upper second premolars, maxillary lateral incisors, and lower central incisors.
HYPERDONTIA
The prevalence of supernumerary permanent teeth in
whites is between 0.1% and 3.8%, with a slightly higher
rate seen in Asian populations. The frequency in the
deciduous dentition is much lower and varies from
0.3% to 0.8%. Approximately 76% to 86% of cases represent single-tooth hyperdontia, with two supernumerary teeth noted in 12% to 23%, and three or more
extra teeth noted in less than 1% of cases. Single-tooth
hyperdontia occurs more frequently in the permanent
dentition, and approximately 95% present in the
maxilla, with a strong predilection for the anterior
region. The most common site is the maxillary incisor
region, followed by maxillary fourth molars and mandibular fourth molars, premolars, canines, and lateral
incisors (Fig. 2-42). Supernumerary mandibular incisors are very rare. Although supernumerary teeth may
be bilateral, most occur unilaterally (Figs. 2-43 and
2-44). In contrast to single-tooth hyperdontia, nonsyndromic multiple supernumerary teeth occur most
frequently in the mandible. These multiple supernumerary teeth occur most often in the premolar region,
followed by the molar and anterior regions, respectively (Fig. 2-45).
Although most supernumerary teeth occur in the
jaws, examples have been reported in the gingiva, maxillary tuberosity, soft palate, maxillary sinus, sphenomaxillary ssure, nasal cavity, and between the orbit
and the brain. The eruption of accessory teeth is
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variable and dependent on the degree of space available; 75% of supernumerary teeth in the anterior
maxilla fail to erupt. Unlike hypodontia, hyperdontia
is positively correlated with macrodontia (see page 83)
and exhibits a 2:1 male predominance. Although
examples may be identied in older adults, most supernumerary teeth develop during the rst two decades
of life.
Several terms have been used to describe supernumerary teeth, depending on their location. A supernumerary tooth in the maxillary anterior incisor region is
termed a mesiodens (see Fig. 2-42); an accessory
fourth molar is often called a distomolar or distodens.
A posterior supernumerary tooth situated lingually or
buccally to a molar tooth is termed a paramolar (Fig.
2-46).
Supernumerary teeth are divided into supplemental (normal size and shape) or rudimentary (abnormal
shape and smaller size) types. Rudimentary supernumerary teeth are classied further into conical
(small, peg-shaped), tuberculate (barrel-shaped anterior with more than one cusp), and molariform (small
premolar-like or molarlike). Although odontomas are
considered hamartomas and could be placed within
this classication, these lesions traditionally are included in the list of odontogenic neoplasms and are discussed in Chapter 15 (page 724). The conical mesiodens
represents one of the more common supernumerary
teeth and can erupt spontaneously, whereas tuberculate examples are less frequent and rarely erupt.
Occasionally, normal teeth may erupt into an inappropriate position (e.g., a canine present between
two premolars). This pattern of abnormal eruption is
called dental transposition. Such misplaced teeth
have been confused with supernumerary teeth; but in
reality, patients exhibiting dental transposition have
been reported to exhibit an increased prevalence of
hypodontia, not hyperdontia. The teeth involved most
frequently in transposition are the maxillary canines
and rst premolars. Crowding or malocclusion of these
normal teeth may dictate reshaping, orthodontics, or
extraction.
Accessory teeth may be present at or shortly after
birth. Historically, teeth present in newborns have
been called natal teeth; those arising within the rst
30 days of life are designated neonatal teeth. This is
an articial distinction, and it appears appropriate to
call all of these teeth natal teeth (Fig. 2-47). Although
some authors have suggested that these teeth may represent predeciduous supernumerary teeth, most are
prematurely erupted deciduous teeth (not supernumerary teeth). Approximately 85% of natal teeth are
mandibular incisors, 11% are maxillary incisors, and
4% are posterior teeth.
Fig. 2-46 Paramolar. A, Rudimentary tooth situated palatal to a maxillary molar in a patient
who also exhibits hypodontia. B, Radiograph of the same patient showing a fully formed tooth
overlying the crown of the adjacent molar.
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DEVELOPMENTAL ALTERATIONS IN
THE SIZE OF TEETH
Tooth size is variable among different races and
between the sexes. The presence of unusually small
teeth is termed microdontia; the presence of teeth
larger than average is termed macrodontia. Although
heredity is the major factor, both genetic and environmental inuences affect the size of developing teeth.
The deciduous dentition appears to be affected more
by maternal intrauterine inuences; the permanent
teeth seem to be more affected by environment.
CLINICAL FEATURES
Although the size of teeth is variable, the two sides of
the jaws are usually symmetrical. Despite this, when
signicant size variation is present, the entire dentition
rarely is affected. Typically, only a few teeth are altered
signicantly in size. Differences in tooth sizes cannot
be considered in isolation. Microdontia is associated
strongly with hypodontia (see page 79); macrodontia
often is seen in association with hyperdontia (see page
80). Females demonstrate a higher frequency of microdontia and hypodontia; males have a greater prevalence of macrodontia and hyperdontia.
MICRODONTIA
The term microdontia should be applied only when
the teeth are physically smaller than usual. Normalsized teeth may appear small when widely spaced
within jaws that are larger than normal. This appearance has been historically termed relative microdontia, but it represents macrognathia (not microdontia).
Diffuse true microdontia is uncommon but may occur
as an isolated nding in Down syndrome, in pituitary
dwarsm, and in association with a small number of
rare hereditary disorders that exhibit multiple abnormalities of the dentition (Fig. 2-48).
Isolated microdontia within an otherwise normal
dentition is not uncommon. The maxillary lateral
incisor is affected most frequently and typically appears
as a peg-shaped crown overlying a root that often is of
normal length (Fig. 2-49). The mesiodistal diameter is
reduced, and the proximal surfaces converge toward
the incisal edge. The reported prevalence varies from
0.8% to 8.4% of the population, and the alteration
appears to be autosomal dominant with incomplete
penetrance. In addition, isolated microdontia often
affects third molars. Interestingly, the maxillary lateral
incisors and the third molars are among the most
frequent teeth to be congenitally missing. When a
peg-shaped tooth is present, the remaining permanent teeth often exhibit a slightly smaller mesiodistal
size.
Fig. 2-49 Isolated microdontia (peg lateral). Small, coneshaped right maxillary lateral incisor.
MACRODONTIA
Analogous to microdontia, the term macrodontia
(megalodontia, megadontia) should be applied only
when teeth are physically larger than usual and should
not include normal-sized teeth crowded within a small
jaw (previously termed relative macrodontia). In
addition, the term macrodontia should not be used to
describe teeth that have been altered by fusion or gemination. Diffuse involvement is rare, and typically only
a few teeth are abnormally large. Diffuse macrodontia
has been noted in association with pituitary gigantism
(see page 831), otodental syndrome, XYY males, and
pineal hyperplasia with hyperinsulinism. Macrodontia
with unilateral premature eruption is not rare in
hemifacial hyperplasia (see page 38). Authors have
postulated that the unilateral bone growth resulting
from this condition may also affect developing teeth on
the altered side. Isolated macrodontia is reported to
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DEVELOPMENTAL ALTERATIONS IN
THE SHAPE OF TEETH
GEMINATION, FUSION, AND
CONCRESCENCE
Double teeth (connated teeth, conjoined teeth) are two
separate teeth exhibiting union by dentin and (perhaps)
their pulps. The union may be the result of fusion of
two adjacent tooth buds or the partial splitting of one
into two. The development of isolated large or joined
(i.e., double) teeth is not rare, but the literature is confusing when the appropriate terminology is presented.
Historically, gemination was dened as an attempt of a
single tooth bud to divide, with the resultant formation
of a tooth with a bid crown and, usually, a common
root and root canal. Conversely, fusion was considered
the union of two normally separated tooth buds with
the resultant formation of a joined tooth with conuence of dentin. Finally, concrescence was the union of
two teeth by cementum without conuence of the
dentin.
Many investigators have found these denitions
confusing and open to debate. A double tooth found in
the place of a maxillary permanent central incisor is a
good example of the controversy. If the joined tooth is
counted as one and the tooth number is correct, then
the anomaly could result from the division of a single
tooth bud or the fusion of the permanent tooth bud
with the bud of an adjacent mesiodens. Some have
suggested that the terms gemination, fusion, and concrescence should be discontinued, and all of these anomalies should be termed twinning. This also is confusing
because other investigators use twinning to refer to the
development of two separate teeth that arose from the
complete separation of one tooth bud (this also is
arguable).
Because of this confusion in terminology, the use of
the term twinning cannot be recommended. Extra teeth
are termed supernumerary, and another name is not
necessary. Even though the exact pathogenesis may be
questionable in some cases (whether caused by fusion
of adjacent buds or partial split of one bud), the terms
CLINICAL FEATURES
GEMINATION AND FUSION
Double teeth (gemination and fusion) occur in both
the primary and the permanent dentitions, with a
higher frequency in the anterior and maxillary regions
(Figs. 2-50 to 2-54). In the permanent dentition, the
prevalence of double teeth in whites is approximately
0.3% to 0.5%, whereas the frequency in deciduous teeth
is greater, with a reported prevalence from 0.5% to
2.5%. Asian populations tend to demonstrate a higher
occurrence that exceeds 5% in some studies. In both
dentitions, incisors and canines are the most commonly affected teeth. Involvement of posterior primary
teeth, premolars, and permanent molars also can occur.
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CONCRESCENCE
Concrescence is two fully formed teeth, joined along
the root surfaces by cementum. The process is noted
more frequently in the posterior and maxillary regions.
The developmental pattern often involves a second
molar tooth in which its roots closely approximate the
adjacent impacted third molar (Fig. 2-57). The postinammatory pattern frequently involves carious molars
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TALON CUSP
Fig. 2-59 Concrescence. Gross photograph of the same
teeth depicted in Fig. 2-58. Histopathologic examination
revealed that union occurred in the area of cemental repair
previously damaged by a periapical inammatory lesion.
ACCESSORY CUSPS
The cuspal morphology of teeth exhibits minor variations among different populations; of these, three
distinctive patterns deserve further discussion: (1)
cusp of Carabelli, (2) talon cusp, and (3) dens evaginatus. When an accessory cusp is present, the other
permanent teeth often exhibit a slightly increased
tooth size.
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DENS EVAGINATUS
Dens evaginatus (central tubercle, tuberculated cusp,
accessory tubercle, occlusal pearl, evaginated odontome, Leong premolar, tuberculated premolar) is a
cusplike elevation of enamel located in the central
groove or lingual ridge of the buccal cusp of premolar
or molar teeth (Fig. 2-63). Although this pattern of
accessory cusps has been reported on molars, dens
evaginatus typically occurs on premolar teeth, is usually
bilateral, and demonstrates a marked mandibular predominance. Deciduous molars are affected infrequently. The accessory cusp normally consists of
enamel and dentin, with pulp present in about half of
the cases. Although the prevalence is variable, most
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Type I
Type II
Type III
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ECTOPIC ENAMEL
Ectopic enamel refers to the presence of enamel in
unusual locations, mainly the tooth root. The most
widely known are enamel pearls. These are hemispheric structures that may consist entirely of enamel
or contain underlying dentin and pulp tissue. Most
enamel pearls project from the surface of the root and
are thought to arise from a localized bulging of the
odontoblastic layer. This bulge may provide prolonged
contact between Hertwigs root sheath and the developing dentin, triggering induction of enamel formation. Similar internal projections of enamel into the
underlying dentin rarely have been reported in the
crowns of teeth.
In addition to enamel pearls, cervical enamel
extensions also occur along the surface of dental roots.
These extensions represent a dipping of the enamel
from the cementoenamel junction toward the bifurcation of molar teeth. This pattern of ectopic enamel
forms a triangular extension of the coronal enamel
that develops on the buccal surface of molar teeth
directly overlying the bifurcation. The base of the triangle is continuous with the inferior portion of the
coronal enamel; the leading point of the triangle
extends directly toward the bifurcation of the tooth.
These areas of ectopic enamel have been called cervical
enamel projections, but this terminology is confusing
because no signicant exophytic projections are seen.
radiodensity extending from the dentinoenamel junction into the underlying coronal dentin.
The enamel surface of pearls precludes normal
periodontal attachment with connective tissue, and a
hemidesmosomal junction probably exists. This junction is less resistant to breakdown; once separation
occurs, rapid loss of attachment is likely. In addition,
the exophytic nature of the pearl is conducive to plaque
retention and inadequate cleansing.
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TAURODONTISM
Taurodontism is an enlargement of the body and pulp
chamber of a multirooted tooth, with apical displacement of the pulpal oor and bifurcation of the roots.
This pattern of molar formation has been found in
ancient Neanderthals, and the overall shape of the taurodont resembles that of the molar teeth of cud-chewing
animals (tauro = bull; dont = tooth).
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Mild
hypotaurodont
Moderate
mesotaurodont
Severe
hypertaurodont
Box 2-8
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Box 2-9
HYPERCEMENTOSIS
Hypercementosis (cemental hyperplasia) is a nonneoplastic deposition of excessive cementum that is
continuous with the normal radicular cementum.
HISTOPATHOLOGIC FEATURES
The periphery of the root exhibits deposition of an
excessive amount of cementum over the original layer
of primary cementum. The excessive cementum may
be hypocellular or exhibit areas of cellular cementum
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that resemble bone (osteocementum). Often the material is arranged in concentric layers and may be applied
over the entire root or be limited to the apical portion.
On routine light microscopy, distinguishing between
dentin and cementum often is difcult, but viewing the
section with polarized light helps to discriminate
between the two different layers (Fig. 2-79).
DILACERATION
Dilaceration is an abnormal angulation or bend in the
root or, less frequently, the crown of a tooth (Figs. 2-80
and 2-81). Although most examples are idiopathic, a
number of teeth with dilaceration appear to arise after
an injury that displaces the calcied portion of the
tooth germ, and the remainder of the tooth is formed
at an abnormal angle. The damage frequently follows
avulsion or intrusion of the overlying primary predecessor, an event that usually occurs before 4 years of
age. Injury-related dilaceration more frequently affects
the anterior dentition and often creates both a functional and a cosmetic dental problem. Less frequently
the bend develops secondary to the presence of an
adjacent cyst, tumor, or odontogenic hamartoma (e.g.,
odontoma, supernumerary tooth) (Fig. 2-82).
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SUPERNUMERARY ROOTS
prevalence of dilaceration but are not highlighted
because of a lack of associated clinical problems in
most instances. Occasionally, involvement of the deciduous teeth is reported, and some have been associated
with prior trauma secondary to neonatal laryngoscopy
and endotracheal intubation. The age of the patient
and the direction and degree of force appear to determine the extent of the tooths malformation. The abnormal angulation may be present anywhere along the
length of the tooth.
Altered maxillary anterior teeth frequently demonstrate the bend in the crown or the coronal half of the
root; failure of eruption is often seen. Affected mandibular incisors also exhibit involvement of the crown
or the supercial portion of the root, but more frequently they erupt into full occlusion. Those that
achieve eruption often follow an altered path and
present in a labial or lingual position. Many of the
affected teeth, especially anterior mandibular teeth,
are nonvital and associated with periapical inammatory lesions. Typically, altered posterior teeth demonstrate involvement of the apical half of the root and
frequently do not exhibit delayed eruption.
The term supernumerary roots refers to the development of an increased number of roots on a tooth
compared with that classically described in dental
anatomy.
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Specic Features
Inheritance
IA
IB
IC
ID
IE
IF
IG
Hypoplastic
Hypoplastic
Hypoplastic
Hypoplastic
Hypoplastic
Hypoplastic
Hypoplastic
Generalized pitted
Localized pitted
Localized pitted
Diffuse smooth
Diffuse smooth
Diffuse rough
Enamel agenesis
Autosomal dominant
Autosomal dominant
Autosomal recessive
Autosomal dominant
X-linked dominant
Autosomal dominant
Autosomal recessive
IIA
IIB
IIC
IID
Hypomaturation
Hypomaturation
Hypomaturation
Hypomaturation
Diffuse pigmented
Diffuse
Snow-capped
Snow-capped
Autosomal recessive
X-linked recessive
X-linked
Autosomal dominant?
IIIA
IIIB
Hypocalcied
Hypocalcied
Diffuse
Diffuse
Autosomal dominant
Autosomal recessive
IVA
IVB
Hypomaturation-hypoplastic
Hypoplastic-hypomaturation
Taurodontism present
Taurodontism present
Autosomal dominant
Autosomal dominant
Modied from Witkop CJ Jr: Amelogenesis imperfecta, dentinogenesis imperfecta and dentin dysplasia revisited: problems in classication, J Oral Pathol
17:547-553, 1988.
DEVELOPMENTAL ALTERATIONS IN
THE STRUCTURE OF TEETH
AMELOGENESIS IMPERFECTA
Amelogenesis imperfecta encompasses a complicated group of conditions that demonstrate developmental alterations in the structure of the enamel in the
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Inheritance
Autosomal dominant
Autosomal dominant
Autosomal dominant
Autosomal dominant
Autosomal dominant
Autosomal recessive
Autosomal recessive
Autosomal recessive
Autosomal recessive
X-linked
X-linked
X-linked
Phenotype
Related Genes
Generalized pitted
Localized hypoplastic
Generalized thin
Hypocalcication
With taurodontism
Localized hypoplastic
Generalized thin
Pigmented hypomaturation
Hypocalcication
Generalized thin
Diffuse hypomaturation
Snow-capped hypomaturation
genesis imperfecta has been claried. This has led investigators to suggest a future classication system based
primarily on the mode of inheritance with secondary
discriminators that include the phenotype and molecular basis (site of chromosomal mutation, when known).
Although the push for a new classication system is not
new, the progress in dening the molecular genetics of
amelogenesis imperfecta has been slow and currently
prevents complete agreement on a transition to a genetics-directed system of classication. As the molecular
basis of the disease becomes better claried, the move
to a new pattern of classication seems inevitable.
Investigations into the genetics are ongoing and producing results that are not only interesting but also
directly applicable to patient care. To date, mutations
in ve genes have been associated with amelogenesis
imperfecta. Each gene can be mutated in a variety of
ways, often creating diverse and distinct phenotypic
patterns.
The AMELX gene is associated with the enamel
protein amelogenin, which constitutes up to 90% of
enamel matrix. AMELX-associated variants of amelogenesis imperfecta are X-linked with 14 different
mutations currently known. Because of the effect of
lyonization, the male and female phenotypes are variable but often associated with the genotype. The male
phenotypes include both the diffuse smooth hypoplastic and the hypomaturation variants.
The ENAM gene is associated with another enamel
protein, enamelin, which represents approximately
1% to 5% of enamel matrix. Mutations of the ENAM
gene have been correlated with some autosomal dominant and recessive patterns of hypoplastic amelogenesis imperfecta, ranging from minor pitting to diffuse
generalized thin enamel.
The MMP-20 gene codes for a proteinase named
enamelysin; mutation of this gene has been associated
ENAM
ENAM
DLX3
MMP20, KLK4
AMELX
AMELX
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Fig. 2-84 Hypoplastic amelogenesis imperfecta, generalized pitted pattern. A, Note the
numerous pinpoint pits scattered across the surface of the teeth. The enamel between the pits
is of normal thickness, hardness, and coloration. B, Occlusal view of same patient showing
diffuse involvement of all maxillary teeth, which would be inconsistent with environmental
damage. (A from Stewart RE, Prescott GH: Oral facial genetics, St Louis, 1976, Mosby; B courtesy of Dr. Joseph S.
Giansanti.)
In the localized pattern, the affected teeth demonstrate horizontal rows of pits, a linear depression, or
one large area of hypoplastic enamel surrounded by a
zone of hypocalcication. Typically, the altered area is
located in the middle third of the buccal surfaces of the
teeth. The incisal edge or occlusal surface usually is not
affected. Both dentitions (or only the primary teeth)
may be affected. All the teeth may be altered, or only
scattered teeth may be affected. When the involvement is not diffuse, the pattern of affected teeth does
not correlate with a specic time in development. The
autosomal recessive type (type IC) is more severe and
typically demonstrates involvement of all teeth in both
dentitions.
In the autosomal dominant smooth pattern, the
enamel of all teeth exhibits a smooth surface and is
thin, hard, and glossy (Fig. 2-85). The absence of appropriate enamel thickness results in teeth that are shaped
like crown preparations and demonstrate open contact
points. The color of the teeth varies from opaque white
to translucent brown. Anterior open bite is not rare.
Radiographically, the teeth exhibit a thin peripheral
outline of radiopaque enamel. Often, unerupted teeth
exhibiting resorption are seen.
The X-linked smooth pattern has been stated to
arise from an X-linked dominant mutation and is a
lesson in the lyonization effect. On approximately the
sixteenth day of embryonic life in all individuals with
two X chromosomes, one member of the pair is inactivated in each cell. As a result of this event, females are
mosaics, with a mixture of cells, some with active
maternal X chromosomes and others with active
paternal X chromosomes. Usually the mix is of
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seen in the smooth patterns, and the teeth are less vulnerable to attrition. Radiographs exhibit a thin peripheral outline of radiodense enamel. Unerupted teeth,
often undergoing resorption, may be seen. An anterior
open bite is common.
As the name implies, enamel agenesis demonstrates a total lack of enamel formation. The teeth are
the shape and color of the dentin, with a yellow-brown
hue, open contact points, and crowns that taper toward
the incisal-occlusal surface. The surface of the dentin
is rough, and an anterior open bite is seen frequently.
Radiographs demonstrate no peripheral enamel overlying the dentin. A lack of eruption of many teeth with
signicant resorption frequently occurs.
Many investigators have difculty subdividing the
diffuse hypoplastic forms of amelogenesis imperfecta
into categories such as smooth, rough, and enamel
agenesis. In the autosomal recessive pattern of amelogenesis imperfecta previously termed enamel agenesis,
the presence of a thin band of enamel has been conrmed in many affected patients. In addition, the separation between smooth and rough forms can be highly
subjective and problematic. Therefore, some investigators have suggested discontinuation of these subdivisions and combining these phenotypic patterns into
one category termed generalized thin hypoplastic
amelogenesis imperfecta.
HYPOMATURATION
AMELOGENESIS IMPERFECTA
In a person with hypomaturation amelogenesis imperfecta, the enamel matrix is laid down appropriately
and begins to mineralize; however, there is a defect in
the maturation of the enamels crystal structure.
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Fig. 2-86 Hypoplastic amelogenesis imperfecta, rough pattern (generalized thin pattern).
A, Small, yellow teeth with rough enamel surface, open contact points, signicant attrition,
and anterior open bite. B, Radiograph of the same patient. Note the impacted tooth and the
thin peripheral outline of radiodense enamel.
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Fig. 2-89 Hypocalcied amelogenesis imperfecta. A, Dentition exhibiting diffuse yellowbrown discoloration. Note numerous teeth with loss of coronal enamel except for the cervical
portion. B, Radiograph of the same patient. Note the extensive loss of coronal enamel and the
similar density of enamel and dentin.
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HISTOPATHOLOGIC FEATURES
The histopathologic alterations present in amelogenesis imperfecta are not evident in routine preparations.
Because decalcication of the teeth is necessary before
processing to allow sectioning of parafn-embedded
specimens, all the enamel is lost. To examine the
enamel structure of altered teeth, ground sections of
nondecalcied specimens are prepared. The alterations discovered are highly diverse and vary with each
clinical type of amelogenesis imperfecta. Detailed
descriptions of such alterations were provided by
Witkop and Sauk.
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Dentinogenesis Imperfecta
Shields
Dentinogenesis imperfecta I
Dentinogenesis imperfecta II
Dentinogenesis imperfecta III
Clinical Presentation
Witkop
Dentinogenesis imperfecta
Hereditary opalescent teeth
Brandywine isolate
Data from Shields ED: A new classication of heritable human enamel defects and a discussion of dentin defects. In Jorgenson RJ, Paul NW: Dentition:
genetic effects (birth defects original article series), vol 19, no. 1, pp 107-127, New York, 1983, Alan R Liss; Witkop CJ Jr: Amelogenesis imperfecta,
dentinogenesis imperfecta and dentin dysplasia revisited: problems in classication, J Oral Pathol 17:547-553, 1988.
DENTINOGENESIS IMPERFECTA
(HEREDITARY OPALESCENT DENTIN;
CAPDEPONTS TEETH)
Dentinogenesis imperfecta is a hereditary developmental disturbance of the dentin in the absence of any
systemic disorder. Similar dental changes may be seen
in conjunction with the systemic hereditary disorder of
bone, osteogenesis imperfecta (see page 613). Dentin
defects associated with this bone disease are termed
osteogenesis imperfecta with opalescent teeth.
Extensive pedigrees of individuals with dentinogenesis
imperfecta have been studied, and none have exhibited other changes suggestive of osteogenesis imperfecta. Genetic research has conrmed that osteogenesis
imperfecta with opalescent teeth clearly is a separate
disease from dentinogenesis imperfecta.
The various types of osteogenesis imperfecta have
been associated with mutation of the COL1A1 or
COL1A2 gene that encodes production of type I
collagen; in contrast, dentinogenesis imperfecta is associated with mutation of the DSPP (dentin sialophosphoprotein) gene. Currently, eight mutations of the
DSPP gene are known; seven are associated with dentinogenesis imperfecta, with the eighth known to create
dentin dysplasia type II.
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107
Disorder
Osteogenesis imperfecta with opalescent teeth
Dentinogenesis imperfecta
Dentin dysplasia type I
Dentin dysplasia type II
Inheritance
COL1A1, COL1A2
DSPP
DSPP
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HISTOPATHOLOGIC FEATURES
As expected, affected teeth demonstrate altered dentin.
The dentin adjacent to the enamel junction appears
similar to normal dentin, but the remainder is distinctly
abnormal. Short misshapen tubules course through an
atypical granular dentin matrix, which often demonstrates interglobular calcication (Fig. 2-96). Scanty
atypical odontoblasts line the pulp surface, and cells
DENTIN DYSPLASIA
Dentin dysplasia was initially categorized in 1939. Two
major patterns exist: type I and type II. By denition,
dentin dysplasia should have no correlation with sys-
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Box 2-10
Calcinosis universalis
Rheumatoid arthritis and vitaminosis D
Sclerotic bone and skeletal anomalies
Tumoral calcinosis
may vary not only from patient to patient but also from
tooth to tooth in a single patient. Because of the shortened roots, the initial clinical signs are extreme tooth
mobility and premature exfoliation, spontaneously or
secondary to minor trauma. Less frequently, delayed
eruption is the presenting symptom. The strength of
the radicular dentin is reduced, with the teeth being
predisposed to fracture during extractions.
Radiographically, the deciduous teeth often are
affected severely, with little or no detectable pulp, and
roots that are markedly short or absent. The permanent
teeth vary according to the proportion of organized
versus disorganized dentin (Fig. 2-99). Several years
ago, a subclassication of dentin dysplasia type I
was proposed and has become widely accepted
(Box 2-11).
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DDIa
DDIb
DDIc
DDId
Fig. 2-99 Dentin dysplasia type I. Illustration demonstrating the variability of the
radiographic appearance according to the degree of dentin disorganization within the root.
Box 2-11
exhibits teeth that are normal clinically. Radiographically the teeth are normal in shape but demonstrate a
radiodense product lling the pulp chambers and
canals. In contrast to dentinogenesis imperfecta, small
foci of radiolucency can be seen in the pulp. In contrast
to dentin dysplasia type I, no crescent pulp chambers
and no decrease in root length are seen. The radiodense
intrapulpal material consists of brotic dentin.
HISTOPATHOLOGIC FEATURES
In patients with dentin dysplasia type I, the coronal
enamel and dentin are normal. Apical to the point of
disorganization, the central portion of the root forms
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Box 2-12
Box 2-13
Ectodermal dysplasia
Epidermal nevi
Hypophosphatasia
Hydrocephalus
Ipsilateral facial hypoplasia
Neurobromatosis
Orbital coloboma
Rh factor incompatibility
Vascular nevi
REGIONAL ODONTODYSPLASIA
(GHOST TEETH)
Regional odontodysplasia is a localized, nonhereditary developmental abnormality of teeth with extensive
adverse effects on the formation of enamel, dentin, and
pulp. Most cases are idiopathic, but a number have
been related to various syndromes, growth abnormalities, neural disorders, and vascular malformations (Box
2-12). A number of causes have been proposed (Box
2-13), but the most popular theory revolves around an
alteration in the vascular supply. Several cases have
occurred in patients with vascular nevi of the head and
neck; in addition, similar changes have been induced
in animals by restricting the vascular ow to an area of
the jaws.
HISTOPATHOLOGIC FEATURES
In ground sections the thickness of the enamel varies,
resulting in an irregular surface. The prism structure
of the enamel is irregular or lacking with a laminated
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The basic approach to therapy of regional odontodysplasia is directed toward retention of the altered teeth,
whenever possible, to allow for appropriate development and preservation of the surrounding alveolar
ridge. Endodontic therapy on nonvital teeth that have
sufcient hard tissue to allow restoration has been performed successfully. Unerupted teeth should remain
untouched, restoring function with a removable partial
prosthesis until the skeletal growth period has passed.
Erupted teeth can be covered with etched-retained restorations or stainless steel crowns until nal restorations can be placed after the completion of growth.
Because of the fragile nature of the coronal hard tissue
and the ease of pulp exposure, tooth preparation is
contraindicated. Severely affected and infected teeth
often are not salvageable and need to be removed.
Although ankylosis has been seen with autotransplanted teeth, normal bicuspids have been autotransplanted into the extraction sites of the abnormal
dentition. This approach can successfully restore masticatory function, allowing appropriate facial development, and preventing ridge atrophy and supereruption
of the opposing dentition. Osseointegrated implants
have been placed in growing children with hypodontia
and could be used in the setting of regional odontodysplasia. Because implants essentially become ankylosed,
they have the potential to become embedded upon
continued gnathic growth in a child. For this reason,
implants generally should be reserved for patients who
have completed pubertal growth.
Although vitality of the abnormal dentition often is
difcult to maintain, such efforts may bring signicant
rewards. Several investigators have shown continued
dentinal development of teeth affected by regional
odontodysplasia. In cases monitored for many years,
the teeth lost their ghostly appearance and revealed a
resultant decrease in pulp size, a signicant increase in
dentin thickness, and ultimate relative normalization
of the radicular anatomy. In contrast, the enamel
remained hypoplastic. The surrounding bone became
well developed and lost its diminished density. Only a
few reports of this phenomenon exist, however, most
likely because the prior treatment of choice has been
extraction.
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Fowler CB, Brannon RB: The paradental cyst: a clinicopathologic
study of six new cases and review of the literature, J Oral
Maxillofac Surg 47:243-348, 1989.
Goldstein AR: Enamel pearls as a contributing factor in periodontal breakdown, J Am Dent Assoc 99:210-211, 1979.
Hou G-L, Tsai C-C: Relationship between periodontal furcation
involvement and molar cervical enamel projections, J Periodontol 58:715-721, 1987.
Kaugars GE: Internal enamel pearls: report of case, J Am Dent
Assoc 107:941-943, 1983.
Matthews DC, Tabesh M: Detection of localized tooth-related
factors that predispose to periodontal infections, Periodontol
2000 34:136-150, 2004.
Moskow BS, Canut PM: Studies on root enamel: (2) enamel
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Clin Periodontol 17:275-281, 1990.
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Pompura JR, Sndor GKB, Stoneman DW: The buccal bifurcation cyst: a prospective study of treatment outcomes in 44
sites, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 83:215221, 1997.
Risnes S: The prevalence, location, and size of enamel pearls on
human molars, Scand J Dent Res 82:403-412, 1974.
Zee K-Y, Bratthall G: Prevalence of cervical enamel projection
and its correlation with furcation involvement in Eskimos
dry skulls, Swed Dent J 27:43-48, 2003.
Taurodontism
Durr DP, Campos CA, Ayers CS: Clinical signicance of taurodontism, J Am Dent Assoc 100:378-381, 1980.
Llamas R, Jimenez-Planas A: Taurodontism in premolars, Oral
Surg Oral Med Oral Pathol 75:501-505, 1993.
Ruprecht A, Batniji S, El-Neweihi E: The incidence of taurodontism in dental patients, Oral Surg Oral Med Oral Pathol
63:743-747, 1987.
Shaw JCM: Taurodont teeth in South African races, J Anat
62:476-498, 1928.
Shifman A, Chanannel I: Prevalence of taurodontism found
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1978.
Tsesis I, Shifman A, Kaufman AY: Taurodontism: an endodontic
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Witkop CJ, Keenan KM, Cervenka J et al: Taurodontism: an
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Hypercementosis
Fox L: Pagets disease (osteitis deformans) and its effect on maxillary bones and teeth, J Am Dent Assoc 20:1823-1829, 1933.
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Leider AS, Garbarino VE: Generalized hypercementosis, Oral
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Dilaceration
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Pediatr Dent 12:321-324, 1990.
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Supernumerary Roots
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Krolls SO, Donahue AH: Double-rooted maxillary primary
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Amelogenesis Imperfecta
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Aldred MJ, Crawford PJM, Savarirayan R et al: Its only teethare
there limits to genetic testing? Clin Genet 63:333-339, 2003.
Aldred MJ, Savarirayan R, Crawford PJM: Amelogenesis imperfecta: a classication and catalogue for the 21st century, Oral
Dis 9:19-23, 2003.
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84:1031-1035, 2005.
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Pulpal and Periapical Disease
CHAPTER OUTLINE
Pulpitis
Secondary and Tertiary Dentin
Pulpal Calcications
Periapical Granuloma
Periapical Cyst
Periapical Abscess
Cellulitis
Osteomyelitis
Diffuse Sclerosing Osteomyelitis
Condensing Osteitis
Osteomyelitis with Proliferative Periostitis
Alveolar Osteitis
PULPITIS
The initial response of the dental pulp to injury is not
signicantly different from that seen in other tissues.
However, the nal result can be different because of
the rigid dentinal walls of the pulp chamber. When
external stimuli reach a noxious level, degranulation
of mast cells, decreased nutrient ow, and cellular
damage occur. Numerous inammatory mediators
(e.g., histamine, bradykinin, neurokinins, neuropeptides, prostaglandins) are released. These mediators
cause vasodilation, increased blood inow, and vascular leakage with edema. In normal tissue, increased
blood ow promotes healing through removal of
inammatory mediators, and swelling of the injured
tissue usually occurs. However, the dental pulp exists
in a very conned area.
Pulpal response to noxious stimuli is meant to eliminate any invading organisms, remove cellular debris,
and limit tissue damage. Paradoxically, the inammatory reaction can lead to increased pulpal injury or
even death of the pulp. Previous theories have suggested that the associated increased vascular pulpal
pressures could compress venous return and lead to
self-strangulation and pulpal necrosis. Today researchers recognize that the increased uid pressure usually
is localized to the area of inamed pulp immediately
adjacent to the affected dentin. Increased interstitial
pressure in areas of inammation leads to increased
ow of uid back into capillaries of adjacent unin-
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REVERSIBLE PULPITIS
When exposed to temperature extremes, teeth with
reversible pulpitis exhibit a sudden mild-to-moderate
pain (pulpalgia) of short duration. Although heat may
initiate pain, the affected tooth responds most to cold
stimuli (e.g., ice, beverages, cold air). Contact with
sweet or sour foods and beverages also may cause pain.
The pain does not occur without stimulation and subsides within seconds after the stimulus is removed.
Typically, the tooth responds to electric pulp testing at
lower levels of current than an appropriate control
tooth. Mobility and sensitivity to percussion are absent.
If the pulpitis is allowed to progress, then the duration
of the pain on stimulation can become longer and the
pulp may become affected irreversibly.
IRREVERSIBLE PULPITIS
Patients with early irreversible pulpitis generally
have sharp, severe pain on thermal stimulation, and the
pain continues after the stimulus is removed. Cold is
especially uncomfortable, although heat or sweet and
acidic foods also can elicit pain. In addition, the pain
may be spontaneous or continuous and may be exacerbated when the patient lies down. The tooth responds
to electric pulp testing at lower levels of current.
In the early stages of irreversible pulpitis, the pain
often can be localized easily to the individual offending tooth; with increasing discomfort, however, the
patient is unable to identify the offending tooth within
a quadrant.
In the later stages of irreversible pulpitis, the pain
increases in intensity and is experienced as a throbbing
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HISTOPATHOLOGIC FEATURES
Basically, the histopathology is primarily of academic
interest and does not usually affect treatment signicantly. Numerous investigations have shown a surprising lack of correlation between histopathologic ndings
and the clinical symptoms in the majority of pulps
examined.
In patients with reversible pulpitis, the pulp usually
shows hyperemia, edema, and a few inammatory
cells underlying the area of affected dentinal tubules
(Fig. 3-4). Tertiary dentin may be noted in the adjacent
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demonstrates brosis and a chronic inammatory inltrate. Pulpal calcications are common in both the
radicular and coronal portions. Often the apical portion
of the pulp tissue is normal, with minimal inammation or brosis.
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HISTOPATHOLOGIC FEATURES
Physiologic secondary dentin consists of regular tubular
dentin that is applied onto the primary dentin. These
two layers of dentin can be separated by a line of
demarcation, often indicated by a bending of the
tubules (Fig. 3-9). With advancing age, as the odontoblasts undergo degenerative changes, the physiologic
secondary dentin becomes more irregular with fewer
tubules.
The quality and appearance of tertiary dentin
depend on the severity of the noxious stimulus that
promoted its formation. Tertiary dentin is localized to
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PULPAL CALCIFICATIONS
Calcications within the dental pulp are not rare, but
the frequency is difcult to determine. Reported rates
vary from 8% to 90%, but several investigators have
documented a prevalence of approximately 20% in
individual teeth reviewed radiographically. Because
radiographically detectable pulp stones typically
exceed 200 m in diameter, the prevalence in a histopathologic review would be expected to be much
higher. There appears to be a strong association
between long-standing chronic pulpitis and the presence of pulpal calcication; in addition, the prevalence
of pulpal calcications increases with age. However,
some examples appear to be developmental with a
familial tendency.
The three types of pulpal calcications are:
1. Denticles
2. Pulp stones
3. Diffuse linear calcications
All pulpal calcications start out as free bodies within
the pulp tissue, but many may become attached or
embedded in the dentinal walls of the pulp.
Denticles are believed to form as a result of an
epitheliomesenchymal interaction within the developing pulp. Epithelial strands originating from the root
sheath, or cervical extensions into the pulp chamber
adjacent to furcations, induce odontoblastic differentiation of the surrounding mesenchyme of the dental
papilla, forming the core of the denticle. Odontoblasts
deposit tubular dentin as they move away from the
central epithelium and produce thimble-shaped structures surrounding the epithelium. Denticles form
during the period of root development and occur in the
root canal and the pulp chamber adjacent to the furcation areas of multirooted teeth. Because denticle development typically precedes completion of the primary
dentin, most denticles become attached to or embedded in the dentin.
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HISTOPATHOLOGIC FEATURES
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In the early stages of infection, neutrophils predominate and radiographic alterations are not present; this
phase of periapical inammatory disease is termed
acute apical periodontitis. The involved inammatory
cells are primarily neutrophils and release prostaglandins, which activate osteoclasts to resorb the surrounding bone, leading to a detectable periapical
radiolucency. Researchers believe that this bone
destruction is an attempt to prevent the spread of the
infection and provide space for the arrival of defense
cells specialized against the infectious process. With
time, chronic inammatory cells begin to dominate the
host response. Mediators released by lymphocytes
reduce further osteoclastic activity while also stimulating
broblasts and the microvasculature. Because of these
actions, chronic lesions often are asymptomatic and
demonstrate little additional change radiographically.
Periapical granulomas may arise after quiescence of
a periapical abscess or may develop as the initial periapical pathosis. These lesions are not necessarily static.
In addition to possible periapical cyst formation, a
worsening of the pulpal infection can lead to a reappearance of inammation, redevelopment of symptoms, and possible enlargement of the associated
radiolucency. Secondary acute inammatory changes
within a periapical granuloma have been termed a
phoenix abscess, after the mythical bird that would die,
only to arise again from its own ashes. In progressive
periapical granulomas, the enlargement often is not
continuous but occurs in spurts associated with periodic acute exacerbations.
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Periapical granulomas consist of inamed granulation
tissue surrounded by a brous connective tissue wall.
The granulation tissue demonstrates a variably dense
lymphocytic inltrate that is intermixed frequently
with neutrophils, plasma cells, histiocytes, and, less frequently, mast cells and eosinophils (Fig. 3-18). When
numerous plasma cells are present, scattered eosinophilic globules of gamma globulin (Russell bodies)
may be seen. In addition, clusters of lightly basophilic
particles (pyronine bodies) also may be present in
association with the plasmacytic inltrate. Both of
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these plasma cell products are not specic for the periapical granuloma and may be found within any accumulation of plasma cells. Epithelial rests of Malassez
may be identied within the granulation tissue. Collections of cholesterol clefts, with associated multinucleated giant cells and areas of red blood cell extravasation
with hemosiderin pigmentation, may be present.
Although the source of the cholesterol is unclear, this
material often is noted in areas of long-term inammation and may accumulate from dying inammatory
cells, disintegrating red blood cells, or degenerating
cystic epithelium. The cholesterol attracts macrophages and foreign body giant cells, which are unable
to degrade the material but release inammatory
and bone resorptive mediators. Signicant cholesterol
accumulation can continue the inammatory process
in the absence of active microbial infection. Small foci
of acute inammation with focal abscess formation
may be seen but do not warrant the diagnosis of periapical abscess.
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drugs (NSAIDs) are benecial; use of systemic antibiotic medications is not recommended unless associated swelling or systemic changes are present.
Teeth treated endodontically should be evaluated at
1- and 2-year intervals (at a minimum) to rule out possible lesional enlargement and to ensure appropriate
healing. In addition, many clinicians believe that evaluations at 1, 3, and 6 months are appropriate. Strong
emphasis should be placed on the importance of the
recall appointments.
Lesions may fail to heal for several reasons:
Cyst formation
Persistent
pulpal infection (e.g., poor access
design, missed canals, perforated canals, vertical
root fractures, inadequate aseptic technique or
instrumentation, leaking llings)
Extraradicular infection (usually localized periapical actinomycotic colonization)
Accumulation of endogenous debris (e.g., cholesterol crystals)
Periapical foreign material
Associated periodontal disease
Penetration of the adjacent maxillary sinus
Fibrous scar formation (see following)
If initial conventional therapy is unsuccessful, endodontic retreatment represents the best approach for
minimizing the bacterial contamination and should
be considered before periapical surgery. Periapical
surgery remains an important tool for resolution of
periapical inammatory disease, but often it is reserved
for lesions larger than 2 cm or those associated with
teeth that are not appropriate for conventional endodontic therapy. Periapical surgery should include
thorough curettage of all periradicular soft tissue,
amputation of the apical portion of the root, and sealing
the foramen of the canal.
All soft tissue removed during periapical surgical
procedures should be submitted for histopathologic
examination. These surgical sites represent areas that
have failed to respond to appropriate therapy; as such,
histopathologic examination and diagnostic conrmation are mandatory. The primary motivation for this
examination is not to discover whether the lesion represents a periapical granuloma or cyst; the examination
is conducted to eliminate the possibility of a more
serious process unrelated to periapical inammatory
disease. In an active oral and maxillofacial pathology
service, discovery of unexpected neoplasms within
specimens removed during periapical surgery is not
rare.
On occasion, the defect created by periapical inammatory lesions may ll with dense collagenous tissue
rather than normal bone (Fig. 3-19). These brous
(periapical) scars occur most frequently when both
the facial and lingual cortical plates have been lost (Fig.
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Fig. 3-23 Periapical cyst. Large unilocular radiolucency
extending from the mandibular rst molar to the
contralateral rst molar. (Courtesy of Dr. John R. Cramer.)
The histopathologic features of all three types of inammatory cysts are similar. The cyst is lined by stratied
squamous epithelium, which may demonstrate exocytosis, spongiosis, or hyperplasia (Fig. 3-30). As seen in
dentigerous cysts, scattered mucous cells or areas of
ciliated pseudostratied columnar epithelium may
be noted in periapical cysts (Fig. 3-31). Although some
maxillary periapical cysts lined by pseudostratied
columnar epithelium may have originated from the
adjacent sinus lining, the presence of mucous cells or
respiratory-like epithelium also can be observed in
mandibular cysts. The ability of odontogenic epithelium to demonstrate such specialized differentiation
represents an example of prosoplasia (forward metaplasia) and highlights the diverse potential of odontogenic
epithelium. The cyst lumen may be lled with uid and
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Fig. 3-25 Lateral radicular cyst. A, Periapical radiograph of the left side of the posterior
mandible taken at time of completion of endodontic therapy of the bicuspid and molars.
B, Subsequent radiograph taken 27 months later. Note radiolucency between bicuspid and
rst molar extending laterally from the mesial root of the rst molar. (Courtesy of Dr. Carroll
Gallagher.)
that exhibits a corrugated periphery of condensed collagen often surrounded by lymphocytes and multinucleated giant cells (Fig. 3-33). The eosinophilic material
may be uniform or contain a variable mixture of lymphocytes, plasma cells, multinucleated giant cells, neutrophils, necrotic debris, and dystrophic calcication.
Initially, these foci were thought to be a vascular degenerative process or a foreign body reaction to machinery
oil or vegetable matter. Subsequently, these bodies
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PERIAPICAL ABSCESS
The accumulation of acute inammatory cells at the
apex of a nonvital tooth is termed a periapical abscess.
Acute inammatory lesions with abscess formation
may arise as the initial periapical pathosis or from an
acute exacerbation of a chronic periapical inammatory lesion (see discussion of phoenix abscess, page
128). Frequently, the source of the infection is obvious.
On occasion, however, pulpal death may be trauma
related, and the tooth may contain neither a cavity nor
a restoration.
In the earliest stage of all forms of periapical inammatory disease, the periapical periodontal ligament
(PDL) bers may exhibit acute inammation but no
frank abscess formation. This localized alteration, best
termed acute apical periodontitis, may or may not
proceed to abscess formation. Although this process
often occurs in association with a nonvital tooth, acute
apical periodontitis may be found in vital teeth secondary to trauma, high occlusal contacts, or wedging by a
foreign object. The clinical presentation often closely
resembles that of a periapical abscess and must be
considered in the differential diagnosis.
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Fig. 3-38 Periapical abscess. A, Same patient as depicted in Fig. 3-36. None of the incisors
demonstrates an obvious periapical radiolucency. (The large radiolucency at the top is the
anterior portion of the maxillary sinus.) B, Gutta-percha point revealed that the right maxillary
incisor was the source of the infection.
HISTOPATHOLOGIC FEATURES
Biopsy specimens from pure abscesses are uncommon
because the material is in liquid form. Abscesses consist
of a sea of polymorphonuclear leukocytes often intermixed with inammatory exudate, cellular debris,
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CELLULITIS
If an abscess is not able to establish drainage through
the surface of the skin or into the oral cavity, it may
spread diffusely through fascial planes of the soft tissue.
This acute and edematous spread of an acute inammatory process is termed cellulitis. Although numerous patterns of cellulitis can be seen from the spread
of dental infections, two especially dangerous forms
warrant further discussion: (1) Ludwigs angina and
(2) cavernous sinus thrombosis.
Ludwigs angina, named after the German physician
who described the seriousness of the disorder in 1836,
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LUDWIGS ANGINA
Ludwigs angina is an aggressive and rapidly spreading
cellulitis that involves the sublingual, submandibular,
and submental spaces. Once the infection enters the
submandibular space, it may extend to the lateral pharyngeal space and then to the retropharyngeal space.
This extension may result in spread to the mediastinum, with several serious consequences.
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OSTEOMYELITIS
Osteomyelitis is an acute or chronic inammatory
process in the medullary spaces or cortical surfaces of
bone that extends away from the initial site of involvement. The term osteomyelitis has been used to encompass a wide variety of pathoses. This section describes
the classic pattern of osteomyelitis. The vast majority of
osteomyelitis cases are caused by bacterial infections
and result in an expanding lytic destruction of the
involved bone, with suppuration and sequestra formation. Many believe that this condition is more appropriately termed suppurative osteomyelitis, bacterial
osteomyelitis, or secondary osteomyelitis. This pattern of
osseous pathosis is in contrast to an ill-dened group
of idiopathic inammatory disorders of bone that do
not respond consistently to antibacterial medications
and typically demonstrate ultimate sclerosis of bone
without suppuration or sequestra formation. This
second pattern of inammatory bone disease is most
appropriately termed primary chronic osteomyelitis but
often is included under the term diffuse sclerosing osteomyelitis. This disorder and several other patterns of
inammatory bone disease (e.g., focal sclerosing osteomyelitis, proliferative periostitis, alveolar osteitis) are
unique and are covered separately later in the chapter.
Osteoradionecrosis is excluded from this discussion
because this is primarily a problem of hypoxia, hypocellularity, and hypovascularity in which the presence
of bacteria represents a secondary colonization of non-
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Fig. 3-47 Chronic osteomyelitis. A, Ill-dened area of radiolucency of the right body of the
mandible adjacent to a recent extraction site. B, After the initial intervention, the patient
failed to return for follow-up because of lack of signicant pain. An enlarged, ill-dened
radiolucency of the right body of the mandible was discovered 2 years after the initial surgery.
(Courtesy of Dr. Charles Waldron.)
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HISTOPATHOLOGIC FEATURES
ACUTE SUPPURATIVE OSTEOMYELITIS
Generation of biopsy material from patients with acute
osteomyelitis is not common because of the predominantly liquid content and lack of a soft tissue component. When submitted, the material consists
predominantly of necrotic bone. The bone shows a
loss of the osteocytes from their lacunae, peripheral
resorption, and bacterial colonization (Fig. 3-48). The
periphery of the bone and the haversian canals contain
necrotic debris and an acute inammatory inltrate
consisting of polymorphonuclear leukocytes. The submitted material will be diagnosed as a sequestrum
unless a good clinicopathologic correlation points to
the appropriate diagnosis of acute osteomyelitis.
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CHRONIC TENDOPERIOSTITIS
Although the mean age of occurrence is 40 years,
chronic tendoperiostitis may occur in people of all
ages. There is no sex predilection. Recurrent pain,
swelling of the cheek, and trismus are classic symptoms. Suppuration and an associated infectious cause
are not found. Microbiologic cultures are typically negative, with the lesions failing to respond to appropriate
antibiotic medications. Uncommon spontaneous resolution with development of radiographic normalcy has
been noted.
In most instances, the sclerosis is limited to a single
quadrant and centers on the anterior region of the
mandibular angle and posterior portion of the mandibular body (i.e., attachment of the masseter muscle).
Occasionally, the cuspid and premolar region and the
anterior mandible (i.e., attachment of the digastric
muscle) may be involved. Relatively radiolucent zones
are apparent within the areas of radiodensity, but histopathologic examination reveals only dense bone, formation of reactive bone, and relatively few signs of
inammation. The inferior border of the mandibular
body is typically affected, and signicant erosion of the
inferior border appears just anterior to the angle of the
mandible.
SAPHO SYNDROME
Patients with SAPHO syndrome are usually younger
than 60 years old and have chronic multifocal osteomyelitis that is typically associated with negative microbiologic cultures and is nonresponsive to antibiotic
therapy. In contrast to bacterial osteomyelitis, the
osteolytic areas are scattered randomly within areas of
sclerotic bone. Periosteal new bone formation is
common but not related to cortical bone perforation.
Investigation of the entire skeleton by bone scintigraphy classically reveals involvement of multiple sites.
The most frequently involved location is the anterior
chest wall, with the sternum, clavicles, and ribs being
affected individually or together. Other bones occasionally involved include the spine, pelvis, and long
bones.
In early gnathic lesions, diffuse osteolytic zones are
more prominent than sclerosis; the affected bone is
enlarged because of signicant production of periosteal new bone. With time, the bone becomes more
sclerotic and decreases in size because of diminished
periosteal apposition, while the osteolytic zones become smaller and fewer. External bone resorption and
HISTOPATHOLOGIC FEATURES
DIFFUSE SCLEROSING OSTEOMYELITIS
Diffuse sclerosing osteomyelitis demonstrates sclerosis
and remodeling of bone. The haversian canals are scattered widely and little marrow tissue can be found.
Although the sclerosis occurs adjacent to areas of inammation, the bone is not typically intermixed with a signicant inammatory soft tissue component. If the
adjacent inammatory process extends into the sclerotic
bone, then necrosis often occurs. The necrotic bone separates from the adjacent vital tissue and becomes surrounded by subacutely inamed granulation tissue.
Secondary bacterial colonization often is visible.
CHRONIC TENDOPERIOSTITIS
Chronic tendoperiostitis demonstrates sclerosis and
remodeling of the cortical and subcortical bone with a
resultant increase in bone volume. If chronic inam-
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CHRONIC TENDOPERIOSTITIS
Fig. 3-51 Primary chronic osteomyelitis. Trabeculae of
sclerotic, pagetoid bone showing numerous resting and
reversal lines.
matory cells are present, then they are located in cortical resorption defects and the subcortical bone adjacent
to sites of muscle insertion.
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these, osteomyelitis and malignant neoplasms are associated most frequently with formation of bone within
a periosteal reaction.
In 1893 a Swiss physician, Carl Garr, reported in
the German literature on patterns of acute osteomyelitis. Since that time, numerous articles have been written
that associate Garrs report with a form of inammatory periosteal hyperplasia demonstrating an onionskin-like reduplication of the cortical plate. (In these
subsequent articles, Garrs name was misspelled consistently as Garr, with an improper accent.) However,
Garr did not have any pathologic specimens for
microscopic examination, and Roentgen did not discover x-rays until 2 years after Garrs publication.
Nowhere in the original publication is there any
mention of periostitis, periosteal duplication, or onionskinning. Although the term Garrs osteomyelitis often
is used synonymously for this condition, it is an
improper designation that should be disassociated with
the entity described in the text that follows.
OSTEOMYELITIS WITH
PROLIFERATIVE PERIOSTITIS
(PERIOSTITIS OSSIFICANS)
Bone formation within a periosteal reaction is a
common nding that occurs in a wide variety of intraosseous pathoses and in all age groups. Causes of periosteal new bone formation include osteomyelitis, trauma,
cysts, infantile cortical hyperostosis, uorosis, avitaminosis C, hypertrophic osteoarthropathy, congenital
syphilis, and neoplasms such as Ewing sarcoma, Langerhans cell histiocytosis, and osteogenic sarcoma. Of
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Fig. 3-54 Proliferative periostitis. A, Firm swelling of the lateral and inferior border of the
right mandible that arose after traumatic injury. B, Computed tomography (CT) image
demonstrating new periosteal bone growth with onionskin laminations. C, Panoramic
radiograph exhibiting new periosteal bone formation along the right inferior border of the
mandible. (Courtesy of Drs. Sherif Mekhail and Benjamin Lin.)
premolar and molar area of the mandible. The hyperplasia is located most frequently along the lower border
of the mandible, but buccal cortical involvement also
is common. Isolated lingual cortical enlargement is
infrequent. Most cases are unifocal, although multiple
quadrants may be affected.
Appropriate radiographs demonstrate radiopaque
laminations of bone that roughly parallel each other
and the underlying cortical surface (Fig. 3-54). The
laminations vary from 1 to 12 in number, and radiolucent separations often are present between the new
bone and the original cortex. Less frequently, the new
bone formation exhibits consolidation and contains
numerous ne bony projections that radiate perpen-
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HISTOPATHOLOGIC FEATURES
Usually, biopsy is not required unless the clinical diagnosis is in question. Specimens often reveal parallel
rows of highly cellular and reactive woven bone in
which the individual trabeculae are frequently oriented perpendicular to the surface. The trabeculae
sometimes form an interconnecting meshwork of bone
or are scattered more widely, resembling the pattern
seen in immature brous dysplasia (Fig. 3-55). Between
the cellular trabeculae, relatively uninamed brous
connective tissue is evident. Sequestra, if included,
demonstrate the typical features of bone necrosis (see
Osteomyelitis, page 141).
CLINICAL FEATURES
The frequency of alveolar osteitis is higher in the mandible and the posterior areas. After oral contraceptive
use is taken into account, there does not appear to be
a signicant sex predilection. The prevalence is
between 1% and 3% of all extractions, but it increases
to 25% to 30% for impacted mandibular third molars.
The frequency appears to be decreased when impacted
teeth are removed prophylactically rather than for
therapeutic reasons after development of chronic
inammation of pericoronal tissues. The overall prevalence is highest between 20 and 40 years of age (when
the majority of teeth are extracted), although the likelihood of developing alveolar osteitis appears greatest
for extractions in the 40- to 45-year-old age group.
The affected extraction site is lled initially with a
dirty gray clot that is lost and leaves a bare bony socket
(dry socket). The detection of the bare socket may be
hindered by partial retention of the clot or by overlying
inamed tissue that covers the site. The diagnosis is
conrmed by probing of the socket, which reveals
exposed and extremely sensitive bone. Typically, severe
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BIBLIOGRAPHY
General References
Cohen S, Hargreaves KM: Pathways of the pulp, ed 9, St Louis,
2005, Mosby.
Ingle JI, Bakland LK: Endodontics, ed 5, Hamilton, Ontario, 2002,
BC Decker.
Pulpitis
Banchs F, Trope M: Revascularization of immature permanent
teeth with apical periodontitis: new treatment protocol? J
Endod 30:196-200, 2004.
Barrieshi-Nusair KM, Qudeimat MA: A prospective clinical study
of mineral trioxide aggregate for partial pulpotomy in cariously exposed permanent teeth, J Endod 32:731-735, 2006.
als
kan MK, ztop F, als
kan G: Histological evaluation of teeth
with hyperplastic pulpitis caused by trauma or caries: case
reports, Int Endod J 36:64-70, 2002.
Heyeraas KJ, Sveen OB, Mjr IA: Pulp-dentin biology in restorative dentistry. Part 3: pulpal inammation and its sequelae,
Quintessence Int 32:611-625, 2001.
Holland GR: Pulpalgia, the Pimpernel of pain, Tex Dent J 120:239247, 2003.
Hyman JL, Cohn ME: The predictive value of endodontic diagnostic tests, Oral Surg Oral Med Oral Pathol 58:343-346,
1984.
Michaelson PL, Holland GR: Is pulpitis painful? Int J Endod
35:829-832, 2002.
Modaresi J, Dianat O, Mozayeni MA: The efcacy comparison of
ibuprofen, acetaminophen-codeine, and placebo premedication therapy on the depth of anesthesia during treatment of
inamed teeth, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 102:339-403, 2006.
Rafter M: Apexication: a review, Dent Traumatol 21:1-8, 2005.
Witherspoon DE, Small JC, Harris GZ: Mineral trioxide aggregate pulpotomies. A case series outcome assessment, J Am
Dent Assoc 137:610-618, 2006.
Secondary and Tertiary Dentin
Amir FA, Gutmann JL, Witherspoon DE: Calcic metamorphosis: a challenge in endodontic diagnosis and treatment, Quintessence Int 32:447-455, 2001.
Mjr IA, Ferrari M: Pulp-dentin biology in restorative dentistry.
Part 6: reactions to restorative materials, tooth-restoration
interfaces, and adhesive techniques, Quintessence Int 33:3563, 2002.
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Condensing Osteitis
Boyne PJ: Incidence of osteosclerotic areas in the mandible and
maxilla, J Oral Surg Anesth Hosp Dent Serv 18:486-491, 1960.
Eliasson S, Halvarsson C, Ljungheimer C: Periapical condensing
osteitis and endodontic treatment, Oral Surg Oral Med Oral
Pathol 57:195-199, 1984.
Eversole LR, Stone CE, Strub D: Focal sclerosing osteomyelitis/
focal periapical osteopetrosis: radiographic patterns, Oral
Surg Oral Med Oral Pathol 58:456-460, 1984.
Farman AG, de V Joubert JJ, Nortj C: Focal osteosclerosis and
apical periodontal pathoses in European and Cape Coloured
dental outpatients, Int J Oral Surg 7:549-557, 1978.
Hedin M, Polhagen L: Follow-up study of periradicular bone
condensation, Scand J Dent Res 79:436-440, 1979.
Osteomyelitis with Proliferative Periostitis
Eversole LR, Leider AS, Corwin JO et al: Proliferative periostitis
of Garr: its differentiation from other neoperiostoses, J Oral
Surg 37:725-731, 1979.
Jacobson HLJ, Baumgartner JC, Marshall JG et al: Proliferative
periostitis of Garr: report of a case, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 94:111-114, 2002.
Kannan SK, Sandhya G, Selvarani R: Periostitis ossicans (Garrs
osteomyelitis) radiographic study of two cases, Int J Paediatr
Dent 16:59-64, 2006.
Kawai T, Hiranuma H, Kishino M et al: Gross periostitis ossicans in mandibular osteomyelitis. Review of the English language literature and radiographic variation, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 86:376-381, 1998.
Kawai T, Murakami S, Sakuda M et al: Radiographic investigation of mandibular periostitis ossicans in 55 cases, Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 82:704-712, 1996.
Nortj CJ, Wood RE, Grotepass F: Periostitis ossicans versus
Garrs osteomyelitis: part II. Radiologic analysis of 93 cases
in the jaws, Oral Surg Oral Med Oral Pathol 66:249-260,
1988.
Wood RE, Nortj CJ, Grotepass F et al: Periostitis ossicans
versus Garrs osteomyelitis: part I. What did Garr really
say? Oral Surg Oral Med Oral Pathol 65:773-777, 1988.
Alveolar Osteitis
Awang MN: The aetiology of dry socket: a review, Int Dent J
39:236-240, 1989.
Birn H: Etiology and pathogenesis of brinolytic alveolitis (dry
socket), Int J Oral Surg 2:215-263, 1973.
Blum IR: Contemporary views on dry socket (alveolar osteitis): a
clinical appraisal of standardization, aetiopathogenesis and
management: a critical review, Int J Oral Maxillofac Surg
31:309-317, 2003.
Caso A, Hung, L-K, Beirne OR: Prevention of alveolar osteitis
with chlorhexidine: a meta-analytic review, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 99:155-159, 2005.
Catellani JE: Review of factors contributing to dry socket through
enhanced brinolysis, J Oral Surg 37:42-46, 1979.
Fazakerley M, Field EA: Dry socket: a painful post-extraction
complication (a review), Dent Update 18(1):31-34, 1991.
Garcia AG, Grana PM, Sampedro FG et al: Does oral contraceptive use affect the incidence of complications after extraction
of a mandibular third molar? Br Dent J 194:453-455, 2003.
Houston JP, McCollum J, Pietz D et al: Alveolar osteitis: a review
of its etiology, prevention, and treatment modalities, Gen Dent
50:457-463, 2002.
Larsen PE: Alveolar osteitis after surgical removal of impacted
mandibular third molars: identication of the patient at risk,
Oral Surg Oral Med Oral Pathol 73:393-397, 1992.
Swanson AE: Prevention of dry socket: an overview, Oral Surg
Oral Med Oral Pathol 70:131-136, 1990.
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CHAPTER OUTLINE
Gingivitis
Necrotizing Ulcerative Gingivitis
Plasma Cell Gingivitis
Granulomatous Gingivitis
Desquamative Gingivitis
Drug-Related Gingival Hyperplasia
Gingival Fibromatosis
Periodontitis
Chronic Periodontitis
GINGIVITIS
Gingivitis refers to inammation limited to the soft
tissues that surround the teeth. It does not include the
inammatory processes that may extend into the
underlying alveolar ridge, periodontal ligament, or
cementum. The primary types of gingivitis are listed in
Box 4-1. This part of the text concentrates on the
plaque-related types. Necrotizing ulcerative gingivitis (NUG), medication-inuenced gingivitis, and a
specic type of allergic gingivitis (plasma cell gingivitis) are presented later in this chapter. Additional
forms of allergic gingivitis are discussed in Chapter 9.
The gingivitis associated with specic infections (e.g.,
herpes simplex, human immunodeciency virus [HIV])
is discussed in Chapters 5 and 7. The gingiva is a frequent site of involvement in several of the dermatologic vesiculoerosive diseases; these are well described
in Chapter 16.
CLINICAL FEATURES
Most cases of gingivitis occur from lack of proper oral
hygiene, which leads to the accumulation of dental
plaque and calculus; however, many other factors can
affect the gingivas susceptibility to the oral ora. The
frequency of gingivitis is high in all age groups, but its
true prevalence is difcult to determine because of the
lack of a standardized method of measurement. Clinically detectable inammatory changes of the gingiva
begin in childhood and increase with age. With similar
amounts of dental plaque, the severity of gingivitis is
greater in adults than in prepubertal children. Around
the time of puberty, there is a period of increased susceptibility to gingivitis (puberty gingivitis), with the
peak prevalence of involvement occurring between the
ages of 9 and 14 years (Fig. 4-1). Between the ages of
11 and 17 years, the frequency declines; then a slow
increase is seen until the prevalence approaches 100%
in the sixth decade of life.
In most age groups, females demonstrate a lower
frequency of gingivitis than do males (although females
have periods of increased susceptibility). This may be
due more to better oral hygiene in females than to a
physiologic difference between the sexes. In addition
to the years of puberty, females exhibit a greater susceptibility to gingivitis when they are exposed to the
high levels of progesterone associated with pregnancy
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Box 4-2
Types of Gingivitis
Plaque-related gingivitis
Necrotizing ulcerative gingivitis (NUG)
Medication-inuenced gingivitis
Allergic gingivitis
Specic infection-related gingivitis
Dermatosis-related gingivitis
1. Hormonal changes
Puberty
Pregnancy
Oral contraceptive use
2. Stress
3. Substance abuse
4. Poor nutrition
Ascorbate (vitamin C) deciency (see page 826)
5. Certain medications (see page 163)
Phenytoin
Calcium channel blockers
Cyclosporine
6. Diabetes mellitus (see page 842)
7. Down syndrome
8. Immune dysfunction
9. Heavy-metal poisoning (see page 313)
Box 4-3
1. Local trauma
2. Tooth crowding with overlapping
3. Dental anomalies
Enamel pearls (see page 93)
Enamel and radicular grooves
4. Tooth fracture
5. Dental caries
6. Gingival recession
7. High frenum attachments
8. Iatrogenic factors
Overhanging restorations
Removable prostheses
Orthodontic appliances
9. Inadequate lip closure
10. Mouth breathing
individual traits seem to determine the severity of gingivitis, independent of the degree of plaque accumulation. Even after removal of the causative plaque and
resolution of the associated gingivitis, individuals identied as being susceptible to gingivitis exhibit measurable differences in gingival crevicular uid volume
from patients who have demonstrated resistance to
plaque-related gingivitis. In addition, evidence suggests that susceptibility to gingivitis appears linked to
susceptibility to future development of periodontitis. In
the future, such research may allow identication of
patients who are susceptible to gingivitis and ultimately
periodontitis, and appropriate interventions could be
instituted.
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HISTOPATHOLOGIC FEATURES
Incipient gingivitis demonstrates a light inammatory
inltrate consisting of polymorphonuclear leukocytes
that accumulate in the connective tissue adjacent to
the sulcular epithelium. With progression, the inltrate becomes more intense and demonstrates a
mixture of lymphocytes, plasma cells, and acute inammatory cells (Fig. 4-7). Areas of brosis, hyperemia,
edema, and hemorrhage may be present.
NECROTIZING ULCERATIVE
GINGIVITIS (VINCENTS INFECTION;
TRENCH MOUTH)
Necrotizing ulcerative gingivitis (NUG) has a distinctive pattern of gingival pathologic changes that
have been recognized for hundreds of years. Until
recently, the name of this process has been preceded
by the term acute (i.e., ANUG); however, several investigators have discontinued the use of this word because
there is no chronic form of the disease. In the 1890s
the French physician Jean Hyacinthe Vincent identied a fusiform bacterium, Bacillus fusiformis (currently
Fusobacterium nucleatum), and a spirochete, Borrelia vincentii, after microscopic examination of plaque samples
from affected sites. Vincent believed that the fusiform
bacteria were principally responsible for the condition,
and the spirochetes mainly were saprophytic opportunists. The spirochete and fusiform bacterium association remains true today, but more sophisticated
techniques have implicated Fusobacterium nucleatum,
Prevotella intermedia, Porphyromonas gingivalis, Treponema spp., and Selenomonas spp. Although the association with bacteria is strong, controversial research has
suggested that viruses such as cytomegalovirus, EpsteinBarr virus, and herpes simplex may contribute to the
onset and progression of the process.
The infection frequently occurs in the presence of
psychologic stress. People in military service exhibit an
increased frequency of NUG; the disorder was so
common in the battleeld trenches during World War
I that the nickname trench mouth became well known.
Stress-related corticosteroid hormones are thought to
alter T4/ T8 lymphocyte ratios and may cause the
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CLINICAL FEATURES
NUG may occur at any age; however, when encountered in the United States or Europe, it is seen most
frequently in young and middle-aged adults. Several
publications have reported a higher frequency in
whites. The prevalence in the normal population is less
than 0.1%; however, in stressed populations (e.g., military recruits) the frequency increases up to 7%. In
developing countries, NUG typically occurs in very
young children suffering from malnutrition. Seasonal
variations in prevalence have been reported by a
number of investigators but have been inconsistent in
different areas of the world.
In a classic case of NUG, the interdental papillae are
highly inamed, edematous, and hemorrhagic. Typically, the affected papillae are blunted and demonstrate areas of punched-out, craterlike necrosis that
are covered with a gray pseudomembrane (Fig. 4-8).
Early cases may be missed easily because the ulceration initially involves only the tip of the interdental
papilla. A fetid odor, exquisite pain, spontaneous hemorrhage, and accumulations of necrotic debris usually
are noted. Although a bad odor is not always noted, its
absence in a patient without predisposing factors
should raise concern for other pathoses such as gonorrhea (see page 193). Occasional ancillary clinical features include lymphadenopathy, fever, and malaise.
The process sometimes can lead to a loss of attachment
and the development of associated periodontitis (necrotizing ulcerative periodontitis) or spread to adjacent soft tissue (necrotizing ulcerative mucositis,
necrotizing stomatitis) (Fig. 4-9). If the necrotizing
infection extends through the mucosa to the skin of the
HISTOPATHOLOGIC FEATURES
The histopathologic features of NUG are not specic.
Typically, affected gingival papillae demonstrate
surface ulceration that is covered by a thickened brinopurulent membrane. The underlying lamina propria
demonstrates an intense acute or mixed inammatory
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Fig. 4-10 Plasma cell gingivitis. A, Diffuse, bright-red enlargement of the free and attached
gingiva. B, Same patient as depicted in A after elimination of the inciting allergen.
CLINICAL FEATURES
Patients with plasma cell gingivitis experience a rapid
onset of sore mouth, which often is intensied by dentifrices and hot or spicy foods. The entire free and
attached gingiva demonstrates a diffuse enlargement
with bright erythema and loss of normal stippling (Fig.
4-10). Extension onto the palate can occur, and edentulous areas typically exhibit less intense changes. On
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HISTOPATHOLOGIC FEATURES
The cases of classic plasma cell gingivitis of the 1970s
demonstrated psoriasiform hyperplasia and spongiosis
of the surface epithelium, with intense exocytosis and
neutrophilic microabscesses. The underlying lamina
propria contains numerous dilated vascular channels
and an extremely dense chronic inammatory inltrate that is composed predominantly of plasma
cells (Fig. 4-11). The more recent cases are similar
but often demonstrate less involvement of the surface
epithelium and a less dense underlying plasmacytic
inltrate.
Investigation of the clonality of the plasma cell inltrate may be necessary to rule out the possibility of a
monoclonal plasma cell neoplasm. All allergic and
idiopathic cases of plasma cell gingivitis demonstrate a
GRANULOMATOUS GINGIVITIS
The discovery of unexplained granulomatous inammation in a gingival biopsy specimen is termed granulomatous gingivitis and represents a diagnostic
challenge for the pathologist, referring clinician, and
patient. The pathologist must rule out histologically
distinctive granulomatous diseases and specic granulomatous infectious processes (e.g., foreign material,
deep fungal infections, acid-fast bacteria) (see Chapters
5 and 6). The clinician must search for signs and symptoms of local and systemic granulomatous diseases
(e.g., Crohns disease, sarcoidosis, chronic granulomatous disease, Wegeners granulomatosis) (see Chapters
9 and 17), and the patient must endure and pay for
these evaluations. Even after a costly workup, some
patients who have localized areas of granulomatous
inammation of the gingiva have no signs or symptoms
of any of the previously mentioned disorders.
Several investigators have reported granulomatous
gingival lesions caused by the introduction of dental
materials into the connective tissue deep to the sulcular epithelium. As more cases have been reported, it
has become evident that the associated inammatory
reaction often is not granulomatous and may mimic
gingival lichen planus or create a nonspecic pattern
of chronic or subacute mucositis. These lesions have
been termed foreign body gingivitis and are thought
to arise when damage to the sulcular epithelium during
restorative or oral hygiene procedures allows the introduction of foreign material into the gingival tissues.
When the material is obvious on light microscopy, the
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association between the gingival pathosis and the material can be made easily. Often the material is smaller
than 1 m in diameter and is so ne that it could be
overlooked.
In a review of 85 cases of foreign body gingivitis,
energy-dispersive radiographic microanalysis revealed
21 different elements embedded with the gingival soft
tissues. The most common elements were silver, aluminum, silicon, tin, sulfur, copper, calcium, phosphorus,
and iron. Elements compatible with ne particles of
amalgam dust were identied most often. Particles
consistent with corundum or silica also were common
(sandpaper disks, polishing paste, toothpaste, and possibly restorative lling material). Materials implicated
less frequently include dust from tungsten carbide
burs, composite material, endodontic sealer components, and temporary cement. This investigation demonstrates that the presumed causative agents are
diverse and can originate from a wide variety of dental
materials.
CLINICAL FEATURES
Both foreign body gingivitis and nonspecic granulomatous gingivitis may occur at any age; however, they
are most frequently encountered in adulthood. The
lesions may be solitary or multifocal, typically with a
diameter less than 2 cm. The affected areas appear as
red or red-and-white macules, which most frequently
involve the interdental papillae but also may occur
along the marginal gingiva (Figs. 4-12 and 4-13). Pain
or sensitivity is a common nding, and the lesions
persist despite conventional therapy and rigorous oral
HISTOPATHOLOGIC FEATURES
A biopsy specimen of granulomatous gingivitis demonstrates focal collections of histiocytes intermixed with
an intense lymphocytic inltrate (Fig. 4-14). On occasion, well-formed histiocytic granulomas with multinucleated giant cells are seen. Special stains for
organisms should be negative. If foreign material is
detected, then the clinician can render a diagnosis of
a foreign body reaction (rather than the more nonspecic term, granulomatous gingivitis). In some cases,
however, the foreign material may be too ne to be
detected.
In the previously mentioned review of 85 cases of
foreign body gingivitis, granulomatous inammation
was present in approximately 20%. In the remainder,
the inammatory inltrate was dominated by lymphocytes, intermixed with plasma cells and macrophages
(Fig. 4-15). In some cases, neutrophils were noted
along with the chronic inammatory cellular inltrate.
In a small number of cases, prominent brosis was
associated with the foreign material. Not infrequently,
the mucositis was lichenoid, with degeneration of the
basal cell layer of the epithelium and a supercial
bandlike inammatory cell inltrate in the supercial
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When all the histopathologic and clinical investigations have been performed, the nal differential diagnosis of granulomatous gingivitis is usually narrowed
down to a localized form of orofacial granulomatosis
(see page 341) or a foreign body reaction. Without
denitive demonstration of foreign material, a complete physical evaluation for diseases known to be associated with orofacial granulomatosis is mandatory. On
occasion, patients with orofacial granulomatosis initially have gingival lesions but eventually develop more
widespread manifestations such as cheilitis granulomatosa, cobblestone buccal mucosa, or vestibular
linear hyperplastic folds.
Surgical excision of the affected tissue is the therapy
of choice for those cases related to foreign material. In
persistently atrophic or erosive areas of foreign body
gingivitis, overlaying the damaged area with a graft
from a healthy gingival donor site may be a better
option than complete excision. In an attempt to prevent
future introduction of iatrogenic foreign material, it
appears appropriate to follow certain guidelines:
The clinician should use extreme care when trimming restorations or using abrasive instruments close
to gingival margins.
Air abrasion (i.e., sandblasting) should be used
cautiously.
Dental
prophylaxis should be delayed for 2
days after scaling, root planing, and curettage
procedures.
Patients who do not respond to surgical removal and
have recurrences of granulomatous gingivitis despite
cautious dental care probably should be classied
as having orofacial granulomatosis and managed
accordingly.
DESQUAMATIVE GINGIVITIS
lamina propria. Because the immune reaction in lichen
planus tends to be composed primarily of lymphocytes,
the presence of signicant numbers of plasma cells,
histiocytes, or neutrophils in the absence of plaquerelated gingivitis should suggest a thorough search for
subtle foreign material.
In the majority of cases, the foreign material appears
as black or brown-black granules. In many cases, colorless, translucent crystal structures are noted and may
be intermixed with black granules. These crystals often
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DRUG-RELATED GINGIVAL
HYPERPLASIA (DRUG-RELATED
GINGIVAL OVERGROWTH)
Drug-related gingival hyperplasia refers to an abnormal growth of the gingival tissues secondary to use of
a systemic medication. The term is a misnomer because
neither the epithelium nor the cells within the connective tissue exhibit either hyperplasia or hypertrophy.
The increased gingival size is due to an increased
amount of extracellular matrix, predominantly collagen. Therefore, several authors designate the alteration
as medication-associated gingival enlargement or
gingival overgrowth. These designations are further
supported by investigators who have suggested the gingival changes arise from interference with normal
intracellular collagen degradation. It is known that gingival collagen constantly undergoes physiologic remodeling, and the process must be tightly controlled to
maintain a constant volume of the gingival tissues.
Investigators have suggested that cyclosporine, phenytoin, and nifedipine are all associated with calcium
deregulation, which disrupts the normal collagen
phagocytosis and remodeling process. If this is true,
then the increased collagen does not occur from hyperplasia but from impaired collagen degradation and
remodeling.
A list of medications reported to be associated with
gingival hyperplasia is provided in Box 4-4. Of these
medications, a strong association has been noted only
with cyclosporine (Fig. 4-16), phenytoin, and nifedipine (Fig. 4-17). In the remainder, the prevalence is
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CLINICAL FEATURES
Because young patients use phenytoin most often, the
gingival hyperplasia it induces is primarily a problem
in people younger than age 25. Cases related to the
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HISTOPATHOLOGIC FEATURES
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GINGIVAL FIBROMATOSIS
(FIBROMATOSIS GINGIVAE;
ELEPHANTIASIS GINGIVAE)
Gingival bromatosis is a slowly progressive gingival
enlargement caused by a collagenous overgrowth of
the gingival brous connective tissue. In spite of the
name, this disorder bears no relationship to the hypercellular and neoplastic bromatoses that can occur in
soft tissue and bone (see pages 515 and 658).
Gingival bromatosis may be familial or idiopathic.
Other ndings sometimes seen in conjunction with
gingival bromatosis include hypertrichosis (Fig.
4-24), generalized aggressive periodontitis, epilepsy,
mental retardation, sensorineural deafness, hypothy-
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CLINICAL FEATURES
In most instances, the enlargement begins before age
20 and often is correlated with the eruption of the
deciduous or permanent teeth (Fig. 4-25). Most investigators believe that the presence of teeth probably is
necessary for the condition to occur. After the process
has begun, it can overgrow the associated teeth and
even interfere with lip closure. Failure or delay in eruption of subsequent teeth may be evident (Fig. 4-26). In
some instances, a tooth may have erupted into a normal
position, but the brous connective tissue continues to
cover the crown and prevent visualization.
The gingival changes may be generalized or localized to one or more quadrants. Either jaw may be
involved, but the maxilla is affected more frequently
and demonstrates a greater degree of enlargement.
Palatal surfaces are typically increased in thickness
more than the buccal side. Typically, extension past the
alveolar mucosal junction into the mucobuccal fold is
not seen, but palatal extensions can cause signicant
distortion of the contour of the palate and, at times,
almost can meet in the midline.
In localized cases, the hyperplasia may involve a
group of teeth and remain stable or, at a later date, may
extend to other segments of one or both jaws. One
distinctive and not uncommon pattern involves the
posterior maxillary alveolar ridge. In this pattern, the
hyperplastic tissue forms bilaterally symmetrical enlargements that extend posteriorly and palatally from
the posterior alveolar ridges (Fig. 4-27). Less commonly, the overgrowth also may be isolated to the facial
gingiva of the lower molars.
The gingiva is rm, normal in color, and covered by
a surface that is smooth or nely stippled. In older
patients, the surface may develop numerous papillary
projections. The frenular attachments may appear to
divide the gingival tissues of the alveolar ridge into
lobules. Associated clinical problems include poor aesthetics, prolonged retention of deciduous teeth, abnormal occlusion, inadequate lip closure, and difculty in
eating and speaking.
HISTOPATHOLOGIC FEATURES
The enlargements of gingival bromatosis consist of
dense hypocellular, hypovascular collagenous tissue,
which forms numerous interlacing bundles that appear
to run in all directions. The surface epithelium often
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PERIODONTITIS
Periodontitis refers to an inammation of the gingival
tissues in association with some loss of both the attachment of the periodontal ligament and bony support.
With progressive loss of attachment, signicant destruction of the periodontal ligament and adjacent alveolar
bone can occur. Apical migration of the crevicular epithelium along the root surface results in the formation
of periodontal pockets. Loosening and eventual loss of
teeth are possible.
For more than a century, the presence of the disease
has been correlated with the accumulation of dental
plaque on the tooth and under the gingiva. Despite this,
current evidence suggests that dental plaque is part of
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Box 4-5
Box 4-6
Classication of Periodontitis
1. Chronic periodontitis
Localized
Generalized
2. Aggressive periodontitis
Localized
Generalized
3. Periodontitis as a manifestation of systemic diseases
Associated with hematologic disorders
Associated with genetic disorders
Not otherwise specied
4. Necrotizing periodontal diseases
Necrotizing ulcerative gingivitis (NUG)
Necrotizing ulcerative periodontitis (NUP)
5. Abscesses of the periodontium
Gingival abscess
Periodontal abscess
Pericoronal abscess (in association with
pericoronitis)
6. Periodontitis associated with endodontic lesions
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Acatalasia
Acrodynia
Acquired immunodeciency syndrome (AIDS)
Blood dyscrasias
Leukemia
Agranulocytosis
Cyclic neutropenia
Chdiak-Higashi syndrome
Cohen syndrome
Crohns disease
Diabetes mellitus
Dyskeratosis congenita
Ehlers-Danlos syndrome, types IV and VIII
Glycogen storage disease
Haim-Munk syndrome
Hemochromatosis
Hypophosphatasia
Kindler syndrome
Langerhans cell disease
Leukocyte dysfunctions with associated extraoral
infections
Oxalosis
Papillon-Lefvre syndrome
Sarcoidosis
Trisomy 21
Advancing age
Smoking
Diabetes mellitus
Osteoporosis
HIV infection
Lower socioeconomic level
Local factors also may predispose patients to isolated periodontal defects; these include tooth shape
and alignment, presence and quality of dental restorations, poor interdental contact, calculus formation,
subgingival dental caries, traumatic occlusion, and
abnormal alveolar bone or gingival anatomy.
Conversely, it appears that the presence of signicant periodontitis may place patients at risk for an
increased prevalence or greater severity of certain
medical disorders. Although controversial, increasing
evidence links periodontitis with an elevated risk for
coronary artery disease, stroke, progressive diabetes
mellitus, respiratory diseases, and delivery of lowbirth
weight babies. If true, then it is unclear if these associations are due to dissemination of triggering host inammatory mediators or the spread of bacteria or their
related toxins. Although strong direct associations have
been documented, the epidemiology is difcult to
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interpret because of the additional risk factors associated with both conditions. For example, cardiovascular
disease has been related to periodontitis, but the nature
of this association is cloudy because both are strongly
associated with smoking. Numerous interventional
studies are ongoing to investigate the possible reduction in these medical disorders secondary to elimination and control of periodontitis.
In chronic periodontitis, no abnormalities of the
immune system are found. Periodontitis begins in
youth and early adulthood, takes years to decades to
progress, and includes cyclic patterns of exacerbation
and remission. The assumption that periodontitis is a
disease of aging has been challenged, and most believe
the increased periodontal destruction observed in
older adults reects a lifetime of disease accumulation
rather than an age-specic disease.
In patients with periodontitis, gingivitis is present
and precedes the development of signicant periodontal lesions. Although many sites may demonstrate gingivitis and few progress to attachment loss, lifelong
local measures directed against sites of gingivitis represent an effective approach for prevention of chronic
periodontitis. As loss of attachment occurs, blunting
and apical positioning of the gingival margins typically
are present (Fig. 4-29). Periodontal disease is present
when a loss of attachment can be demonstrated through
the use of a periodontal probe. In the absence of signicant gingival hyperplasia, a measurement of pocket
depths greater than 3 to 4 mm indicates destruction of
the periodontal ligament and resorption of adjacent
alveolar bone; however, clinical attachment loss is the
best measurement of accumulated periodontal destruction and represents the diagnostic gold standard. Highquality dental radiographs exhibit a decreased vertical
height of the bone surrounding the affected teeth (Fig.
PERIODONTAL ABSCESS
A periodontal abscess (Figs. 4-31 and 4-32) is a localized purulent infection of the gingiva with involvement
of the adjacent periodontal attachment and alveolar
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Throbbing pain
Extreme sensitivity to palpation of the affected
gingiva
Sensitivity, mobility, or extrusion of the adjacent
tooth
Foul taste
Lymphadenopathy
Fever, leukocytosis, and malaise (occasionally)
Probing or gentle pressure on the affected gingiva
often results in the expression of pus from the sulcus.
The abscess may drain through an overlying sinus tract.
With drainage, the abscess becomes asymptomatic but
can demonstrate acute exacerbations if the mucosa
heals over and the pressure builds again. Radiographs
often demonstrate bone loss associated with the previous periodontal defect or additional radiolucency secondary to the current acute process. In some cases, the
infection can spread into the periapical region and
create a combined periodontal-endodontic lesion.
PERICORONITIS
Pericoronitis is an inammatory process that arises
within the tissues surrounding the crown of a partially
erupted tooth. The inammatory reaction often arises
when food debris and bacteria are present beneath the
gingival ap overlying the crown. Other predisposing
factors include stress and upper respiratory infections,
especially tonsillitis or pharyngitis.
These gingival aps can exhibit long periods of
chronic inammation without symptoms. If the debris
and bacteria become entrapped deep within the gingival ap, then abscess formation develops. Abscess
development is seen most frequently in association
with the mandibular third molars, and the predominant symptoms are extreme pain in the area, a foul
taste, and inability to close the jaws. The pain may
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HISTOPATHOLOGIC FEATURES
When soft tissue from areas of periodontitis is examined microscopically, gingivitis is present and the crevicular epithelium lining the pocket is hyperplastic,
with extensive exocytosis of acute inammatory cells.
The adjacent connective tissue exhibits an increased
vascularity and contains an inammatory cellular inltrate consisting predominantly of lymphocytes and
plasma cells, but with a variable number of polymorphonuclear leukocytes. Frequently, large colonies of
microorganisms, representing plaque and calculus, are
noted.
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PERIODONTAL ABSCESS
A gingival or periodontal abscess is treated by drainage
through the sulcus or by an incision through the overlying mucosa. Thorough cleansing of the area with
removal of all foreign material, plaque, and calculus
should be performed. Penicillin or other antibiotic
drugs are prescribed when a fever is present. Analgesic
agents are prescribed, and the patient receives a soft
diet, is told to use warm saltwater rinses, and is
instructed to return each day until the symptoms have
resolved. After the acute phase has passed, the patient
PERICORONITIS
Acute pericoronitis is treated with gentle antiseptic
lavage under the gingival ap to remove gross food
debris and bacteria. Systemic antibiotic agents are used
if a fever or general symptoms are noted. The patient
is instructed to use warm saltwater rinses and to return
in 24 hours. Once the acute phase has subsided, the
tooth can be extracted if long-term maintenance is contraindicated. If tooth retention is desirable, then the
overlying gingival ap is removed surgically, followed
by elimination of all food debris and bacterial colonies
by thorough curettage.
AGGRESSIVE PERIODONTITIS
Although periodontitis is much more frequent in older
adults, it also can be a signicant problem in children
and young adults. Before the 1999 reclassication by
the American Academy of Periodontology, destructive
periodontal disease in younger patients was termed
early-onset periodontitis and subdivided into prepubertal, localized juvenile, generalized juvenile, and
rapidly progressing forms of periodontitis. The earlyonset designation was discontinued during the 1999
workshop because the term was deemed too restrictive. Many argued that this pattern of periodontitis can
occur at any age and is not restricted to patients younger
than 35 years old. It was agreed that an appropriate
classication system should not be based on age but
should consider primarily the clinical, radiographic,
historical, and laboratory ndings.
The 1999 workshop concluded that the most logical
classication system should not be age dependent or
require knowledge of rates of progression. In general,
the new designation of localized aggressive periodontitis replaces the older term, localized juvenile
periodontitis, whereas generalized aggressive periodontitis supersedes generalized juvenile periodontitis. The pattern previously designated as prepubertal
periodontitis has been associated with a systemic leukocyte dysfunction termed leukocyte adhesion syndrome.
This disease currently is classied as one of the forms
of periodontitis presenting as a manifestation of a systemic disease.
By denition, aggressive periodontitis occurs in otherwise healthy people; there should be no association
with a systemic disease process. In keeping with this
denition, the diagnosis is one of exclusion, and all
systemic disorders known to be related to premature
loss of attachment (see Box 4-6) should be ruled out
before the denitive diagnosis is made.
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Fig. 4-35 Localized aggressive periodontitis. A, Loss of bone support in the area of the rst
molars and incisors of both maxillary and mandibular right quadrants in a 14-year-old patient.
B, Left quadrants of the same patient depicted in A. Note the similar pattern of bone loss in the
area of the rst molars and incisors.
In contrast to chronic disease, aggressive periodontitis appears to be correlated with one or more deciencies in the immune response, rather than with
inappropriate accumulations of plaque and calculus.
Researchers believe that aggressive periodontitis represents a number of different pathoses that have been
grouped together because of similar clinical presentations. Suspected pathogens that are commonly found
in these diseases include Actinobacillus actinomycetemcomitans, Prevotella intermedia, Porphyromonas gingivalis,
and a variety of other less common organisms. The
response to therapy often hinges on the successful
elimination of these organisms. As mentioned in the
discussion of periodontitis (see page 168), an association with a number of viruses has been suggested but
disputed by others.
The majority of patients with aggressive periodontitis have a demonstrable neutrophil dysfunction but
without systemic manifestations. In the localized
variant, a number of affected patients demonstrate
a specic defect of bactericidal activity toward A.
actinomycetemcomitans. Although this is a controversial topic, several investigators have suggested that
aggressive periodontitis requires specic bacterial
ora and the presence of a selective immune dysfunction that allows these pathogens to ourish. This
unique pattern of immune alteration may explain the
failure to defend appropriately against certain periodontal pathogens without exhibiting systemic signs of
immunodeciency.
Familial aggregation of patients with aggressive
periodontitis is noted and suggests an underlying
genetic foundation, which may be transmitted in some
families as an autosomal dominant trait with reduced
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this nding has been disputed. The rate of bone destruction is three to ve times faster than that seen in chronic
periodontitis.
In the rst molar regions, radiographs reveal vertical bone resorption that often is bilateral and symmetrical. In classic cases an arc-shaped zone of bone loss
extends from the distal aspect of the second bicuspid
to the mesial aspect of the second molar. Similar
involvement is apparent around the anterior teeth.
Tooth migration and mobility are common. If untreated,
then the process often continues until the teeth are
exfoliated. In about one third of patients affected with
localized aggressive periodontitis, progression to more
generalized disease occurs.
Of all the pathogens in dental plaque, A. actinomycetemcomitans appears to be predominant in localized
aggressive periodontitis. This bacterium is present
in disease sites in more than 90% of cases. Its ability
to invade gingival tissue has created difculties in
mechanical eradication. Knowledge of its importance
to the disease process has led to remarkable advances
in therapy.
Generalized aggressive periodontitis may not represent a distinct disease entity but, rather, may occur
in a collection of young adults with advanced periodontal disease. Many cases may represent localized aggressive periodontitis that has become more generalized
with time; other cases initially demonstrate generalized disease. As with the localized variant, a signicant
percentage of cases demonstrate neutrophil dysfunction. The American Academy of Periodontology recognizes the following features:
Usually diagnosed in patients younger than 30 years
old but may occur at any age
Poor serum antibody response to infecting agents
Pronounced episodic destruction of periodontal
attachment and alveolar bone
Generalized loss of attachment that must affect at
least three teeth other than the rst molars and
incisors
Most affected patients are between the ages of 12
and 32. In contrast to many examples of the localized
variant, heavy plaque, calculus, and marked gingival
inammation may be present. Compared with the
localized variant, more teeth are affected and the bone
loss is not restricted to specic areas of the jaws.
Although the localized pattern is associated primarily with A. actinomycetemcomitans, the pathogens active
in the generalized variant are more complex, more
closely aligned to chronic periodontitis, and also involve
organisms such as Prevotella intermedia, Porphyromonas
gingivalis, Tannerella forsythensis, Fusobacterium nuclea-
HISTOPATHOLOGIC FEATURES
The microscopic examination of granulation tissue
removed from sites of aggressive periodontitis does not
differ dramatically from that seen in chronic periodontitis. In spite of this, initial histopathologic examination
of the material removed from active sites of disease is
mandatory to rule out the possibility of other disease
processes, such as Langerhans cell disease (see page
590). Even when the attachment loss presents in a
classic localized pattern, systemic disease cannot be
eliminated without an examination of tissue. The denitive diagnosis centers on the clinical, radiographic,
histopathologic, and microbiologic ndings, combined
with the family history and leukocyte function tests.
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PAPILLON-LEFVRE SYNDROME
In 1924, Papillon and Lef vre initially described the
syndrome that bears their names. This autosomal recessive disorder predominantly demonstrates oral and
dermatologic manifestations; similar dermatologic
changes can be seen in the absence of oral ndings
(keratoderma palmoplantar of Unna-Thost syndrome and Meleda disease). Because of the autosomal recessive inheritance pattern, the parents typically
are not affected; consanguinity is noted in approximately one third of cases. The predominant oral nding
is accelerated periodontitis that appears to be caused
by defects in neutrophil function and multiple immunemediated mechanisms.
Genetic studies of patients with Papillon-Lef vre
syndrome have mapped the major gene locus to chromosome 11q14-q21 and revealed mutation and loss of
function of the cathepsin C gene. This gene is important in the structural growth and development of the
skin and is critical for appropriate immune response of
myeloid and lymphoid cells. Researchers believe that
the loss of appropriate function of the cathepsin C gene
results in an altered immune response to infection. In
addition, the altered gene may affect the integrity of the
junctional epithelium surrounding the tooth.
A closely related disease, Haim-Munk syndrome,
also exhibits palmoplantar keratosis, progressive periodontal disease, recurrent skin infections, and several
skeletal malformations. In this syndrome, the skin
manifestations are more severe and the periodontal
disease is milder. Studies have demonstrated that
Haim-Munk syndrome and many examples of prepubertal periodontitis also exhibit mutation of the cathepsin C gene and represent allelic variants of the mutated
gene responsible for Papillon-Lef vre syndrome.
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HISTOPATHOLOGIC FEATURES
Once again, the histopathologic features of PapillonLef vre syndrome resemble those seen in chronic
periodontitis and are not specic. Submitted tissue
often contains hyperplastic crevicular epithelium with
exocytosis. The underlying connective tissue exhibits
increased vascularity and a mixed inammatory cellular inltrate consisting predominantly of polymorphonuclear leukocytes, lymphocytes, histiocytes, and
plasma cells. Initially, histopathologic examination is
recommended to rule out other pathologic causes of
the periodontal destruction.
Fig. 4-38 Papillon-Lefvre syndrome. Multifocal sites of
bone loss in all four quadrants. (From Giansanti JS, Hrabak RP,
Waldron CA: Palmoplantar hyperkeratosis and concomitant periodontal
destruction [Papillon-Lefvre syndrome], Oral Surg Oral Med Oral Pathol
36:40, 1973.)
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BIBLIOGRAPHY
General Reference
Newman MG, Takei H, Carranza FA et al: Clinical periodontology,
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Gingivitis
American Academy of Periodontology: Parameter on plaqueinduced gingivitis, J Periodontol 71(suppl):851-852, 2000.
American Academy of Periodontology: Treatment of plaqueinduced gingivitis, chronic periodontitis, and other clinical
conditions, J Periodontol 72:1790-1800, 2001.
Fransson C, Berglundh T, Lindhe J: The effects of age on the
development of gingivitis. Clinical, microbiological and histological ndings, J Clin Periodontol 23:379-385, 1996.
Gunsolley JC: A meta-analysis of six-month studies of antiplaque
and antigingivitis agents, J Am Dent Assoc 137:1649-1657,
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Granulomatous Gingivitis
Daley TD, Wysocki GP: Foreign body gingivitis: an iatrogenic
disease? Oral Surg Oral Med Oral Pathol 69:708-712, 1990.
Gordon SC, Daley TD: Foreign body gingivitis: clinical and
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Gordon SC, Daley TD: Foreign body gingivitis: identication of
the foreign material by energy-dispersive x-ray microanalysis,
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Gravitis K, Daley TD, Lochhead MA: Management of patients
with foreign body gingivitis: report of 2 cases with histologic
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Koppang HS, Roushan A, Sralzadeh A et al: Foreign body gingival lesions: distribution, morphology, identication by x-ray
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Lombardi T, Kuffer R, Dubrez B: Polishing-paste-induced silica
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Mignogna MD, Fedele S, LoRusso L et al: Orofacial granulomatosis with gingival onset, J Clin Periodontol 28:692-696, 2001.
Gingival Fibromatosis
Coletta RD, Graner E: Hereditary gingival bromatosis: a systematic review, J Periodontol 77:753-764, 2006.
Hart TC, Zhang Y, Gorry MC et al: A mutation in the SOS1 gene
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Jorgenson RJ, Cocker ME: Variation in the inheritance and
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Mangino M, Pizzuti A, Dallapiccola B et al: Hereditary gingival
bromatosis (HGF) with hypertrichosis is unlinked to the
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Rushton MA: Hereditary or idiopathic hyperplasia of the gums,
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Shashi V, Pallos D, Pettenati MJ et al: Genetic heterogeneity of
gingival bromatosis on chromosome 2p, J Med Genet 36:683686, 1999.
Takagi M, Yamamoto H, Mega H et al: Heterogeneity in the gingival bromatoses, Cancer 68:2202-2212, 1991.
Xiao S, Bu L, Zhu L et al: A new locus for hereditary gingival
bromatosis (GINGF2) maps to 5q13-q22, Genomics 74:180185, 2001.
Ye X, Shi L, Cheng Y et al: A novel locus for autosomal dominant
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Periodontitis
Albandar JM: Global risk factors and risk indicators for periodontal diseases, Periodontol 2000 29:177-206, 2002.
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5
Bacterial Infections
CHAPTER OUTLINE
Impetigo
Erysipelas
Streptococcal Tonsillitis and Pharyngitis
Scarlet Fever
Tonsillar Concretions and Tonsillolithiasis
Diphtheria
Syphilis
IMPETIGO
Impetigo is a supercial infection of the skin that is
caused by Streptococcus pyogenes (group A streptococcus) and Staphylococcus aureus, either separately or
together. The term impetigo is derived from a Latin
word meaning attack, because of its common presentation as a scabbing eruption. Two clinically distinctive
patterns are seen, nonbullous impetigo and bullous
impetigo. Intact epithelium is normally protective
against infection; therefore, many cases arise in
damaged skin such as preexisting dermatitis, cuts,
abrasions, or insect bites. Secondary involvement of an
area of dermatitis has been termed impetiginized
dermatitis. An increased prevalence is associated with
debilitating systemic conditions such as human immunodeciency virus (HIV) infection, type 2 diabetes
mellitus, or dialysis.
CLINICAL FEATURES
Nonbullous impetigo (impetigo contagiosa) is the
more prevalent pattern and occurs most frequently on
the legs, with less common involvement noted on the
trunk, scalp, or face. The facial lesions usually develop
around the nose and mouth. In many patients with
facial involvement, the pathogenic bacteria are harbored in the nose and spread onto the skin into previ-
Gonorrhea
Tuberculosis
Leprosy
Noma
Actinomycosis
Cat-Scratch Disease
Sinusitis
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ERYSIPELAS
Fig. 5-2 Impetigo. Scaly and amber-colored crusts of the
perioral skin.
DIAGNOSIS
A strong presumptive diagnosis can normally be made
from the clinical presentation. When the diagnosis is
not obvious clinically or the infection fails to respond
to standard therapy within 7 days, the denitive diagnosis requires isolation of S. pyogenes or S. aureus from
cultures of involved skin.
CLINICAL FEATURES
Erysipelas tends to occur primarily in young and older
adult patients or in those who are debilitated, diabetic,
immunosuppressed, obese, or alcoholic. Patients who
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STREPTOCOCCAL TONSILLITIS
AND PHARYNGITIS
Fig. 5-3 Erysipelas. Red, swollen area of the left cheek.
(Courtesy Dr. Arthur Gonty).
CLINICAL FEATURES
Although the infection can occur at any age, the greatest prevalence occurs in children 5 to 15 years old,
with most cases in temperate climates arising in the
winter or early spring. The signs and symptoms of tonsillitis and pharyngitis vary from mild to intense.
Common ndings include sudden onset of sore throat,
temperature of 101 to 104 F, dysphagia, tonsillar
hyperplasia, redness of the oropharynx and tonsils,
palatal petechiae, cervical lymphadenopathy, and a
yellowish tonsillar exudate that may be patchy or
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DIAGNOSIS
Although the vast majority of pharyngitis cases are
caused by a viral infection, reviews have shown that
about 70% of adults in the United States receive antibiotic therapy. In an attempt to minimize overuse, antibiotics should not be prescribed without conrmation
of bacterial infection. Except for very rare infections
such as Corynebacterium diphtheriae (see page 186) and
Neisseria gonorrhoeae (see page 193), antibiotics are of
no benet for acute pharyngitis except for those related
to group A streptococci.
Patients exhibiting features strongly suggestive of a
viral infection (see previous section) should not receive
antibiotic therapy or microbiologic testing for streptococcal infection. Because the clinical features of streptococcal pharyngitis overlap those of viral origin, the
diagnosis cannot be based solely on clinical features;
however, laboratory testing of all patients with sore
throat cannot be justied. Diagnostic testing is recommended only for those patients with clinical and epidemiologic ndings that suggest streptococcal infection
or for those in close contact with a well-documented
case. Although less sensitive than throat culture, rapid
antigen detection testing provides quick results and
exhibits good sensitivity and specicity. If negative
CLINICAL FEATURES
Scarlet fever is most common in children from the ages
of 3 to 12 years. The enanthem of the oral mucosa
involves the tonsils, pharynx, soft palate, and tongue
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DIAGNOSIS
A culture of throat secretions may be used to conrm
the diagnosis of streptococcal infection, but this has
been replaced by several methods of rapid detection of
antigens that are specic for group A, -hemolytic
streptococci. Failure to respond to appropriate antibiotics should alert the clinician that the detected streptococci may represent an intercurrent carrier state,
and other causes of infection should be investigated.
Fig. 5-5 Scarlet fever. Dorsal surface of the tongue
exhibiting white coating in association with numerous
enlarged and erythematous fungiform papillae (white
strawberry tongue).
TONSILLAR CONCRETIONS
AND TONSILLOLITHIASIS
Anatomically, the pharyngeal tonsils demonstrate
numerous deep, twisted, and epithelial-lined invaginations. These tonsillar crypts function to increase the
surface area for interaction between the immune cells
within the lymphoid tissue and the oral environment.
These convoluted crypts commonly are lled with desquamated keratin and foreign material and secondarily become colonized with bacteria, usually
Actinomyces spp. The contents of the invaginations often
become compacted and form a mass of foul-smelling
material known as a tonsillar concretion. Occasionally, the condensed necrotic debris and bacteria
undergo dystrophic calcication and form a tonsillolith. Recurrent tonsillar inammation may promote
the development of these tonsillar concretions.
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DIAGNOSIS
A strong presumptive diagnosis can be made through
a combination of the clinical and radiographic features.
After detection on a panoramic radiograph, if further
DIPHTHERIA
Diphtheria is a life-threatening infection produced
by Corynebacterium diphtheriae. The disease was rst
described in 1826, and C. diphtheriae (also termed
Klebs-Lfer bacillus) was discovered initially by Klebs in
1883 and isolated in pure culture by Lfer in 1884.
Humans are the sole reservoir, and the infection is
acquired through contact with an infected person or
carrier. The bacterium produces a lethal exotoxin
that causes tissue necrosis, thereby providing nutrients
for further growth and leading to peripheral spread.
However, an effective antitoxin has been available
since 1913, and immunization has been widespread in
North America since 1922.
In the rst edition of this textbook, it was stated that
diphtheria was included mainly for historical interest
because the world was on the threshold of virtual eradication of this infection in developed countries.
However, a relatively recent epidemic in Russia reveals
how rapidly such advances can be reversed in the
absence of an effective immunization program. The
epidemic began in Moscow and spread to involve all of
the newly independent states of the former Soviet
Union. During this outbreak, more than 150,000 cases
were reported with approximately 4500 deaths. This
one epidemic represented more than 90% of all cases
reported between 1990 and 1995. The process was
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CLINICAL FEATURES
The signs and symptoms of diphtheria arise 1 to 5 days
after exposure to the organism. The initial systemic
symptoms, which include low-grade fever, headache,
malaise, anorexia, sore throat, and vomiting, arise gradually and may be mild. Although skin wounds may be
involved, the infection predominantly affects mucosal
surfaces and may produce exudates of the nasal, tonsillar, pharyngeal, laryngotracheal, conjunctival, or genital
areas. Involvement of the nasal cavity is often accompanied with prolonged mucoid or hemorrhagic discharge. The oropharyngeal exudate begins on one or
both tonsils as a patchy, yellow-white, thin lm that
thickens to form an adherent gray covering. With time,
the membrane may develop patches of green or black
necrosis. The supercial epithelium is an integral
portion of this exudate, and attempts at removal are
difcult and may result in bleeding. The covering may
continue to involve the entire soft palate, uvula, larynx,
or trachea, resulting in stridor and respiratory difculties. Palatal perforation has rarely been reported.
During the Russian epidemic, patients with lesions
isolated to the oral cavity were documented. In these
patients, scattered areas of necrosis were noted on the
buccal mucosa, upper and lower lips, hard and soft
palate, or tongue. Such localization is rare and makes
diagnosis more difcult.
The severity of the infection correlates with the
spread of the membrane. Local obstruction of the
airway can be lethal. Involvement of the tonsils leads
to signicant cervical lymphadenopathy, which often
is associated with an edematous neck enlargement
known as bull neck. Toxin-related paralysis may affect
oculomotor, facial, pharyngeal, diaphragmatic, and
intercostal muscles. The soft palatal paralysis can lead
to nasal regurgitation during swallowing. Oral or nasal
involvement has been reported to spread to the adjacent skin of the face and lips.
Cutaneous diphtheria can occur anywhere on the
body and is characterized by chronic skin ulcers that
frequently are associated with infected insect bites and
DIAGNOSIS
Although the clinical presentation can be distinctive in
severe cases, laboratory conrmation should be sought
in all instances. The specimen for culture should be
obtained from underneath the diphtheric membrane,
if possible, or from the surface of the membrane.
Culture material also should be obtained from the
nasal mucosa. Diphtheria also must be kept in mind
for any patient who has traveled to a disease-endemic
area and has chronic skin ulcerations. In these cases,
wound swab specimens should be examined for
C. diphtheriae.
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SYPHILIS (LUES)
Syphilis is a worldwide chronic infection produced by
Treponema pallidum. The organism is extremely vulnerable to drying; therefore, the primary modes of transmission are sexual contact or from mother to fetus.
Although the risk of infection from blood transfusion
is negligible because of serologic testing of donors,
transmission through exposure to infected blood is
theoretically possible because the organism may
survive up to 5 days in refrigerated blood. Humans are
the only proven natural host for syphilis.
After the advent of penicillin therapy in the 1940s,
the incidence of syphilis slowly decreased for many
years but often demonstrated peaks and troughs in
approximately 10-year cycles. In 2000 the United
States had the fewest reported cases of primary and
secondary syphilis since reporting began in 1941.
From 2001 to 2004, the rate increased primarily as a
result of increases among men who have sex with men
(MSM). In 2004, 84% of reported cases occurred in
men, and the Centers for Disease Control and Prevention (CDC) estimates 64% of the total number was
among MSM. In women, the prevalence decreased
each year from 2000 to 2003 but leveled off and
remained stable in 2004. In 2004, men were affected
5.9 times more frequently than women.
Although the data vary from year to year, a signicant and prolonged increased prevalence has been
seen in blacks, with the rate in 2004 being 5.6 times
greater than that among whites. Most of the recent
increases have been found in black men. Because of
the recent trends in the surveillance data, current
national health policy is stressing enhanced prevention
measures directed toward blacks and MSM.
Oral sex is thought to have played an increasingly
important contribution to the recent surge in a number
of sexually transmitted diseases in MSM. Because the
risk of HIV transmission through oral sex is lower than
the rate associated with vaginal or anal sex, many
falsely believed that unprotected oral sex was a safe or
no-risk sexual practice and represented a good replacement for other higher-risk behaviors.
In patients with syphilis, the infection undergoes a
characteristic evolution that classically proceeds
through three stages. A syphilitic patient is highly infectious only during the rst two stages, but pregnant
women also may transmit the infection to the fetus
CLINICAL FEATURES
PRIMARY SYPHILIS
Primary syphilis is characterized by the chancre that
develops at the site of inoculation, becoming clinically
evident 3 to 90 days after the initial exposure. The
majority of chancres are solitary, although multiple
lesions may be seen occasionally. The external genitalia and anus are the most common sites, and the
affected area begins as a papular lesion, which develops a central ulceration. Less than 2% of chancres occur
in other locations, but the oral cavity is the most
common extragenital site. Oral lesions are seen most
commonly on the lip, but other sites include the tongue,
palate, gingiva, and tonsils (Fig. 5-7). The upper lip is
affected more frequently in males, whereas lower lip
involvement is predominant in females. Some believe
this selective labial distribution may reect the surfaces most actively involved during fellatio and cunnilingus. The oral lesion appears as a painless, clean-based
ulceration or, rarely, as a vascular proliferation resembling a pyogenic granuloma. Regional lymphadenopathy, which may be bilateral, is seen in most patients.
At this time the organism is spreading systemically
through the lymphatic channels, setting the stage for
future progression. If untreated, then the initial lesion
heals within 3 to 8 weeks.
SECONDARY SYPHILIS
The next stage is known as secondary (disseminated)
syphilis and is discovered clinically 4 to 10 weeks after
the initial infection. The lesions of secondary syphilis
may arise before the primary lesion has resolved com-
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On occasion, especially in the presence of a compromised immune system, secondary syphilis can exhibit
an explosive and widespread form known as lues
maligna. This form has prodromal symptoms of fever,
headache, and myalgia, followed by the formation of
necrotic ulcerations, which commonly involve the face
and scalp. Oral lesions are present in more than 30%
of affected patients. Malaise, pain, and arthralgia are
seen occasionally. Several cases of lues maligna have
been reported in patients with acquired immunodeciency syndrome (AIDS) (see page 264), and this possibility should be kept in mind whenever HIV-infected
patients have atypical ulcerations of the skin or oral
mucosa.
TERTIARY SYPHILIS
CONGENITAL SYPHILIS
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HISTOPATHOLOGIC FEATURES
The histopathologic picture of the oral lesions in the
syphilitic patient is not specic. During the rst two
stages, the pattern is similar. The surface epithelium is
ulcerated in primary lesions and may be ulcerated or
hyperplastic in the secondary stage. The underlying
lamina propria may demonstrate an increase in the
number of vascular channels, and an intense chronic
inammatory reaction is present. The inltrate is composed predominantly of lymphocytes and plasma cells
and often demonstrates a perivascular pattern (Fig.
5-16). Although the presence of plasma cells within the
inltrate may suggest the diagnosis of syphilis on the
skin, their presence in areas of oral ulceration is commonplace and therefore not necessarily of diagnostic
signicance. In secondary syphilis, ulceration may
not be present and the surface epithelium often
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Table 5-1
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Stigmata of Congenital
Syphilisa
Frontal bossing
Short maxilla
High-arched palate
Saddle nose
Mulberry molars
Hutchinsons incisors
Higoumenakis signb
Relative prognathism of
mandible
Interstitial keratitis
Rhagadesc
Saber shind
Eighth nerve deafness
Scaphoid scapulaee
Cluttons jointf
Number of
Patients
% Affected
235
227
207
199
176
171
107
70
86.7
83.8
76.4
73.4
64.9
63.1
39.4
25.8
24
19
11
9
2
1
8.8
7.0
4.1
3.3
0.7
0.3
Fig. 5-17 Secondary syphilis, condyloma lata. A, Lowpower photomicrograph of biopsy from patient in Fig. 5-11,
which shows papillary epithelial hyperplasia and a heavy
plasmacytic inltrate in the connective tissue. B, High-power
view showing intense exocytosis of neutrophils into the
epithelium. C, Immunoperoxidase reaction for Treponema
pallidum demonstrating numerous spirochetes in the
epithelium.
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DIAGNOSIS
The diagnosis of syphilis can be conrmed by demonstrating the spiral organism by dark-eld examination
of a smear of the exudate of an active lesion. False-positive results are possible in the oral cavity because of
morphologically similar oral inhabitants, such as Treponema microdentium, T. macrodentium, and T. mucosum.
Demonstration of the organism on a smear or in biopsy
material should be conrmed through the use of specic immunouorescent antibody or serologic tests.
Several nonspecic and not highly sensitive serologic screening tests for syphilis are available. These
include the Venereal Disease Research Laboratory
(VDRL) and the rapid plasma reagin (RPR). After the
rst 3 weeks of infection, the screening tests are positive strongly throughout the rst two stages. After the
development of latency, the positivity generally subsides with time. As part of appropriate prenatal care,
all pregnant women should receive one of the nonspecic screening tests.
Specic and highly sensitive serologic tests for syphilis also are available. These include the uorescent
treponemal antibody absorption (FTA-ABS), T. pallidum
hemagglutination assay (TPHA), T. pallidum particle
agglutination assay (TPPA), and microhemagglutination assay for antibody to T. pallidum (MHA-TP). These
test results become positive at the time of the development of the rst lesion of primary syphilis and remain
positive for life. This lifelong persistence of positivity
limits their usefulness in the diagnosis of a second incidence of infection. Therefore, in cases of possible reinfection, the organisms should be demonstrated within
the tissue or exudates.
second-line therapy, although tetracycline, erythromycin, and ceftriaxone also have demonstrated antitreponemal activity.
In 50% of patients with primary syphilis and 90%
of those with secondary syphilis, an unusual initial
response to therapy occurs known as the JarischHerxheimer reaction. This process occurs secondary
to release of endotoxin when antibiotics kill large
numbers of organisms. Clinical evidence of this reaction occurs about 8 hours after the rst injection of
penicillin and most commonly includes mild fever,
malaise, headache, and an exacerbation of skin or
mucosal lesions. These signs and symptoms are very
temporary and rapidly fade.
Treatment failures occur in approximately 5% of
patients. When treating primary, secondary, or early
latent syphilis, some experts recommend serologic
follow-up at 6, 12, 18, and 24 months. Pregnant women
treated for syphilis should be retested at the twentyeighth week and again at delivery. Infants born to seropositive mothers are treated with IV penicillin.
Even in patients who obtain a clinical and serologic
cure with penicillin, it must be remembered that
T. pallidum can escape the lethal effects of the antibiotic
when the organism is located within the connes of
lymph nodes or the central nervous system. Therefore,
antibiotic therapy may not always result in a total cure
in patients with neurologic involvement but may arrest
only the clinical presentations of the infection. Patients
with immunosuppression, such as those with AIDS,
may not respond appropriately to standard antibiotic
regimens, and numerous reports have documented a
continuation to neurosyphilis despite seemingly appropriate single-dose therapy.
In the review of the recent increase of syphilis in
MSM, high rates of coinfection with HIV have been
documented. Although many factors are involved, the
mucosal damage created by the spirochetes probably
provides greater access for HIV infection. Patients
diagnosed with syphilis, especially MSM, also should
be tested for HIV.
GONORRHEA
Gonorrhea, a sexually transmitted disease that is produced by Neisseria gonorrhoeae, represents the most
common reportable bacterial infection in the United
States, with an estimated 700,000 to 800,000 persons
infected each year. The disease is epidemic, especially
in urban areas; worldwide, millions of people are
infected each year. The prevalence of gonorrhea has
been declining since a peak in 1975. In 2004, the last
year with complete data from the CDC, the rate of
infection was the lowest ever reported. Despite this, the
rate in the United States remains the highest of any
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CLINICAL FEATURES
The infection is spread through sexual contact, and
most lesions occur in the genital areas. Indirect infection is rare because the organism is sensitive to drying
and cannot penetrate intact stratied squamous epithelium. The incubation period is typically 2 to 5 days.
Affected areas often demonstrate signicant purulent
discharge, but approximately 10% of men and up
to 80% of women who contract gonorrhea are
asymptomatic.
In men the most frequent site of infection is the
urethra, resulting in purulent discharge and dysuria.
Less common primary sites include the anorectal and
pharyngeal areas. The cervix is the primary site of
involvement in women, and the chief complaints are
increased vaginal discharge, intermenstrual bleeding,
genital itching, and dysuria. The organism may ascend
to involve the uterus and ovarian tubes, leading to the
most important female complication of gonorrhea
pelvic inammatory disease (PID). The symptoms
of PID include cramps and abnormal bleeding, which
may be severe or mild. The long-term complications of
PID include ectopic pregnancies or infertility from
tubal obstruction.
Between 0.5% and 3.0% of untreated patients with
gonorrhea will have disseminated gonococcal infections from systemic bacteremia. The most common
signs of dissemination are myalgia, arthralgia, polyarthritis, and dermatitis. In 75% of patients with disseminated disease, a characteristic skin rash develops. The
dermatologic lesions consist of discrete papules and
pustules that often exhibit a hemorrhagic component
and occur primarily on the extremities. Less common
alterations secondary to gonococcal septicemia include
fever, endocarditis, pericarditis, meningitis, and oral
mucosal lesions of the soft palate and oropharynx,
which are similar to aphthous ulcerations.
The prevalence of oral sex appears to be increasing
and is thought by many to be the result of the misconception that it represents a low-risk sexual practice and
a safe alternative to high-risk activities such as anal or
vaginal sex. Most cases of oral gonorrhea appear to be
a result of fellatio, although oropharyngeal gonorrhea
may be the result of gonococcal septicemia, kissing, or
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DIAGNOSIS
In males with a urethral discharge, a Gram stain of the
purulent material can be used to demonstrate gramnegative diplococci within the neutrophils; additional
testing usually is not indicated. Although Gram stains
may be benecial in women, conrmation of the diagnosis is recommended by culture of endocervical swabs
if conditions are adequate to maintain viability of the
organisms. A number of other diagnostic studies have
been available for many years. Nucleic acid amplication tests (NAATs) amplify and detect N. gonorrhoeae
specic DNA or RNA sequences and are recommended
for the diagnosis when conditions are not adequate
to maintain the viability of the organisms. In spite of
the availability of NAATs, culture remains the preferred diagnostic method for diagnosis of oropharyngeal infections.
TUBERCULOSIS
Tuberculosis (TB) is a chronic infectious disease
caused by Mycobacterium tuberculosis. Worldwide, it
is estimated that 2 billion people (one third of the population) are infected; each year 9 million additional
individuals become infected. It is estimated that
approximately 2 million deaths annually can be attributed to TB. In the United States the disease has been
declining since the 1800s, especially since the introduction of effective antimicrobials in the 1940s. The
decline ceased abruptly in the early 1980s and
appeared to be the result of a combination of several
factors. Wars and famine in the developing world, the
HIV epidemic, increased immigration from countries
with endemic TB, transmission of TB in crowded or
unsanitary environments, a decline of the health care
infrastructure, and an increased prevalence of multidrug-resistant TB have been implicated in the recent
resurgence.
In the 1990s an increased emphasis was placed on
TB control and prevention, with a resultant steady
decline in the frequency of this serious infection since
1993. In 2006 the directed interventions resulted in
the lowest number of recorded cases in the United
States since reporting began in 1953, but the average
annual decline has slowed since 2000. Immigration
and the increased prevalence of multidrug-resistant TB
are thought to be largely responsible for the slowing
rate of decline of the infection. In 2006 the infection
rate in foreign-born persons in the United States was
9.5 times that of persons born in the United States,
with more cases reported among Hispanics than any
other racial or ethnic population. At the same time, the
rate of infection in Hispanics, blacks, and Asians was
respectively 7.6, 8.4, and 21.2 higher than in whites.
Most infections are the result of direct person-to-person
spread through airborne droplets from a patient with
active disease.
Nontuberculous mycobacterial disease can occur
from a variety of organisms. Before the tuberculin
testing of dairy herds, many cases arose from the consumption of milk infected with Mycobacterium bovis.
Except for HIV-infected individuals, most other cases
of nontuberculous mycobacterial disease appear as
localized chronic cervical lymphadenitis in otherwise
healthy children. In patients with AIDS (see page 274),
M. avium-intracellulare is a common cause of opportunistic infections.
Infection must be distinguished from active disease.
Primary tuberculosis occurs in previously unexposed
people and almost always involves the lungs. Most
infections are the result of direct person-to-person
spread through airborne droplets from a patient with
active disease. The organism initially elicits a nonspecic, chronic inammatory reaction. In most individuals, the primary infection results only in a localized,
brocalcied nodule at the initial site of involvement.
However, viable organisms may be present in these
nodules and remain dormant for years to life.
Only about 5% to 10% of patients with TB progress
from infection to active disease, and an existing state of
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It is unclear whether these lesions develop from hematogenous spread or from exposure to infected sputum.
The reported prevalence of clinically evident oral
lesions varies from 0.5% to 5.0%. However, one autopsy
study revealed a prevalence of close to 20% when the
tongues of those infected were examined microscopically. The discovery of pulmonary TB as a result of the
investigation of oral lesions occurs but is unusual.
Primary oral TB without pulmonary involvement
is rare and is more common in children and
adolescents.
When present, primary oral TB usually involves the
gingiva, mucobuccal fold, and areas of inammation
adjacent to teeth or in extraction sites; secondary oral
lesions are mostly present on the tongue, palate, and
lip (Figs. 5-19 and 5-20). Primary oral lesions are
usually associated with enlarged regional lymph nodes.
Tuberculous osteomyelitis has been reported in the
jaws and appears as ill-dened areas of radiolucency.
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Nontuberculous mycobacterial infections from contaminated milk are currently rare in the industrialized
world because of pasteurization of milk, as well as
rapid identication and elimination of infected cows.
Drinking contaminated milk can result in a form of
mycobacterial infection known as scrofula. Scrofula is
characterized by enlargement of the oropharyngeal
lymphoid tissues and cervical lymph nodes (Fig. 5-21).
On occasion, the involved nodes may develop signicant caseous necrosis and form numerous sinus tracts
through the overlying skin (Fig. 5-22). In addition,
areas of nodal involvement may radiographically
appear as calcied lymph nodes that may be confused
with sialoliths (Fig. 5-23). Pulmonary involvement is
unusual in patients with scrofula.
HISTOPATHOLOGIC FEATURES
The cell-mediated hypersensitivity reaction is responsible for the classic histopathologic presentation of TB.
Areas of infection demonstrate the formation of granulomas, which are circumscribed collections of epithelioid histiocytes, lymphocytes, and multinucleated
giant cells, often with central caseous necrosis (Fig.
5-24). In a person with TB, one of these granulomas
is called a tubercle. Special stains, such as the
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DIAGNOSIS
Approximately 2 to 4 weeks after initial exposure, a
cell-mediated hypersensitivity reaction to tubercular
antigens develops. This reaction is the basis for the
puried protein derivative (PPD) skin test (i.e., tuberculin skin test), which uses a ltered precipitate of
heat-sterilized broth cultures of M. tuberculosis. Positivity runs as high as 80% in developing nations; only 5%
to 10% of the population in the United States is positive.
A positive tuberculin skin test result indicates exposure
to the organism and does not distinguish infection from
active disease. A negative tuberculin skin test result
does not totally rule out the possibility of TB. Falsenegative reactions have been documented in older
adults; the immunocompromised; patients with sarcoidosis, measles, or Hodgkins lymphoma; and when
the antigen was placed intradermally. The false-negative rate may be as high as 66% in patients with AIDS.
Special mycobacterial stains and culture of infected
sputum or tissue must be used to conrm the diagnosis
of active disease. Even if detected with special stains,
identication of the organism by culture is appropriate.
This identication is important because some forms
of nontuberculous mycobacteria have a high level of
resistance to traditional antituberculous therapy and
frequently require surgical excision. Because 4 to 6
weeks may be required to identify the organism in
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CLINICAL FEATURES
Currently, leprosy is classied into two separate categories, paucibacillary and multibacillary, with the
distinction inuencing the recommended form of
therapy. Because laboratory services such as skin
smears often are not available, patients are increasingly
being classied on clinical grounds using the number
of lesions (primarily skin) and the number of body
areas affected.
Paucibacillary leprosy corresponds closely to the
tuberculoid pattern of leprosy and exhibits a small
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HISTOPATHOLOGIC FEATURES
Biopsy specimens of paucibacillary leprosy typically
reveal the tuberculoid pattern that demonstrates granulomatous inammation with well-formed clusters of
Fig. 5-28 Paucibacillary (tuberculoid) leprosy. Wellformed granulomatous inammation demonstrating clusters
of lymphocytes and histiocytes.
epithelioid histiocytes, lymphocytes, and multinucleated giant cells (Fig. 5-28). A paucity of organisms
exists; when present, they can be demonstrated only
when stained with acid-fast stains, such as the Fite
method. Multibacillary leprosy is associated with a
lepromatous pattern that demonstrates no well-formed
granulomas; the typical nding is sheets of lymphocytes intermixed with vacuolated histiocytes known as
lepra cells (Fig. 5-29). Unlike tuberculoid leprosy, an
abundance of organisms can be demonstrated with
acid-fast stains in the lepromatous variant (Fig. 5-30).
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DIAGNOSIS
The denitive diagnosis is based on the clinical presentation and supported by the demonstration of acid-fast
organisms on a smear or in the tissue. The organism
cannot be cultivated on articial media, but M. leprae
can be identied by using molecular biologic techniques. No reliable test is available to determine
whether a person has been exposed to M. leprae without
developing the disease; this creates difculties in establishing the diagnosis and determining the prevalence
of the infection.
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Fig. 5-31 Necrotizing ulcerative mucositis. A, Large area of soft tissue necrosis of the
posterior soft palate on the left side. B, Healing site of necrotizing mucositis 6 days after
initiation of tetracycline therapy.
CLINICAL FEATURES
Noma usually arises in children from 1 to 10 years of
age, although it also can occur in adults with a major
debilitating disease (e.g., diabetes mellitus, leukemia,
lymphoma, HIV infection). The infection often begins
on the gingiva as NUG, which may extend either facially
or lingually to involve the adjacent soft tissue and form
areas called necrotizing ulcerative mucositis. Zones
of necrosis also may develop in soft tissue not continuous with the gingiva, particularly in areas of trauma
(Fig. 5-31). The necrosis can extend into deeper tissues;
over the next few days, zones of blue-black discoloration of the overlying skin surface may develop (Fig.
5-32). Often the necrotic zone is cone shaped, with a
small point of cutaneous necrosis overlying a larger
zone of oral mucosal destruction. Unlike other infections, the process does not follow tissue planes and
tends to spread through anatomic barriers such as
muscle. These discolored zones break down into areas
of yellowish necrosis that also frequently spreads
into adjacent bone, with large areas of osteomyelitis
possible. In most instances the necrotic area is well
dened and unilateral. Fetid odor, signicant pain,
fever, malaise, tachycardia, increased respiratory rate,
anemia, leukocytosis, and regional lymphadenopathy
are typical. Additional lesions also may occur in distant
sites, such as the scalp, neck, ear, shoulders, chest,
perineum, and vulva.
The majority of affected children also demonstrate
signicant stunting of growth. Although many families
will have numerous children living in the same environment, those affected with noma typically are isolated, which suggests additional factors at work. Some
have suggested that victims of intrauterine growth
retardation and premature birth may be predisposed
to future development of noma. Others have suggested
that infection with certain herpesviruses, such as cytomegalovirus, may lower local immunity and promote
development of noma.
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ACTINOMYCOSIS
Although the term actinomycosis seems to imply a
fungal infection, it is an infection of lamentous,
branching, gram-positive anaerobic bacteria. Actinomycetes are normal saprophytic components of the
oral ora. Documented sites of colonization in healthy
patients include the tonsillar crypts, dental plaque and
calculus, carious dentin, gingival sulci, and periodontal
pockets. The colonies within the tonsillar crypts may
form concretions and become large enough for the
patient to feel the rm plugs within the crypts (see page
185). In surveys of documented actinomycosis, Actinomyces israelii is the causative organism in the majority,
with A. viscosus being a close second. Much less frequent causes of the infection are A. naeslundii, A. odontolyticus, A. meyeri, A. pyogenes, A. viscosus, and A. bovis,
along with Arachnia propionica and Bidobacterium
dentium. In most such cases the primary organism is
combined synergistically with streptococci and
staphylococci.
CLINICAL FEATURES
Actinomycosis may be either an acute, rapidly progressing infection or a chronic, slowly spreading lesion
that is associated with brosis. Approximately 55% of
cases of actinomycosis are diagnosed in the cervicofacial region, with 25% occurring in the abdominal and
pelvic region and 15% in the pulmonary system. The
remaining 5% exhibits a variety of patterns, such as
supercial skin infections, or infections of the genitourinary region (often linked to use of intrauterine contraceptive devices).
The suppurative reaction of the infection may discharge large yellowish ecks that represent colonies of
the bacteria called sulfur granules. Although common,
sulfur granules are not present invariably. In addition,
another infection that also can produce sulfur granules
and mimic actinomycosis is botryomycosis, an unrelated process that represents an unusual host reaction
to Staphylococcus aureus and other bacteria.
In the cervicofacial region, the organism typically
enters tissue through an area of prior trauma, such as
a soft tissue injury, periodontal pocket, nonvital tooth,
extraction socket, or infected tonsil. The infection does
not spread along the typical fascial planes and usually
disregards the normal lymphatic and vascular routes.
Direct extension through soft tissue is seen, and lymph
nodes become involved only if they are in the path of
the process. The classic description is of a wooden
indurated area of brosis, which ultimately forms a
central, softer area of abscess. The infection may extend
to the surface, forming a sinus tract (Fig. 5-33). Pain
often is minimal. The soft tissues of the submandibular,
submental, and cheek areas are common areas of
involvement, with the area overlying the angle of the
mandible being the most frequently affected site.
Localized abscesses without the associated chronic
brosing reaction have been reported in soft tissue that
has received minor trauma. The tongue is the most
frequently mentioned site, but any oral mucosal location is possible. Involvement of the tonsillar crypts may
produce infectious symptoms; in most cases, however,
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the primary change is one of variable hyperplasia. Tonsillar hyperplasia thought to be secondary to actinomycotic infestation of the crypts does not appear responsive
to antibiotics, probably because of the supercial location of the bacterial colonies. Tonsillectomy is generally the most effective treatment for this situation.
Salivary gland involvement also is not unusual.
Intraductal colonization by the organism may lead to
infections in both the submandibular and parotid
glands, resulting in abscess formation in the submandibular and masseter spaces, respectively. In addition,
more localized infections occur in minor salivary gland
ducts, which also may demonstrate mucous plugs or
sialoliths.
Actinomycotic osteomyelitis of the mandible and
maxilla has been reported. Trauma, periodontal infections, nonvital teeth, and extraction sites have all provided access. Ill-dened areas of radiolucency, often
surrounded by radiopacity, may be found with or
without involvement of the overlying soft tissue.
Intrabony colonization of dentigerous cysts without
other signicant clinical or radiographic spread has
been reported. Periapical inammatory lesions
involved by the bacteria can result in lesions that are
difcult to resolve with standard endodontic treatment,
but such lesions typically remain localized and do not
evolve into invasive cervicofacial actinomycosis.
HISTOPATHOLOGIC FEATURES
The tissue removed from areas of active infection demonstrates a peripheral band of brosis encasing a zone
of chronically inamed granulation tissue surrounding
large collections of polymorphonuclear leukocytes
and, with luck, colonies of organisms (Fig. 5-34). The
colonies consist of club-shaped laments that form a
DIAGNOSIS
The diagnosis of actinomycosis is achieved ideally by
culture, but less than 50% of cases are positive because
of the overgrowth of associated bacteria, prior antibiotic therapy, or improper anaerobic media conditions.
Lacking positive culture results, a strong presumptive
diagnosis can be obtained through a demonstration of
the typical colonies in lesional biopsy material. The
material for culture and histopathologic examination is
typically obtained during surgical exploration, with
ne-needle aspiration being a satisfactory substitute in
many cases. Sulfur granules in infections other than
actinomycosis are so rare that their demonstration
strongly supports the diagnosis. If desired, then uorescein-conjugated antiserum can be used on the granules
to specically identify the Actinomyces species.
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CAT-SCRATCH DISEASE
Cat-scratch disease is an infectious disorder that
begins in the skin but classically spreads to the adjacent
lymph nodes. This infection is the most common cause
of chronic regional lymphadenopathy in children, with
an estimated 22,000 cases occurring annually in the
United States. This disease has been recognized since
1931, but the denitive cause was not determined
until the 1980s. Isolation and culture of the organism
were nally achieved in 1988. The causative organism
was initially named Rochalimaea henselae but was reclassied as Bartonella henselae. On very rare occasions, catscratch disease is caused by related species, Bartonella
quintana or Bartonella clarridgeiae.
Almost all cases arise after contact with a cat, usually
a kitten. Cat eas appear to be involved in the transmission of the causative organism among cats, but the role
of eas in the transmission from cats to humans is
unclear. Most human infections appear to follow
scratches, licks, or bites from domestic cats. Infection
from other sources is highly unlikely, but the disease
rarely has been described via dogs, monkeys, porcupine quills, and thorns. Person-to-person transmission
has not been documented.
CLINICAL FEATURES
Eighty percent of the cases occur in patients younger
than 21 years of age. Cat-scratch disease begins as a
papule or pustule that develops in 3 to 14 days along
the initial scratch line (Fig. 5-36). The lymph node
changes develop in approximately 3 weeks and often
may be accompanied by fever or malaise (Fig. 5-37).
Scratches on the face typically lead to submandibular
lymphadenopathy, and the patient may be referred to
dental practitioners to rule out an odontogenic infection. Often the primary site of trauma may have
resolved by the time that the symptomatic lymphadenopathy is diagnosed. Therefore, cat-scratch disease
must be considered strongly in the differential diagnosis of patients with unexplained symptomatic lymphadenopathy. In about half of the cases, a single node is
involved. Multiple regional nodes are affected in about
20%, and nodal enlargement is discovered in multiple
sites in about 33%. Suppuration is noted in approximately 10% of affected patients.
A few patients with cat-scratch disease demonstrate
unusual presentations. The infection can appear as an
intraoral mass in the buccal mucosa when lymphoid
aggregates become involved from an adjacent cutaneous primary site. Scratches in the preauricular area
may localize in parotid lymphoid tissue and can
cause signicant parotid pain or even temporary facial
paralysis. Other less common problems include granulomatous osteomyelitis, arthralgias, encephalopathy,
erythematous and maculopapular rashes, splenomegaly, hepatic lesions, thrombocytopenia, pneumonia,
anemia, pleural effusions, and recurrent bacterial
infections.
Primary lesions adjacent to the eye can result in a
conjunctival granuloma that is associated with preauricular lymphadenopathy (oculoglandular syndrome
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HISTOPATHOLOGIC FEATURES
DIAGNOSIS
Today the diagnosis of cat-scratch disease usually is
established via serologic tests that demonstrate a high
degree of sensitivity and specicity. The most widely
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E
MM
SINUSITIS
Sinusitis is one of the most common health complaints
in the United States. To understand the problem, the
clinician must rst have some knowledge of sinus
anatomy. Adults have bilateral maxillary, frontal, sphenoid, ethmoid, and mastoid sinuses. Except for the
mastoid sinuses, these cavities drain into the nose
through openings called ostia. The frontal, sphenoid,
and maxillary sinuses must drain through the middle
meatus. In addition, the ethmoids are located bilaterally in this area of the nose and present as a labyrinth
of 3 to 15 small sinuses, which drain through smaller
ostia. The ostiomeatal complex, with its numerous
narrow openings (Fig. 5-39), is the key to sinus disease
because it is the primary nasal site for the deposition
of foreign matter from inspired air.
Normal sinuses are lined by pseudostratied columnar epithelium with cilia. The cilia are necessary to
move the sinus secretions toward the ostia. Gravity also
is benecial in removing the secretions, except in the
maxillary sinus where there is a superior location of the
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BIBLIOGRAPHY
General References
Gorbach SL, Bartlett JG, Blacklow NR: Infectious diseases, ed 2,
Philadelphia, 1998, WB Saunders.
Holmes KK: Sexually transmitted diseases, ed 3, New York, 1999,
McGraw-Hill.
Katz SL, Gershon AA, Hotez PJ et al: Krugmans infectious diseases
of children, ed 10, St Louis, 1999, Mosby.
Streptococcal Infections (Impetigo; Erysipelas; Streptococcal
Pharyngitis and Tonsillitis; Scarlet Fever)
Bialecki C, Feder HM, Grant-Kels JM: The six classic childhood
exanthems: a review and update, J Am Acad Dermatol 21:891903, 1989.
Bisno AL, Gerber MA, Gwaltney Jr JM et al: Practice guidelines
for the diagnosis and management of group A streptococcal
pharyngitis, Clin Infect Dis 35:113-125, 2002.
Bonnetblanc J-M, Bdane C: Erysipelas. Recognition and management, Am J Clin Dermatol 4:157-163, 2003.
Bratton RL, Neese RE: St. Anthonys re: diagnosis and management of erysipelas, Am Fam Physician 51:401-404, 1995.
Gerber MA: Diagnosis and treatment of pharyngitis in children,
Pediatr Clin North Am 52:729-747, 2005.
Giunta JL: Comparison of erysipelas and odontogenic cellulitis,
J Endod 13:291-294, 1987.
Hirschmann JV: Impetigo: etiology and therapy, Curr Clin Top
Infect Dis 22:42-51, 2002.
Jaggi P, Shulman ST: Group A streptococcal infections, Pediatr
Rev 27:99-105, 2006.
Katzenell U, Shemer J, Bar-Dayan Y: Streptococcal contamination of food: an unusual cause of epidemic pharyngitis, Epidemiol Infect 127:179-184, 2001.
Kolokotronis A, Doumas S, Lambroudi M et al: Facial and perioral primary impetigo: a clinical study, J Clin Pediatr Dent
29:341-346, 2005.
Koning S, Verhagen AP, van Suijlekom-Smit LW et al: Interventions for impetigo, Cochrane Database Syst Rev 2:CD003261,
2004.
Ochs MW, Dolwick MF: Facial erysipelas: report of a case and
review of the literature, J Oral Maxillofac Surg 49:1116-1120,
1991.
sterlund A, Kahlmeter G, Hggman S et al: Staphylococcus
aureus resistance to fusidic acid among Swedish children: a
follow-up study, Scand J Infect Dis 38:332-334, 2006.
Pavlotsky F, Amrani S, Trau H: Recurrent erysipelas: risk factors,
J Dtsch Dermatol Ges 2:89-95, 2004.
Pichichero M, Casy J: Comparison of European and U.S. results
for cephalosporin versus penicillin treatment of group A
streptococcal tonsillopharyngitis, Eur J Clin Microbiol Infect Dis
25:354-364, 2006.
Trk L: Uncommon manifestations of erysipelas, Clin Dermatol
23:515-518, 2005.
Watkins P: Impetigo: aetiology, complications and treatment
options, Nurs Stand 19:50-54, 2005.
Tonsillar Concretions and Tonsillolithiasis
Cooper MM, Steinberg JJ, Lastra M et al: Tonsillar calculi: report
of a case and review of the literature, Oral Surg Oral Med Oral
Pathol 55:239-243, 1983.
Finkelstein Y, Talmi YP, Ophir D et al: Laser cryptolysis for the
treatment of halitosis, Otolaryngol Head Neck Surg 131:372377, 2004.
zcan E, Ural A, ktemer TK et al: Bilateral tonsillolithiasis: a
case report, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
102:e17-18, 2006.
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Fungal and Protozoal Diseases
CHAPTER OUTLINE
Candidiasis
Pseudomembranous Candidiasis
Erythematous Candidiasis
Chronic Hyperplastic Candidiasis
Mucocutaneous Candidiasis
Histoplasmosis
Blastomycosis
Paracoccidioidomycosis
Coccidioidomycosis
Cryptococcosis
Zygomycosis
Aspergillosis
Toxoplasmosis
CANDIDIASIS
Infection with the yeastlike fungal organism Candida
albicans is termed candidiasis or, as the British prefer,
candidosis. An older name for this disease is moniliasis;
the use of this term should be discouraged because it
is derived from the archaic designation Monilia albicans.
Other members of the Candida genus, such as C. tropicalis, C. krusei, C. parapsilosis, and C. guilliermondii, may also
be found intraorally, but they rarely cause disease.
Like many other pathogenic fungi, C. albicans may
exist in two formsa trait known as dimorphism. The
yeast form of the organism is believed to be relatively
innocuous, but the hyphal form is usually associated
with invasion of host tissue.
Candidiasis is by far the most common oral fungal
infection in humans and has a variety of clinical manifestations, making the diagnosis difcult at times. In
fact, C. albicans may be a component of the normal oral
microora, with as many as 30% to 50% of people
simply carrying the organism in their mouths without
clinical evidence of infection. This rate of carriage has
been shown to increase with age, and C. albicans can be
recovered from the mouths of nearly 60% of dentate
patients older than 60 years who have no sign of oral
mucosal lesions. At least three general factors may determine whether clinical evidence of infection exists:
1. The immune status of the host
2. The oral mucosal environment
3. The strain of C. albicans
CLINICAL FEATURES
Candidiasis of the oral mucosa may exhibit a variety of
clinical patterns, which are summarized in Table 6-1.
Many patients will display a single pattern, although
some individuals will exhibit more than one clinical
form of oral candidiasis.
PSEUDOMEMBRANOUS CANDIDIASIS
The best recognized form of candidal infection is pseudomembranous candidiasis. Also known as thrush,
pseudomembranous candidiasis is characterized by
the presence of adherent white plaques that resemble
cottage cheese or curdled milk on the oral mucosa
(Figs. 6-1 and 6-2). The white plaques are composed of
tangled masses of hyphae, yeasts, desquamated epithe213
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Table 6-1
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Clinical Type
Pseudomembranous (thrush)
Erythematous
Angular cheilitis
Denture stomatitis (chronic
atrophic candidiasis,
denture sore mouth)
Hyperplastic (candidal
leukoplakia)
Mucocutaneous
Endocrine-candidiasis
syndromes
Appearance and
Symptoms
Common Sites
Creamy-white plaques,
removable; burning
sensation, foul taste
Red macules, burning
sensation
Antibiotic therapy,
immunosuppression
Immunosuppression, idiopathic
Angles of mouth
Idiopathic, immunosuppression,
loss of vertical dimension
Probably not true infection;
denture often is positive on
culture but mucosa is not
Idiopathic, immunosuppression;
care must be taken not to
confuse this with other
keratotic lesions with
superimposed candidiasis
Rare; inherited or sporadic
idiopathic immune
dysfunction
Rare; endocrine disorder
develops after candidiasis
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Fig. 6-2 Pseudomembranous candidiasis. A, Classic curdled milk appearance of the oral lesions
of pseudomembranous candidiasis. This patient had no apparent risk factors for candidiasis
development. B, Removal of one of the pseudomembranous plaques (arrow) reveals a mildly
erythematous mucosal surface. (From Allen CM, Blozis GG: Oral mucosal lesions. In Cummings CW, Fredrickson JM,
Harker LA et al, editors: Otolaryngology: head and neck surgery, ed 3, St Louis, 1998, Mosby.)
ERYTHEMATOUS CANDIDIASIS
In contrast to the pseudomembranous form, patients
with erythematous candidiasis either do not show
white ecks, or a white component is not a prominent
feature. Erythematous candidiasis is undoubtedly
more common than pseudomembranous candidiasis,
although it is often overlooked clinically. Several clinical presentations may be seen. Acute atrophic candidiasis or antibiotic sore mouth, typically follows a
course of broad-spectrum antibiotic therapy. Patients
often complain that the mouth feels as if a hot beverage
had scalded it. This burning sensation is usually accompanied by a diffuse loss of the liform papillae of the
dorsal tongue, resulting in a reddened, bald appearance of the tongue (Fig. 6-3). Burning mouth syndrome
(see page 873) frequently manifests with a scalded sensation of the tongue; however, the tongue appears
normal in that condition. Patients who suffer from
xerostomia for any reason (e.g., pharmacologic, postradiation therapy, Sjgren syndrome) have an increased
prevalence of erythematous candidiasis that is commonly symptomatic as well.
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Fig. 6-4 Erythematous candidiasis. A, Severe presentation of central papillary atrophy. In this
patient the lesion was asymptomatic. B, Marked regeneration of the dorsal tongue papillae occurred
2 weeks after antifungal therapy with uconazole.
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Fig. 6-5 Candidiasis. A, Multifocal oral candidiasis characterized by central papillary atrophy of the
tongue and other areas of involvement. B, Same patient showing a kissing lesion of oral candidiasis
on the hard palate.
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The diagnosis is conrmed by the presence of candidal hyphae associated with the lesion and by complete resolution of the lesion after antifungal therapy
(Fig. 6-12).
MUCOCUTANEOUS CANDIDIASIS
Severe oral candidiasis may also be seen as a component of a relatively rare group of immunologic disorders known as mucocutaneous candidiasis. Several distinct
immunologic dysfunctions have been identied, and
the severity of the candidal infection correlates with
the severity of the immunologic defect. Most cases are
sporadic, although an autosomal recessive pattern of
inheritance has been identied in some families. The
immune problem usually becomes evident during the
rst few years of life, when the patient begins to have
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HISTOPATHOLOGIC FEATURES
Fig. 6-11 Hyperplastic candidiasis. This lesion of the
anterior buccal mucosa clinically resembles a leukoplakia
because it is a white plaque that cannot be removed by
rubbing. With antifungal therapy, such a lesion should resolve
completely.
Fig. 6-12 Hyperplastic candidiasis. A, These diffuse white plaques clinically appear as leukoplakia,
but they actually represent an unusual presentation of hyperplastic candidiasis. B, Treatment with
clotrimazole oral troches shows complete resolution of the white lesions within 2 weeks, essentially
conrming the diagnosis of hyperplastic candidiasis. If any white mucosal alteration had persisted,
a biopsy of that area would have been mandatory.
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6-14). The PAS method stains carbohydrates, contained in abundance by fungal cell walls; the organisms
are easily identied by the bright-magenta color
imparted by the stain. To make a diagnosis of candidiasis, one must be able to see hyphae or pseudohyphae
(which are essentially elongated yeast cells). These
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POLYENE AGENTS
NYSTATIN
In the 1950s the polyene antibiotic nystatin was the
rst effective treatment for oral candidiasis. Nystatin is
formulated for oral use as a suspension or pastille
(lozenge). Many patients report that nystatin has a very
bitter taste, which may reduce patient compliance;
therefore, the taste has to be disguised with sucrose
and avoring agents. If the candidiasis is due to xerostomia, the sucrose content of the nystatin preparation
may contribute to xerostomia-related caries in these
patients. The gastrointestinal tract poorly absorbs
nystatin and the other polyene antibiotic, amphotericin; therefore, their effectiveness depends on direct
contact with the candidal organisms. This necessitates
multiple daily doses so that the yeasts are adequately
exposed to the drug. Nystatin combined with triamcinolone acetonide cream or ointment can be applied
topically and is effective for angular cheilitis that does
not have a bacterial component.
AMPHOTERICIN B
Fig. 6-16 Candidiasis. This high-power photomicrograph
shows the tubular hyphae of Candida albicans embedded in
the parakeratin layer. (PAS stain.)
DIAGNOSIS
The diagnosis of candidiasis is usually established by
the clinical signs in conjunction with exfoliative cytologic examination. Although a culture can denitively
identify the organism as C. albicans, this process may
not be practical in most ofce settings. The cytologic
ndings should demonstrate the hyphal phase of the
organism, and antifungal therapy can then be instituted. If the lesion is clinically suggestive of chronic
hyperplastic candidiasis but does not respond to antifungal therapy, then a biopsy should be performed to
rule out the possibility of C. albicans superimposed on
epithelial dysplasia, squamous cell carcinoma, or lichen
planus.
For many years in the United States, the use of amphotericin B was restricted to intravenous (IV) treatment
of life-threatening systemic fungal infections. This
medication subsequently became available as an oral
suspension for the management of oral candidiasis.
Unfortunately, the interest in this formulation of the
drug was scant, and it is no longer marketed in the
United States.
IMIDAZOLE AGENTS
The imidazole-derived antifungal agents were developed during the 1970s and represented a major step
forward in the management of candidiasis. The two
drugs of this group that are used most frequently are
clotrimazole and ketoconazole.
CLOTRIMAZOLE
Like nystatin, clotrimazole is not well absorbed and
must be administered several times each day. It is
formulated as a pleasant-tasting troche (lozenge) and
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Table 6-2
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Antifungal Medications
Generic Name
Trade Name
Indications
Dosage
Nystatin
Mycostatin pastilles
Oral candidiasis
Clotrimazole
Oral candidiasis
Dissolve 1 troche (10 mg) slowly in the mouth, 5 times daily for
10-14 days
Ketoconazole
Nizoral tablets
Oral candidiasis
Blastomycosis
One tablet (200 mg) daily for 1-2 weeks for candidiasis
Coccidioidomycosis
Histoplasmosis
Paracoccidioidomycosis
Oral candidiasis
Fluconazole
Diucan tablets
Cryptococcal meningitis
Itraconazole
Sporanox capsules
Blastomycosis
Histoplasmosis
Aspergillosis refractory to
amphotericin B therapy
Itraconazole
Oral candidiasis
Amphotericin B
Oral candidiasis
TID, Three times a day; QID, four times a day; PC, after meals; HS, at bedtime.
KETOCONAZOLE
Ketoconazole was the rst antifungal drug that could
be absorbed across the gastrointestinal tract, thereby
providing systemic therapy by an oral route of administration. The single daily dose was much easier for
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Drug Interactions
None known
implicated in drug interactions with macrolide antibiotics (e.g., erythromycin), the gastrointestinal motility
enhancing agent cisapride, and the antihistamine
astemizole, all of which may produce potentially lifethreatening cardiac arrhythmias.
TRIAZOLES
The triazoles are the newest group of antifungal drugs.
Both uconazole and itraconazole have been approved
for treating candidiasis in the United States.
Clinically or potentially signicant side effects have been noted with the
following medications: oral hypoglycemic agents, coumarin-like drugs,
phenytoin, cyclosporine, rifampin, theophylline, terfenadine, cisapride,
astemizole, rifabutin, and tacrolimus
Serious and/or life-threatening interactions with terfenadine,
astemizole, pimozide, quinidine, oral triazolam, oral midazolam, and
cisapride
FLUCONAZOLE
Fluconazole appears to be more effective than ketoconazole; it is well absorbed systemically, and an acidic
environment is not required for absorption. A relatively
long half-life allows for once-daily dosing, and liver
toxicity is rare at the doses used to treat oral candidiasis. Some reports have suggested that uconazole may
not be appropriate for long-term preventive therapy
because resistance to the drug seems to develop in
some instances. Known drug interactions include a
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ITRACONAZOLE
Itraconazole has proven efcacy against a variety of
fungal diseases, including histoplasmosis, blastomycosis, and fungal conditions of the nails. Recently, itraconazole solution was approved for management of
oropharyngeal candidiasis, and this appears to have
an efcacy equivalent to clotrimazole and uconazole.
As with uconazole, signicant drug interactions are
possible, and itraconazole is contraindicated for
patients taking astemizole, triazolam, midazolam, and
cisapride. (See Table 6-2 for other potential drug
interactions.)
POSACONAZOLE
This new triazole compound has been shown to be
effective in the management of oropharyngeal candidiasis in patients with HIV infection. Given the cost of
this drug and the proven effectiveness of other, less
expensive, oral antifungal agents, the use of this medication for treatment of routine oral candidiasis would
be difcult to justify.
ECHINOCANDINS
This new class of antifungal drugs acts by interfering
with candidal cell wall synthesis. The formation of
-1,3-glucan, which is a principal component of the
candidal cell wall, is disrupted and results in permeability of the cell wall with subsequent demise
of the candidal organism. These medications are not
well absorbed; consequently they must be administered intravenously and are reserved for more lifethreatening candidal infections. Examples include
caspofungin, micafungin, and anidulafungin.
HISTOPLASMOSIS
Histoplasmosis, the most common systemic fungal
infection in the United States, is caused by the organism Histoplasma capsulatum. Like several other pathogenic fungi, H. capsulatum is dimorphic, growing as a
yeast at body temperature in the human host and as a
mold in its natural environment. Humid areas with soil
enriched by bird or bat excrement are especially suited
to the growth of this organism. This habitat preference
explains why histoplasmosis is seen endemically in
fertile river valleys, such as the region drained by the
Ohio and Mississippi Rivers in the United States. Airborne spores of the organism are inhaled, pass into the
terminal passages of the lungs, and germinate.
Approximately 500,000 new cases of histoplasmosis are thought to develop annually in the United States.
Other parts of the world, such as Central and South
America, Europe, and Asia, also report numerous cases.
Epidemiologic studies in endemic areas of the United
States suggest that 80% to 90% of the population in
these regions has been infected.
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HISTOPATHOLOGIC FEATURES
Microscopic examination of lesional tissue shows either
a diffuse inltrate of macrophages or, more commonly,
collections of macrophages organized into granulomas
(Fig. 6-20). Multinucleated giant cells are usually seen
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DIAGNOSIS
The diagnosis of histoplasmosis can be made by histopathologic identication of the organism in tissue sections or by culture. Other helpful diagnostic studies
include serologic testing in which antibodies directed
against H. capsulatum are demonstrated and antigen
produced by the yeast is identied.
BLASTOMYCOSIS
Blastomycosis is a relatively uncommon disease
caused by the dimorphic fungus known as Blastomyces
dermatitidis. Although the organism is rarely isolated
from its natural habitat, it seems to prefer rich, moist
soil, where it grows as a mold. Much of the region in
which it grows overlaps the territory associated with
H. capsulatum (affecting the eastern half of the United
States). The range of blastomycosis extends farther
north, however, including Wisconsin, Minnesota, and
the Canadian provinces surrounding the Great Lakes.
Sporadic cases have also been reported in Africa, India,
Europe, and South America. By way of comparison,
histoplasmosis appears to be at least ten times more
common than blastomycosis. In several series of cases,
a prominent adult male predilection has been noted,
often with a male-to-female ratio as high as 9:1.
Researchers have attributed this to the greater degree
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HISTOPATHOLOGIC FEATURES
Histopathologic examination of lesional tissue typically
shows a mixture of acute inammation and granulomatous inammation surrounding variable numbers of
yeasts. These organisms are 8 to 20 m in diameter.
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DIAGNOSIS
Fig. 6-24 Blastomycosis. These irregular ulcerations of the
tongue represent blastomycosis. Direct inoculation was
thought to have occurred from the patients habit of chewing
dried horse manure (Kentucky eld candy), in which the
organism was probably growing.
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PARACOCCIDIOIDOMYCOSIS (SOUTH
AMERICAN BLASTOMYCOSIS)
Paracoccidioidomycosis is a deep fungal infection
that is caused by Paracoccidioides brasiliensis. The condition is seen most frequently in patients who live in
either South America (primarily Brazil, Colombia,
Venezuela, Uruguay, and Argentina) or Central
America. However, immigrants from those regions and
visitors to those areas can acquire the infection. Within
some endemic areas, the nine-banded armadillo has
been shown to harbor P. brasiliensis (similar to the situation seen with leprosy) (see page 198). Although there
is no evidence that the armadillo directly infects
humans, it may be responsible for the spread of the
organism in the environment.
Paracoccidioidomycosis has a distinct predilection
for males, with a 15:1 male-to-female ratio typically
reported. This striking difference is thought to be
attributable to a protective effect of female hormones
(because -estradiol inhibits the transformation of the
hyphal form of the organism to the pathogenic yeast
form). This theory is supported by the nding of an
equal number of men and women who have antibodies
directed against the yeast.
CLINICAL FEATURES
Patients with paracoccidioidomycosis are typically
middle-aged at the time of diagnosis, and most are
employed in agriculture. Most cases of paracoccidioidomycosis are thought to appear initially as pulmonary
infections after exposure to the spores of the organism.
Although infections are generally self-limiting, P. brasiliensis may spread by a hematogenous or lymphatic
route to a variety of tissues, including lymph nodes,
skin, and adrenal glands. Adrenal involvement often
results in hypoadrenocorticism (Addisons disease)
(see page 841).
Oral lesions appear as mulberry-like ulcerations
that most commonly affect the alveolar mucosa,
gingiva, and palate (Fig. 6-27). The lips, tongue, oropharynx, and buccal mucosa are also involved in a signicant percentage of cases. In most patients with oral
lesions, more than one oral mucosal site is affected.
HISTOPATHOLOGIC FEATURES
Microscopic evaluation of tissue obtained from an oral
lesion may reveal pseudoepitheliomatous hyperplasia
in addition to ulceration of the overlying surface epithelium. P. brasiliensis elicits a granulomatous inammatory host response that is characterized by collections
of epithelioid macrophages and multinucleated giant
cells (Fig. 6-28). Scattered, large (up to 30 m in diam-
DIAGNOSIS
Demonstration of the characteristic multiple budding
yeasts in the appropriate clinical setting is usually
adequate to establish a diagnosis of paracoccidioidomycosis. Specimens for culture can be obtained, but
P. brasiliensis grows quite slowly.
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COCCIDIOIDOMYCOSIS
(SAN JOAQUIN VALLEY FEVER;
VALLEY FEVER; COCCI)
Coccidioides immitis is the fungal organism responsible
for coccidioidomycosis. C. immitis grows saprophytically in the alkaline, semiarid, desert soil of the southwestern United States and Mexico, with isolated regions
also noted in Central and South America. As with
several other pathogenic fungi, C. immitis is a dimorphic organism, appearing as a mold in its natural environment of the soil and as a yeast in tissues of the
infected host. Arthrospores produced by the mold
become airborne and can be inhaled into the lungs of
the human host, producing infection.
Coccidioidomycosis is conned to the Western
hemisphere and is endemic throughout the desert
regions of southwestern United States and Mexico;
however, with modern travel taking many visitors to
and from the Sunbelt, this disease can be encountered
virtually anywhere in the world. It is estimated that
100,000 people are infected annually in the United
States, although 60% of this group are asymptomatic.
CLINICAL FEATURES
Most infections with C. immitis are asymptomatic,
although approximately 40% of infected patients experience a ulike illness and pulmonary symptoms within
1 to 3 weeks after inhaling the arthrospores. Fatigue,
cough, chest pain, myalgias, and headache are commonly reported, lasting several weeks with spontaneous resolution in most cases. Occasionally, the immune
response may trigger a hypersensitivity reaction that
causes the development of an erythema multiforme
like cutaneous eruption (see page 776) or erythema
nodosum. Erythema nodosum is a condition that
usually affects the skin of the legs and is characterized
by the appearance of multiple painful erythematous
inammatory nodules in the subcutaneous connective tissue. This hypersensitivity reaction occurring in
conjunction with coccidioidomycosis is termed valley
fever, and it resolves as the host cellmediated immune
response controls the pulmonary infection.
Chronic progressive pulmonary coccidioidomycosis is relatively rare. It mimics tuberculosis, with its
clinical presentation of persistent cough, hemoptysis,
chest pain, low-grade fever, and weight loss.
Disseminated coccidioidomycosis occurs when
the organism spreads hematogenously to extrapulmonary sites. This occurs in less than 1% of cases, but it is
a more serious problem. The most commonly involved
areas include skin, lymph nodes (including cervical
lymph nodes), bone and joints, and the meninges.
Immunosuppression greatly increases the risk of dissemination. The following groups are particularly
susceptible:
Patients taking large doses of systemic corticosteroids (organ transplant recipients)
Patients who are being treated with cancer
chemotherapy
Patients in the end stages of HIV infection
Patients who are pregnant
Infants and older adult patients, both of whom may
have suboptimally functioning immune systems, also
may be at increased risk for disseminated disease.
Persons of color (e.g., blacks, Filipinos, Native Americans) also seem to have an increased risk, but it is unclear
whether their susceptibility is due to genetic causes or
socioeconomic factors, such as poor nutrition.
The cutaneous lesions may appear as papules, subcutaneous abscesses, verrucous plaques, and granulomatous nodules. Of prime signicance to the clinician
is the predilection for these lesions to develop in the
area of the central face, especially the nasolabial fold.
Oral lesions are distinctly uncommon, and these have
been described as ulcerated granulomatous nodules.
HISTOPATHOLOGIC FEATURES
Biopsy material shows large (20 to 60 m), round
spherules that may contain numerous endospores. The
host response may be variable, ranging from a suppurative, neutrophilic inltrate to a granulomatous inammatory response. In some cases the two patterns of
inammation are seen concurrently. Special stains,
such as the PAS and Grocott-Gomori methenamine
silver methods, enable the pathologist to identify the
organism more readily.
DIAGNOSIS
The diagnosis of coccidioidomycosis can be conrmed
by culture or identication of characteristic organisms
in biopsy material. If the organisms do not have a
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classic microscopic appearance, then in situ hybridization studies using specic complementary DNA probes
for C. immitis can be performed to denitively identify
the fungus. Cytologic preparations from bronchial
swabbings or sputum samples may also reveal the
organisms.
Serologic studies are helpful in supporting the diagnosis, and they may be performed at the same time as
skin testing. Skin testing by itself may be of limited
value in determining the diagnosis because many
patients in endemic areas have already been exposed
to the organism and have positive test ndings.
TREATMENT
CLINICAL FEATURES
CRYPTOCOCCOSIS
Cryptococcosis is a relatively uncommon fungal
disease caused by the yeast Cryptococcus neoformans.
This organism normally causes no problem in immunocompetent people, but it can be devastating to the
immunocompromised patient. The incidence of cryptococcosis increased dramatically during the 1990s,
primarily because of the AIDS epidemic. At that time,
this was the most common life-threatening fungal
infection in these patients. However, with the advent
of highly active anti-retroviral therapy (HAART) (see
page 280), this complication has become less of a
problem in the United States. In countries where the
population cannot afford HAART, cryptococcosis
remains a signicant cause of death for AIDS patients.
The disease has a worldwide distribution because of its
association with the pigeon (with the organism living
HISTOPATHOLOGIC FEATURES
Microscopic sections of a cryptococcal lesion generally
show a granulomatous inammatory response to the
organism. The extent of the response may vary,
however, depending on the hosts immune status and
the strain of the organism. The yeast appears as a
round-to-ovoid structure, 4 to 6 m in diameter, surrounded by a clear halo that represents the capsule.
Staining with the PAS or Grocott-Gomori methenamine silver method readily identies the fungus;
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DIAGNOSIS
The diagnosis of cryptococcosis can be made by several
methods, including biopsy and culture. Detection of
cryptococcal polysaccharide antigen in the serum or
cerebrospinal uid is also useful as a diagnostic
procedure.
ZYGOMYCOSIS (MUCORMYCOSIS;
PHYCOMYCOSIS)
Zygomycosis is an opportunistic, frequently fulminant,
fungal infection that is caused by normally saprobic
organisms of the class Zygomycetes, including such
genera as Absidia, Mucor, Rhizomucor, and Rhizopus.
HISTOPATHOLOGIC FEATURES
Histopathologic examination of lesional tissue shows
extensive necrosis with numerous large (6 to 30 m in
diameter), branching, nonseptate hyphae at the periphery (Fig. 6-33). The hyphae tend to branch at 90-degree
angles. The extensive tissue destruction and necrosis
associated with this disease are undoubtedly attribut-
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DIAGNOSIS
Fig. 6-31 Zygomycosis. The extensive black, necrotic
lesion of the palate represents zygomycotic infection that
extended from the maxillary sinus in a patient with poorly
controlled type I diabetes mellitus. (Courtesy of Dr. Michael Tabor.)
Diagnosis of zygomycosis is usually based on the histopathologic ndings. Because of the grave nature of this
infection, appropriate therapy must be instituted in a
timely manner (often without the benet of denitive
culture results).
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ASPERGILLOSIS
Aspergillosis is a fungal disease that is characterized
by noninvasive and invasive forms. Noninvasive aspergillosis usually affects a normal host, appearing either
as an allergic reaction or a cluster of fungal hyphae.
Localized invasive infection of damaged tissue may be
seen in a normal host, but a more extensive invasive
infection is often evident in the immunocompromised
patient. With the advent of intensive chemotherapeutic regimens, the AIDS epidemic, and both solid-organ
and bone marrow transplantation, the prevalence of
invasive aspergillosis has increased dramatically in the
past 20 years. Patients with uncontrolled diabetes mellitus are also susceptible to Aspergillus spp. infections.
Rarely, invasive aspergillosis has been reported to
affect the paranasal sinuses of apparently normal
immunocompetent individuals.
Normally, the various species of the Aspergillus genus
reside worldwide as saprobic organisms in soil, water,
or decaying organic debris. Resistant spores are
released into the air and inhaled by the human host,
resulting in opportunistic fungal infection second in
frequency only to candidiasis. Interestingly, most
species of Aspergillus cannot grow at 37 C; only the
pathogenic species have the ability to replicate at body
temperature.
The two most commonly encountered species of
Aspergillus in the medical setting are A. avus and A.
fumigatus, with A. fumigatus being responsible for 90%
of the cases of aspergillosis. The patient may acquire
such infections in the hospital (nosocomial infection), especially if remodeling or building construction
is being performed in the immediate area. Such activity often stirs up the spores, which are then inhaled by
the patient.
CLINICAL FEATURES
The clinical manifestations of aspergillosis vary,
depending on the host immune status and the presence or absence of tissue damage. In the normal host,
the disease may appear as an allergy affecting either
the sinuses (allergic fungal sinusitis) or the bronchopulmonary tract. An asthma attack may be triggered by
inhalation of spores by a susceptible person. Sometimes a low-grade infection becomes established in the
maxillary sinus, resulting in a mass of fungal hyphae
called an aspergilloma. Occasionally, the mass will
undergo dystrophic calcication, producing a radiopaque body called an antrolith within the sinus.
Another presentation that may be encountered by
the oral health care provider is aspergillosis after tooth
extraction or endodontic treatment, especially in the
maxillary posterior segments. Presumably, tissue
HISTOPATHOLOGIC FEATURES
Tissue sections of invasive Aspergillus spp. lesions show
varying numbers of branching, septate hyphae, 3 to
4 m in diameter (Figs. 6-35 and 6-36). These hyphae
show a tendency to branch at an acute angle and to
invade adjacent small blood vessels. Occlusion of the
vessels often results in the characteristic pattern of
necrosis associated with this disease. In the immunocompetent host, a granulomatous inammatory
responsein addition to necrosiscan be expected. In
the immunocompromised patient, however, the inam-
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DIAGNOSIS
Although the diagnosis of fungal infection can be
established by identication of hyphae within tissue
sections, this nding is only suggestive of aspergillosis
TOXOPLASMOSIS
Toxoplasmosis is a relatively common disease caused
by the obligate intracellular protozoal organism Toxoplasma gondii. For normal, healthy adults, the organism
poses no problems, and an estimated 16% to 23% of
adults in the United States may have had asymptomatic
infection, based on an epidemiologic study that examined serologic samples from more than 4000 randomized individuals. However, the prevalence of infection
has considerable geographic variation around the
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CLINICAL FEATURES
In the normal, immunocompetent individual, infection
with T. gondii is often asymptomatic. If symptoms
develop, they are usually mild and resemble infectious
mononucleosis; patients may have a low-grade fever,
cervical lymphadenopathy, fatigue, and muscle or joint
pain. These symptoms may last from a few weeks to
a few months, although the host typically recovers
without therapy. Sometimes the lymphadenopathy
involves one or more of the lymph nodes in the paraoral region, such as the buccal or submental lymph
node. In such instances, the oral health care provider
may discover the disease.
In immunosuppressed patients, toxoplasmosis may
represent a new, primary infection or, more frequently,
reactivation of previously encysted organisms. The
principal groups at risk include the following:
AIDS patients
Transplant recipients
Cancer patients
Manifestations of infection can include necrotizing
encephalitis, pneumonia, and myositis or myocarditis.
In the United States, it is estimated that from 3% to 10%
of AIDS patients (see page 264) will experience CNS
involvement. CNS infection is very serious. Clinically,
the patient may complain of headache, lethargy, disorientation, and hemiparesis.
Congenital toxoplasmosis occurs when a nonimmune mother contracts the disease during her pregnancy and the organism crosses the placental barrier,
infecting the developing fetus. The potential effects of
blindness, mental retardation, and delayed psychomotor development are most severe if the infection occurs
during the rst trimester of pregnancy.
HISTOPATHOLOGIC FEATURES
Histopathologic examination of a lymph node obtained
from a patient with active toxoplasmosis shows characteristic reactive germinal centers exhibiting an accumulation of eosinophilic macrophages. The macrophages encroach on the germinal centers and
accumulate within the subcapsular and sinusoidal
regions of the node (Fig. 6-37).
DIAGNOSIS
The diagnosis of toxoplasmosis is usually established by
identication of rising serum antibody titers to T. gondii
within 10 to 14 days after infection. Immunocompromised patients, however, may not be able to generate
an antibody response; therefore, the diagnosis may rest
on the clinical ndings and the response of the patient
to therapy.
Biopsy of an involved lymph node may suggest the
diagnosis, and the causative organisms can sometimes
be detected immunohistochemically using antibodies
directed against T. gondiispecic antigens (Fig. 6-38).
The diagnosis should also be conrmed by serologic
studies, if possible.
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Godoy H, Reichart PA: Oral manifestations of paracoccidioidomycosis. Report of 21 cases from Argentina, Mycoses 46:412417, 2003.
Gorete dos Santos-Nogueira M, Queiroz-Andrade GM, Tonelli E:
Clinical evolution of paracoccidioidomycosis in 38 children
and teenagers, Mycopathologia 161:73-81, 2006.
Paes de Almeida O, Jorge J, Scully C: Paracoccidioidomycosis of
the mouth: an emerging deep mycosis, Crit Rev Oral Biol Med
14:268-274, 2003.
San-Blas G: Paracoccidioidomycosis and its etiologic agent Paracoccidioides brasiliensis, J Med Vet Mycol 31:99-113, 1993.
San-Blas G, Restrepo A, Clemons K et al: Paracoccidioidomycosis, J Med Vet Mycol 30(suppl 1):59-71, 1992.
Sposto MR, Mendes-Giannini MJ, Moraes RA et al: Paracoccidioidomycosis manifesting as oral lesions: clinical, cytological
and serological investigation, J Oral Pathol Med 23:85-87,
1994.
Sposto MR, Scully C, Paes de Almeida O et al: Oral paracoccidioidomycosis: a study of 36 South American patients, Oral Surg
Oral Med Oral Pathol 75:461-465, 1993.
Coccidioidomycosis
Ampel NM, Dols CL, Galgiani JN: Coccidioidomycosis during
human immunodeciency virus infection: results of a prospective study in a coccidioidal endemic area, Am J Med
94:235-240, 1993.
Arnold MG, Arnold JC, Bloom DC et al: Head and neck manifestations of disseminated coccidioidomycosis, Laryngoscope
114:747-752, 2004.
Biller JA, Scheuller MC, Eisele DW: Coccidioidomycosis causing
massive cervical lymphadenopathy, Laryngoscope 114:18921894, 2004.
Chiller TM, Galgiani JN, Stevens DA: Coccidioidomycosis, Infect
Dis Clin North Am 17:41-57, 2003.
Crum NF, Ballon-Landa G: Coccidioidomycosis in pregnancy:
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DiCaudo DJ: Coccidioidomycosis: a review and update, J Am
Acad Dermatol 55:929-942, 2006.
Galgiani JN, Ampel NM, Blair JE et al: Coccidioidomycosis, Clin
Infect Dis 41:1217-1223, 2005.
Galgiani JN, Catanzaro A, Cloud GA et al: Comparison of oral
uconazole and itraconazole for progressive, nonmeningeal
coccidioidomycosis, Ann Intern Med 133:676-686, 2000.
Kim A, Parker SS: Coccidioidomycosis: case report and update
on diagnosis and management, J Am Acad Dermatol 46:743747, 2002.
Rodriguez RA, Konia T: Coccidioidomycosis of the tongue, Arch
Pathol Lab Med 129:e4-e6, 2005.
Schneider E, Hajjeh RA, Spiegel RA et al: A coccidioidomycosis
outbreak following the Northridge, Calif, earthquake, J Am
Med Assoc 277:904-908, 1997.
Cryptococcosis
Christianson JC, Engber W, Andes D: Primary cutaneous cryptococcosis in immunocompetent and immunocompromised
hosts, Med Mycol 41:177-188, 2003.
Leggiadro RJ, Barrett FF, Hughes WT: Extrapulmonary cryptococcosis in immunocompromised infants and children,
Pediatr Infect Dis J 11:43-47, 1992.
Levitz SM: The ecology of Cryptococcus neoformans and the epidemiology of cryptococcosis, Rev Infect Dis 13:1163-1169,
1991.
Mehrabi M, Bagheri S, Leonard MK et al: Mucocutaneous manifestation of cryptococcal infection: report of a case and review
of the literature, J Oral Maxillofac Surg 63:1543-1549, 2005.
Monteil RA, Hofman P, Michiels JF et al: Oral cryptococcosis:
case report of salivary gland involvement in an AIDS patient,
J Oral Pathol Med 26:53-56, 1997.
Namiq AL, Tollefson T, Fan F: Cryptococcal parotitis presenting
as a cystic parotid mass: report of a case diagnosed by neneedle aspiration cytology, Diagn Cytopathol 33:36-38, 2005.
Nosanchuk JD, Shoham S, Fries BC et al: Evidence of zoonotic
transmission of Cryptococcus neoformans from a pet cockatoo
to an immunocompromised patient, Ann Intern Med 132:205208, 2000.
Patz EF, Goodman PC: Pulmonary cryptococcosis, J Thorac
Imaging 7:51-55, 1992.
Perfect JR, Casadevall A: Cryptococcosis, Infect Dis Clin North Am
16:837-874, 2002.
Ruhnke M: Mucosal and systemic fungal infections in patients
with AIDS, Drugs 64:1163-1180, 2004.
Schmidt-Westhausen A, Grunewald T, Reichart PA et al: Oral
cryptococcosis in a patient with AIDS. A case report, Oral Dis
1:77-79, 1995.
Scully C, Paes De Almeida O: Orofacial manifestations of the
systemic mycoses, J Oral Pathol Med 21:289-294, 1992.
Subramanian S, Mathai D: Clinical manifestations and management of cryptococcal infection, J Postgrad Med 51(suppl 1):
S21-S26, 2005.
Yao Z, Liao W, Chen R: Management of cryptococcosis in nonHIV-related patients, Med Mycol 43:245-251, 2005.
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Zygomycosis
Chayakulkeeree M, Ghannoum MA, Perfect JR: Zygomycosis:
the re-emerging fungal infection, Eur J Clin Microbiol Infect Dis
25:215-229, 2006.
Gonzalez CE, Rinaldi MG, Sugar AM: Zygomycosis, Infect Dis Clin
North Am 16:895-914, 2002.
Greenberg RN, Mullane K, van Burik J-AH et al: Posaconazole
as salvage therapy for zygomycosis, Antimicrob Agents Chemother 50:126-133, 2006.
Huang J-S, Kok S-H, Lee J-J et al: Extensive maxillary sequestration resulting from mucormycosis, Br J Oral Maxillofac Surg
43:532-534, 2005.
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unusual presentation of rhinofacial zygomycosis due to Cunninghamella sp. in an immunocompetent patient: a case report
and literature review, Oral Dis 12:67-69, 2006.
Kyrmizakis DE, Doxas PG, Hajiioannou JK et al: Palate ulcer due
to mucormycosis, J Laryngol Otol 116:146-147, 2002.
Jones AC, Bentsen TY, Freedman PD: Mucormycosis of the oral
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61:1354-1358, 2003.
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Aspergillosis
Clancy CJ, Nguyen MH: Invasive sinus aspergillosis in apparently immunocompetent hosts, J Infect 37:229-240, 1998.
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Viral Infections
CHAPTER OUTLINE
Human Herpes Viruses
Herpes Simplex Virus
Varicella
Herpes Zoster
Infectious Mononucleosis
Cytomegalovirus
Enteroviruses
Herpangina
Hand-Foot-and-Mouth Disease
Acute Lymphonodular Pharyngitis
Rubeola
Rubella
Mumps
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investigators believe that up to 60% of mucosal erythema multiforme may be triggered by HSV. In some
instances, the attacks of erythema multiforme are frequent enough to warrant antiviral prophylaxis. An
association with cluster headaches and a number of
cranial neuropathies has been proposed, but denitive
proof is lacking.
On rare occasions, asymptomatic release of HSV
will coincide with attacks of aphthous ulcerations. The
ulcerations are not infected with the virus. In these rare
cases, the virus may be responsible for the initiation of
the autoimmune destruction; conversely, the immune
dysregulation that produces aphthae may have allowed
the release of the virions. In support of the lack of
association between HSV and aphthae in the general
population of patients with aphthous ulcerations, prophylactic oral acyclovir does not decrease the recurrence rate of the aphthous ulcerations. Although the
association between HSV and recurrent aphthous
ulcerations is weak, it may be important in small subsets
of patients (see page 331).
HSV also has been associated with oral carcinomas,
but much of the evidence is circumstantial. The DNA
from HSV has been extracted from the tissues of some
tumors but not from others. HSV may aid carcinogenesis through the promotion of mutations, but the oncogenic role, if any, is uncertain.
CLINICAL FEATURES
Acute herpetic gingivostomatitis (primary herpes)
is the most common pattern of symptomatic primary
HSV infection, and more than 90% are the result of
HSV-1. In a study of more than 4000 children with
antibodies to HSV-1, Juretic found that only 12% of
those infected had clinical symptoms and signs severe
enough to be remembered by the affected children or
their parents. Some health care practitioners suspect
that the percentage of primary infections that exhibit
clinical symptoms is much higher, whereas others
believe the prevalence is lower. Many primary infections may manifest as pharyngitis that mimics the
pattern seen in common colds. Further studies are
needed to fully answer this question.
Most cases of acute herpetic gingivostomatitis arise
between the ages of 6 months and 5 years, with the
peak prevalence occurring between 2 and 3 years of
age. In spite of these statistics, occasional cases have
been reported in patients over 60 years of age. Development before 6 months of age is rare because of protection by maternal anti-HSV antibodies. The onset is
abrupt and often accompanied by anterior cervical
lymphadenopathy, chills, fever (103 to 105 F), nausea,
anorexia, irritability, and sore mouth lesions. The manifestations vary from mild to severely debilitating.
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As mentioned previously, when the primary infection occurs in adults, some symptomatic cases exhibit
pharyngotonsillitis. Sore throat, fever, malaise, and
headache are the initial symptoms. Numerous small
vesicles develop on the tonsils and posterior pharynx.
The vesicles rapidly rupture to form numerous shallow
ulcerations, which often coalesce with one another. A
diffuse, gray-yellow exudate forms over the ulcers in
many cases. Involvement of the oral mucosa anterior
to Waldeyers ring occurs in less than 10% of these
cases. HSV appears to be a signicant cause of pharyngotonsillitis in young adults who are from the higher
socioeconomic groups with previously negative test
ndings for HSV antibodies. Most of these infections
are HSV-1, but increasing proportions are HSV-2. The
clinical presentation closely resembles pharyngitis secondary to streptococci or infectious mononucleosis,
making the true frequency difcult to determine.
Recurrent herpes simplex infections (secondary
herpes, recrudescent herpes) may occur either at the
site of primary inoculation or in adjacent areas of
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HISTOPATHOLOGIC FEATURES
The virus exerts its main effects on the epithelial cells.
Infected epithelial cells exhibit acantholysis, nuclear
clearing, and nuclear enlargement, which has been
termed ballooning degeneration (Fig. 7-12). The
acantholytic epithelial cells are termed Tzanck cells
(not specic for herpes; refers to a free-oating epithelial cell in any intraepithelial vesicle). Nucleolar fragmentation occurs with a condensation of chromatin
around the periphery of the nucleus. Multinucleated,
infected epithelial cells are formed when fusion occurs
between adjacent cells (see Fig. 7-12). Intercellular
edema develops and leads to the formation of an
intraepithelial vesicle (Fig. 7-13). Mucosal vesicles
rupture rapidly; those on the skin persist and develop
secondary inltration by inammatory cells. Once they
have ruptured, the mucosal lesions demonstrate a
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DIAGNOSIS
With a thorough knowledge of the clinical presentations, the clinician can make a strong presumptive
diagnosis of HSV infection. On occasion, HSV infections can be confused with other diseases, and laboratory conrmation is desirable. Viral isolation from
tissue culture inoculated with the uid of intact vesicles is the most denitive diagnostic procedure. The
problem with this technique in primary infections is
that up to 2 weeks can be required for a denitive
result. Laboratory tests to detect HSV antigens by direct
uorescent assay or viral DNA by polymerase chain
reaction (PCR) of specimens of active lesions also are
available. Serologic tests for HSV antibodies are positive 4 to 8 days after the initial exposure. Conrmation
of primary infection by serology requires a specimen
obtained within 3 days of the presentation and a second
sample approximately 4 weeks later. In such cases the
initial specimen should be negative, with antibodies
discovered only in the convalescent sample. These
antibody titers are useful in documenting past exposure and are used primarily in epidemiologic studies.
Intact vesicles are rare intraorally. Therefore, using
intraoral viral culture as the sole means of diagnostic
conrmation of HSV infection is inappropriate.
Research has shown that asymptomatic oral HSV shedding occurs in up to 9% of the general population.
During periods of mental or physical stress, asymptomatic viral shedding rises to approximately one third of
those previously exposed to the virus. In immunocompromised patients, the prevalence rises to 38%; this
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VARICELLA (CHICKENPOX)
The varicella-zoster virus (VZV, HHV-3) is similar to
herpes simplex virus (HSV) in many respects. Chickenpox represents the primary infection with the VZV;
latency ensues, and recurrence is possible as herpes
zoster, often after many decades. The virus is presumed to be spread through air droplets or direct
contact with active lesions. Most cases of chickenpox
arise between the ages of 5 and 9, with greater than
90% of the U.S. population being infected by 15 years
of age. In contrast to infection with HSV, most cases
are symptomatic. The incubation period is 10 to 21
days, with an average of 15 days.
CLINICAL FEATURES
The symptomatic phase of VZV infection usually begins
with malaise, pharyngitis, and rhinitis. In older children and adults, additional symptoms (e.g., headache,
myalgia, nausea, anorexia, vomiting) occasionally are
seen. This is followed by a characteristic, intensely pruritic exanthem. The rash begins on the face and trunk,
followed by involvement of the extremities. Each lesion
rapidly progresses through stages of erythema, vesicle,
pustule, and hardened crust (Figs. 7-14 and 7-15). The
early vesicular stage is the classic presentation. The
centrally located vesicle is surrounded by a zone of
erythema and has been described as a dewdrop on a
rose petal. In contrast to herpes simplex, the lesions
typically continue to erupt for 4 days; in some cases the
exanthems arrival may extend to 7 or more days. Old
crusted lesions intermixed with newly formed and
intact vesicles are commonplace. Affected individuals
are contagious from 2 days before the exanthem until
all the lesions crust. Fever usually is present during the
active phase of the exanthem. The severity of the cutaneous involvement is variable and often more severe
in adults and in household members secondarily
infected by the initial patient.
Perioral and oral manifestations are fairly common
and may precede the skin lesions. The vermilion border
of the lips and the palate are the most common sites
of involvement, followed by the buccal mucosa. Occasionally, gingival lesions resemble those noted in
primary HSV infections, but distinguishing between
the two is not difcult because the lesions of varicella
tend to be relatively painless. The lesions begin as 3- to
4-mm, white, opaque vesicles that rupture to form 1- to
3-mm ulcerations (Fig. 7-16). The prevalence and
number of the oral lesions correlate with the severity of
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HISTOPATHOLOGIC FEATURES
The cytologic alterations are virtually identical to those
described for HSV. The virus causes acantholysis, with
formation of numerous free-oating Tzanck cells,
which exhibit nuclear margination of chromatin and
occasional multinucleation.
DIAGNOSIS
The diagnosis of chickenpox usually can be made from
a history of exposure to VZV within the last 3 weeks
and the presence of the typical exanthem. Conrmation can be obtained through a demonstration of viral
cytopathologic effects present within the epithelial
cells harvested from the vesicular uid. These cytologic
changes are identical to those found in herpes simplex,
and further conrmation sometimes is desired. Viral
isolation in cell culture or rapid diagnosis from uorescein-conjugated VZV monoclonal antibodies can be
performed. Finally, serum samples can be obtained
during the acute stage and 14 to 28 days later. The later
sample should demonstrate a signicant (fourfold)
increase in antibody titers to VZV.
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CLINICAL FEATURES
The clinical features of herpes zoster can be grouped
into three phases: (1) prodrome, (2) acute, and (3)
chronic. During initial viral replication, active ganglionitis develops with resultant neuronal necrosis and
severe neuralgia. This inammatory reaction is responsible for the prodromal symptoms of intense pain that
precedes the rash in more than 90% of the cases. As the
virus travels down the nerve, the pain intensies and
has been described as burning, tingling, itching, boring,
prickly, or knifelike. The pain develops in the area of
epithelium innervated by the affected sensory nerve
(dermatome). Typically, one dermatome is affected,
but involvement of two or more can occur. The tho-
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HISTOPATHOLOGIC FEATURES
The active vesicles of herpes zoster are identical microscopically to those seen in the primary infection, varicella. For more information, refer to the previous
portions of the chapter on the histopathologic presentation of varicella and herpes simplex.
DIAGNOSIS
The diagnosis of herpes zoster often can be made from
the clinical presentation, but other procedures may be
necessary in atypical cases. Viral culture can conrm
the clinical impression but takes at least 24 hours.
Cytologic smears demonstrate viral cytopathologic
effects, as seen in varicella and HSV. In most cases the
clinical presentation allows the clinician to differentiate zoster from HSV, but cases of zosteriform recurrent
HSV infection, although uncommon, do exist. A rapid
diagnosis can be obtained through the use of direct
staining of cytologic smears with uorescent monoclonal antibodies for VZV. This technique gives positive
results in almost 80% of the cases. Molecular techniques such as dot-blot hybridization and PCR also can
be used to detect VZV.
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blocks, and topical anesthetics. As mentioned previously, postherpetic neuralgia may be related to chronic
VZV ganglionitis and respond to long-term famciclovir.
In those who do not respond to famciclovir, IV acyclovir often leads to clinical improvement.
One topical treatment, capsaicin, has had signicant
success, with almost 80% of patients experiencing some
pain relief; however, the medications effect often does
not occur until 2 weeks or more of therapy. Capsaicin
is derived from red peppers and is not recommended
for placement on mucosa or open cutaneous lesions.
Capsaicin has been associated with signicant burning,
stinging, and redness in 40% to 70% of patients, with up
to 30% discontinuing therapy because of this side effect.
After use, patients must be warned to wash their hands
and avoid contact with mucosal surfaces.
Corticosteroid therapy has been used in the hope
it might decrease the neural inammation and
associated chronic pain. Although conicting research
has been published, studies have shown no longterm benet when corticosteroids are added to an
acyclovir regimen. In addition, an increased prevalence of side effects was noted in groups treated with
corticosteroids.
A live attenuated VZV vaccine has been approved
for use in adults 60 years of age or older. The vaccine,
Zostavax, is 14 times more potent than Varivax, the
vaccine for chickenpox. In a study of more than 38,000
adults, Zostavax markedly decreased the prevalence of
herpes zoster, as well as the morbidity and frequency
of postherpetic neuralgia in those who did develop the
infection. In an October 2006 press release, the Advisory Committee on Immunization Practices of the
Centers for Disease Control and Prevention (CDC)
recommended that the vaccine be given to all people
60 years of age and older. This recommendation is
being reviewed and becomes ofcial only when published in the CDCs Morbidity and Mortality Weekly
Report.
INFECTIOUS MONONUCLEOSIS
(MONO; GLANDULAR FEVER;
KISSING DISEASE)
Infectious mononucleosis is a symptomatic disease
resulting from exposure to Epstein-Barr virus (EBV,
HHV-4). The infection usually occurs by intimate
contact. Intrafamilial spread is common, and once a
person is exposed, EBV remains in the host for life.
Children usually become infected through contaminated saliva on ngers, toys, or other objects. Adults
usually contract the virus through direct salivary transfer, such as shared straws or kissing, hence, the nickname kissing disease. Exposure during childhood
usually is asymptomatic, and most symptomatic infec-
tions arise in young adults. In developing nations, exposure usually occurs by age 3 and is universal by
adolescence. In the United States, introduction to the
virus often is delayed, with close to 50% of college students lacking previous exposure. These unexposed
adults become infected at a rate of 10% to 15% per year
while in college. Infection in adulthood is associated
with a higher risk (i.e., 30% to 50%) for symptomatic
disease.
Besides infectious mononucleosis, EBV has been
demonstrated in the lesions of oral hairy leukoplakia
(OHL) (see page 268) and has been associated with a
number of lymphoproliferative disorders, a variety of
lymphomas (most notably African Burkitts lymphoma)
(see page 600), nasopharyngeal carcinoma (see page
428), some gastric carcinomas, possibly breast and
hepatocellular carcinomas, salivary lymphoepithelial
carcinomas, and occasional smooth muscle tumors.
However, direct proof of a cause-and-effect relationship is lacking.
CLINICAL FEATURES
Most EBV infections in children are asymptomatic. In
children younger than 4 years of age with symptoms,
most have fever, lymphadenopathy, pharyngitis, hepatosplenomegaly, and rhinitis or cough. Children older
than 4 years of age are affected similarly but exhibit a
much lower prevalence of hepatosplenomegaly, rhinitis, and cough.
Most young adults experience fever, lymphadenopathy, pharyngitis, and tonsillitis. Hepatosplenomegaly
and rash are seen less frequently. In adults older than
40 years of age, fever and pharyngitis are the predominant ndings, with less than 30% demonstrating lymphadenopathy. Less frequent signs and symptoms in this
group include hepatosplenomegaly, rash, and rhinitis
or cough. Possible signicant complications include
splenic rupture, thrombocytopenia, autoimmune hemolytic anemia, aplastic anemia, and neurologic problems
with seizures. These complications are uncommon at
any age but more frequently develop in children.
In classic infectious mononucleosis in a young adult,
prodromal fatigue, malaise, and anorexia occur up to
2 weeks before the development of pyrexia. The body
temperature may reach 104 F and lasts from 2 to 14
days. Prominent lymphadenopathy is noted in more
than 90% of the cases and typically appears as enlarged,
symmetrical, and tender nodes, frequently with involvement of the posterior and anterior cervical chains.
Enlargement of parotid lymphoid tissue rarely has
been reported and can be associated with facial nerve
palsy. More than 80% of affected young adults have
oropharyngeal tonsillar enlargement, sometimes with
diffuse surface exudates and secondary tonsillar
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symptoms of chronic fatigue, fever, pharyngitis, myalgias, headaches, arthralgias, paresthesias, depression,
and cognitive defects. These patients often demonstrate
elevations in EBV antibody titers, but this nding alone
is insufcient to prove a denite cause-and-effect relationship. Several studies have cast serious doubt on a
relationship between EBV and the chronic fatigue
syndrome.
DIAGNOSIS
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CYTOMEGALOVIRUS
Cytomegalovirus (CMV, HHV-5) is similar to the
other human herpes viruses (i.e., after the initial infection, latency is established and reactivation is possible
under conditions favorable to the virus). CMV can
reside latently in salivary gland cells, endothelium,
macrophages, and lymphocytes. Most clinically evident
disease is found in neonates or in immunosuppressed
adults. In infants, the virus is contracted through the
placenta, during delivery, or during breast-feeding. The
next peak of transmission occurs during adolescence,
predominantly from the exchange of bodily uids as
this group begins sexual activity. Transmission also has
been documented from blood transfusion and organ
transplantation. The prevalence of neonatal CMV
infection varies from 0.5% to 2.5%. By the age of 30,
almost 40% of the population is infected; by age 60,
80% to 100% are infected. Screening of healthy middleaged adult blood donors reveals that approximately
50% have been exposed to CMV.
CLINICAL FEATURES
At any age, almost 90% of CMV infections are asymptomatic. In clinically evident neonatal infection, the
infant appears ill within a few days. Typical features
include hepatosplenomegaly, extramedullary cutaneous erythropoiesis, and thrombocytopenia (often with
associated petechial hemorrhages). Signicant encephalitis frequently leads to severe mental and motor
retardation.
Although the majority of acute CMV infections are
asymptomatic, less than 10% may include a nonspecic
pattern of symptoms that ranges from an inuenza-like
presentation to lethal multiorgan involvement. In a
review of 115 hospitalized immunocompetent adults
with CMV infection, the most common symptoms
(in order) include fever, joint and muscle pain, shivering, abdominal pain, nonproductive cough, cutaneous eruption (maculopapular rash), and diarrhea.
Associated signs include hepatomegaly, splenomegaly,
adenopathy, pharyngitis, jaundice, and evidence of
meningeal irritation. The authors stress that symptomatic CMV infection should not be dismissed in immunocompetent patients and should be considered in any
patient with unexplained persistent fever.
In contrast to patients with infectious mononucleosis, only about one third of patients with CMV infection
demonstrate pharyngitis and lymphadenopathy.
Rarely, immunocompetent patients may show signs of
an acute sialadenitis that diffusely involves all of the
major and minor salivary glands. In such cases, xerostomia often is noted and the affected glands are
painful. Involvement of the major glands usually results
in clinically obvious enlargements of the parotid and
submandibular glands. Unusual complications of
primary CMV infection include myocarditis, pneumonitis, and septic meningitis.
Evident CMV involvement is not unusual in immunocompromised transplant patients. In some cases a
temporary mild fever is the only evidence; in others,
the infection becomes aggressive and is characterized
by signicant hepatitis, leukopenia, pneumonitis, gastroenteritis, and, more rarely, a progressive wasting
syndrome.
CMV disease is common in patients with AIDS (see
page 264). CMV chorioretinitis affects almost one third
of patients with AIDS and tends to progress rapidly,
often resulting in blindness. Bloody diarrhea from
CMV colitis is fairly common but may respond to
appropriate antiviral medications.
Although oral lesions from CMV infection have
been documented in a number of immunosuppressive
conditions, reports of oral involvement by CMV
have been increasing since the advent of the AIDS
epidemic. Most affected patients have chronic mucosal
ulcerations, and CMV changes are found on biopsy.
Occasionally, chronic oral ulcerations in immunocompromised patients will demonstrate coinfection (usually
CMV combined with HSV).
Neonatal CMV infection also can produce developmental tooth defects. Examination of 118 people with
a history of neonatal CMV infection revealed tooth
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Biopsy specimens of intraoral CMV lesions usually
demonstrate changes within the vascular endothelial
cells. Scattered infected cells are extremely swollen,
showing both intracytoplasmic and intranuclear inclusions and prominent nucleoli. This enlarged cell has
been called an owl eye cell. Gomoris methenamine
silver and periodic acid-Schiff (PAS) stains demonstrate the cytoplasmic inclusions but not the intranuclear changes. Salivary ductal epithelium also may be
affected and form owl eye cells (Fig. 7-22).
ENTEROVIRUSES
DIAGNOSIS
The diagnosis of CMV infection is made by considering
a combination of the clinical features and by conducting other examinations. Biopsy material can demonstrate cellular changes that suggest infection. Because
effective therapies exist for CMV infections in immunocompromised patients, biopsies are recommended
for chronic ulcerations that are not responsive to conservative therapy. More specic verication can be
made by electron microscopy, detection of viral antigens by immunohistochemistry, in situ hybridization,
polymerase chain reaction (PCR), demonstration of
rising viral antibody titers, or viral culture. Enzymelinked immunosorbent assay (ELISA) serologic testing
for CMV is inexpensive, demonstrates good specicity,
and should be considered in any patient with an unexplained fever or signs of CMV infection.
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CLINICAL FEATURES
In many countries, epidemics occur every 2 to 3 years
and primarily affect children aged 1 to 4 years. The
timing of the epidemics appears to be correlated to the
accumulation of a new population of susceptible young
children. In all three clinical patterns, the severity and
signicant complications are variable and appear associated with the particular strain that is responsible. In
general, most strains produce a self-limiting disease
that requires no therapy, but occasional strains can
produce epidemics with an increased number of signicant complications and occasional mortalities. Systemic complications include pneumonia, pulmonary
edema and hemorrhage, acute accid paralysis,
encephalitis, meningitis, and carditis. Infection with
coxsackie B virus during pregnancy occasionally has
been associated with fetal and neonatal death, whereas
cardiac anomalies have been noted in infants who
survive the initial infection.
HERPANGINA
Herpangina begins with an acute onset of signicant
sore throat, dysphagia, and fever, occasionally accompanied by cough, rhinorrhea, anorexia, vomiting, diarrhea, myalgia, and headache. Most cases, however, are
mild or subclinical. A small number of oral lesions,
usually two to six, develop in the posterior areas of the
mouth, usually the soft palate or tonsillar pillars (Fig.
7-23). The affected areas begin as red macules, which
form fragile vesicles that rapidly ulcerate. The ulcerations average 2 to 4 mm in diameter. The systemic
symptoms resolve within a few days; as would be
expected, the ulcerations usually take 7 to 10 days to
heal.
HAND-FOOT-AND-MOUTH DISEASE
Hand-foot-and-mouth disease is the most well-known
enterovirus infection. Like herpangina, the skin rash
and oral lesions typically are associated with ulike
symptoms (e.g., sore throat, dysphagia, fever), occasion-
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ally accompanied by cough, rhinorrhea, anorexia, vomiting, diarrhea, myalgia, and headache.
The name fairly well describes the location of the
lesions. Oral lesions and those on the hands almost
always are present; involvement of other cutaneous
sites is more variable. The oral lesions arise without
prodromal symptoms and precede the development of
the cutaneous lesions. Sore throat and mild fever are
present. The cutaneous lesions range from a few to
dozens and primarily affect the borders of the palms
and soles and the ventral surfaces and sides of the
ngers and toes (Fig. 7-24). Rarely other sites, especially the buttocks, external genitals, and legs, may be
involved. The individual cutaneous lesions begin as
erythematous macules that develop central vesicles
and heal without crusting (Fig. 7-25).
The oral lesions resemble those of herpangina but
may be more numerous and are not conned to the
posterior areas of the mouth. The number of lesions
ranges from 1 to 30. The buccal mucosa, labial mucosa,
and tongue are the most common sites to be affected,
but any area of the oral mucosa may be involved (Fig.
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sillar pillars (Fig. 7-27). The nodules represent hyperplastic lymphoid aggregates and resolve within 10 days
without vesiculation or ulceration. Few cases have
been described, and whether this represents a distinct
clinical entity is as yet unresolved. The possibility that
the sore throat and palatal lymphoid hyperplasia represent features of herpangina or some other infection
cannot be excluded without further documentation of
additional cases.
HISTOPATHOLOGIC FEATURES
In patients with herpangina and hand-foot-and-mouth
disease, the areas of affected epithelium exhibit intracellular and intercellular edema, which leads to extensive spongiosis and the formation of an intraepithelial
vesicle. The vesicle enlarges and ruptures through the
epithelial basal cell layer, with the resultant formation
of a subepithelial vesicle. Epithelial necrosis and ulceration soon follow. Inclusion bodies and multinucleated
epithelial cells are absent.
DIAGNOSIS
The diagnoses of herpangina, hand-foot-and-mouth
disease, and acute lymphonodular pharyngitis usually
are made from the distinctive clinical manifestations.
In patients with atypical presentations, laboratory conrmation appears prudent. Viral isolation from culture
can be performed, and analysis of stool specimens is
the best technique in patients with only mucosal
lesions. Throat culture ndings tend to be positive predominantly during the early acute stage. The culture of
cutaneous lesions is best for the diagnosis of hand-footand-mouth disease. A serologic demonstration of rising
enteroviral antibody titers between the acute and convalescent stages can be used to conrm the diagnosis
in questionable cases. Polymerase chain reaction (PCR)
RUBEOLA (MEASLES)
Rubeola is an infection produced by a virus in the
family Paramyxovirus, genus Morbillivirus, and exhibits
a variable prevalence that is correlated to the degree
of vaccine use. Measles vaccine has been in wide use
in the United States since 1963 and is 95% effective,
resulting in a 98% reduction in the prevalence of this
infection. Before 1963, virtually all children acquired
measles, but the vaccine produced a continued and
signicant decline until the late 1980s. From 1989 to
1991, a major resurgence occurred with an increasing proportion of cases among unvaccinated preschool-aged children, particularly minority residents of
densely populated urban areas. In addition, a smaller
number of cases appeared to be associated with vaccine
failure.
CLINICAL FEATURES
Most cases of measles arise in the winter and are spread
through respiratory droplets. The incubation period is
from 10 to 12 days, and affected individuals are infectious from 2 days before becoming symptomatic until
4 days after appearance of the associated rash. The
virus is associated with signicant lymphoid hyperplasia that often involves sites such as the lymph nodes,
tonsils, adenoids, and Peyers patches. Giant cell inltration is noted in various tissues along with a vasculitis
that is responsible for the characteristic skin rash.
There are three stages of the infection, with each
stage lasting 3 days and justifying the designation nineday measles. The rst 3 days are dominated by the three
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HISTOPATHOLOGIC FEATURES
Because of the reduced prevalence of measles and the
transient nature of Kopliks spots, few oral and maxillofacial pathologists have had the opportunity to view
these lesions microscopically. Initially, Kopliks spots
represent areas of focal hyperparakeratosis in which
the underlying epithelium exhibits spongiosis, intercellular edema, dyskeratosis, and epithelial syncytial giant
cells. The number of nuclei within these giant cells
ranges from three to more than 25. Close examination
of the epithelial cells often reveals pink-staining inclusions in the nuclei or, less commonly, in the cytoplasm.
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DIAGNOSIS
The diagnosis of typical measles in an epidemic setting
usually is straightforward and based on the clinical
features and history. Laboratory conrmation can be of
value in isolated or atypical cases. Viral isolation or
rapid detection of viral antigens is possible, but conrmation usually is established through a demonstration
of rising serologic antibody titers. The antibodies appear
within 1 to 3 days after the beginning of the exanthem
and peak in about 3 to 4 weeks.
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DIAGNOSIS
The diagnosis of rubella is contingent on laboratory
tests because the clinical presentation of the acquired
infection is typically subclinical, mild, or nonspecic.
Although viral culture is possible, serologic analysis is
the mainstay of diagnosis.
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the prevalence in the older age groups, it is recommended that individuals lacking a history of mumps or
MMR vaccination be immunized. This primarily affects
those born between 1967 and 1977 and, to a lesser
extent, those born between 1957 and 1967. For health
care workers born before 1957, a single dose of MMR
is recommended unless there is a physicians diagnosis of mumps or laboratory evidence of mumps
immunity.
In 2006 an outbreak of mumps virus occurred in
the United States, with an epicenter in Iowa and surrounding states. During this outbreak, only 7% of
infected individuals were proven to be unvaccinated,
and 49% had received at least the recommended two
doses of the MMR. After two doses of MMR, the vaccine
appears to be 98% effective against measles but only
90% effective against mumps. In spite of the vaccine
failures in the recent outbreak, the high vaccination
coverage most likely prevented thousands of additional
cases of mumps. Some investigators wonder if such
outbreaks may lead to a recommendation for a third
dose of the MMR vaccine in the future.
The mumps virus can be transmitted through urine,
saliva, or respiratory droplets. The incubation period
usually is 16 to 18 days, with a range of about 2 to 4
weeks. Patients are contagious from 1 day before the
clinical appearance of infection to 14 days after its
clinical resolution.
CLINICAL FEATURES
Approximately 30% of mumps infections are subclinical. In symptomatic cases, prodromal symptoms of lowgrade fever, headache, malaise, anorexia, and myalgia
arrive rst. Most frequently, these nonspecic ndings
are followed within 1 day by signicant salivary gland
changes. The parotid gland is involved most frequently,
but the sublingual and submandibular glands also can
be affected. Discomfort and swelling develop in the
tissues surrounding the lower half of the external ear
and extending down along the posterior inferior border
of the adjacent mandible (Fig. 7-31). The enlargement
typically peaks within 2 to 3 days, and the pain is most
intense during this period of maximal enlargement.
Chewing movements of the jaw or eating saliva-stimulating foods tends to increase the pain. Enlargement of
the glands usually begins on one side and is followed
by contralateral glandular changes within a few days.
Unilateral involvement is seen in about 25% of
patients.
The second most common nding is epididymoorchitis, which occurs in about 25% of postpubertal
males. In those affected the testicle exhibits rapid
swelling, with signicant pain and tenderness. The
enlargement can range from a minimal swelling to a
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DIAGNOSIS
The diagnosis of mumps can be made easily from the
clinical presentation when the infection is occurring in
an epidemic fashion; however, isolated cases must be
differentiated from other causes. The most frequently
used conrmatory measures are demonstration of
mumps-specic IgM or a fourfold rise of mumpsspecic IgG titers when measured during the acute
phase and about 2 weeks later. In addition, a swab
of secretions obtained from parotid or other affected
salivary gland ducts can be used for viral isolation
or reverse-transcriptasepolymerase chain reaction
testing.
HUMAN IMMUNODEFICIENCY
VIRUS AND ACQUIRED
IMMUNODEFICIENCY SYNDROME
During the last 2 decades, more articles have been
written on human immunodeciency virus (HIV)
and its related disease states than any other infectious
process. A complete bibliography alone easily would
be thicker than this chapter. Entire texts dedicated to
HIV infection and acquired immunodeciency syndrome (AIDS) are available and should be consulted
for more detailed information.
The rst cases of AIDS reported in the United States
were documented by the Centers for Disease Central
and Prevention (CDC) in the Morbidity and Mortality
Weekly Report on June 5, 1981. This publication detailed
Pneumocystis carinii pneumoniae in ve previously
healthy men from Los Angeles, California. More than
25 years have passed. During this time, 65 million individuals worldwide have become infected with HIV and
more than 25 million individuals have died of AIDS.
Through 2004, a total of 529,113 deaths as a result of
AIDS in the United States have been reported to the
CDC, and more than 1 million individuals are living
with HIV. Worldwide in 2005 alone, 4.1 million new
infections occurred, 38.6 million were living with HIV,
and an estimated 2.8 million individuals died of AIDS.
At the time of publication of the rst edition of this
text, the infection was thought to be nearly 100% fatal.
Through treatment advances, the annual incidence of
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RACE
White, non-Hispanic
Black, non-Hispanic
Hispanic
Asian/Pacic Islander
Native American/Alaska Native
1981-1995 (%)
2001-2004 (%)
46.5
34.6
17.9
0.7
0.3
28.3
49.5
20.3
1.1
0.5
84.7
15.3
73.4
26.6
51.2
26.8
7.8
10.1
1.3
2.9
40.8
22.8
4.9
30.1
0.2
1.3
SEX
Male
Female
TRANSMISSION CATEGORY
Male-to-male sexual contact
Injection-drug use
Male-to-male sexual contact/injection-drug use
Heterosexual contact
Perinatal
Other
AIDS and related deaths have been altered dramatically in the United States. Cases of AIDS in the United
States expanded rapidly during the 1980s, peaked in
1992 (estimated 78,000), and decreased each year
from that time until 1998 when the annual incidence
stabilized at about 40,000. Highly active anti-retroviral
therapy (HAART) (see Treatment and Prognosis
section) is changing the face of HIV infection, with
affected individuals demonstrating extended survival
(resulting in an increased percentage of the population
living with the virus). The percentage of individuals
surviving 2 years after the diagnosis of AIDS has
increased from 44% in 1981 to 1992, to 64% in 1993
to 1995, to 85% in 1996 to 2000.
In infected individuals, the virus can be found
in most bodily uids. HIV has been recovered from
serum, blood, saliva, semen, tears, urine, breast milk,
ear secretions, and vaginal secretions. The most frequent routes of transmission are sexual contact, parenteral exposure to blood, or transmission from mother
to fetus during the perinatal period. Infection also has
been documented to be caused by articial insemination, breast-feeding from infected mothers, and organ
transplantation. Although heterosexual transmission is
increasing, most of the adults infected in the United
States have been homosexual or bisexual men, intravenous (IV) drug abusers, hemophiliac patients receiving
factor VIII before 1985, recipients of blood products, or
heterosexual contacts with one of the other high-risk
groups.
Researchers have debated the infectiousness of oral
uids. HIV has been found to be present in oral uids,
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CLINICAL FEATURES
HIV infection initially may be asymptomatic, or an
acute response may be seen. The acute viral syndrome
that occurs typically develops within 1 to 6 weeks after
exposure in 50% to 70% of infected patients. The symptoms bear some resemblance to those of infectious
mononucleosis (e.g., generalized lymphadenopathy,
sore throat, fever, maculopapular rash, headache,
myalgia, arthralgia, diarrhea, photophobia, peripheral
neuropathies). Oral changes may include mucosal erythema and focal ulcerations.
The acute viral syndrome clears within a few weeks;
during this period, HIV infection usually is not considered or investigated. A variable asymptomatic period
follows. Some patients have persistent generalized
lymphadenopathy (PGL), which may later resolve. In
some patients (before development of overt AIDS),
there is a period of chronic fever, weight loss, diarrhea,
oral candidiasis, herpes zoster, and/or oral hairy leukoplakia (OHL). This has been termed AIDS-related
complex (ARC).
The presentation of symptomatic, overt AIDS is
highly variable and often is affected by a persons prior
exposure to a number of chronic infections. The signs
and symptoms described under ARC are often present,
along with an increasing number of opportunistic
infections or neoplastic processes. In 50% of the cases,
pneumonia caused by the protozoan Pneumocystis
carinii is the presenting feature leading to the diagnosis.
Other infections of diagnostic signicance include disseminated cytomegalovirus (CMV) infection, severe
herpes simplex virus (HSV) infection, atypical mycobacterial infection, cryptococcal meningitis, and central nervous system (CNS) toxoplasmosis. Persistent
diarrhea is commonplace and may be bacterial or protozoal in origin. Clinically signicant neurologic dysfunction is present in 30% to 50% of patients, and the
most common manifestation is a progressive encephalopathy known as AIDS-dementia complex.
The most widely accepted classication of the oral
manifestations of AIDS was compiled by the EC-Clearinghouse on Problems Related to HIV Infection and
the WHO Collaborating Centre on Oral Manifestations of the Immunodeciency Virus. This classication divided the manifestations into three groups: (1)
strongly associated, (2) less commonly associated, and
(3) seen in patients HIV infection (Box 7-1). The discussion here concentrates primarily on the clinical
presentations. (For detailed information on the histopathology, diagnosis, and treatment of each condition,
see the text covering the individual disease.) When the
infections are treated differently in HIV-infected
patients, these variations are presented here. The most
common manifestations are presented rst, followed
by a selection of the less frequently encountered
disorders.
The prevalence and mixture of oral manifestations
noted in HIV-infected patients has been altered dramatically by the current antiretroviral therapies.
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Box 7-1
EC-Clearinghouse Classication of
the Oral Manifestations of HIV
Disease in Adults
GROUP 1: STRONGLY ASSOCIATED WITH
HIV INFECTION
Candidiasis: erythematous, pseudomembranous,
angular cheilitis
Hairy leukoplakia
Kaposis sarcoma (KS)
Non-Hodgkins lymphoma
Periodontal diseases: linear gingival erythema, necrotizing gingivitis, necrotizing periodontitis
GROUP 2: LESS COMMONLY ASSOCIATED WITH
HIV INFECTION
Bacterial infections: Mycobacterium avium-intracellulare, Mycobacterium tuberculosis
Melanotic hyperpigmentation
Necrotizing ulcerative stomatitis
Salivary gland disease: dry mouth, unilateral or bilateral swelling of major salivary glands
Thrombocytopenia purpura
Oral ulcerations NOS (not otherwise specied)
Viral infections: herpes simplex, human
papillomavirus, varicella-zoster
GROUP 3: SEEN IN HIV INFECTION
Bacterial infections: Actinomyces israelii, Escherichia
coli, Klebsiella pneumonia
Cat-scratch disease (Bartonella henselae)
Epithelioid (bacillary) angiomatosis (Bartonella
henselae)
Drug reactions: ulcerative, erythema multiforme,
lichenoid, toxic epidermolysis
Fungal infections other than candidiasis: Cryptococcus
neoformans, Geotrichum candidum, Histoplasma capsulatum, Mucoraceae (mucormycosis/zygomycosis),
Aspergillus avus
Neurologic disturbances: facial palsy, trigeminal
neuralgia
Recurrent aphthous stomatitis
Viral infections: cytomegalovirus, molluscum
contagiosum
HIV, Human immunodeciency virus.
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what distinctive (but not diagnostic) pattern of hyperkeratosis and epithelial hyperplasia.
Most cases of OHL occur on the lateral border of the
tongue and range in appearance from faint white vertical streaks to thickened and furrowed areas of leukoplakia, exhibiting a shaggy keratotic surface (Fig. 7-34).
The lesions infrequently may become extensive and
cover the entire dorsal and lateral surfaces of the
tongue. Rarely, the buccal mucosa, soft palate, pharynx,
or esophagus may be involved.
Histopathologically, OHL exhibits thickened parakeratin that demonstrates surface corrugations or thin
projections (Fig. 7-35). The epithelium is acanthotic
and exhibits a bandlike zone of lightly stained cells
with abundant cytoplasm (balloon cells) in the upper
spinous layer (Fig. 7-36). Close examination of the
supercial epithelium reveals scattered cells with
nuclear clearing and a characteristic pattern of peripheral margination of chromatin termed nuclear beading
(see Fig. 7-36, inset), caused by extensive EBV replication that displaces the chromatin to the nuclear margin.
Dysplasia is not noted. Heavy candidal infestation of
the parakeratin layer is typical, although the normal
inammatory reaction to the fungus usually is absent.
In the routine management of patients with HIV
infection, the clinical features of OHL typically are sufcient for a presumptive diagnosis. When denitive
diagnosis is necessary, demonstration of EBV within
the lesion is required and can be achieved by in situ
hybridization, PCR, immunohistochemistry, Southern
blotting, or electron microscopy (Fig. 7-37).
Treatment of OHL usually is not needed, although
slight discomfort or aesthetic concerns may necessitate
therapy. Systemic antiherpesviral drugs produce rapid
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resolution, but recurrence is expected with discontinuation of therapy. Topical treatment with retinoids or
podophyllum resin has resulted in temporary remissions. Surgical excision or cryotherapy has been used
by some. A signicantly reduced prevalence of OHL
has been noted in patients on HAART who have demonstrated decreased viral load and an improved CD4
count. In underdeveloped countries with patients
located great distances from urban health centers, the
presence or absence of OHL can be used along with
oral candidiasis as a clinical guide to assist in judging
the effectiveness of antiviral therapy.
Although rare instances of OHL have been reported
in immunocompetent individuals, most cases arise in
immunocompromised persons. OHL also has been
reported in heart, kidney, liver, and bone marrow
transplant recipients, but its presence in the absence of
a known cause of immunosuppression strongly suggests HIV infection. Discovery of OHL in normal
patients mandates a thorough physical evaluation to
rule out immunocompromised status. The presence of
OHL in HIV-infected patients is a signal of severe
immune suppression and more advanced disease.
KAPOSIS SARCOMA
Kaposis sarcoma (KS) is a multifocal neoplasm of
vascular endothelial cell origin that was described initially in patients over the age of 60 (see page 557).
However, since the beginning of the AIDS epidemic,
most cases in the United States have been seen in association with HIV infection, with about 15% to 20% of
patients with AIDS demonstrating KS. Human herpesvirus type 8 (HHV-8, Kaposis sarcomaassociated herpesvirus [KSHV]) is noted within the tumor and
believed to be responsible for the neoplasms development. In Western countries, AIDS-associated KS has
been reported primarily in homosexuals and is thought
to be related to sexual transmission of HHV-8. Further
evidence from Africa has demonstrated acquisition of
HHV-8 infection before sexual activity and suggests
alternate transmission pathways. HHV-8 has been
found in saliva, serum, plasma, throat swabs, and bronchoalveolar lavage uids. In Africa, HIV-related KS
does not demonstrate a strong association with homosexual activity, exhibits an equal prevalence in men
and women, and is not rare in children. In a recent
North American study of healthy adults, HHV-8 was
detected in oral epithelial cells and in the oropharynx,
suggesting that the oral cavity may represent the predominant reservoir of infectious virus. These studies
suggest that saliva represents an important route for
transmission of HHV-8 in both heterosexual and homosexual populations.
KS typically manifests as multiple lesions of the skin
or oral mucosa, although occasionally a solitary lesion
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PERSISTENT GENERALIZED
LYMPHADENOPATHY
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The treatment usually is combination chemotherapy, and radiation is reserved for local control of the
disease. These malignancies are aggressive, and survival usually is measured in months from the date of
discovery. Although HAART has dramatically reduced
the prevalence of many opportunistic infections and
KS in HIV-infected patients, the effect on NHL appears
to vary with the type of lymphoma and has been inconsistent. Although many forms of NHL continue to contribute to the morbidity and mortality of HIV-infected
patients, others categories of NHL, such as plasmablastic lymphoma, have declined signicantly because of
HAART.
NON-HODGKINS LYMPHOMA
Non-Hodgkins lymphoma (NHL) is the second most
common malignancy in HIV-infected individuals. This
neoplasm occurs in approximately 3% to 5% of those
with the virus, a prevalence 60 times greater than the
normal population. Typically, NHL in patients with
AIDS presents as a high-grade and aggressive disease
that frequently is associated with widespread involvement and short survival times. In AIDS the relative risk
for developing a low-grade NHL is 15 times greater,
compared with a 400 times greater risk for a high-grade
NHL. The majority of the NHLs are B-cell lymphomas
and include AIDS Burkitts lymphoma, anaplastic large
cell lymphoma, diffuse large cell lymphoma, immunoplasmacytoid lymphoma, primary effusion lymphoma,
and plasmablastic lymphoma. Although a large number
of these neoplasms demonstrate a relationship with
EBV, studies have suggested that plasmablastic lymphoma and primary effusion lymphoma may be associated with both EBV and HHV-8.
Lymphoma in patients with AIDS usually occurs in
extranodal locations, with the CNS being the most
common site. Oral lesions are seen in approximately
4% of patients with AIDS-related NHL and most frequently involve the gingiva, palate, tongue, tonsil, or
maxillary sinus (Fig. 7-44). Intraosseous involvement
also has been documented and may resemble diffuse
progressive periodontitis with loss of periodontal
attachment and loosening of teeth. In these cases, widening of the periodontal ligament and loss of lamina
dura frequently are noted and represent clues to the
diagnosis.
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believe linear gingival erythema results from an abnormal host immune response to subgingival bacteria,
data suggest that this pattern of gingivitis may represent an unusual pattern of candidiasis. Most instances
respond to systemic antifungal medications such as uconazole or ketoconazole.
Necrotizing ulcerative gingivitis (NUG) (see page
157) refers to ulceration and necrosis of one or more
interdental papillae with no loss of periodontal attachment. Patients with NUG have interproximal gingival
necrosis, bleeding, pain, and halitosis (Fig. 7-46).
Necrotizing ulcerative periodontitis (NUP) previously was termed HIV-associated periodontitis; however,
it has not been deemed to be specic for HIV infection.
NUP is characterized by gingival ulceration and necrosis associated with rapidly progressing loss of periodontal attachment. Although severe cases can affect all
teeth, multiple isolated defects often are seen and con-
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the oral mucosa separate from the gingiva (not overlying bone).
In the absence of gingival involvement, the clinical
features of necrotizing stomatitis are nonspecic and
mandate biopsy. In many instances, the areas of soft
tissue ulceration and necrosis demonstrate infection
with one of more agents, such as HSV, CMV, and
EBV.
In addition to these three atypical forms of HIVrelated periodontal disease, patients also may demonstrate conventional gingivitis, chronic periodontitis,
and progressive nonnecrotizing periodontitis. Studies
have shown that periodontal attachment loss can be
combated successfully with regular professional
removal of supra- and subgingival plaque in patients
who optimize their personal oral hygiene techniques.
Because smoking has been associated strongly with all
forms of periodontal disease, patients should be encouraged to discontinue their tobacco habit.
The best known mycobacterial infection is tuberculosis (TB), which typically is caused by Mycobacterium
tuberculosis (see page 195). Infections with other mycobacteria include M. avium and M. intracellulare (M.
avium-intracellulare complex), M. bovis, M. scrofulaceum,
M. africanum, and M. haemophilum, although these
usually are found only in the immunocompromised
patient. Worldwide, one in three individuals contracts
TB sometime during their life, with more than 2 million
associated deaths each year. Those coinfected with
HIV are at greater risk of death and account for 15% of
AIDS-related deaths worldwide. It is estimated that
more than 4.4 million individuals are coinfected with
TB and HIV, with more than half a million individuals
exhibiting active TB.
Oral lesions are uncommon and occur in less than
5% of individuals with active TB. When present, the
tongue is affected most frequently, but lesions also can
develop on the buccal mucosa, gingiva, oor of mouth,
lips, and palate. The affected areas present as chronic
ulcerations, granular leukoplakias, or exophytic proliferative masses. Jaw involvement also has been reported.
Conrming the diagnosis of TB often can be difcult
in AIDS patients, because up to 80% do not react to
tuberculin skin tests. In such cases, identifying the
organism by examining AFB-stained sections of biopsy
material and conrming its presence on culture of
infected tissue are important.
Management is difcult because of increasing drug
resistance and difculty in ensuring patient compliance with the extended treatment protocols. Agents
frequently used in the triple-drug regimens include
rifampicin, isoniazid, and pyrazinamide, with ethambutol added when isoniazid resistance is likely.
HYPERPIGMENTATION
Hyperpigmentation of the skin, nails, and mucosa
has been reported in HIV-infected patients. The
changes are similar microscopically to focal melanosis,
with increased melanin pigmentation observed in the
basal cell layer of the affected epithelium. Several medications taken by AIDS patients (e.g., ketoconazole,
clofazimine, pyrimethamine, zidovudine) may cause
the increased melanin pigmentation. Adrenocortical
destruction has been reported from several of the
infections associated with AIDS, resulting in an addisonian pattern of pigmentation. Finally, pigmentation
with no apparent cause has arisen in HIV-infected
patients, and some investigators have theorized that
this may be a direct result of the HIV infection.
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THROMBOCYTOPENIA
Thrombocytopenia (see page 584) has been reported
in up to 40% of patients with HIV infection, may occur
at any time during the course of the disease, and
frequently is the rst clinical manifestation of HIV
infection. The causes are diverse and include direct
infection by HIV, immune dysfunction, alteration of
platelet production, loss because of associated infectious diseases, and drug reactions. Cutaneous lesions
are present in most cases, but oral lesions do occur
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VARICELLA-ZOSTER VIRUS
Recurrent varicella-zoster virus (VZV) infection
(herpes zoster) is fairly common in HIV-infected
patients, but the course is more severe, with increased
morbidity and mortality rates. Many of these patients
are younger than age 40, in contrast to cases in immunocompetent patients that usually arise later in life. In
the early stages of HIV-related immunosuppression,
herpes zoster usually is conned to a dermatome but
persists longer than usual. In full-blown AIDS, herpes
zoster usually begins in a classic dermatomal distribution; however, subsequent cutaneous dissemination is
not unusual. When present intraorally, the involvement often is severe and occasionally leads to bone
sequestration and loss of teeth. In many instances, the
associated osteonecrosis and tooth exfoliation may be
delayed a month or more after the initial onset of the
herpes zoster. Associated pain typically is intense.
Although peroral antiviral medications are benecial
in immunocompetent patients, intravenous acyclovir is
recommended for severe herpes zoster in the absence
of an intact immune system.
HUMAN PAPILLOMAVIRUS
Human papillomavirus (HPV) is responsible for several
facial and oral lesions in immunocompetent patients,
the most frequent of which are the verruca vulgaris
(common wart) (see page 364) and oral squamous
papilloma (see page 362). An increased prevalence of
HPV-related lesions is noted in HIV-infected patients,
and most are located in the anogenital areas. Oral
involvement also may be seen. Although usual types of
HPV may be present in intraoral lesions, HIV-infected
patients often demonstrate more unusual variants such
as HPV-7 (associated with butchers warts) or HPV-32
(often noted in multifocal epithelial hyperplasia) (see
page 367).
An increased prevalence of HPV-related lesions has
been reported from several centers in patients responding to HAART. Although the exact cause is not clear,
some wonder if the virus remains latent in many
patients until partial immune reconstitution leads to a
local inammatory response, viral reactivation, and the
initiation of clinically evident lesions. In several cohorts,
the risk of oral HPV lesions increased with the effectiveness of the antiretroviral therapy.
The oral lesions usually are multiple and may be
located on any mucosal surface. The labial mucosa,
tongue, buccal mucosa, and gingiva are frequent sites.
The lesions may exhibit a cluster of white, spikelike
projections, pink cauliower-like growths, or slightly
elevated sessile papules (Fig. 7-51).
Histopathologically, the lesions may be sessile or
papillary and covered by acanthotic or even hyperplastic stratied squamous epithelium (Fig. 7-52). The
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Histoplasmosis, the most common endemic respiratory fungal infection in the United States, is produced
by Histoplasma capsulatum (see page 224). In healthy
patients the infection typically is subclinical and selflimiting, but clinically evident infections do occur in
immunocompromised individuals. Although a number
of deep fungal infections are possible in patients with
AIDS, histoplasmosis is the most common, with disseminated disease noted in approximately 5% of AIDS
patients residing in areas where the fungus is endemic.
In patients with AIDS, diagnosis of histoplasmosis also
has been documented in nonendemic areas, possibly
from reactivation of a previous subclinical infection.
The signs and symptoms associated with dissemination are nonspecic and include fever, weight loss,
splenomegaly, and pulmonary inltrates. Oral lesions
are not uncommon and usually are caused by bloodborne organisms or spread from pulmonary involvement. On occasion, the initial diagnosis is made from
the oral changes, with some patients demonstrating
involvement isolated to the oral cavity. Although intrabony infection in the jaws has been reported, the most
common oral presentation of histoplasmosis is a
chronic, indurated mucosal ulceration with a raised
border (Fig. 7-55). The oral lesions may be single or
multiple, and any area of the oral mucosa may be
involved.
Microscopically, the small fungal organisms are
visible within the cytoplasm of histiocytes and
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APHTHOUS ULCERATIONS
Lesions that are clinically similar to aphthous ulcerations occur with increased frequency in patients
infected with HIV. All three forms (minor, major, and
herpetiform) are seen; surprisingly, however, almost
two thirds of the patients have the usually uncommon herpetiform and major variants (Fig. 7-57). As
immunosuppression becomes more profound, major
aphthous ulcerations demonstrate an increased
prevalence.
Treatment with potent topical or intralesional corticosteroids has been successful in a number of patients.
Not all lesions respond, and recurrences are common.
Secondary candidiasis may be a complication of
therapy. Systemic corticosteroid drugs also may prove
benecial but typically are avoided in an attempt to
prevent further immune depression. For lesions nonresponsive to topical corticosteroids, thalidomide has
been found to be advantageous in many patients. Thalidomide must be used cautiously for only a short term
because of its association with an irreversible peripheral neuropathy and its ability to enhance the production of HIV. In a limited number of patients, granulocyte
colony-stimulating factor (G-CSF) has produced rapid
and sustained resolution of aphthous ulcerations that
were resistant to therapy with topical corticosteroids,
cyclosporine, and thalidomide.
Biopsy of any chronic mucosal ulceration clinically
diagnosed as an aphthous ulceration should be considered if the lesion is atypical clinically or does not
respond to therapy (Fig. 7-58). In such cases, biopsy
often reveals another cause, such as HSV, CMV, deep
fungal infection, or neoplasia. (For further information
on aphthous ulcerations and the pathogenesis of these
lesions in patients infected with HIV, see page 331.)
MOLLUSCUM CONTAGIOSUM
Molluscum contagiosum is an infection of the skin
caused by a poxvirus (see page 371). The lesions are
small, waxy, dome-shaped papules that often demonstrate a central depressed crater. In immunocompetent individuals, the lesions are self-limiting and
typically involve the genital region or trunk. In patients
with AIDS, hundreds of lesions may be present, with
many exhibiting little tendency to undergo spontaneous resolution, and some occasionally obtaining large
size. Approximately 5% to 10% of HIV-infected patients
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DIAGNOSIS
Box 7-2
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
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Box 7-3
Antiretroviral Therapy
1. Nucleoside reverse-transcriptase inhibitors
Abacavir, didanosine, emtricitabine, lamivudine,
stavudine, tenofovir, zalcitabine, or zidovudine
2. Nucleotide reverse-transcriptase inhibitors
Adefovir or tenofovir
3. Nonnucleoside reverse-transcriptase inhibitors
Capravirine, delavirdine, efavirenz, emivirine, or
nevirapine
4. Protease inhibitors
Amprenavir, atazanavir, darunavir, fosamprenavir,
indinavir, lopinavir/ritonavir, nelnavir, ritonavir,
saquinavir, saquinavir-SGC, or tipranavir
5. Fusion inhibitors
Enfuvirtide
6. Integrase inhibitors
MK-0518 (experimental)
7. CCR5 inhibitors
Maraviroc (experimental), vicriviroc (experimental)
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Parlette EC, Polo JM: Inoculation herpes barbae, Skinmed 4:186187, 2005.
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Raborn GW, Martel AY, Lassonde M et al: Effective treatment of
herpes simplex labialis with penciclovir cream. Combined
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Spruance SL, Freeman DJ, Stewart JC et al: The natural history
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herpes simplex virus 1 infection and oropharyngeal cancer
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Woo, S-K, Challacombe SJ: Management of recurrent oral herpes
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Varicella-Zoster Virus
Alper BS, Lewis PR: Does treatment of acute herpes zoster
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Badger GR: Oral signs of chickenpox (varicella): report of two
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Centers for Disease Control and Prevention: Decline in annual
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Mercante DE, Leigh JE, Lilly EA et al: Assessment of the association between HIV viral load and CD4 cell count on the occur-
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Physical and Chemical Injuries
CHAPTER OUTLINE
Linea Alba
Morsicatio Buccarum
Traumatic Ulcerations
Electrical and Thermal Burns
Chemical Injuries of the Oral Mucosa
Aspirin
Hydrogen Peroxide
Silver Nitrate
Phenol
Endodontic Materials
Noninfectious Oral Complications of Antineoplastic
Therapy
Bisphosphonate-Associated Osteonecrosis
Orofacial Complications of Methamphetamine
Abuse
Anesthetic Necrosis
Exfoliative Cheilitis
LINEA ALBA
Linea alba (white line) is a common alteration of the
buccal mucosa that most likely is associated with pressure, frictional irritation, or sucking trauma from the
facial surfaces of the teeth. In one study of 256 young
men, the alteration was present in 13%; in another
study of 993 adolescents, linea alba was the second
most common oral mucosal pathosis and affected 5.3%.
No other associated problem, such as insufcient horizontal overlap or rough restorations of the teeth, is
necessary for the development of linea alba.
Submucosal Hemorrhage
Oral Trauma from Sexual Practices
Amalgam Tattoo and Other Localized Exogenous
Pigmentations
Oral Piercings and Other Body Modications
Systemic Metallic Intoxication
Smokers Melanosis
Drug-Related Discolorations of the Oral Mucosa
Reactive Osseous and Chondromatous Metaplasia
Oral Ulceration with Bone Sequestration
Pseudocysts and Cysts of the Maxillary Sinus
Antral Pseudocyst
Sinus Mucoceles
Retention Cysts
Cervicofacial Emphysema
Myospherulosis
sal plane of the adjacent teeth (Fig. 8-1). The line varies
in prominence and usually is restricted to dentulous
areas. It often is more pronounced adjacent to the
posterior teeth.
HISTOPATHOLOGIC FEATURES
Biopsy is rarely indicated. If a biopsy is performed,
hyperorthokeratosis is seen overlying otherwise normal
oral mucosa. On occasion, intracellular edema of the
epithelium and mild chronic inammation of the
underlying connective tissue may be noted.
CLINICAL FEATURES
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CLINICAL FEATURES
Most frequently, the lesions in patients with morsicatio
are found bilaterally on the anterior buccal mucosa.
They also may be unilateral, combined with lesions of
the lips or the tongue, or isolated to the lips or tongue.
Thickened, shredded, white areas may be combined
with intervening zones of erythema, erosion, or focal
traumatic ulceration (Figs. 8-2 and 8-3). The areas of
white mucosa demonstrate an irregular ragged surface,
and the patient may describe being able to remove
shreds of white material from the involved area.
The altered mucosa typically is located in the midportion of the anterior buccal mucosa along the occlusal plane. Large lesions may extend some distance
above or below the occlusal plane in patients whose
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DIAGNOSIS
In most cases the clinical presentation of morsicatio
buccarum is sufcient for a strong presumptive diagnosis, and clinicians familiar with these alterations
rarely perform biopsy. Some cases of morsicatio may
not be diagnostic from the clinical presentation, and
biopsy may be necessary. In patients at high risk for
HIV infection with isolated involvement of the lateral
border of the tongue, further investigation is desirable
to rule out HIV-associated OHL.
TRAUMATIC ULCERATIONS
Acute and chronic injuries of the oral mucosa are frequently observed. Injury can result from mechanical
damage, such as contact with sharp foodstuffs or
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CLINICAL FEATURES
Most injuries are unintentional and arise from a variety
of causes. As would be expected, simple chronic traumatic ulcerations occur most often on the tongue, lips,
and buccal mucosasites that may be injured by the
dentition (Fig. 8-5). Lesions of the gingiva, palate, and
mucobuccal fold may occur from other sources of
irritation. Overzealous toothbrushing can create linear
erosions along the free gingival margins. Although
these areas may supercially resemble a number of the
chronic vesiculoerosive processes, thorough questioning of the patient often leads to the appropriate diagnosis. The individual lesions appear as areas of erythema
surrounding a central removable, yellow brinopurulent membrane. In many instances, the lesion develops
a rolled white border of hyperkeratosis immediately
adjacent to the area of ulceration (Fig. 8-6).
Eosinophilic ulcerations are not uncommon but frequently are not reported. The lesions occur in people
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HISTOPATHOLOGIC FEATURES
Simple traumatic ulcerations are covered by a brinopurulent membrane that consists of brin intermixed
with neutrophils. The membrane is of variable thickness, and the adjacent surface epithelium may be
normal or may demonstrate slight hyperplasia with or
without hyperkeratosis. The ulcer bed consists of granulation tissue that supports a mixed inammatory
inltrate of lymphocytes, histiocytes, neutrophils, and,
occasionally, plasma cells. In patients with eosinophilic
ulcerations, the pattern is very similar; however, the
inammatory inltrate extends into the deeper tissues
and exhibits sheets of lymphocytes and histiocytes
intermixed with eosinophils. In addition, the vascular
connective tissue deep to the ulceration may become
hyperplastic and cause surface elevation.
Atypical eosinophilic ulcerations exhibit numerous
features of the traumatic eosinophilic ulceration, but
the deeper tissues are replaced by a highly cellular
proliferation of large lymphoreticular cells. The inltrate is pleomorphic, and mitotic features are somewhat common. Intermixed with the large atypical cells
are mature lymphocytes and numerous eosinophils.
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PHENOL
Hydrogen peroxide became a popular intraoral medication for prevention of periodontitis in the late 1970s.
Since that time, mucosal damage has been seen more
frequently as a result of this application. Concentrations
at 3% or greater are associated most often with adverse
reactions. Epithelial necrosis has been noted with dilutions as low as 1%, and many over-the-counter oral
medications exceed this concentration (Fig. 8-15).
SILVER NITRATE
ENDODONTIC MATERIALS
ASPIRIN
Mucosal necrosis from aspirin being held in the mouth
is not rare (Fig. 8-14). Aspirin is available not only in
the well-known tablets but also as powder.
HYDROGEN PEROXIDE
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CLINICAL FEATURES
HISTOPATHOLOGIC FEATURES
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CLINICAL FEATURES
Fig. 8-19 Chemical-related epithelial necrosis. Oral
mucosa exhibiting supercial coagulative necrosis of the
epithelial cells.
NONINFECTIOUS ORAL
COMPLICATIONS OF
ANTINEOPLASTIC THERAPY
No systemic anticancer therapy currently available is
able to destroy tumor cells without causing the death
of at least some normal cells, and tissues with rapid
turnover (e.g., oral epithelium) are especially susceptible. The mouth is a common site (and one of the most
visible areas) for complications related to cancer
therapy. Both radiation therapy and systemic chemotherapy may cause signicant oral problems. The more
potent the treatment, the greater the risk of complications. Each year almost 400,000 patients in the United
States suffer acute or chronic oral side effects from
anticancer treatments. With the advancement of
medical practice, these complications are becoming
HEMORRHAGE
Intraoral hemorrhage is typically secondary to thrombocytopenia, which develops from bone marrow suppression. Intestinal or hepatic damage, however, may
cause lower vitamin Kdependent clotting factors, with
resultant increased coagulation times. Conversely,
tissue damage related to therapy may cause release of
tissue thromboplastin at levels capable of producing
potentially devastating disseminated intravascular
coagulation (DIC). Oral petechiae and ecchymosis secondary to minor trauma are the most common presentations. Any mucosal site may be affected, but the
labial mucosa, tongue, and gingiva are involved most
frequently.
MUCOSITIS
Recent research suggests that mucosal damage secondary to cancer therapy is much more complex than previously thought and appears to arise from an extended
series of molecular and cellular events that take place
not only in the epithelium but also in the underlying
stroma. Genetic differences in the rate of tissue apop-
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DERMATITIS
Acute dermatitis of the skin in the elds of radiation
is common and varies according to the intensity of the
therapy. Patients with mild radiation dermatitis experi-
XEROSTOMIA
Salivary glands are very sensitive to radiation, and
xerostomia is a common complication. When a portion
of the salivary glands is included in the elds of radiation, the remaining glands undergo compensatory
hyperplasia in an attempt to maintain function. The
changes begin within 1 week of initiation of radiation
therapy, with a dramatic decrease in salivary ow
noted during the rst 6 weeks of treatment. Even
further decreases may be noted for up to 3 years.
Serous glands exhibit an increased radiosensitivity
when compared with the mucous glands. On signicant exposure, the parotid glands are affected dramatically and irreversibly. In contrast, the mucous glands
partially recover and, over several months, may achieve
ow that approaches 50% of preradiation levels. Symptomatic dry mouth appears most strongly associated
with a decrease in palatal mucous secretions, with the
loss of parotid serous secretion exerting a less noticeable effect. In addition to the discomfort of a mouth
that lacks proper lubrication, diminished ow of saliva
leads to a signicant decrease of the bactericidal action
and self-cleansing properties of saliva.
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LOSS OF TASTE
In patients who receive signicant radiation to the oral
cavity, a substantial loss of all four tastes (hypogeusia)
often develops within several weeks. Although these
tastes return within 4 months for most patients, some
patients are left with permanent hypogeusia; others
may have persistent dysgeusia (altered sense of taste)
(see page 875).
OSTEORADIONECROSIS
C
Without intervention, patients often develop symptomatic dry mouth that affects their ability to eat comfortably, wear dentures, speak, and sleep. In addition,
there often is an increase in the caries index (xerostomia-related caries), regardless of the patients past
caries history (Fig. 8-23). The decay is predominantly
Osteoradionecrosis is one of the most serious complications of radiation to the head and neck; however, it
is seen less frequently today because of better treatment modalities and prevention. The current prevalence rate is approximately 5%, whereas the frequency
approached 15% less than 20 years ago. Although the
risk is low, it increases dramatically if a local surgical
procedure is performed within 21 days of therapy
initiation or within 12 months after therapy.
In the past, many researchers believed that radiation induced an osseous endarteritis that led to tissue
hypoxia, hypocellularity, and hypovascularity and
created a predisposition to necrosis if a minor injury
occurred. This theory led to widespread use of hyperbaric oxygen in the prevention and treatment of this
pathosis. However, many now believe the process is
more complex and may involve radiation damage to
osseous cells; when these cells lose normal function,
bone turnover is suppressed in a manner similar to
the effect on osteoclasts associated with use of
bisphosphonates (see page 299). Researchers believe
that damage to these cells not only disrupts their
primary function but also affects bone vascularity
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be eliminated; excellent oral hygiene should be initiated and maintained. A healing time of at least 3 weeks
between extensive dental procedures and the initiation
of radiotherapy signicantly decreases the chance of
bone necrosis. Extraction of teeth or any bone trauma
is strongly contraindicated during radiation therapy.
TRISMUS
Trismus may develop and can produce extensive difculties concerning access for hygiene and dental
treatment. Tonic muscle spasms with or without brosis of the muscles of mastication and the temporomandibular joint (TMJ) capsule can cause difculties in jaw
opening. When these structures are radiated heavily,
jaw-opening exercises may help to decrease or prevent
problems.
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DEVELOPMENTAL ABNORMALITIES
Antineoplastic therapy during childhood can affect
growth and development. The changes vary according
to the age at treatment and the type and severity of
therapy. Radiation can alter the facial bones and result
in micrognathia, retrognathia, or malocclusion. Developing teeth are very sensitive and can exhibit a number
of changes, such as root dwarsm, blunting of roots,
dilaceration of roots, incomplete calcication, premature closure of pulp canals in deciduous teeth, enlarged
canals in permanent teeth, microdontia, and hypodontia (see page 58).
MUCOSITIS
In an attempt to decrease the severity, duration, and
symptoms associated with oral mucositis, a large
number of treatments such as anesthetic, analgesic,
antimicrobial, and coating agents have been tried with
mixed reviews. Few have been proven to be consistently benecial in well-designed placebo-controlled
trials. A low-cost salt and soda rinse often has demonstrated similar effectiveness and a lower adverse
reaction prole when compared with many other
interventions. When all treatments fail, the degree of
mucositis and associated pain may mandate systemic
morphine therapy.
Cryotherapy (placement of ice chips in the mouth 5
minutes before chemotherapy and continued for 30
minutes) has been shown to reduce signicantly the
prevalence and severity of oral mucositis secondary to
bolus injection of chemotherapeutic drugs with a short
half-life, such as 5-uorouracil or edatrexate. Although
limited by the hardware expense and necessity for specialized training, low-level helium-neon laser therapy
also appears to reduce the frequency and severity of
chemotherapy-associated mucositis.
A new avenue of research is concentrating on growth
factors that may affect the prevalence of oral mucositis.
Recently, intravenous (IV) recombinant human keratinocyte growth factor (palifermin) became the
rst compound approved by the U.S. Food and Drug
XEROSTOMIA
Xerostomic patients should be counseled to avoid all
agents that may decrease salivation, especially the use
of tobacco products and alcohol. To combat xerostomia-related caries, a regimen of daily topical uoride
application should be instituted.
The problem of chronic xerostomia has been
approached through the use of salivary substitutes and
sialagogues. Because the mucous glands often demonstrate signicant recovery after radiation, the sialagogues show promise because they stimulate the
residual functional glands. Moisturizing gels, sugarless
candies, and chewing gum are used, but the most efcacious product in controlled clinical studies has been
systemic use of one of the cholinergic drugs, pilocarpine or cevimeline. Although these drugs may be benecial for many patients, they are contraindicated in
patients with asthma, gastrointestinal ulcerations, labile
hypertension, glaucoma, chronic obstructive pulmonary disease, and signicant cardiovascular disease.
Adverse reactions are uncommon but include excess
sweating, rhinitis, headache, nausea, uropoiesis, atulence, and circulatory disorders.
Other systemic salivary stimulants that are associated with a less dramatic inuence on ow include
bethanechol and anetholetrithione. Anetholetrithione
appears to act by increasing the number of salivary
gland receptors. Although somewhat effective when
used alone, this medication has been combined with
one of the cholinergic medications and achieved
improvement in patients who failed to respond to the
use of a single agent.
LOSS OF TASTE
Although the taste buds often regenerate within 4
months after radiation therapy, the degree of long-term
impairment is highly variable. In those with continu-
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Although prevention must be stressed, cases of osteoradionecrosis do occur. Use of hyperbaric oxygen has
numerous contraindications and possible adverse reactions. Because of the newer theories of pathogenesis
for osteoradionecrosis, many clinicians are less inclined
to use hyperbaric oxygen except in selected cases.
Therapy consists of antibiotics, dbridement, irrigation, and removal of diseased bone. The amount of
bone removed is determined by clinical judgment,
with the surgery extended until brightly bleeding edges
are seen.
BISPHOSPHONATE-ASSOCIATED
OSTEONECROSIS
The initial association between use of bisphosphonates
and subsequent development of gnathic osteonecrosis
was documented in 2003. Bisphosphonates comprise
a unique class of medications that has been shown to
inhibit osteoclasts and possibly interfere with angiogenesis through actions such as inhibition of vascular
endothelial growth factor. These medications can be
delivered by mouth (PO) or intravenously (IV) and are
used primarily to slow osseous involvement of a number
of cancers (multiple myeloma and metastatic breast or
prostate carcinoma), to treat Pagets disease (see page
623), and to reverse osteoporosis.
The rst-generation bisphosphonates have a relatively low potency and are readily metabolized by
osteoclasts. Addition of a nitrogen side chain was added
subsequently, creating a more potent second generation of these drugs, designated aminobisphosphonates (Box 8-1). In contrast to the rst generation,
these formulations are incorporated into the skeleton
and demonstrate an extended half-life (e.g., estimated
to be 12 years for alendronate). Currently, strong association with gnathic osteonecrosis has been limited to
the aminobisphosphonates.
Although bone may seem to be a stable tissue, it
constantly is undergoing a process of resorption and
reapposition throughout life. The typical lifespan of an
osteoblast/osteocyte is approximately 150 days. Osteoclasts also play a critical role in the maintenance of
normal bone by repairing microfractures and resorbing areas of bone that contain foci of older nonvital
osteocytes. On resorption of bone, cytokines and growth
factors such as bone morphogenetic protein are
released and induce formation of active bone-forming
osteoblasts. If osteoclastic function declines, then
microfractures accumulate and the lifespan of the
299
Box 8-1
Bisphosphonate Medications
FIRST-GENERATION DRUGS
Bonefos (clodronate)
Relative potency of 10
PO and IV formulations
Didronel (etidronate disodium)
Relative potency of 1
PO
Skelid (tiludronic disodium)
Relative potency of 10
PO
AMINOBISPHOSPHONATE DRUGS
Actonel (risedronate sodium)
Relative potency of 5000
PO
Aredia (pamidronate disodium)
Relative potency 100
IV
Boniva (ibandronate sodium)
Relative potency 10,000
PO and IV formulations
Fosamax (alendronate sodium)
Relative potency 1000
PO
Reclast (zoledronic acid)
Relative potency 100,000
IV formulation
Infused annually for osteoporosis
FDA approval pending
Zometa (zoledronic acid)
Relative potency 100,000
IV
PO, By mouth; IV, intravenous; FDA, U.S. Food and Drug Administration.
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the IV formulations (primarily pamidronate and zoledronic acid) for cancer, with 85% being reported in
patients with multiple myeloma. Current estimates
indicate that the prevalence of osteonecrosis in patients
taking aminobisphosphonates for cancer is 6% to 10%.
Prospective trials will be necessary to conrm these
gures.
Osteonecrosis related to use of oral aminobisphosphonates is most uncommon (conservative estimate by
drug industry: annual incidence is 0.7 per 100,000);
however, prospective trials for the true incidence of
this complication have yet to be performed. Risk factors
for BON associated with the PO formulations include
advanced patient age (older than 65 years), corticosteroid use, use of chemotherapy drugs, diabetes, smoking
or alcohol use, poor oral hygiene, and duration of drug
use exceeding 3 years. A predictive test for those at risk
for bisphosphonate osteonecrosis has not been conrmed. Some investigators recently have suggested
use of a serum marker for bone turnover, serum Ctelopeptide (CTX), but additional prospective studies
are needed to conrm the utility of this test.
Although a mandibular predominance has been
noted, involvement of the maxilla or both jaws is not
uncommon (Fig. 8-27). In 60% of these patients, the
necrosis has followed an invasive dental procedure,
with the remainder occurring spontaneously (Fig.
8-28). On occasion, the necrosis can occur after minor
trauma to bony prominences, such as tori or other
exostoses (Fig. 8-29). Affected patients have areas of
exposed, necrotic bone that is asymptomatic in approximately one third.
Investigators have suggested that bone at imminent
risk for osteonecrosis often will demonstrate increased
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HISTOPATHOLOGIC FEATURES
Biopsy of vital bone altered by aminobisphosphonates
is not common. In such cases the specimen often
reveals irregular trabeculae of pagetoid bone, with
adjacent enlarged and irregular osteoclasts that often
demonstrate numerous intracytoplasmic vacuoles (Fig.
8-32). Specimens of active areas of BON reveal trabeculae of sclerotic lamellar bone, which demonstrate
loss of the osteocytes from their lacunae and frequent
peripheral resorption with bacterial colonization (Fig.
8-33). Although the peripheral bacterial colonies often
resemble actinomycetes, the infestation is not consistent with cervicofacial actinomycosis.
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OROFACIAL COMPLICATIONS OF
METHAMPHETAMINE ABUSE
Methamphetamine (meth) is a drug with stimulant
effects on the central nervous system (CNS). In 1937
the drug was approved in the United States for the treatment of narcolepsy and attention decit hyperactivity
disorder. Within a few years, many began to use the
drug to increase alertness, control weight, and combat
depression. Because methamphetamine users perceive
increased physical ability, greater energy, and euphoria, illegal use and manufacture of the drug began to
develop. Because of greater control over the main
ingredient, pseudoephedrine, production of homemade methamphetamine is decreasing but often being
replaced by illegal importation of the nished product.
The drug is a powdered crystal that dissolves easily in
liquid and can be smoked, snorted, injected, or taken
orally. The drug is known by nicknames that include
chalk, crank, crystal, re, glass, ice, meth, and speed.
CLINICAL FEATURES
Although methamphetamine abuse may occur throughout society, most users are men between the ages of 19
and 40 years. The effects of the medication last up to
12 hours, and the typical abuser reports use that
exceeds 20 days per month, creating an almost continuous effect of the drug. The short-term effects of
methamphetamine include insomnia, aggressiveness,
agitation, hyperactivity, decreased appetite, tachycardia, tachypnea, hypertension, hyperthermia, vomiting,
tremors, and xerostomia. Long-term effects additionally include strong psychologic addiction, violent
behavior, anxiety, confusion, depression, paranoia,
auditory hallucinations, delusions, mood changes, skin
lesions, and a number of cardiovascular, CNS, hepatic,
gastrointestinal, renal, and pulmonary disorders.
Many addicts develop delusions of parasitosis (formication, from the Latin word formica, which translates to ant), a neurosis that produces the sensation of
snakes or insects crawling on or under the skin. This
sensation causes the patient to attempt to remove the
perceived parasites, usually by picking at the skin with
ngernails, resulting in widespread traumatic injury.
The factitial damage can alter dramatically the facial
appearance in a short period of time, and these lesions
have been nicknamed speed bumps, meth sores, or crank
bugs.
Rampant dental caries is another common manifestation and exhibits numerous similarities with milkbottle caries. The carious destruction initially affects
ANESTHETIC NECROSIS
Administration of a local anesthetic agent can, on rare
occasions, be followed by ulceration and necrosis at the
site of injection. Researchers believe that this
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CLINICAL FEATURES
Anesthetic necrosis usually develops several days after
the procedure and most commonly appears on the
hard palate (Fig. 8-35). A well-circumscribed area of
ulceration develops at the site of injection. The ulceration often is deep, and, on occasion, healing may be
delayed. One report has documented sequestration of
bone at the site of tissue necrosis.
EXFOLIATIVE CHEILITIS
Exfoliative cheilitis is a persistent scaling and aking
of the vermilion border, usually involving both lips.
The process arises from excessive production and
subsequent desquamation of supercial keratin. A
CLINICAL FEATURES
A marked female predominance is seen in cases of
factitious origin, with most cases affecting those
younger than 30 years of age. Mild cases feature chronic
dryness, scaling, or cracking of the vermilion border of
the lip (Fig. 8-36). With progression, the vermilion can
become covered with a thickened, yellowish hyperkeratotic crust that can be hemorrhagic or that may
exhibit extensive ssuring. The perioral skin may
become involved and exhibit areas of crusted erythema
(Fig. 8-37). Although this pattern may be confused with
perioral dermatitis (see page 352), the most appropri-
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In those cases associated with an obvious cause, elimination of the trigger typically results in resolution of the
changes. In those cases with no underlying physical,
infectious, or allergic cause, psychotherapy (often combined with mild tranquilization or stress reduction)
may achieve resolution. In cases for which no cause
can be found, therapeutic interventions often are not
successful.
Cases that result from candidal infections often do
not resolve until the chronic trauma also is eliminated.
Initial topical antifungal agents, antibiotics, or both
can be administered to patients in whom chronic
trauma is not obvious or is denied. If the condition
does not resolve, then further investigation is warranted in an attempt to discover the true source of the
lip alterations.
Hydrocortisone and iodoquinol (antibacterial and
antimycotic) cream has been used to resolve chronic
lip ssures in some patients (Fig. 8-38). Other reported
therapies include various corticosteroid preparations,
topical tacrolimus, sunscreens, and moisturizing preparations. In many cases, resistance to topical therapy or
frequent recurrence is noted. In these cases, cryotherapy or excision with or without Z-plasty has been used
successfully.
SUBMUCOSAL HEMORRHAGE
Everyone has experienced a bruise from minor trauma.
This occurs when a traumatic event results in hemorrhage and entrapment of blood within tissues. Different terms are used, depending on the size of the
hemorrhage:
Minute hemorrhages into skin, mucosa, or serosa
are termed petechiae.
If a slightly larger area is affected, the hemorrhage
is termed a purpura.
Any accumulation greater than 2 cm is termed an
ecchymosis.
If the accumulation of blood within tissue produces a mass, this is termed a hematoma.
Blunt trauma to the oral mucosa often results in
hematoma formation. Less well known are petechiae
and purpura, which can arise from repeated or prolonged increased intrathoracic pressure (Valsalva
maneuver) associated with such activities as repeated
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Fig. 8-38 Lip ssure. A, Chronic ssure of the vermilion border of the upper lip. B, Same
site 2 weeks later, after use of hydrocortisone and iodoquinol cream.
CLINICAL FEATURES
Submucosal hemorrhage appears as a nonblanching
at or elevated zone with a color that varies from red
or purple to blue or blue-black (Fig. 8-40). As would be
expected, traumatic lesions are located most frequently
on the labial or buccal mucosa. Blunt facial trauma
often is responsible, but injuries such as minor as cheek
biting may produce a hematoma or areas of purpura
(Fig. 8-41). Mild pain may be present.
The hemorrhage associated with increased intrathoracic pressure usually is located on the skin of the
face and neck and appears as widespread petechiae
that clear within 24 to 72 hours. Although it has not
been as well documented as the cutaneous lesions,
mucosal hemorrhage can be seen in the same setting
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Fig. 8-41 Hematoma. A, Dark-purple nodular mass of the buccal mucosa in a patient on
coumadin therapy. B, Near resolution of the lesion 8 days later after discontinuation of the
medication. (Courtesy of Dr. Charles Ferguson.)
CLINICAL FEATURES
The most commonly reported lesion related to orogenital sex is submucosal palatal hemorrhage secondary to
fellatio. The lesions appear as erythema, petechiae,
purpura, or ecchymosis of the soft palate. The areas
often are asymptomatic and resolve without treatment
in 7 to 10 days (Fig. 8-42). Recurrences are possible
with repetition of the inciting (exciting?) event. The
erythrocytic extravasation is thought to result from the
musculature of the soft palate elevating and tensing
against an environment of negative pressure. Similar
lesions have been induced from coughing, vomiting,
or forceful sucking on drinking straws and glasses.
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These suction-related lesions reveal subepithelial accumulations of red blood cells that may be extensive
enough to separate the surface epithelium from underlying connective tissue. Patchy degeneration of the
epithelial basal cell layer can occur. The epithelium
classically demonstrates migration of erythrocytes and
leukocytes from the underlying lamina propria.
HISTOPATHOLOGIC FEATURES
With an appropriate index of suspicion, biopsy usually
is not required; however, a biopsy has been performed
in some cases of palatal lesions secondary to fellatio.
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HISTOPATHOLOGIC FEATURES
Microscopic examination of amalgam tattoos reveals
pigmented fragments of the metal within the connective tissue. Scattered, large, dark, solid fragments or
numerous ne, black, or dark-brown granules may be
seen (Fig. 8-50). The silver salts of the dental amalgam
preferentially stain the reticulin bers, especially those
encircling nerves and vascular channels (Fig. 8-51).
The biologic response to amalgam appears related
to particle size and the elemental composition of the
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mucosal side and a round ball for the cutaneous surface (Fig. 8-53).
If no complications occur, healing of the piercing
site takes place within 4 to 6 weeks. Potential acute
complications include pain, prolonged or profuse
bleeding, swelling (to the point of airway obstruction
in rare cases), infection including Ludwigs angina and
cerebellar brain abscess, lingual nerve damage, speech
impediment, and allergy to the jewelry. Chronic complications include mucosal or gingival trauma, chipped
or fractured teeth, hypersalivation, aspiration or swallowing of jewelry, tissue hyperplasia around the posts,
and embedded jewelry. Gingival recession (labrets,
barbells) and tooth fracture (barbells) are extremely
common, with the prevalence closely related to the
duration of use. Molars and premolars are fractured
most frequently, with the damage associated more
often with a short-stem barbell, whereas greater severity of gingival recession is associated with long-stem
barbells and labrets.
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Fig. 8-55 Susuk (charm needles). Panoramic radiograph showing multiple radiopaque
needles superimposed on the jaws. (Courtesy of Dr. Jeff Bayme.)
LEAD
Little is known about the prevalence of lead poisoning
(plumbism), but lead is one of the most widespread
environmental toxins affecting children in the United
States. Lead solder for plumbing was not banned until
1986. Homes built before then have the potential for
signicant water contamination, and one of the primary
causes of lead intoxication in infants is formula preparation using tap water tainted by the metal.
Another signicant source of lead poisoning in children is lead-based paint; children may ingest chips of
the paint in older homes or be exposed to the fumes or
dust during sanding and renovation. Paint with a high
lead content was not restricted until 1977 and still
remains in many homes. Removal of lead from gasoline began in 1972 but was not completed until 1995.
These sources of lead combined with previous indus-
trial emissions have resulted in sites with highly contaminated soil, especially in urban areas. Despite the
widespread publicity and signicant efforts to restrict
exposure to lead during childhood, signicant risk
remains.
Adult exposure also occurs and often is related to
industry. The potential for exposure exists during handling of lead oxide batteries, in lead-processing industries, and from the welding of lead-covered surfaces.
Some food and drink containers or vegetables grown
in lead-contaminated soil also may contain inappropriate levels of the metal. Lead contamination in illicit
alcohol has made the distinction between symptoms of
lead intoxication and chronic alcohol abuse very difcult in certain sections of the American Deep South.
Lead also can be found in brass xtures, ceramics,
crystal, electrical cable, radiation shielding, folk remedies, and cosmetics. Rarely, plumbism arises from
retained lead bullet fragments in gunshot victims.
MERCURY
The danger of mercury exposure is well known. Elemental mercury is poorly absorbed, and its ingestion is
relatively harmless. In contrast, inhalation of mercury
vapor is very hazardous, with a high rate of absorption
and systemic retention. Ingestion of mercury salts (e.g.,
mercurous chloride) also is associated with signicant
adverse reactions. Exposure has occurred in association with the use of mercury in teething powders,
cathartic agents, and anthelmintic preparations.
A great deal of attention has been directed toward
the mercury released from dental amalgams, but no
well-documented adverse health effects have been
identied (except for relatively rare contact hypersensitivity to mercury, see page 354). The level of mercury
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that is released from amalgams does not appear sufciently high to cause disease and has been shown not
to exceed the range expected from background exposure to environmental mercury. In an attempt to shed
light on this controversy, the National Institutes of
Health (NIH) funded two large randomized clinical
trials that compared the neurologic and renal effects of
dental amalgam in a 7-year study of a large cohort of
children. In these pivotal investigations, no adverse
effects from dental amalgam were seen. Interestingly,
the control group that received only composite restorations demonstrated a 50% higher need for additional
restorative treatment because of the failure of their
restorations during the long-term study.
SILVER
Silver has known antibacterial properties and has been
associated with a number of additional health benets.
In the past, silver compounds were used topically in
nose drops and systemically for a variety of disorders
including mental illness, epilepsy, nicotine addition,
common colds, sinusitis, gastrointestinal ulcerations,
syphilis, and gonorrhea. Because of the numerous complications, including silver intoxication, the FDA concluded that the risk of systemic silver products exceeded
their benets. In 1999 the use of colloidal silver or
silver salts was banned in over-the-counter products.
Several silver nitrate and silver sulfadiazine formulations remain available by prescription. These products
should be used only under strict supervision. Welldocumented examples of generalized argyria have
been seen secondary to long-term treatment of aphthous ulcerations, denture sores, and minor gingival
hemorrhage with topical silver nitrate.
Devices for production of homemade colloidal silver
suspension and a number of colloidal silver proteins
continue to be marketed over the Internet and in health
food stores as essential mineral supplements for diseases such as arthritis, cancer, diabetes, AIDS, and
herpes. These unregulated silver products have no
known physiologic function, and their continued use
cannot be supported.
GOLD
Gold has been used in medical treatment in the past
and continues to be used today in selected cases of
active rheumatoid arthritis and other immunologically
mediated diseases. In these cases the side effects are
well known, and physicians observe the patients closely.
In reviews of large-scale skin testing, gold has been
found to be among the top 10 most frequent allergens,
with positive reactions seen in about 10% of the population, including increased prevalence in patients who
have gold dental restorations.
CLINICAL FEATURES
LEAD
Lead poisoning results in nonspecic systemic signs
and symptoms, thereby making the ultimate diagnosis
very difcult. The presentation is extremely variable
and determined by the type of lead (organic or inorganic) and the age of the patient. Patients with acute
cases most often have abdominal colic, which may
occur along with anemia, fatigue, irritability, and weakness. Encephalopathy and renal dysfunction also may
occur. Chronic exposure causes dysfunction of the
nervous system, kidneys, marrow, bone, and joints.
Symptoms generally include fatigue, musculoskeletal
pain, and headache. Bones and teeth represent a major
reservoir in patients with chronic plumbism, with 90%
of the bodys deposition being within bone. In radiographs of the long bones in infants, a radiopaque lead
line often is noted along the epiphyseal plates. In addition, abdominal radiographs often will reveal small
radiopaque paint chips in the gastrointestinal tract.
Oral manifestations include ulcerative stomatitis
and a gingival lead line (Burtons line). The lead line
appears as a bluish line along the marginal gingiva
resulting from the action of bacterial hydrogen sulde
on lead in the gingival sulcus to produce a precipitate
of lead sulde. Gray areas also may be noted on the
buccal mucosa and tongue. Additional manifestations
include the following:
Tremor of the tongue on thrusting
Advanced periodontal disease
Excessive salivation
Metallic taste
MERCURY
Mercury poisoning also may be acute or chronic. With
acute cases, abdominal pain, vomiting, diarrhea, thirst,
pharyngitis, and gingivitis typically are present. With
chronic cases, gastrointestinal upset and numerous
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SILVER
Acute silver intoxication can produce coma, pleural
edema, hemolysis, and bone marrow failure. Chronic
systemic silver intoxication is known as argyria. Silver
is disseminated throughout the body with substantial
amounts accumulating as subepithelial deposits in the
skin. These deposits result in a diffuse grayish discoloration that develops primarily in the sun-exposed areas
(Fig. 8-56). The sclerae and nails also may be pig-
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BISMUTH
Chronic bismuth exposure can result in a diffuse bluegray discoloration of the skin. The conjunctiva and oral
cavity also may be involved. A blue-gray line along the
gingival margin similar to that seen from lead intoxication is the most common intraoral presentation.
Bismuth combines with bacterial hydrogen sulde to
form bismuth sulde, which is irritating locally but not
as destructive as mercuric sulde. Associated ptyalism,
burning, stomatitis, and ulceration may be seen. Intoxication from bismuth-containing surgical packs has
been associated with CNS symptoms such as delirium.
Chronic use of bismuth subsalicylate tablets can create
a removable black discoloration of the otherwise
normal liform papillae. Although the lingual alteration may resemble black hairy tongue, the papillae are
not elongated.
ARSENIC
In addition to widespread effects on numerous organ
systems, signicant dermatologic alterations frequently
occur. Prolonged ingestion of arsenic often results in a
diffuse macular hyperpigmentation. The discoloration
is due to both the presence of the metal and an
increased melanin production. In addition, palmar and
plantar hyperkeratosis often is noted, as well as numerous premalignant skin lesions called arsenical keratoses. Development of basal cell carcinoma and cutaneous
squamous cell carcinoma has been seen after years of
exposure. Oral manifestations are rare and typically
appear as excessive salivation and painful areas of necrotizing ulcerative stomatitis. In the past, extensive
dorsal hyperkeratosis of the tongue was seen in patients
with syphilis and may be related to arsenic therapy
used before the advent of antibiotic therapy.
GOLD
The most common complication of gold therapy is dermatitis, which often is preceded by a warning signal:
pruritus. Although a generalized exfoliative dermatitis
with resultant alopecia and loss of nails can be seen,
dermatitis about the face, eyelids, and at direct sites of
skin contact is the most common presentation. Because
of the high frequency of allergy to gold, skin testing
often is performed before administration of gold drug
therapy.
The second most common adverse reaction to gold
is severe oral mucositis, which most frequently involves
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SMOKERS MELANOSIS
Oral pigmentations are increased signicantly in heavy
smokers. In one investigation of more than 31,000
whites, 21.5% of tobacco smokers exhibited areas of
melanin pigmentation compared with 3% among those
not using tobacco. In another study of an ethnically
pigmented population, smokers had more oral surfaces
exhibiting melanin pigmentation.
Melanin pigmentation in the skin exerts a wellknown protective effect against ultraviolet (UV)
damage. Investigations of melanocytes located away
from sun-exposed areas have shown the ability of
melanin to bind to noxious substances. Exposure to
polycyclic amines (e.g., nicotine and benzpyrene) has
been shown to stimulate melanin production by melanocytes that also are known to bind strongly to nicotine. Research has suggested that melanin production
in the oral mucosa of smokers serves as a protective
CLINICAL FEATURES
Although any mucosal surface may be affected, smokers melanosis most commonly affects the anterior
facial gingiva (Fig. 8-57). Most people affected by this
condition are cigarette users. In contrast, pipe smokers
frequently exhibit pigmentations located on the commissural and buccal mucosae. Reverse smokers show
alterations of the hard palate.
The areas of pigmentation signicantly increase
during the rst year of smoking and appear correlated
to the number of cigarettes smoked each day. A higher
frequency is seen in females, and researchers have
suggested that female sex hormones exert a synergistic
effect when combined with smoking. Reports from
Sweden, Germany, and Japan have shown tobacco
smoking to be the most common cause for mucosal
pigmentation in light-skinned adult populations.
HISTOPATHOLOGIC FEATURES
Biopsy specimens of affected areas in people with
smokers melanosis reveal increased melanin pigmentation of the basal cell layer of the surface epithelium,
similar to a melanotic macule (see page 379). In addition, collections of incontinent melanin pigmentation
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DIAGNOSIS
The clinician can make the diagnosis by correlating the
smoking history with the clinical presentation and
medical history. Other causes of melanin pigmentation, such as trauma, neurobromatosis, Peutz-Jeghers
syndrome, drug-related pigmentation, endocrine disturbances, hemochromatosis, chronic pulmonary
disease, and racial pigmentation should be excluded.
DRUG-RELATED DISCOLORATIONS
OF THE ORAL MUCOSA
An expanding number of medications have been implicated as a cause of oral mucosal discolorations.
Although many medications stimulate melanin production by melanocytes, deposition of drug metabolites
is responsible for the color change in others. These
pigmentary alterations have been associated with use
of phenolphthalein, minocycline, tranquilizers, antimalarial medications, estrogen, chemotherapeutic
agents, and some medications used in the treatment of
patients with AIDS.
The antimalarial agents that are most frequently
implicated are chloroquine, hydrochloroquine, quinidine, and quinacrine; chlorpromazine represents the
most frequently implicated tranquilizer. Besides treating malaria, antimalarial agents are used for many
other disorders, including lupus erythematosus and
rheumatoid arthritis.
Oral mucosal pigmentation associated with chemotherapeutic medications is most commonly reported
with use of doxorubicin, busulfan, cyclophosphamide,
or 5-uorouracil. Although idiopathic hyperpigmentation also may occur, AIDS patients receiving zidovudine (AZT), clofazimine, or ketoconazole have
demonstrated increased melanin pigmentation.
CLINICAL FEATURES
The clinical presentations of pigmentations related to
drug use vary. Most agents produce a diffuse melanosis
of the skin and mucosal surfaces, but others may cause
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Fig. 8-63 Osseous and chondromatous metaplasia. Highpower photomicrograph demonstrating cellular woven bone
and metaplastic cartilage.
Steven Tucker.)
HISTOPATHOLOGIC FEATURES
Histopathologic examination of reactive osseous and
chondromatous metaplasia typically demonstrates a
mass of hypercellular periosteum that blends into
areas of osseous and chondromatous tissue. The bone
and cartilage frequently exhibit atypical features, such
as hypercellularity, pleomorphism, nuclear hyperchromatism, and occasional binucleated or multinucleated
cells (Fig. 8-63). These alterations are worrisome for
sarcoma, but the appropriate diagnosis can be made
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HISTOPATHOLOGIC FEATURES
The sequestra consist of well-organized lamellar bone
that exhibits loss of the osteocytes from their lacunae,
along with peripheral resorption and bacterial
colonization.
Antral pseudocysts are common ndings on panoramic radiographs. They appear as dome-shaped,
faintly radiopaque lesions arising from the oor of the
maxillary sinus. In the past these sinus changes were
incorrectly termed sinus mucoceles, because previous investigators thought the lesions resulted from
mucus extravasation similar to that seen in salivary
glands of soft tissue. In fact, it appears that no comparable mucus extravasation occurs in the maxillary
sinus.
ANTRAL PSEUDOCYST
Antral pseudocyst is the best term for the dome-shaped
lesion of the sinus oor. The process usually consists of
an inammatory exudate (serum, not mucin) that has
accumulated under the maxillary sinus mucosa and
caused a sessile elevation (Fig. 8-65). The exudate is
surrounded by connective tissue, and the epithelial
lining of the sinus is superior to the uid. Reviews of
large numbers of radiographs have determined the
prevalence, which varies from 1.5% to 14% of the population. The cause of the inammatory inltrate has not
been denitively determined, but in a radiographic
review, most cases showed a possible source from an
adjacent odontogenic infection. Primary irritation of
the sinus lining, such as that seen from a sinus infection
or allergies, also can theoretically result in the subperiosteal inammatory inltrate.
An increased prevalence of pseudocysts has been
noted during the cold winter months, leading some
investigators to associate these lesions with an increased
frequency of upper respiratory tract infections or irritation from dry, forced-air heating. Although allergies
have been proposed as a cause, no increased prevalence has been noted during the time of peak pollen
exposure.
SINUS MUCOCELES
True sinus mucoceles are accumulations of mucin that
are completely encased by epithelium. They occur in
two situations. One type of sinus mucocele occurs after
trauma or surgery to the sinus; this type is best known
as a surgical ciliated cyst, traumatic ciliated cyst, or
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Fig. 8-66 Antral pseudocyst. Three-dimensional conebeam radiograph showing dome-shaped radiopacity within
the maxillary sinus. (Courtesy of Dr. Scott Jenkins and Dr. Nick Morrow.)
Fluid
True mucocele
RETENTION CYSTS
Retention cysts of the maxillary sinus arise from the
partial blockage of a duct of the seromucous glands or
from an invagination of the respiratory epithelium. The
mucin is surrounded by epithelium, and no extravasation occurs. Most retention cysts are located around the
ostium or within antral polyps. The majority of cysts are
small, not evident clinically, and discovered during histopathologic examination of antral polyps.
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inammatory cells (Fig. 8-69). Collections of cholesterol clefts and scattered small dystrophic calcications
may be seen. True sinus mucoceles and surgical ciliated cysts are true cystic structures lined by ciliated
pseudostratied columnar epithelium, squamous epithelium with mucous cells, or metaplastic squamous
epithelium (Fig. 8-70). A sinus retention cyst shows
focal dilatation of a duct associated with the seromucous glands of the sinus lining. The lumen of the dilated
duct is lled with thick mucus, often intermixed with
chronic inammatory cells.
HISTOPATHOLOGIC FEATURES
Typically, pseudocysts of the maxillary sinus are harmless, and no treatment is necessary. The adjacent teeth
should be evaluated thoroughly, and any foci of infec-
Coleman.)
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CERVICOFACIAL EMPHYSEMA
Cervicofacial emphysema arises from the introduction of air into subcutaneous or fascial spaces of the
face and neck. The forced air may spread through the
spaces to the retropharyngeal and mediastinal areas.
The rst case was reported almost 100 years ago and
occurred as a result of blowing into a bugle a short time
after tooth extraction.
Cervicofacial emphysema of dental origin may arise
in several ways:
After the use of compressed air by the clinician
After difcult or prolonged extractions
As a result of increased intraoral pressure (e.g.,
sneezing, blowing) after an oral surgical
procedure
From no obvious cause
Introduction of air within tissue has been seen after
a large number of dental procedures, but most instances
involve either surgical extraction of teeth, osteotomies,
signicant trauma, or the use of air or water syringes.
In addition, the prevalence has increased as a result of
the use of air-driven handpieces during oral surgery.
On occasion, cervicofacial emphysema has resulted
from compressed air being accidentally forced into
small intraoral lacerations located away from the eld
of operation. Conservative surgical ap design without
extension into fascial planes and limited use of airdriven handpieces during surgical procedures may
minimize the chance of occurrence. Rare reports of
cervicofacial emphysema after self-induced oral injury
have been reported in prisoners attempting to escape
by simulation of a medical emergency and a drug
abuser with Munchausen syndrome who was trying to
access unnecessary medical intervention.
An analogous problem termed pneumoparotid
can arise when air enters the parotid duct, leading to
enlargement of the parotid gland caused by air insufation. This can be accidental, self-induced, or occupa-
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MYOSPHERULOSIS
Placement of topical antibiotic in a petrolatum base
into a surgical site may occasionally result in a unique
foreign body reaction, known as myospherulosis. The
resultant histopathologic pattern is most unusual and
was thought initially to represent a previously undescribed endosporulating fungus.
dure in which a gauze packing coated with an antibiotic ointment was used.
The involved area may exhibit swelling or be discovered as an asymptomatic and circumscribed radiolucency in a previous extraction site (Fig. 8-72). In some
cases pain and purulent drainage have resulted. On
exploration of the lesion, a black, greasy, tarlike material is found.
HISTOPATHOLOGIC FEATURES
The histopathologic pattern is unique; it is the result of
a tissue interaction with both the petroleum base and
the antibiotic, typically tetracycline. Dense collagenous
tissue is intermixed with a granulomatous inammatory response showing macrophages and multinucleated giant cells. Within the connective tissue are
multiple cystlike spaces that contain numerous brownto black-staining spherules (Fig. 8-73). The collections
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BIBLIOGRAPHY
Linea Alba
Kashani HG, Mackenzie IC, Kerber PE: Cytology of linea alba
using a lter imprint technique, Clin Prev Dent 2:21-24,
1980.
Parlak AH, Koybasi S, Yavuz et al: Prevalence of oral lesions in
13- to 16-year old students in Duzce, Turkey, Oral Dis 12:553558, 2006.
Wood NK, Goaz PW: Differential diagnosis of oral and maxillofacial
lesions, ed 5, pp 98-99, St Louis, 1997, Mosby.
Morsicatio Buccarum
Bouquot JE: Common oral lesions found during a mass screening
examination, J Am Dent Assoc 112:50-57, 1986.
Hjrting-Hansen E, Holst E: Morsicatio mucosae oris and suctio
mucosae oris: an analysis of oral mucosal changes due to
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biting and sucking habits, Scand J Dent Res 78:492-499,
1970.
Kocsard E, Schwarz L, Stephen BS et al: Morsicatio buccarum,
Br J Dermatol 74:454-457, 1962.
Reichart PA, Philipsen HP: Betel chewers mucosaa review,
J Oral Pathol Med 27:239-242, 1998.
Romero M, Vicente A, Bravo LA: Prevention of habitual
cheek biting: a case report, Spec Care Dentist 25:214-216,
2005.
Schidt M, Larsen V, Bessermann M: Oral ndings in glassblowers, Community Dent Oral Epidemiol 8:195-200, 1980.
Sewerin I: A clinical and epidemiologic study of morsicatio buccarum/labiorum, Scand J Dent Res 79:73-80, 1971.
Van Wyk CW, Staz J, Farman AG: The chewing lesion of the
cheeks and lips: its features and the prevalence among a
selected group of adolescents, J Dent 5:193-199, 1977.
Eosinophilic Ulcerations
Aloebeid B, Pan L-X, Milligan L et al: Eosinophil-rich CD30+
lymphoproliferative disorder of the oral mucosa, Am J Clin
Pathol 121:43-50, 2004.
Baghdadi ZD: Riga-Fede disease: report of a case and review,
J Clin Pediatr Dent 25:209-213, 2001.
Bhaskar SN, Lilly GE: Traumatic granuloma of the tongue (human
and experimental), Oral Surg Oral Med Oral Pathol 18:206218, 1964.
El-Mofty SK, Swanson PE, Wick MR et al: Eosinophilic ulcer of
the oral mucosa: report of 38 new cases with immunohistochemical observations, Oral Surg Oral Med Oral Pathol 75:716722, 1993.
Eversole LR, Leider AS, Jacobsen PL et al: Atypical histiocytic
granuloma: light microscopic, ultrastructural, and histochemical ndings in an unusual pseudomalignant reactive lesion
of the oral cavity, Cancer 55:1722-1729, 1985.
Ficarra G, Prignano F, Romagnoli P: Traumatic eosinophilic
granuloma of the oral mucosa: a CD30+ (Ki-1) lymphoproliferative disorder, Oral Oncol 33:375-379, 1997.
Hirshberg A, Amariglio N, Akrish S et al: Traumatic ulcerative
granuloma with stromal eosinophilia, Am J Clin Pathol
126:522-529, 2006.
Kabani S, Cataldo E, Folkerth R et al: Atypical lymphohistiocytic
inltrate (pseudolymphoma) of the oral cavity, Oral Surg Oral
Med Oral Pathol 66:587-592, 1988.
Regezi JA, Zarbo RJ, Daniels TE et al: Oral traumatic granuloma:
characterization of the cellular inltrate, Oral Surg Oral Med
Oral Pathol 75:723-727 1993.
Throndson RR, Wright JM, Watkins D: Atypical histiocytic granuloma of the oral mucosa: an unusual clinicopathologic entity
simulating malignancy, J Oral Maxillofac Surg 59:822-826,
2001.
Zaenglein AL, Chang MU, Meehan SA et al: Extensive Riga-Fede
disease of the lip and tongue, J Am Acad Dermatol 47:445-447,
2002.
Electrical Burns
Czerepak CS: Oral splint therapy to manage electrical burns of
the mouths in children, Clin Plast Surg 11:685-692, 1984.
Goto R, Miyabe K, Mori N: Thermal burn of the pharynx and
larynx after swallowing hot milk, Auris Nasus Larynx 29:301303, 2002.
Gormley MB, Marshall J, Jarrett W et al: Thermal trauma: a
review of 22 electrical burns of the lip, J Oral Surg 30:531533, 1972.
Leake JE, Curtin JW: Electrical burns of the mouth in children,
Clin Plast Surg 11:669-683, 1986.
Taylor LB, Walker J: A review of selected microstomia prevention appliances, Pediatr Dent 19:413-418, 1997.
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Submucosal Hemorrhage
Kalpidis CDR, Setayesh RM: Hemorrhaging associated with
endosseous implant placement in the anterior mandible: a
review of the literature, J Periodontol 75:631-645, 2004.
Kravitz P: The clinical picture of cough purpura, benign and
nonthrombocytopenic eruption, Va Med 106:373-374,
1979.
Lee B-J, Park H-J, Heo S-C: Organized hematoma of the maxillary sinus, Acta Otolaryngol 123:869-872, 2003.
Tabaee A, Kacker A: Hematoma of the maxillary sinus presenting
as a massa case report and review of the literature, Int J
Pediatr Otorhinolaryngol 65:153-157, 2002.
Woo BM, Al-Bustani S, Ueeck BA: Floor of mouth haemorrhage
and life-threatening airway obstruction during immediate
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Moore JW, Brekke JH: Foreign body giant cell reaction related
to placement of tetracycline-treated polylactic acid: report of
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Sarkar S, Gangane N, Sharma S: Myospherulosis of maxillary
sinusa case report with review of literature, Indian J Pathol
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Sindwani R, Cohen JT, Pilch BZ et al: Myospherulosis following
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Allergies and Immunologic Diseases
CHAPTER OUTLINE
Transient Lingual Papillitis
Recurrent Aphthous Stomatitis
Minor Aphthous Ulcerations
Major Aphthous Ulcerations
Herpetiform Aphthous Ulcerations
Behets Syndrome
Sarcoidosis
Orofacial Granulomatosis
Wegeners Granulomatosis
CLINICAL FEATURES
Three patterns of transient lingual papillitis have been
documented. The rst pattern is localized and involves
one to several fungiform papillae that become enlarged
and present as elevated papules that are red but may
demonstrate a yellow, ulcerated cap (Fig. 9-1). The
lesions appear most frequently on the anterior portion
of the dorsal surface, are associated with mild to moderate pain, and resolve spontaneously within hours to
several days. In a survey of 163 dental school staff
members, 56% reported previous episodes of transient
lingual papillitis. There was a female predominance,
and the vast majority reported a single affected papilla.
HISTOPATHOLOGIC FEATURES
On histopathologic examination of the rst two variants, affected papillae demonstrate normal surface
epithelium that may reveal focal areas of exocytosis or
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Box 9-1
Behets syndrome
Celiac disease
Cyclic neutropenia
Nutritional deciencies (iron, folate, zinc, B1, B2, B6,
B12)
IgA deciency
Immunocompromised conditions, including human
immunodeciency virus (HIV) disease
Inammatory bowel disease
MAGIC syndrome (mouth and genital ulcers with
inamed cartilage)
PFAPA syndrome (periodic fever, aphthous
stomatitis, pharyngitis, cervical adenitis)
Reactive arthritis
Sweets syndrome
Ulcus vulvae acutum
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1. Minor
2. Major
3. Herpetiform
Minor aphthous ulcerations (Mikuliczs aphthae)
are the most common and represent the pattern present
in more than 80% of those affected. Major aphthous
ulcerations (Suttons disease or periadenitis mucosa
necrotica recurrens [PMNR]) occur in approximately
10% of the patients referred for treatment. The remaining patients have herpetiform aphthous ulcerations.
The minor and major forms most likely represent variations of the same process, although herpetiform
aphthae demonstrate a unique pattern. Some investigators differentiate the herpetiform variant because of
supposed evidence of a viral cause, but the proof is
weak and does not justify its distinction from the other
aphthous ulcerations. Some authors include Behets
syndrome as an additional variation of aphthous stomatitis, but this multisystem disorder is more complex
and is considered later in this chapter.
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CLINICAL FEATURES
Aphthous ulcerations are noted more frequently in
children and young adults, with approximately 80% of
affected individuals reporting their rst ulceration
before the age of 30. In one large series of 17,235
adults older than 17 years of age, the point prevalence
of aphthous ulcerations was 0.89%, with the annual
incidence in adults younger than 40 years old being
almost twice that of older adults (22.5% versus
13.4%).
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rence rate is highly variable, ranging from one ulceration every few years to two episodes per month.
HISTOPATHOLOGIC FEATURES
The histopathologic picture of aphthous stomatitis is
characteristic but not pathognomonic. The early ulcerative lesions demonstrate a central zone of ulceration,
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Fig. 9-10 Major aphthous ulceration. A, Large ulceration of the left anterior buccal mucosa.
B, Same lesion after 5 days of therapy with betamethasone syrup used in a swish-and-swallow
method. The patient was free of pain by the second day of therapy. The ulceration healed
completely during the next week.
DIAGNOSIS
No laboratory procedure provides denitive diagnosis.
The diagnosis is made from the clinical presentation
and from exclusion of other diseases that produce
ulcerations that closely resemble aphthae (see Box
9-1). In patients with complex aphthous ulcerations, a
systematic evaluation for an underlying trigger or associated systemic condition is prudent. In a review of 244
patients with complex aphthous ulcerations, an associated triggering condition (e.g., hematologic deciency,
gastrointestinal disease, immunodeciency, drug reaction) was discovered in almost 60%. Because the histopathologic features are nonspecic, a biopsy is useful
only in eliminating differential possibilities and is not
benecial in arriving at the denitive diagnosis.
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thermore, some of these treatments may have signicant side effects or may be quite expensive. Included
within the list of therapies are acyclovir, amlexanox,
topical 5-aminosalicylic acid, azelastine hydrochloride,
benzydamine hydrochloride, carbenoxolone sodium,
chemical cauterizing agents, chlorhexidine, colchicine, cyclosporine, dapsone, deglycyrrhizinated
liquorice, gamma globulin, hydrogen peroxide, hydroxypropyl cellulose lms, interferon-, irsogladine maleate,
levamisole, LongoVital, monoamine oxidase (MAO)
inhibitors, pentoxifylline, prostaglandin E-2 gel, sucralfate, sodium cromoglycate (cromolyn), tacrolimus, tetracyclines, thalidomide, transfer factor (extract of
immunocytes), triclosan, and vitamin and mineral supplements (especially zinc sulfate). The success of these
therapies is highly variable. These treatments do not
resolve the underlying problem and are merely an
attempt to beat back brush res. Recurrences often
continue, although breaking up the cycle may induce
longer disease-free intervals between attacks. Surgical
removal of aphthous ulcerations has been used but is
an inappropriate therapy. Although laser ablation
shortens the duration and decreases associated symptoms, its use is of very limited practical benet because
patients cannot return on each recurrence.
Chemical cautery with silver nitrate continues to be
suggested as an effective therapy, but it can no longer
be recommended because of the numerous safer alternatives and its rare association with massive necrosis
(see page 292) and systemic argyria (see page 315). An
over-the-counter cautery that uses sulfuric acid and
phenolic agents is indicated in certain situations, but
patients must be warned of the potential for signicant
local tissue necrosis related to its misuse.
Patients with complex aphthosis require a more
extensive evaluation for occult systemic disease and a
search for possible triggers of the immune-mediated
mucosal destruction. To go beyond the management of
individual recurrences is difcult, expensive, and often
frustrating. In spite of this, patients with severe disease
should be offered the opportunity to investigate the
underlying causes.
As previously mentioned, the immune attacks are
usually a result of immunodysregulation, a decreased
mucosal barrier, or an elevated antigenic stimulus. The
evaluation for systemic disorders usually eliminates
the rst two causes. Typically, this is followed by patch
tests for antigen stimuli or an elimination diet for possible offending foods. Therapeutic trials might be instituted against the viruses and bacteria that have been
implicated in subsets of patients with aphthous stomatitis. The investigator should explain to the patient that
the underlying causation is diverse; even with the most
exhaustive search, the answer may be elusive. In many
cases, stress appears involved, and all evaluations in
CLINICAL FEATURES
As mentioned previously, the highest prevalence occurs
in the Middle East and Japan, with a much lower frequency noted in northern Europe, the United States,
and the United Kingdom. At the time of discovery,
most patients are young adults, with the disease diagnosed uncommonly in blacks, children, and older
adults.
Oral involvement is an important component of
Behets syndrome, and it is the rst manifestation in
25% to 75% of the cases. Oral lesions occur at some
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Aphthaelike ulcerations
Anterior or posterior uveitis, cells in vitreous on slit-lamp examination, or retinal vasculitis
Erythema nodosum, pseudofolliculitis or papulopustular lesions, or acneiform nodules
noted in postadolescent patients not receiving corticosteroids
Read by physician at 24-48 hours
DIAGNOSIS
No laboratory nding is diagnostic of Behets syndrome. In an attempt to standardize diagnoses, denitive criteria have been developed. Table 9-1 delineates
the requirements proposed by the Behets International Study Group. Although this system is used widely,
many authorities exclude acneiform skin lesions in
young adults from the criteria because of the high
prevalence of this nding in an otherwise normal
population.
HISTOPATHOLOGIC FEATURES
The histopathologic features are not specic for
Behets syndrome and can be seen in many disorders,
including aphthous stomatitis. The pattern most fre-
SARCOIDOSIS
Sarcoidosis is a multisystem granulomatous disorder
of unknown cause. Jonathan Hutchinson initially
described the disease in 1875, but Boeck coined the
term sarcoidosis (Greek meaning eshlike condition)
14 years later. The evidence implicates improper degradation of antigenic material with the formation of
noncaseating granulomatous inammation. The nature
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of the antigen is unknown, and probably several different antigens may be responsible. Possible involved
antigens include infectious agents (e.g., mycobacterium, propionibacteria, Epstein-Barr virus, human herpesvirus 8 [HHV-8]) and a number of environmental
factors (e.g., wood dust, pollen, clay, mold, silica). The
inappropriate defense response may result from prolonged or heavy antigenic exposure, an immunodysregulation (genetic or secondary to other factors) that
prevents an adequate cell-mediated response, a defective regulation of the initial immune reaction, or a
combination of all three of these factors. Several investigators have conrmed a genetic predisposition and
positive associations with certain HLA types.
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CLINICAL FEATURES
Sarcoidosis has a worldwide distribution but is recognized more commonly in the developed world. In
North America, blacks are affected 10 to 17 times
more frequently than whites. There is a slight female
predominance, and the disease exhibits a bimodal age
distribution, with the rst peak between 25 and 35
years of age and the second peak between 45 and 65
years of age.
Sarcoidosis most commonly appears acutely over a
period of days to weeks, and the symptoms are variable. Common clinical symptoms include dyspnea, dry
cough, chest pain, fever, malaise, fatigue, arthralgia,
and weight loss. Less frequently, sarcoidosis arises
insidiously over months to years, without signicant
symptoms; when clinically evident, pulmonary symptoms are most common. Approximately 20% of patients
have no symptoms, and the disease is discovered on
routine chest radiographs.
Although any organ may be affected, the lungs,
lymph nodes, skin, eyes, and salivary glands are the
predominant sites. Lymphoid tissue is involved in
almost all cases. The mediastinal and paratracheal
lymph nodes are involved commonly, and chest radiographs frequently reveal bilateral hilar lymphadenopathy. Approximately 90% of affected patients will reveal
an abnormal chest radiograph sometime during the
course of the disease. Cutaneous manifestations occur
about 25% of the time. These often appear as chronic,
violaceous, indurated lesions that are termed lupus
pernio and frequent the nose, ears, lips, and face (Fig.
9-14). Symmetrical, elevated, indurated, purplish
plaques also are seen commonly on the limbs, back,
and buttocks. Scattered, nonspecic, tender erythematous nodules, known as erythema nodosum, frequently occur on the lower legs.
Ocular involvement is noted in 25% of the cases and
most often appears as anterior uveitis. Lesions of the
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HISTOPATHOLOGIC FEATURES
DIAGNOSIS
The diagnosis is established by the clinical and radiographic presentations, the histopathologic appearance,
and the presence of negative ndings with both special
stains and cultures for organisms. Elevated serum
angiotensin-converting enzyme (ACE) levels and
appropriate documentation of pulmonary involvement
strongly support the diagnosis. Other laboratory
abnormalities that may be seen include eosinophilia;
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Systemic Cause
Chronic granulomatous disease
Crohns disease
Sarcoidosis
Tuberculosis
DISEASES
OROFACIAL GRANULOMATOSIS
Since Wiesenfeld introduced it 1985, orofacial granulomatosis has become a well-accepted and unifying
term encompassing a variety of clinical presentations
that, on biopsy, reveal the presence of nonspecic
granulomatous inammation. The conditions previously designated as Melkersson-Rosenthal syndrome
and cheilitis granulomatosa of Miescher are subsets of
orofacial granulomatosis, and neither represents a
specic disease.
The disorder is somewhat analogous to aphthous
stomatitis, in that the cause is idiopathic but appears to
represent an abnormal immune reaction. Sometimes
oral lesions are seen that are identical to idiopathic
orofacial granulomatosis but represent a secondary
reaction to one or more of a variety of factors. Table 9-2
delineates systemic diseases that may mimic orofacial
granulomatosis, and Table 9-3 lists possible local
causes. Although many researchers have presented
evidence that the immune response appears secondary
to a chronic antigenic stimulus, the pathosis most likely
has numerous triggers, resulting in various theories
that are correct only in subsets of patients.
The majority of patients are adults; however, the
process may occur at any age. When noted in children
and adults younger than 30 years old, some investiga-
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Local Cause
Chronic oral infection
Foreign material
Allergy
Intervention
Eliminate all oral foci of infection.
The foreign debris noted in iatrogenic gingivitis is often subtle and difcult to associate
denitively with the diffuse inammatory process. If lesions are nonmigrating and isolated
to gingiva, then response to local excision of a single focus should be evaluated.
Cosmetics, foods, food additives, avorings, oral hygiene products (e.g., toothpaste, mouth
rinses), and dental restorative metals have been implicated. Patch testing (i.e., contact
dermatitis standard series with oral battery) or elimination diet may discover the offending
antigen.
CLINICAL FEATURES
The clinical presentation of orofacial granulomatosis is
highly variable. By far, the most frequent site of involvement is the lips. The labial tissues demonstrate a nontender, persistent swelling that may involve one or
both lips (Fig. 9-19). On rare occasions, supercial
amber vesicles, resembling lymphangiomas, are found.
When these signs are combined with facial paralysis
and a ssured tongue, the clinical presentation is called
Melkersson-Rosenthal syndrome (Figs. 9-20 and
9-21). Involvement of the lips alone is called cheilitis
granulomatosa (of Miescher). Some consider cheilitis granulomatosa an oligosymptomatic form of
Melkersson-Rosenthal syndrome, but it appears best to
include all of these under the term orofacial granulomatosis. In addition to labial edema, swelling of other parts
of the face may be seen, and cervical lymphadenopathy
rarely has been noted.
Intraoral sites also can be affected, and the predominant lesions are edema, ulcers, and papules. The tongue
may develop ssures, edema, paresthesia, erosions, or
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DIAGNOSIS
HISTOPATHOLOGIC FEATURES
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Fig. 9-24 Orofacial granulomatosis. A, Diffuse enlargement of the upper lip. B, Same
patient after intralesional triamcinolone injections.
Fig. 9-25 Orofacial granulomatosis. Same patient depicted in Fig. 9-24. A, Clinical
appearance before local therapy. B, Signicant resolution after intralesional corticosteroid
therapy.
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WEGENERS GRANULOMATOSIS
Wegeners granulomatosis is a well-recognized,
although uncommon, disease process of unknown
cause. The initial description of the syndrome by
Wegener included necrotizing granulomatous lesions
of the respiratory tract, necrotizing glomerulonephritis, and systemic vasculitis of small arteries and veins.
Hypotheses about the cause of the disease include an
abnormal immune reaction secondary to a nonspecic
infection or an aberrant hypersensitivity response to an
inhaled antigen. A possible hereditary predisposition
has been mentioned in some cases.
Before the current treatment modalities were initiated, the disorder was uniformly fatal. The disease
begins as a localized process, which may become more
widely disseminated if left untreated. Most patients
respond favorably to treatment; consequently, early
diagnosis and appropriate therapy are critical.
CLINICAL FEATURES
Wegeners granulomatosis demonstrates a wide age
range from childhood to old age, with a mean of
approximately 40 years and no sex predilection. The
disease can involve almost every organ system in the
body. With classic Wegeners granulomatosis, patients
initially show involvement of the upper and lower
respiratory tract; if the condition remains untreated,
then renal involvement often rapidly develops (generalized Wegeners granulomatosis).
Limited Wegeners granulomatosis is diagnosed
when there is involvement of the respiratory system
without rapid development of renal lesions. One subset
of patients exhibits lesions primarily of the skin and
mucosa, a condition termed supercial Wegeners
granulomatosis. In this form of the disease, systemic
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HISTOPATHOLOGIC FEATURES
Wegeners granulomatosis appears as a pattern of
mixed inammation centered around blood vessels.
Involved vessels demonstrate transmural inammation, often with areas of heavy neutrophilic inltration,
necrosis, and nuclear dust (leukocytoclastic vasculitis).
The connective tissue adjacent to the vessel has an
inammatory cellular inltrate, which contains a variable mixture of histiocytes, lymphocytes, eosinophils,
and multinucleated giant cells (Fig. 9-28). Special
stains for organisms are negative, and no foreign material can be found. In oral biopsy specimens, the oral
epithelium may demonstrate pseudoepitheliomatous
hyperplasia and subepithelial abscesses. Because of the
paucity of large vessels in many oral mucosal biopsies,
vasculitis may be difcult to demonstrate, and the histopathologic presentation may be one of ill-dened
collections of epithelioid histiocytes intermixed with
eosinophils, lymphocytes, and multinucleated giant
cells. In addition, the lesions of strawberry gingivitis
typically demonstrate prominent vascularity with
extensive red blood cell extravasation (Fig. 9-29).
DIAGNOSIS
The diagnosis of Wegeners granulomatosis is made
from the combination of the clinical presentation and
the microscopic nding of necrotizing and granulomatous vasculitis. Radiographic evaluation of the chest
and sinuses is recommended to document possible
involvement of these areas. The serum creatinine and
urinalysis results are used to rule out signicant renal
alterations.
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Box 9-2
Box 9-4
Analgin
Barbiturates
Co-trimoxazole
Dapsone
Phenazone derivatives
Phenolphthalein
Salicylates
Sulfonamides
Tetracycline
Carbamazepine
Chlorpromazine
Etanercept
Ethosuximide
Gold
Griseofulvin
Hydantoins
Hydralazine
Iniximab
Isoniazid
Lithium
Methyldopa
Penicillamine
Primidone
Procainamide
Quinidine
Reserpine
Streptomycin
Thiouracil
Trimethadione
Box 9-3
Box 9-5
Medications Implicated in
Lichenoid Eruptions
Allopurinol
Amiphenazole
Amphotericin
Arsenicals
Bismuth
Captopril
Carbamazepine
Chloroquine
Chlorothiazide
Chlorpropamide
Cimetidine
Cyanamide
Dapsone
Fenclofenac
Furosemide
Gold salts
Hydroxychloroquine
Ketoconazole
Levamisole
Lithium
Lorazepam
Mercury
Methyldopa
Metopromazine
Oxyprenolol
Palladium
Paraaminosalicylic acid
Penicillamine
Phenothiazines
Phenylbutazone
Practolol
Propranolol
Pyrimethamine
Pyritinol
Quinacrine
Quinidine
Spironolactone
Streptomycin
Sulfonylureas
Tetracycline
Tolbutamide
Triprolidine
Medications Implicated in
Pemphigus-Like Eruptions
Penicillamine
Phenobarbital
Phenylbutazone
Piroxicam
Practolol
Propranolol
Pyritinol chlorhydrate
Rifampin
Thiopromine
Box 9-6
-Mercaptopropionyl
glycine
Ampicillin
Captopril
Cephalexin
Ethambutol
Glibenclamide
Gold
Heroin
Ibuprofen
Captopril
Gold salts
Hydroxyurea
Indomethacin
Losartan
Meprobamate
Methyldopa
Naproxen
Nicorandil
Penicillamine
Phenylbutazone
Propranolol
Spironolactone
Thiazide diuretics
Tolbutamide
CLINICAL FEATURES
The patterns of mucosal alterations associated with the
systemic administration of medications are varied,
almost as much as the number of drugs that result in
these changes. Anaphylactic stomatitis may occur alone
or in conjunction with urticarial skin lesions or other
signs and symptoms of anaphylaxis (e.g., hoarseness,
respiratory distress, vomiting). The affected mucosa
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HISTOPATHOLOGIC FEATURES
Anaphylactic stomatitis typically reveals a nonspecic
pattern of subacute mucositis that contains lymphocytes intermixed with eosinophils and neutrophils.
Fixed drug eruptions also reveal a mixed inammatory
cellular inltrate that consists of lymphocytes, eosinophils, and neutrophils, often combined with spongiosis
and exocytosis of the epithelium. Vacuolar change of
the basal cell layer and individual necrotic epithelial
cells are occasionally noted. The drug reactions that
simulate lichen planus, lupus erythematosus, and pemphigus resemble their namesakes. The histopathologic
and immunologic features of these chronic drug reactions cannot be used reliably to separate them from
their associated primary immunologic disease.
Immunouorescence has been used in an attempt
to separate drug reactions from primary vesiculoerosive disease. In most instances, this technique has
proven to be unsatisfactory. In spite of these ndings,
a unique pattern of reaction has been seen when indirect immunouorescence for IgG has been performed
in patients with lichenoid drug reactions. In many of
these patients, a distinctive annular uorescent pattern,
termed string of pearls, has been noted along the cell
membrane of the basal cell layer of stratied squamous
epithelium. The detected circulating antibody has been
termed basal cell cytoplasmic antibody. Although
further study is desirable, this technique may prove to
be a useful adjunct during evaluation of oral lichenoid
lesions.
DIAGNOSIS
A detailed medical history must be obtained, and the
patient should be questioned closely concerning the
use of both prescription and over-the-counter medica-
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tions. Once a potentially offending medication is discovered, a temporal relationship between the drugs
use and the mucosal alteration must be established.
The association may be acute and obvious, or the onset
of the oral lesions may be delayed. If more than one
medication is suspected, then serial elimination of the
medications can be performed in collaboration with
the patients physician until the offending agent is
discovered.
In chronic drug reactions, denitive diagnosis can
be made if the mucosal alterations resolve after resolution of the medication and recur on reintroduction of
the agent. Presumptive diagnosis is usually sufcient
and justied when the mucosal alterations clear after
cessation of the offending medication.
In possible lupuslike drug reactions, serum evaluation for generic antinuclear antibodies (ANAs) and
antibodies against double-stranded DNA and histones
often can be benecial. Lupuslike drug reactions typically are associated with circulating generic ANAs and
antibodies against histones, whereas lupus erythematosus also reveals antibodies to double-stranded DNA
(a nding not typically noted in drug reactions). This
pattern does not hold true in reactions associated with
the TNF- antagonists, iniximab and etanercept,
which simulate systemic lupus erythematosus (SLE)
very closely and are associated with antibodies to
double-stranded DNA.
CLINICAL FEATURES
ALLERGIC CONTACT STOMATITIS
(STOMATITIS VENENATA)
The list of agents reported to cause allergic contact
stomatitis reactions in the oral cavity is extremely
diverse. Numerous foods, food additives, chewing
gums, candies, dentifrices, mouthwashes, glove and
rubber dam materials, topical anesthetics, restorative
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DIAGNOSIS
Usually, the diagnosis of acute contact stomatitis is
straightforward because of the temporal relationship
between the use of the agent and the resultant eruption. If an acute oral or circumoral reaction is noted
within 30 minutes of a dental visit, then allergy to all
used dental materials, local anesthetics, and gloves
should be investigated.
The diagnosis of chronic contact stomatitis is much
more difcult. Most investigators require good oral
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PERIORAL DERMATITIS
Perioral dermatitis refers to a unique inammatory
skin disease that involves the circumoral area. Although
the exact mechanism is uncertain, many investigators
believe the process arises from an idiosyncratic
response to a variety of exogenous substances; once this
process is initiated, potent topical corticosteroid use
worsens the condition. Although the vast majority of
affected patients report topical corticosteroid use, only
a minority initiate this therapy before initial development of the dermatitis. Exogenous substances reported
to initiate the rash include tartar-control toothpaste,
bubble gum, moisturizers, night creams, and other
cosmetic products (e.g., foundation). Some of these
substances may initially induce an irritant or allergic
contact dermatitis, whereas others are thought to
produce inappropriate occlusion of the skin surface
with subsequent proliferation of skin ora.
CLINICAL FEATURES
Perioral dermatitis appears with persistent erythematous papules and papulopustules that involve the skin
surrounding the vermilion border of the upper and
lower lips (Fig. 9-35). Classically, there is a zone of
spared skin immediately adjacent to the vermilion
border. Pruritus is variable. In adults, more than 90%
of affected patients are women, lending further support
to the association with cosmetic use. The prevalence of
perioral dermatitis appears to be increasing and may
be related to the greater percentage of cosmeticwearing women in the workforce. In children, the
female predominance is dramatically reduced or is
nonexistent in some studies. In addition, an identical
pattern of periorbital and perinasal dermatitis often
HISTOPATHOLOGIC FEATURES
Biopsy of perioral dermatitis demonstrates a variable
pattern. In many cases there is a chronic lymphohistiocytic dermatitis that often exhibits spongiosis of the
hair follicles. In other patients a rosacea-like pattern is
noted in which there is perifollicular granulomatous
inammation. On occasion, this histopathologic pattern
has been misdiagnosed as sarcoidosis.
Mucosal abnormalities secondary to the use of articially avored cinnamon products are fairly common,
but the range of changes was not widely recognized
until the late 1980s. Cinnamon oil is used as a avoring
agent in confectionery, ice cream, soft drinks, alcoholic
beverages, processed meats, gum, candy, toothpaste,
breath fresheners, mouthwashes, and even dental oss.
Concentrations of the avoring are up to 100 times
that in the natural spice. The reactions are documented
most commonly in those products associated with prolonged or frequent contact, such as candy, chewing
gum, and toothpaste. The anticalculus components of
tartar-control toothpastes have a strong bitter avor
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CLINICAL FEATURES
The clinical presentations of contact stomatitis vary
somewhat, according to the medium of delivery. Toothpaste results in a more diffuse pattern; the signs associated with chewing gum and candy are more localized.
Pain and burning are common symptoms in all cases.
The gingiva is the most frequent site affected by
toothpaste, often resembling plasma cell gingivitis
(see page 159); enlargement, edema, and erythema are
common. Sloughing of the supercial oral epithelium
without creation of an erosion is seen commonly. Erythematous mucositis, occasionally combined with
erosion, has been reported on the buccal mucosa and
tongue. Exfoliative cheilitis and circumoral dermatitis
also may occur.
Reactions from chewing gum and candy are more
localized and typically do not affect the lip vermilion
or perioral skin. Most of the lesions appear on the
buccal mucosa and lateral borders of the tongue. Buccal
mucosal lesions often are oblong patches that are
aligned along the occlusal plane (Fig. 9-36). Individual
lesions have an erythematous base but often are predominantly white as a result of hyperkeratosis of the
surface epithelium. Ulceration within the lesions may
occur. Hyperkeratotic examples often exhibit a ragged
surface and occasionally may resemble the pattern
seen in morsicatio (see page 286). Lingual involvement
may become extensive and spread to the dorsal surface
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(Fig. 9-37). Signicant thickening of the surface epithelium can occur and may raise clinical concern for oral
hairy leukoplakia (OHL) (see page 268) or carcinoma
(Fig. 9-38).
HISTOPATHOLOGIC FEATURES
Usually, the epithelium in contact stomatitis from articial cinnamon avoring is acanthotic, often with elongated rete ridges and thinning of the suprapapillary
plates. Hyperkeratosis and extensive neutrophilic exocytosis may be present. The supercial lamina propria
demonstrates a heavy inammatory cell inltrate that
consists predominantly of lymphocytes that may be
intermixed with plasma cells, histiocytes, or eosinophils. This inltrate often obscures the epithelium and
connective tissue interface (Fig. 9-39). A characteristic
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patient with an atypical pattern of gingivitis. Dietrelated examples often are the most difcult to diagnose and may necessitate cutaneous allergy patch
testing or a diet diary to isolate the cause.
DIAGNOSIS
With a high index of suspicion and knowledge of the
variations of the clinical pattern, the diagnosis of localized contact stomatitis often can be made from the
clinical appearance and the history of cinnamon use.
Often biopsies are performed for atypical or extensive
cases because of the differential diagnosis, which
includes several signicant vesiculoerosive and neoplastic conditions. The histopathologic features are not
specic, but they are sufcient to raise a high index of
suspicion in an oral and maxillofacial pathologist
who is familiar with the pattern. Use of cinnamoncontaining toothpaste should be investigated in every
LICHENOID CONTACT
STOMATITIS FROM DENTAL
RESTORATIVE MATERIALS
Since the nineteenth century when dental amalgam
began to have widespread use, the material has been
associated in the lay press with almost every medical
ailment known to man. Such accusations tend to occur
in cycles. Mercury within amalgam has been accused
of producing Alzheimers disease, neurotoxicity, kidney
dysfunction, reduced immunocompetence, alterations
of oral and intestinal bacteria, birth defects, and adverse
effects on general health. In spite of intense scrutiny,
there appears to be no relationship between any of
these physical disorders and the use of amalgam restorations (see the discussion of systemic intoxication
from mercury, page 313). An investigation of patients
with concerns associated with their amalgam restorations reveals that most of their complaints can be associated with oral, dental, or medical problems unrelated
to the restorations.
A review of the ill effects of mercury in dental
amalgam demonstrates that the occurrence of toxicity
is negligible, but a small percentage (1% to 2%) of those
who are allergic to mercury can react to the mercury
released from dental amalgams. The frequency of
adverse effects to dental amalgam is estimated to be
one case per million. Acute hypersensitivity reactions
typically appear 2 to 24 hours after the removal and
replacement of dental amalgam, and the symptoms
disappear after 10 to 14 days.
In contrast, chronic reactions are not rare and may
arise from hypersensitivity or a chronic toxic reaction
from almost any dental metal. When the reaction is
related to hypersensitivity, the most frequent antigen
is mercury or a mercury compound; gold is a distant
second. Even less commonly, copper, palladium, silver,
tin, zinc, beryllium, chromium, cobalt, or platinum is
responsible. Some investigators have called these alterations galvanic lesions, but neither clinical nor experi-
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Fig. 9-41 Oral mucosal contact reaction to dental amalgam. A, Hyperkeratotic lesion with
a peripheral radiating pattern on the lateral border of the tongue on the right side; the altered
mucosa contacted the amalgams of the adjacent mandibular molar teeth. The lesion remained
in the same location for 5 years and periodically became erosive and symptomatic. Smoothing
and polishing of the adjacent restorations had no effect. B, Appearance of previously altered
area of the tongue 14 days after removal of adjacent amalgams. Note total resolution of the
mucosal alterations.
CLINICAL FEATURES
The most commonly affected sites for lichenoid contact
stomatitis are the posterior buccal mucosa and the
ventral surface of the lateral borders of the tongue.
Gingival cuffs adjacent to subgingival metallic restorations and porcelain-fused-to-metal (PFM) crowns with
metal collars also may be affected. The lesions usually
are conned to the area of contact but may extend up
to 1 cm beyond the point of mucosal association. The
affected mucosa may be white or erythematous, with
or without peripheral striae (Fig. 9-41). Most patients
have no symptoms, but periodic erosion may be noted.
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DIAGNOSIS
The diagnosis is made from the clinical appearance of
the lesions, the lack of migration, and the correlation
to adjacent dental metal (Fig. 9-42). Although the histopathologic features may be indistinguishable from
lichen planus, biopsy occasionally is performed to
conrm the clinical impression and to rule out other
pathoses such as epithelial dysplasia. Although patch
testing is not necessary for a strong presumptive diagnosis, the procedure does help identify patients who
are predisposed to react to the metal (possibly advantageous in a patient with a single site of lichenoid stomatitis who also has numerous similar, but less corroded,
restorations demonstrating mucosal contact). In addition, the patch testing will include a battery of additional dental metals that will assist in the choice of
material for future restorations.
HISTOPATHOLOGIC FEATURES
Biopsy of allergic contact stomatitis from dental materials exhibits numerous features of lichen planus. The
surface epithelium may be hyperkeratotic, atrophic, or
ulcerated. Areas of hydropic degeneration of the basal
cell layer often are present. The supercial lamina
propria contains a dense bandlike chronic inammatory cellular inltrate consisting predominantly of lymphocytes, but there may be scattered plasma cells. On
occasion, deeper lymphoid aggregates may be noted,
often in a perivascular orientation.
ANGIOEDEMA (ANGIONEUROTIC
EDEMA; QUINCKES DISEASE)
Angioedema is a diffuse edematous swelling of the
soft tissues that most commonly involves the subcutaneous and submucosal connective tissues but may
affect the gastrointestinal or respiratory tract, occasionally with fatal results. The disorder has been referred
to as Quinckes disease, after the clinician who initially related the changes to an alteration in vascular
permeability. The outdated term angioneurotic
edema also has been used, because affected patients
often complained of a choking sensation and were
labeled neurotic.
The most common cause is mast cell degranulation,
which leads to histamine release and the typical clinical alterations. IgE-mediated hypersensitivity reactions
caused by drugs, foods, plants, dust, and inhalants
produce mast cell degranulation and are fairly common.
Contact allergic reactions to foods, cosmetics, topical
medications, and even dental rubber dams also have
been responsible. Mast cell degranulation can even
result from physical stimuli, such as heat, cold, exercise, emotional stress, solar exposure, and signicant
vibration.
An unusual pattern of drug reaction that can produce
severe forms of angioedema that are not mediated by
IgE is the type associated with use of drugs called angiotensin-converting enzyme (ACE) inhibitors. These medications are a popular treatment of essential hypertension
and chronic heart failure; commonly prescribed ACE
inhibitors include captopril, enalapril, and lisinopril.
The swelling associated with these drugs does not
respond well to antihistamines and was thought to be
the result of excess bradykinin (ACE degrades bradykinin). In an attempt to avoid this angioedema, a second
generation of medications called angiotensin II receptor
blockers (e.g., losartan, valsartan) was developed specically to avoid any inhibition of bradykinin degradation.
These newer medications lower the frequency of
angioedema, but do not eliminate the adverse reaction.
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The prevalence of this pattern of angioedema is estimated to be 0.1% to 0.2% of those who use ACE inhibitors. In the majority of affected patients, the angioedema
arises within hours of initial use of the drug. In up to
30% of the cases, the angioedema is delayed, with the
longest reported interval between drug use initiation
and the initial attack being 7 years. Attacks precipitated by dental procedures have been reported in longterm users of ACE inhibitors. Many clinicians overlook
the association between angioedema and ACE inhibitors, with studies demonstrating continued administration of the medication in more than 50% of affected
patients.
Angioedema also can result from activation of
the complement pathway. This may be hereditary or
acquired. Two rare autosomal dominant hereditary
forms are seen. Type I, comprising 85% of the hereditary cases, is caused by a quantitative reduction in the
inhibitor that prevents the transformation of C1 to C1
esterase. Without adequate levels of C1 esterase inhibitor (C1-INH), C1 esterase cleaves C4 and C2 and
results in angioedema. Type II exhibits normal levels
of C1-INH, but the inhibitor is dysfunctional.
The acquired type of C1-INH deciency is seen in
association with certain types of lymphoproliferative
diseases or in patients who develop specic autoantibodies. In lymphoproliferative diseases, monoclonal
antibodies directed against the tumor cells activate C1
and lead to consumption of C1-INH. In the autoimmune variant, the antibody attaches to the C1 receptor
on the C1-INH molecule, leading to decreased functional C1-INH and consumption of C1. In both the
acquired and the hereditary forms of abnormal C1INH activity, minor trauma, such as a dental procedure, can precipitate an attack.
Finally, angioedema has been seen in the presence
of high levels of antigen-antibody complexes (e.g., lupus
erythematosus, viral or bacterial infections) and in
patients with grossly elevated peripheral blood eosinophil counts.
CLINICAL FEATURES
Angioedema is characterized by the relatively rapid
onset of soft, nontender tissue swelling, which may
be solitary or multiple (Fig. 9-43). In the hereditary
forms, the initial onset typically is noted in childhood
or adolescence. The episodes are unpredictable and
intermixed with edema-free intervals. Recurrent skin
swelling and abdominal pain are the most frequent
presentations. The extremities are the most common
cutaneous sites of involvement, although the face, genitals, trunk, and neck also can be affected. Although not
individually frequent, edema of the larynx, pharynx,
uvula, or soft palate may be noted when patients are
357
monitored for extended periods (and may be associated with respiratory distress). A deeper voice, hoarseness, aphonia, and dyspnea are important warning
signs. Recurrent snoring-induced edema of the soft
palate has been reported and associated with severe
dyspnea. Isolated tongue involvement is uncommon.
Involvement of the skin and mucous membranes can
cause enlargements that may measure up to several
centimeters in diameter (Fig. 9-44). Although pain is
unusual, itching is common and erythema may be
present. The enlargement typically resolves over 24 to
72 hours. In contrast to the hereditary variants, allergic, acquired, and ACE inhibitorassociated angioedema demonstrate signicant involvement of the
head and neck, such as the face, lips, tongue, oor of
mouth, pharynx, and larynx. The risk of angioedema
associated with ACE inhibitors is signicantly greater
in blacks (three to four times that of other races), and
this pattern is the type most frequently encountered by
oral health practitioners.
DIAGNOSIS
In cases of allergic causation, the diagnosis of angioedema often is made from the clinical presentation in
conjunction with the known antigenic stimulus. When
multiple antigenic exposures occur, the diagnosis of
the offending agent can be difcult and involves dietary
diaries and antigenic testing.
Those patients whose conditions cannot be related
to antigenic exposure or medications should be evaluated for the presence of adequate functional C1-INH.
In the hereditary types, both forms exhibit normal
levels of C1 and decreased levels of functional C1-INH.
Type I demonstrates a decreased quantity of C1-INH;
type II exhibits normal levels of the inhibitor (but it is
not functional). Both acquired forms demonstrate low
levels of both C1-INH and C1.
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Fig. 9-44 Angioedema. A, Soft, nontender tissue swelling of the face arose relatively rapidly
after dental treatment. B, Facial appearance after resolution of edematous facial enlargement.
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BIBLIOGRAPHY
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Pedersen A, Hougen HP, Kenrad B: T-lymphocyte subsets in oral
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Rivera-Hidalgo F, Shulman JD, Beach MM: The association of
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Wray D, Graykowski EA, Notkins AL: Role of mucosal injury in
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Behets Syndrome
Escudier M, Bagan J, Scully C: Mucosal disease series. Number
VII. Behets disease (Adamantiades syndrome), Oral Dis
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Helm TN, Camisa C, Allen C et al: Clinical features of Behets
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McCarty MA, Garton RA, Jorizzo JL: Complex aphthosis and
Behets disease, Dermatol Clin 21:41-48, 2003.
Sarcoidosis
Batal H, Chou LL, Cottrell DA: Sarcoidosis: medical and dental
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Marx RE, Hartman KS, Rethman KV: A prospective study comparing incisional labial to incisional parotid biopsies in the
detection and conrmation of sarcoidosis, Sjgrens disease,
sialosis and lymphoma, J Rheumatol 15:621-629, 1988.
Saboor SA, Johnson NM: Sarcoidosis, Br J Hosp Med 48:293-302,
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Suresh L, Aguirre A, Buhite RJ et al: Intraosseous sarcoidosis of
the jaws mimicking aggressive periodontitis: a case report
and literature review, J Periodontol 75:478-182, 2004.
Suresh L, Radfar L: Oral sarcoidosis: a review of the literature,
Oral Dis 11:138-145, 2005.
Tozman ECS: Sarcoidosis: clinical manifestations, epidemiology,
therapy, and pathophysiology, Curr Opin Rheumatol 3:155159, 1991.
Orofacial Granulomatosis
Allen CM, Camisa C, Hamzeh S et al: Cheilitis granulomatosa:
report of six cases and review of the literature, J Am Acad
Dermatol 23:444-450, 1990.
Gibson J, Neilly JB, Wray APM et al: 99Tcm-HMPAO leucocyte
labelling in orofacial granulomatosis and gastrointestinal
Crohns disease in childhood and early adulthood, Nucl Med
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Kauzman A, Quesnel-Mercier A, Lalonde B: Orofacial granulomatosis: 2 case reports and literature review, J Can Dent Assoc
72:325-329, 2006.
Leo JC, Hodgson T, Scully C et al: Review article: orofacial
granulomatosis, Aliment Pharmacol Ther 20:1019-1027, 2004.
Mignogna MD, Fedele S, LoRusso L et al: Effectiveness of smallvolume, intralesional, delayed-release triamcinolone injections in orofacial granulomatosis: a pilot study, J Am Acad
Dermatol 51:265-268, 2004.
Patton DW, Ferguson MM, Forsyth A et al: Oro-facial granulomatosis: a possible allergic basis, Br J Oral Maxillofac Surg
23:235-242, 1985.
Rees TD: Orofacial granulomatosis and related conditions,
Periodontol 2000 21:145-157, 1999.
Sanderson J, Numes C, Escudier M et al: Oro-facial granulmatosis: Crohns disease or a new inammatory bowel disease,
Inamm Bowel Dis 11:840-846, 2005.
van der Waal RIF, Schulten EAJM, van der Meij EH et al: Cheilitis granulomatosa: overview of 13 patients with long-term
follow-upresults of management, Int J Dermatol 41:225-229,
2002.
White A, Nunes C, Escudier M et al: Improvement of orofacial
granulomatosis on a cinnamon- and benzoate-free diet,
Inamm Bowel Dis 12:508-514, 2006.
Wiesenfeld D, Ferguson MM, Mitchell DN et al: Oro-facial granulomatosisa clinical and pathological analysis, Q J Med
54:101-113, 1985.
Worsaae N, Christensen KC, Schidt M et al: MelkerssonRosenthal and cheilitis granulomatosa: a clinicopathologic
study of thirty-three patients with special reference to their
oral lesions, Oral Surg Oral Med Oral Pathol 54:404-413,
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Rogers RS, Bruce AJ: Lichenoid contact stomatitis. Is organic
mercury the culprit? Arch Dermatol 140:1524-1525, 2004.
Angioedema
Abdi R, Dong VM, Lee CJ et al: Angiotensin II receptor blockerassociated angioedema: on the heels of ACE inhibitor angioedema, Pharmacotherapy 22:1173-1175, 2002.
Angostoni A, Cicardi M: Hereditary and acquired C1-inhibitor
deciency: biological and clinical characteristics in 235
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Bork K, Meng G, Staubach P et al: Hereditary angioedema: new
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Dobson G, Edgar D, Trinder J: Angioedema of the tongue due to
acquired C1 esterase inhibitor deciency, Anaesth Intensive
Care 31:99-102, 2003.
Greaves M, Lawlor F: Angioedema: manifestations and management, J Am Acad Dermatol 25:155-165, 1991.
Megerian CA, Arnold JE, Berer M: Angioedema: 5 years experience, with a review of the disorders presentation and treatment, Laryngoscope 102:256-260, 1992.
Nielsen EW, Gramstad S: Angioedema from angiotensinconverting enzyme (ACE) inhibitor treated with complement
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region, Oral Dis 3:39-42, 1997.
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Epithelial Pathology
Revised by ANGELA C. CHI
CHAPTER OUTLINE
Spitz Nevus
Blue Nevus
Leukoplakia
Erythroplakia
Smokeless Tobacco Use and Smokeless Tobacco
Keratosis
Oral Submucous Fibrosis
Nicotine Stomatitis
Actinic Keratosis
Actinic Cheilosis
Keratoacanthoma
Squamous Cell Carcinoma
Verrucous Carcinoma
Spindle Cell Carcinoma
Adenosquamous Carcinoma
Basaloid Squamous Carcinoma
Carcinoma of the Maxillary Sinus
Sinonasal Undifferentiated Carcinoma
Nasopharyngeal Carcinoma
Basal Cell Carcinoma
Merkel Cell Carcinoma
Melanoma
Squamous Papilloma
Verruca Vulgaris
Condyloma Acuminatum
Multifocal Epithelial Hyperplasia
Sinonasal Papillomas
Fungiform Papilloma
Inverted Papilloma
Cylindrical Cell Papilloma
Molluscum Contagiosum
Verruciform Xanthoma
Seborrheic Keratosis
Sebaceous Hyperplasia
Ephelis
Actinic Lentigo
Lentigo Simplex
Melasma
Oral Melanotic Macule
Oral Melanoacanthoma
Acquired Melanocytic Nevus
Variants of Melanocytic Nevus
Congenital Melanocytic Nevus
Halo Nevus
SQUAMOUS PAPILLOMA
The squamous papilloma is a benign proliferation of
stratied squamous epithelium, resulting in a papillary
or verruciform mass. Presumably, this lesion is induced
by the human papillomavirus (HPV). HPV comprises
a large family (more than 100 types) of double-stranded
DNA viruses of the papovavirus subgroup A. Research
has shown that 81% of normal adults have buccal
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nohistochemical analysis, and polymerase chain reaction (PCR) techniques, but it is not visible with routine
histopathologic staining. Viral subtypes 6 and 11 have
been identied in up to 50% of oral papillomas, as
compared with less than 5% in normal mucosal cells.
The exact mode of transmission is unknown. Transmission by sexual and nonsexual person-to-person
contact, contaminated objects, saliva, or breast milk
has been proposed. In contrast to other HPV-induced
lesions, the viruses in oral squamous papillomas appear
to have an extremely low virulence and infectivity rate.
A latency or incubation period of 3 to 12 months has
been suggested.
The squamous papilloma occurs in one of every 250
adults and makes up approximately 3% of all oral
lesions submitted for biopsy. In addition, researchers
have estimated that oral squamous papillomas
comprise 7% to 8% of all oral masses or growths in
children.
CLINICAL FEATURES
The squamous papilloma occurs with equal frequency
in both men and women. Some authors have asserted
that it develops predominantly in children, but epidemiologic studies indicate that it can arise at any age
and, in fact, is diagnosed most often in persons 30 to
50 years of age. Sites of predilection include the tongue,
lips, and soft palate, but any oral surface may be
affected. This lesion is the most common of the soft
tissue masses arising from the soft palate.
The squamous papilloma is a soft, painless, usually
pedunculated, exophytic nodule with numerous ngerlike surface projections that impart a cauliower
or wartlike appearance (Fig. 10-1). Projections may be
pointed or blunted (Figs. 10-2 and 10-3), and the lesion
may be white, slightly red, or normal in color, depend-
ing on the amount of surface keratinization. The papilloma is usually solitary and enlarges rapidly to a
maximum size of about 0.5 cm, with little or no change
thereafter. However, lesions as large as 3.0 cm in greatest diameter have been reported.
It is sometimes difcult to distinguish this lesion
clinically from verruca vulgaris (see page 364), condyloma acuminatum (see page 366), verruciform
xanthoma (see page 372), or multifocal epithelial
hyperplasia (see page 367). In addition, extensive
coalescing papillary lesions (papillomatosis) of the
oral mucosa may be seen in several skin disorders,
including nevus unius lateris, acanthosis nigricans, and
focal dermal hypoplasia (Goltz-Gorlin) syndrome.
Laryngeal papillomatosis, a rare and potentially devastating disease of the larynx and hypopharynx, has
two distinct types: (1) juvenile-onset and (2) adult-
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HISTOPATHOLOGIC FEATURES
The papilloma is characterized by a proliferation of
keratinized stratied squamous epithelium arrayed in
ngerlike projections with brovascular connective
tissue cores (Fig. 10-4). The connective tissue cores
may show inammatory changes, depending on the
amount of trauma sustained by the lesion. The keratin
layer is thickened in lesions with a whiter clinical
appearance, and the epithelium typically shows a
normal maturation pattern. Occasional papillomas
demonstrate basilar hyperplasia and mitotic activity,
which can be mistaken for mild epithelial dysplasia.
Koilocytes, virus-altered epithelial clear cells with
small dark (pyknotic) nuclei, are sometimes seen high
in the prickle cell layer.
VERRUCA VULGARIS
(COMMON WART)
Verruca vulgaris is a benign, virus-induced, focal
hyperplasia of stratied squamous epithelium. One or
more of the associated human papillomavirus (HPV)
types 2, 4, 6, and 40 are found in virtually all examples.
Verruca vulgaris is contagious and can spread to other
parts of a persons skin or mucous membranes by way
of autoinoculation. It infrequently develops on oral
mucosa but is extremely common on the skin.
CLINICAL FEATURES
Verruca vulgaris is frequently discovered in children,
but occasional lesions may arise even into middle age.
The skin of the hands is usually the site of infection (Fig.
10-5). When the oral mucosa is involved, the lesions
are usually found on the vermilion border, labial
mucosa, or anterior tongue.
Typically, the verruca appears as a painless papule
or nodule with papillary projections or a rough pebbly
surface (Figs. 10-6 and 10-7). It may be pedunculated
or sessile. Cutaneous lesions may be pink, yellow, or
white; oral lesions are almost always white. Verruca
vulgaris enlarges rapidly to its maximum size (usually
<5 mm), and the size remains constant for months or
years thereafter unless the lesion is irritated. Multiple
or clustered lesions are common. On occasion, extreme
accumulation of compact keratin may result in a hard
surface projection several millimeters in height, termed
a cutaneous horn or keratin horn. Other cutaneous
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HISTOPATHOLOGIC FEATURES
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CONDYLOMA ACUMINATUM
(VENEREAL WART)
Condyloma acuminatum is a virus-induced proliferation of stratied squamous epithelium of the genitalia,
perianal region, mouth, and larynx. One or more of the
human papillomavirus (HPV) types 2, 6, 11, 53, and 54
are usually detected in the lesion. However, the highrisk types 16, 18, and 31 also may be present, especially
in anogenital lesions. Condyloma is considered to be a
sexually transmitted disease (STD), with lesions developing at a site of sexual contact or trauma. This lesion
represents 20% of all STDs diagnosed in STD clinics
and may be an indicator of sexual abuse when diagnosed in young children. In addition, studies of oral and
pharyngeal HPV infection in infants have suggested
that vertical transmission from mothers with genital
HPV infection may occur perinatally or perhaps in
utero; however, reported transmission rates have varied
widely (ranging from 4% to >80%). It is not unusual for
oral and anogenital condylomata to be present concurrently. The incubation period for a condyloma is 1 to 3
months from the time of sexual contact. Once present,
autoinoculation to other mucosal sites is possible.
CLINICAL FEATURES
Condylomata are usually diagnosed in teenagers and
young adults, but people of all ages are susceptible.
Oral lesions most frequently occur on the labial mucosa,
soft palate, and lingual frenum. The typical condyloma
appears as a sessile, pink, well-demarcated, nontender
exophytic mass with short, blunted surface projections
(Fig. 10-9). The condyloma tends to be larger than the
papilloma and is characteristically clustered with other
HISTOPATHOLOGIC FEATURES
Condyloma acuminatum appears as a benign proliferation of acanthotic stratied squamous epithelium with
mildly keratotic papillary surface projections (Fig.
10-10). Thin connective tissue cores support the papillary epithelial projections, which are more blunted and
broader than those of squamous papilloma and verruca
vulgaris, imparting an appearance of keratin-lled
crypts between prominences. In some cases, lesions
extending from the surface mucosa to involve underlying salivary ductal epithelium have been reported;
such lesions should be distinguished from salivary
ductal papillomas (see page 485).
The covering epithelium is mature and differentiated, but the prickle cells often demonstrate pyknotic,
crinkled (or raisinlike) nuclei surrounded by clear
zones (koilocytes), a microscopic feature of HPV infec-
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MULTIFOCAL EPITHELIAL
HYPERPLASIA (HECKS DISEASE;
MULTIFOCAL PAPILLOMA VIRUS
EPITHELIAL HYPERPLASIA; FOCAL
EPITHELIAL HYPERPLASIA)
Multifocal epithelial hyperplasia is a virus-induced,
localized proliferation of oral squamous epithelium
that was rst described in Native Americans and Inuit.
Fig. 10-12 Multifocal epithelial hyperplasia. Multiple, attopped papules and nodules of normal coloration are seen on
the lower lip of a child. (Courtesy of Dr. Mark Casafrancisco.)
CLINICAL FEATURES
Although multifocal epithelial hyperplasia is usually a
childhood condition, it occasionally affects young and
middle-aged adults. Previous studies have reported
either a slight female predilection or no signicant
gender bias. The most common sites of involvement
include the labial, buccal, and lingual mucosa, but gingival, palatal, and tonsillar lesions also have been
reported. In addition, involvement of the conjunctiva
has been described very rarely.
This disease typically appears as multiple soft,
nontender, attened or rounded papules, which are
usually clustered and the color of normal mucosa,
although they may be scattered, pale, or rarely white
(Fig. 10-12). Occasional lesions show a slight papillary
surface change (Fig. 10-13). Individual lesions are
small (0.3 to 1.0 cm), discrete, and well demarcated,
but they frequently cluster so closely together that
the entire area takes on a cobblestone or ssured
appearance.
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Carlos.)
HISTOPATHOLOGIC FEATURES
The hallmark of multifocal epithelial hyperplasia is
an abrupt and sometimes considerable acanthosis of
the oral epithelium (Fig. 10-14). Because the thickened
mucosa extends upward, not down into underlying connective tissues, the lesional rete ridges are at the same
depth as the adjacent normal rete ridges. The ridges
themselves are widened, often conuent, and sometimes club shaped. Some supercial keratinocytes show
a koilocytic change similar to that seen in other HPV
infections. Others occasionally demonstrate an altered
nucleus that resembles a mitotic gure (mitosoid cell)
(Fig. 10-15). Viruslike particles have been noted ultrastructurally within both the cytoplasm and the nuclei of
cells within the prickle cell layer, and the presence of
HPV has been demonstrated with both DNA in situ
hybridization and immunohistochemical analysis.
Spontaneous regression of multifocal epithelial hyperplasia has been reported after months or years and is
inferred from the rarity of the disease in adults. Conservative surgical excision may be performed for diagnostic or aesthetic purposes or for lesions subject to
recurrent trauma. Lesions also can be removed by
cryotherapy or carbon dioxide (CO2) laser ablation.
Use of topical interferon- and systemic interferon-
has been reported in a few cases, although with variable results. The risk of recurrence after therapy is
minimal, and there seems to be no malignant transformation potential.
SINONASAL PAPILLOMAS
Papillomas of the sinonasal tract are benign, localized
proliferations of the respiratory mucosa of this region.
This mucosa gives rise to three histomorphologically
distinct papillomas:
1. Fungiform
2. Inverted
3. Cylindrical cell
Lesions exhibiting features of both the inverted and
the cylindrical cell types may be termed mixed or hybrid
papillomas. In addition, a keratinizing squamous
papilloma, similar to the oral squamous papilloma (see
page 362), rarely may occur in the nasal vestibule.
Collectively, sinonasal papillomas represent 10%
to 25% of all tumors of the nasal and paranasal region.
Half of the sinonasal papillomas arise from the mucosa
of the lateral nasal wall; the remainder predominantly
involve the maxillary and ethmoid sinuses and the
nasal septum. Multiple lesions may be present.
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the ngerlike projections seldom is keratinized. Respiratory epithelium or transitional epithelium (intermediate between squamous and respiratory) may be
seen in some lesions. Mucous (goblet) cells and intraepithelial microcysts containing mucus often are present.
Mitoses are infrequent, and dysplasia is rare. The
underlying connective tissue consists of delicate brous
tissue with a minimal inammatory component, unless
it is irritated.
The cause of sinonasal papillomas remains controversial and unclear. Some authorities say that these
lesions represent neoplasms; others consider them to
be a reactive hyperplasia secondary to a variety of environmental stimulants, such as allergy, chronic bacterial
or viral (HPV type 11) infection, and tobacco smoking.
Recent molecular genetic investigations have shown
that inverted papillomas arise from a single progenitor
cell (i.e., monoclonal), suggesting that these lesions are
neoplastic and recurrence may result from growth of
residual transformed cells.
CLINICAL FEATURES
The fungiform papilloma arises almost exclusively on
the nasal septum and is twice as common in men as in
women. It occurs primarily in people 20 to 50 years of
age. Typically, it exhibits unilateral nasal obstruction or
epistaxis and appears as a pink or tan, broad-based
nodule with papillary or warty surface projections
(Fig. 10-16).
HISTOPATHOLOGIC FEATURES
The fungiform papilloma has a microscopic appearance similar to that of the oral squamous papilloma,
although the stratied squamous epithelium covering
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seen. Mitoses often are noted within the basilar or parabasilar cells, and varying degrees of dysplasia may be
seen. Papillary surface projections are present, and
deep clefts may be seen between projections. The
stroma consists of dense brous or loose myxomatous
connective tissue with or without inammatory cells.
Destruction of underlying bone frequently is noted.
Immunohistochemical expression of CD44, a cell
adhesion molecule, is increased in this papilloma,
which may help to distinguish it from invasive papillary squamous cell carcinoma, which lacks this feature.
Although some authors have suggested that hyperkeratosis, prominent epithelial hyperplasia, and high
mitotic index are negative prognostic indicators, no
histopathologic parameters have been found to be reliably predictive of recurrence or malignant transformation among inverted papillomas.
HISTOPATHOLOGIC FEATURES
Microscopically, the inverted papilloma is characterized by squamous epithelial proliferation into the submucosal stroma (Fig. 10-18). The basement membrane
remains intact, and the epithelium appears to be
pushing into underlying connective tissue. Goblet
(mucous) cells and mucin-lled microcysts frequently
are noted within the epithelium. Keratin production is
uncommon, but thin surface keratinization may be
The inverted papilloma has a signicant growth potential and, if neglected, may extend into the nasopharynx,
middle ear, orbit, or cranial base. In some studies, recurrence after conservative surgical excision has occurred
in nearly 75% of all cases. However, with more aggressive surgical therapy, consisting of medial maxillectomy
via a lateral rhinotomy or midfacial degloving approach,
recurrence rates of less than 14% have been reported.
Although an open surgical approach historically has
been regarded as the standard of care, advances in
transnasal endoscopic surgery have led to wider acceptance of this method as an alternative, particularly for
patients with limited and easily accessible disease.
Several investigators, using modern endoscopic techniques and careful patient selection, have reported
recurrence rates comparable to those for conventional
lateral rhinotomy with medial maxillectomy. Recurrences are usually noted within 2 years of surgery but
can happen much later. Hence, long-term follow-up is
essential. Continued tobacco smoking is associated with
an increased risk of multiple recurrences.
The inverted papilloma also is associated with malignancy, usually squamous cell carcinoma, in 3% to 24%
of cases. In such an eventuality, of course, the lesion
is treated as a malignancy, typically by performing
more radical surgery, with or without adjunctive
radiotherapy.
CYLINDRICAL CELL
PAPILLOMA (ONCOCYTIC
SCHNEIDERIAN PAPILLOMA)
The cylindrical cell papilloma accounts for less than
7% of sinonasal papillomas. This lesion is considered by
some authorities to be a variant of the inverted
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CLINICAL FEATURES
Cylindrical cell papilloma typically occurs in adults 20
to 50 years of age. There is a strong male predominance, with a predilection for the maxillary antrum,
lateral nasal cavity wall, and ethmoid sinus. The presenting symptom is usually unilateral nasal obstruction, and it appears as a beefy-red or brown mass with
a multinodular surface.
HISTOPATHOLOGIC FEATURES
Microscopically, the cylindrical cell papilloma demonstrates both endophytic and exophytic growth. Surface
papillary projections have a brovascular connective
tissue core and are covered by a multilayered epithelium of tall columnar cells with small, dark nuclei
and eosinophilic, occasionally granular, cytoplasm.
The lesional epithelial cell is similar to an oncocyte.
Cilia may be seen on the surface, and there are numerous intraepithelial microcysts lled with mucin,
neutrophils, or both.
MOLLUSCUM CONTAGIOSUM
Molluscum contagiosum is a virus-induced epithelial
hyperplasia produced by the molluscum contagiosum
virus, a member of the DNA poxvirus group. At least
6% of the population (more in older age groups) has
antibodies to this virus, although few ever develop
lesions. After an incubation period of 14 to 50 days,
infection produces multiple papules of the skin or,
rarely, mucous membranes. These remain small for
months or years and then spontaneously involute.
During its active phase, the molluscum contagiosum
virus is sloughed from a central core in each papule.
Routes of transmission include sexual contact (in
adults) and such nonsexual contacts (in children and
teenagers) as sharing clothing, wrestling, communal
bathing, and swimming. Lesions have a predilection for
warm portions of the skin and sites of recent injury.
Florid cases have been reported in immunocompromised patients, and the prevalence among the human
Fig. 10-19 Molluscum contagiosum. Multiple, smoothsurfaced papules, with several demonstrating small keratinlike plugs, are seen on the neck of a child.
immunodeciency virus (HIV)-positive patient population is estimated to be 5% to 18% (see page 278). Patients
with atopic dermatitis and Dariers disease also are at
risk for developing severe and extensive disease.
CLINICAL FEATURES
Molluscum contagiosum is usually seen in children
and young adults. The papules almost always are multiple and occur predominantly on the skin of the
neck, face (particularly eyelids), trunk, and genitalia.
Infrequently, oral involvement occurs, usually on the
lips, buccal mucosa, palate, or gingiva.
Lesions are pink, smooth-surfaced, sessile, nontender, and nonhemorrhagic papules that are 2 to
4 mm in diameter (Fig. 10-19). Many show a small
central indentation or keratin-like plug from which a
curdlike substance can be expressed. Some are surrounded by a mild inammatory erythema and may be
slightly tender or pruritic. Eczematous eruptions occasionally may develop in the vicinity of molluscum contagiosum lesions, particularly in patients with atopic
dermatitis.
In immunocompromised patients, atypical lesions
that are unusually large, verrucous, or markedly hyperkeratotic have been described.
HISTOPATHOLOGIC FEATURES
Molluscum contagiosum appears as a localized lobular
proliferation of surface stratied squamous epithelium
(Fig. 10-20). The central portion of each lobule is
lled with bloated keratinocytes that contain large,
intranuclear, basophilic viral inclusions called molluscum bodies (or Henderson-Paterson bodies)
(Fig. 10-21). These bodies begin as small eosinophilic
structures in cells just above the basal layer. As they
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VERRUCIFORM XANTHOMA
CLINICAL FEATURES
Verruciform xanthoma is typically seen in whites, 40
to 70 years of age, with a slight male predilection.
Approximately half of the intraoral lesions occur on the
gingiva and alveolar mucosa, but any oral site may be
involved.
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The lesion appears as a well-demarcated, soft, painless, sessile, slightly elevated mass with a white, yellowwhite, or red color and a papillary or roughened
(verruciform) surface (Figs. 10-22 and 10-23). Rarely,
at-topped nodules are seen without surface projections. Most lesions are smaller than 2 cm in greatest
diameter; no oral lesion larger than 4 cm has been
reported. Multiple lesions occasionally have been
described. Clinically, verruciform xanthoma may be
similar to squamous papilloma, condyloma acuminatum, or early carcinoma.
(H&E) staining, the keratin layer often exhibits a distinctive orange coloration (Fig. 10-24). Clefts or crypts
between the epithelial projections are lled with parakeratin, and rete ridges are elongated to a uniform
depth. The most important diagnostic feature is the
accumulation of numerous large macrophages with
foamy cytoplasm, which typically are conned to the
connective tissue papillae. These foam cells, also known
as xanthoma cells, contain lipid and periodic acidSchiff (PAS)-positive, diastase-resistant granules.
With immunohistochemical stains, the xanthoma
cells are positive for markers consistent with monocyte-macrophage lineage, including CD68 (KP1) and
cathepsin B.
HISTOPATHOLOGIC FEATURES
Verruciform xanthoma demonstrates papillary, acanthotic surface epithelium covered by a thickened layer
of parakeratin. On routine hematoxylin and eosin
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SEBORRHEIC KERATOSIS
Seborrheic keratosis is an extremely common skin
lesion of older people and represents an acquired,
benign proliferation of epidermal basal cells. The cause
is unknown, although there is a positive correlation
with chronic sun exposure, sometimes with a hereditary (autosomal dominant) tendency. In addition,
recent genetic studies have suggested that somatic
mutations in the FGFR3 (broblast growth factor
receptor 3) gene are important in the development of
these lesions. Seborrheic keratosis does not occur in
the mouth.
CLINICAL FEATURES
Seborrheic keratoses begin to develop on the skin of
the face, trunk, and extremities during the fourth
decade of life, and they become more prevalent with
each passing decade. Lesions are usually multiple,
beginning as small tan to brown macules that are indistinguishable clinically from actinic lentigines (see
page 377), and which gradually enlarge and elevate
(Figs. 10-25 and 10-26). Individual lesions are sharply
demarcated plaques and have surfaces that are nely
ssured, pitted, or verrucous, but may be smooth. They
tend to appear stuck onto the skin and are usually less
than 2 cm in diameter.
HISTOPATHOLOGIC FEATURES
Seborrheic keratosis consists of an exophytic proliferation of basilar epithelial cells that exhibit varying
degrees of surface keratinization, acanthosis, and papillomatosis (Fig. 10-28). Characteristically, the entire
epithelial hyperplasia extends upward, above the
normal epidermal surface. The lesion usually exhibits
deep, keratin-lled invaginations that appear cystic on
cross-section; hence, they are called horn cysts or
pseudo-horn cysts (Fig. 10-29). Melanin pigmentation often is seen within the basal layer.
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SEBACEOUS HYPERPLASIA
Several histopathologic patterns may be seen in seborrheic keratoses. The most common is the acanthotic
form, which exhibits little papillomatosis and marked
acanthosis with minimal surface keratinization. The
hyperkeratotic form is characterized by prominent
papillomatosis and hyperkeratosis with minimal acanthosis. The adenoid form consists of anastomosing trabeculae of lesional cells with little hyperkeratosis or
papillomatosis. The lesions of dermatosis papulosa
nigra are predominantly of the adenoid and acanthotic
types.
Chronic trauma may alter these histopathologic features, and the lesion known as inverted follicular
keratosis of Helwig is thought to represent an irritated seborrheic keratosis. This lesion shows a mild
degree of proliferation into the connective tissue and a
Sebaceous hyperplasia is characterized by a localized proliferation of sebaceous glands of the skin. It has
no known cause and is common on the facial skin. In
some cases an association with cyclosporine, systemic
corticosteroids, hemodialysis, and Muir-Torre syndrome (a rare autosomal dominant disorder characterized by visceral malignancies, sebaceous adenomas
and carcinomas, and keratoacanthomas) has been
described. The major signicance of this entity is its
clinical similarity to more serious facial tumors, such
as basal cell carcinoma.
CLINICAL FEATURES
Cutaneous sebaceous hyperplasia usually affects adults
older than 40 years of age. It occurs most commonly
on the skin of the face, especially the nose, cheeks, and
forehead. Less commonly, lesions may involve the
genital area, chest, and areola. The condition is characterized by one or more soft, nontender papules with
white, yellow, or normal coloration (Fig. 10-30). Lesions
are usually umbilicated, with a small central depression, representing the area where the ducts of the
involved sebaceous lobules terminate. Most lesions are
smaller than 5 mm in greatest diameter and take considerable time to reach even this small size.
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EPHELIS (FRECKLE)
HISTOPATHOLOGIC FEATURES
Histopathologically, sebaceous hyperplasia is characterized by a collection of enlarged but otherwise normal sebaceous gland lobules grouped around one or
more centrally located sebaceous ducts (Fig. 10-31).
An ephelis is a common small hyperpigmented macule of the skin that represents a region of increased
melanin production. Ephelides are seen most often on
the face, arms, and back of fair-skinned, blue-eyed, redor light-blond haired persons; they may be associated
with a strong genetic predilection (autosomal dominant). Recent studies have demonstrated a strong
relationship between certain variants of the MC1R
(melanocortin-1-receptor) gene and the development
of ephelides. The skin discoloration is produced by a
relative excess of melanin deposition in the epidermis,
not by a local increase in the number of melanocytes.
CLINICAL FEATURES
Ephelides become noticeable during the rst decade
of life, and new macules seldom arise after the teenage
years. During adult life the macules typically become
less prominent. There is no sex predilection; however,
persons with blond or red hair are more likely to have
ephelides. The lesions become more pronounced after
sun exposure and are associated closely with a history
of painful sunburns in childhood.
Each individual macule is round or oval, and typically remains less than 3 mm in diameter (Fig. 10-32).
It has a uniform light-brown coloration and is sharply
demarcated from the surrounding skin. There is great
variability in the numbers of ephelides present. Many
individuals have less than 10, whereas some have hundreds of macules. The brown color is not as dark as the
lentigo simplex (see page 378), and there is never ele-
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HISTOPATHOLOGIC FEATURES
The ephelis is composed of stratied squamous epithelium with abundant melanin deposition in the basal
cell layer. Despite the increased melanin, the number
of melanocytes is normal or may be somewhat reduced.
In contrast to lentigo simplex, there is no elongation of
rete ridges.
Fig. 10-33 Actinic lentigines. Multiple lesions on the sunexposed skin of the hand of an older adult. Lesions are brown
macules with irregular borders.
CLINICAL FEATURES
Actinic lentigo is common on the dorsa of the hands, on
the face, and on the arms of older whites (Figs. 10-33
and 10-34). It is typically multiple, but individual lesions
appear as uniformly pigmented brown to tan macules
with well-demarcated but irregular borders. Although
the lesion may reach more than 1 cm in diameter, most
examples are smaller than 5 mm. Adjacent lesions may
coalesce, and new ones continuously arise with age.
Unlike ephelides, no change in color intensity is seen
after exposure to UV light.
HISTOPATHOLOGIC FEATURES
Rete ridges are elongated and club shaped in actinic
lentigines, with thinning of the epithelium above the
connective tissue papillae (Fig. 10-35). The ridges
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LENTIGO SIMPLEX
Lentigo simplex is one of several forms of benign
cutaneous melanocytic hyperplasia of unknown cause.
It usually occurs on skin that is not exposed to sunlight,
but it may occur on any skin surface and at any age. Its
color intensity does not change with variations in sun
exposure. Lentigo simplex is darker in color than the
common ephelis (see page 376). Ephelides, moreover,
are found predominantly on sun-exposed skin, become
more pronounced with increased sun exposure, and
represent merely an increase in local melanin production rather than an increase in the number of productive melanocytes.
Some investigators believe that lentigo simplex represents the earliest stage of another common skin lesion,
the melanocytic nevus (see page 382). Oral lesions have
been reported, but they are rare and may be examples
of the oral melanotic macule (see page 379).
HISTOPATHOLOGIC FEATURES
Lentigo simplex shows an increased number of benign
melanocytes within the basal layer of the epidermis,
and these often are clustered at the tips of the rete
ridges. Abundant melanin is distributed among the
melanocytes and basal keratinocytes, as well as within
the papillary dermis in association with melanophages
(melanin incontinence).
CLINICAL FEATURES
Lentigo simplex usually occurs in children but may
occur at any age. The typical lesion is a sharply demarcated macule smaller than 5 mm in diameter, with a
uniformly tan to dark-brown color (Fig. 10-36). It is
usually solitary, although some patients may have
several lesions scattered on the skin of the trunk and
extremities. Lentigo simplex reaches its maximum size
in a matter of months and may remain unchanged
indenitely thereafter.
Melasma is an acquired, symmetrical hyperpigmentation of the sun-exposed skin of the face and neck. The
cause is unknown, but it is classically associated with
pregnancy. Exposure to exogenous estrogen and progesterone in the form of either oral contraceptives
*Lentigines (multiple), electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of
growth, and deafness (sensorineural).
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CLINICAL FEATURES
Melasma appears in adult women as bilateral light- to
dark-brown cutaneous macules that vary in size from
a few millimeters to more than 2 cm in diameter (Fig.
10-37). Lesions develop slowly with sun exposure and
occur primarily on the midface, forehead, upper lip,
chin, and (rarely) the arms. It is not unusual for the
entire face to be involved. The pigmentation may
remain faint or darken over time. Rarely, melasma is
seen in men.
HISTOPATHOLOGIC FEATURES
Melasma is characterized by increased melanin deposition within an otherwise unremarkable epidermis.
Pigment also may be seen within numerous melanophages in the dermis.
CLINICAL FEATURES
The oral melanotic macule occurs at any age in both
men and women; however, biopsy samples demonstrate a 2:1 female predilection. The average age of
patients is 43 years at the time of diagnosis. The vermilion zone of the lower lip is the most common site
of occurrence (33%), followed by the buccal mucosa,
gingiva, and palate. Rare examples have been reported
on the tongue in newborns.
The typical lesion appears as a solitary (17% are multiple), well-demarcated, uniformly tan to dark-brown,
asymptomatic, round or oval macule with a diameter
of 7 mm or smaller (Figs. 10-38 and 10-39). Occasional lesions may be blue or black. Lesions are not
reported to enlarge after diagnosis, which suggests that
the maximum dimension is achieved rather rapidly
and remains constant thereafter.
HISTOPATHOLOGIC FEATURES
The oral melanotic macule is characterized by an
increase in melanin (and perhaps melanocytes) in the
basal and parabasal layers of an otherwise normal
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ORAL MELANOACANTHOMA
(MELANOACANTHOSIS)
Oral melanoacanthoma is a benign, relatively uncommon acquired pigmentation of the oral mucosa
characterized by dendritic melanocytes dispersed
throughout the epithelium. The lesion appears to be a
reactive process; in some cases an association with
trauma has been reported. Oral melanoacanthoma
appears to be unrelated to the melanoacanthoma of
skin, which most authorities believe represents a
variant of seborrheic keratosis.
CLINICAL FEATURES
Oral melanoacanthoma is seen almost exclusively in
blacks, shows a female predilection, and is most
common during the third and fourth decades of life.
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Box 10-1
The buccal mucosa is the most common site of occurrence. The lips, palate, gingiva, and alveolar mucosa
also may be involved. Most patients exhibit solitary
lesions, although bilateral or multifocal involvement is
possible as well. Oral melanoacanthomas typically are
asymptomatic; however, pain, burning, and pruritus
have been reported in a few unusual cases. The lesion
is smooth, at or slightly raised, and dark-brown to
black in color (Fig. 10-41). Lesions often demonstrate
a rapid increase in size, and they occasionally reach a
HISTOPATHOLOGIC FEATURES
The oral melanoacanthoma is characterized by
numerous benign dendritic melanocytes (cells that are
normally conned to the basal cell layer) scattered
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Box 10-2
Epidermal nevus
Nevus sebaceus
Nevus ammeus (see page 543)
Basal cell nevus (nevoid basal cell carcinoma) (see
page 688)
White sponge nevus (see page 743)
CLINICAL FEATURES
Acquired melanocytic nevi begin to develop on the
skin during childhood, and most cutaneous lesions are
present before 35 years of age. They occur in both men
and women, although women usually have a few more
than men. Racial differences are seen. Whites have
more nevi than Asians or blacks. Most lesions are distributed above the waist, and the head and neck region
is a common site of involvement.
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Fig. 10-44 Melanocytic (intradermal) nevus. A welldemarcated, dome-shaped papule is seen at the edge of the
vermilion border of the upper lip.
adult years, many acquired melanocytic nevi will involute and disappear; therefore, fewer of these lesions
can be detected in older persons.
Intraoral melanocytic nevi are distinctly uncommon. Most arise on the palate, mucobuccal fold, or
gingiva, although any oral mucosal site may be affected
(Fig. 10-46). Intraoral melanocytic nevi have an evolution and appearance similar to skin nevi, although
mature lesions typically do not demonstrate a papillary
surface change. More than one in ve intraoral nevi
lack clinical pigmentation (Fig. 10-47). Approximately
two thirds of intraoral examples are found in females;
the average age at diagnosis is 35 years.
HISTOPATHOLOGIC FEATURES
The acquired melanocytic nevus is characterized by a
benign, unencapsulated proliferation of small, ovoid
cells (nevus cells). The lesional cells have small, uniform
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nuclei and a moderate amount of eosinophilic cytoplasm, with indistinct cell boundaries. These cells demonstrate a variable capacity to produce melanin, with
the pigment primarily evident in the supercial aspects
of the lesion. Nevus cells typically lack the dendritic
processes that melanocytes possess. A characteristic
microscopic feature is that the supercial nevus cells
tend to be organized into small, round aggregates
(thques).
Melanocytic nevi are classied histopathologically
according to their stage of development, which is
reected by the relationship of the nevus cells to the
surface epithelium and underlying connective tissue.
In the early stages, thques of nevus cells are found
only along the basal cell layer of the epithelium, especially at the tips of the rete ridges. Because the lesional
cells are found at the junction between the epithelium
and the connective tissue, this stage is known as a junctional nevus (Fig. 10-48). As the nevus cells proliferate, groups of cells begin to drop off into the underlying
dermis or lamina propria. Because cells are now
present along the junctional area and within the underlying connective tissue, the lesion then is called a
compound nevus (Fig. 10-49).
In the later stages, nests of nevus cells are no longer
found within the epithelium but are found only within
the underlying connective tissue. Because of the connective tissue location of the lesional cells, on the skin
this stage is called an intradermal nevus. The intraoral counterpart is called an intramucosal nevus (Fig.
10-50). Zones of differentiation often are seen throughout the lesion. The supercial cells typically appear
larger and epithelioid, with abundant cytoplasm, frequent intracellular melanin, and a tendency to cluster
into thques. Nevus cells of the middle portion of the
lesion have less cytoplasm, are seldom pigmented, and
appear much like lymphocytes. Deeper nevus cells
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CLINICAL FEATURES
The small congenital melanocytic nevus may be similar
in appearance to an acquired melanocytic nevus, but
it is frequently larger in diameter (Figs. 10-51 and
10-52). The large congenital lesion classically appears
as a brown to black plaque, usually with a rough surface
or multiple nodular areas. However, the clinical appearance often changes with time. Early lesions are at and
light tan, becoming elevated, rougher, and darker with
age. A common feature is the presence of hypertricho-
HISTOPATHOLOGIC FEATURES
The histopathologic appearance of the congenital
melanocytic nevus is similar to that of the acquired
melanocytic nevus, and some small congenital nevi
cannot be distinguished microscopically from the
acquired nevus. Both congenital and acquired types
are composed of nevus cells, which may have a junctional, compound, or intradermal pattern. The congenital nevus is usually of the compound or intradermal
type. In contrast to the acquired melanocytic nevus, the
congenital nevus often shows extension of nevus cells
into the deeper levels of the dermis, with inltration
of cells between collagen bundles. In addition, congenital nevus cells often are seen intermingled with
neurovascular bundles in the reticular dermis and surrounding normal adnexal skin structures (e.g., hair follicles, sebaceous glands). Large congenital melanocytic
nevi may show extension of nevus cells into the subcutaneous fat.
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HALO NEVUS
Halo nevus is a melanocytic nevus with a pale hypopigmented border or halo of the surrounding epithelium, apparently as a result of nevus cell destruction by
the immune system. The halo develops because the
immune cells also attack the melanocytes adjacent to
the nevus. The cause of the immune attack is unknown,
but regression of the nevus usually results. Interestingly, the development of multiple halo nevi has been
seen in patients who have had a recent excision of a
melanoma.
CLINICAL FEATURES
The halo nevus is typically an isolated phenomenon
associated with a preexisting acquired melanocytic
nevus. It is most common on the skin of the trunk
during the second decade of life. The lesion typically
appears as a central pigmented papule or macule, surrounded by a uniform, 2- to 3-mm zone of hypopigmentation (Fig. 10-53). Sometimes this peripheral
zone is much wider.
HISTOPATHOLOGIC FEATURES
Histopathologically, the halo nevus differs from the
routine acquired melanocytic nevus only in the
presence of an intense chronic inammatory cell
inltrate, which surrounds and inltrates the nevus
cell population.
CLINICAL FEATURES
The Spitz nevus typically develops on the skin of the
extremities or the face during childhood. It appears as
a solitary, dome-shaped, pink to reddish-brown papule,
usually smaller than 6 mm in greatest diameter. The
young age at presentation and the relatively small size
of the Spitz nevus are useful features to help distinguish it from melanoma.
HISTOPATHOLOGIC FEATURES
The Spitz nevus has the overall microscopic architecture of a compound nevus, showing a zonal differentiation from the supercial to deep aspects of the lesion
and good symmetry. Lesional cells are either spindle
shaped or plump (epithelioid), and the two types often
are intermixed. The epithelioid cells may be multinucleated and appear somewhat bizarre, often lacking
cell cohesiveness. Mitotic gures, all normal in appearance, may be seen in the supercial aspects of the
lesion. Ectatic supercial blood vessels, which probably
impart much of the reddish color of some lesions, are
seen frequently. The nevocellular nature of the lesional
cells is demonstrated by immunohistochemical reactivity for S-100 protein and neuron-specic enolase.
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HISTOPATHOLOGIC FEATURES
CLINICAL FEATURES
The common blue nevus may affect any cutaneous or
mucosal site, but it has a predilection for the dorsa of
the hands and feet, the scalp, and the face. Mucosal
lesions may involve the oral mucosa, conjunctiva, and,
rarely, sinonasal mucosa. Oral lesions are found almost
always on the palate. The lesion usually occurs in children and young adults, and a female predilection is
seen. It appears as a macular or dome-shaped, blue
or blue-black lesion smaller than 1 cm in diameter
(Fig. 10-54).
The cellular blue nevus is much less common and
usually develops during the second to fourth decades
of life, but it may be congenital. More than 50% of cellular blue nevi arise in the sacrococcygeal or buttock
region, although they may be seen on other cutaneous
or mucosal surfaces. Clinically, this nevus appears as a
slow-growing, blue-black papule or nodule that sometimes attains a size of 2 cm or more. Occasional lesions
remain macular.
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Box 10-3
LEUKOPLAKIA (LEUKOKERATOSIS;
ERYTHROLEUKOPLAKIA)
Oral leukoplakia (leuko = white; plakia = patch) is
dened by the World Health Organization (WHO) as
a white patch or plaque that cannot be characterized
clinically or pathologically as any other disease. The
term is strictly a clinical one and does not imply a specic histopathologic tissue alteration.
The denition of leukoplakia is unusual in that it
makes the diagnosis dependent not so much on denable appearances as on the exclusion of other entities
that appear as oral white plaques. Such lesions as
lichen planus, morsicatio (chronic cheek nibbling),
frictional keratosis, tobacco pouch keratosis, nicotine
stomatitis, leukoedema, and white sponge nevus must
be ruled out before a clinical diagnosis of leukoplakia
can be made. As with most oral white lesions, the clinical color results from a thickened surface keratin layer,
which appears white when wet, or a thickened spinous
layer, which masks the normal vascularity (redness) of
the underlying connective tissue.
Although leukoplakia is not associated with a specic histopathologic diagnosis, it is typically considered
to be a precancerous or premalignant lesion. When the
outcome of a large number of leukoplakic lesions is
reviewed, the frequency of transformation into malignancy is greater than the risk associated with normal
or unaltered mucosa. Because there is considerable
misunderstanding of this concept, Box 10-3 provides
denitions that are used throughout the chapter.
CAUSE
The cause of leukoplakia remains unknown, although
hypotheses abound.
TOBACCO
The habit of tobacco smoking appears most closely
associated with leukoplakia development. More than
80% of patients with leukoplakia are smokers. When
large groups of adults are examined, smokers are much
more likely to have leukoplakia than nonsmokers.
Heavier smokers have greater numbers of lesions and
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ALCOHOL
Alcohol, which seems to have a strong synergistic effect
with tobacco relative to oral cancer production, has not
been associated with leukoplakia. People who excessively use mouth rinses with an alcohol content greater
than 25% may have grayish buccal mucosal plaques,
but these are not considered true leukoplakia.
SANGUINARIA
Persons who use toothpaste or mouth rinses containing
the herbal extract, sanguinaria, may develop a true
leukoplakia. This type of leukoplakia (sanguinariaassociated keratosis) is usually located in the maxillary vestibule or on the alveolar mucosa of the maxilla
(Fig. 10-56). More than 80% of individuals with vestibular or maxillary alveolar leukoplakia have a history of
using products that contain sanguinaria, compared
with 3% of the normal population.
The affected epithelium may demonstrate dysplasia
identical to that seen in other leukoplakias, although
the potential for the development of cancer is uncertain. The leukoplakic plaque may not disappear even
after the patient stops using the product; some lesions
have persisted for years afterwards.
ULTRAVIOLET RADIATION
Ultraviolet radiation is accepted as a causative factor
for leukoplakia of the lower lip vermilion. This is usually
associated with actinic cheilosis (see page 405). Immunocompromised persons, especially transplant patients,
are especially prone to the development of leukoplakia and squamous cell carcinoma of the lower lip
vermilion.
MICROORGANISMS
Several microorganisms have been implicated in the
cause of leukoplakia. Treponema pallidum, for example,
produces glossitis in the late stage of syphilis, with or
without the arsenic therapy in popular use before the
advent of modern antibiotics. The tongue is stiff and
frequently has extensive dorsal leukoplakia.
Tertiary syphilis is rare today, but oral infections
by another microorganism, Candida albicans, are not.
Candida organisms can colonize the supercial epithelial layers of the oral mucosa, often producing a thick,
granular plaque with a mixed white and red coloration
(Fig. 10-57). The terms candidal leukoplakia and
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CLINICAL FEATURES
Leukoplakia usually affects persons older than 40 years
of age. Prevalence increases rapidly with age, especially for males, and as many as 8% of men older than
TRAUMA
90
80
Males
70
Females
60
50
40
30
20
10
0
15
25
35
45
55
Age (in years)
65
75+
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Fig. 10-66 Proliferative verrucous leukoplakia (PVL). A, Large, diffuse, and corrugated
white lesions of the buccal mucosa and tongue. B, Same patient showing the extensive
thickened and ssured alteration of the tongue.
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Normal
mucosa
Thin,
smooth
leukoplakia
Thick,
fissured
leukoplakia
Granular,
verruciform
leukoplakia
Erythroleukoplakia
(speckled leukoplakia)
Erythroplakia
Chapter 10
LEGEND
Normal
epithelium
Dysplastic
epithelial
cells
Lymphocytes
Candida
hyphae
Keratin
layer
Hyperkeratosis Hyperkeratosis
Acanthosis
Acanthosis
Irregular hyperkeratosis
(verruciform hyperkeratosis)
Lymphocytes
(occasional)
Lymphocytes
(occasional)
Dysplasia
(mild/moderate)
Moderate/severe dysplasia
Irregular hyperkeratosis
Bulbous and crowded rete pegs (on left)
Epithelial atrophy (on right)
Lymphocytes (moderate to numerous)
Severe dysplasia (on left)
Congested vessels
Candida hyphae (maybe)
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transforming into a full-edged squamous cell carcinoma. Because of the variable clinical and histopathologic appearance of PVL, careful correlation of the
clinical and microscopic ndings is required for
diagnosis.
Most leukoplakic lesions demonstrate no dysplasia
on biopsy. Evidence of epithelial dysplasia is found in
only 5% to 25% of cases if all oral sites are considered.
When present, these dysplastic changes typically begin
in the basilar and parabasilar portions of the epithelium. The more dysplastic the epithelium becomes, the
more the atypical epithelial changes extend to involve
the entire thickness of the epithelium. The histopathologic alterations of dysplastic epithelial cells are similar
to those of squamous cell carcinoma and may include
the following:
Enlarged nuclei and cells
Large and prominent nucleoli
Increased nuclear-to-cytoplasmic ratio
Hyperchromatic (excessively dark-staining) nuclei
Pleomorphic (abnormally shaped) nuclei and
cells
Dyskeratosis (premature keratinization of individual cells)
Increased mitotic activity (excessive numbers of
mitoses)
Abnormal mitotic gures (tripolar or star-shaped
mitoses or mitotic gures above the basal layer)
In addition, histomorphologic alterations of dysplastic epithelium are evident at low-power magnication,
including the following:
Bulbous or teardrop-shaped rete ridges
Loss of polarity (lack of progressive maturation
toward the surface)
Keratin or epithelial pearls (focal, round collections of concentrically layered keratinized cells)
Loss of typical epithelial cell cohesiveness
When epithelial dysplasia is present, the pathologist
provides a descriptive adjective relating to its severity
or intensity. Mild epithelial dysplasia refers to alterations limited principally to the basal and parabasal
layers (Fig. 10-71). Moderate epithelial dysplasia
demonstrates involvement from the basal layer to the
midportion of the spinous layer (Fig. 10-72). Severe
epithelial dysplasia demonstrates alterations from
the basal layer to a level above the midpoint of the
epithelium (Fig. 10-73). Sometimes dysplasia will be
seen to extend down the duct of a minor salivary
gland, especially in lesions of the oor of the mouth
(Fig. 10-74).
When the entire thickness of the epithelium is
involved, the term carcinoma in situ is used. Carcinoma in situ is dened as dysplastic epithelial cells that
extend from the basal layer to the surface of the mucosa
HISTOPATHOLOGIC FEATURES
Microscopically, leukoplakia is characterized by a
thickened keratin layer of the surface epithelium
(hyperkeratosis), with or without a thickened spinous
layer (acanthosis). Some leukoplakias demonstrate
surface hyperkeratosis but show atrophy or thinning
of the underlying epithelium. Frequently, variable
numbers of chronic inammatory cells are noted
within the subjacent connective tissue.
The keratin layer may consist of parakeratin (hyperparakeratosis), orthokeratin (hyperorthokeratosis),
or a combination of both (Fig. 10-70). With parakeratin, there is no granular cell layer and the epithelial
nuclei are retained in the keratin layer. With orthokeratin, the epithelium demonstrates a granular cell
layer and the nuclei are lost in the keratin layer.
Verrucous leukoplakia has papillary or pointed
surface projections, varying keratin thickness, and
broad, blunted rete ridges. It may be difcult to differentiate it from early verrucous carcinoma.
PVL shows a variable microscopic appearance,
depending on the stage of the lesions. Early PVL
appears as a benign hyperkeratosis that is indistinguishable from other simple leukoplakic lesions. With
time, the condition progresses to a papillary, exophytic
proliferation that is similar to localized lesions of verrucous leukoplakia (or what is sometimes termed verrucous hyperplasia). In later stages this papillary
proliferation exhibits downgrowth of well-differentiated squamous epithelium with broad, blunt rete
ridges. This epithelium demonstrates invasion into the
underlying lamina propria; at this stage it is indistinguishable from verrucous carcinoma. In the nal stages
the invading epithelium becomes less differentiated,
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recurrence rate is increased. The depth of ductal dysplasia does not appear to be a signicant factor.
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ERYTHROPLAKIA (ERYTHROPLASIA;
ERYTHROPLASIA OF QUEYRAT)
As with leukoplakia, erythroplakia is dened as a red
patch that cannot be clinically or pathologically diagnosed as any other condition. Queyrat originally used
the term erythroplasia to describe a precancerous red
lesion that develops on the penis. Oral erythroplakia is
clinically and histopathologically similar to the genital
process. Almost all true erythroplakias demonstrate
signicant epithelial dysplasia, carcinoma in situ, or
invasive squamous cell carcinoma. The causes of
erythroplakia are unknown, but they are presumed to
be the same as those associated with invasive squamous cell carcinoma of the mouth (see page 409).
The point prevalence rate (number of persons with
active lesions at a given point in time) of oral erythroplakia has been estimated as 1 per 2500 adults. The
reported prevalence among several large-scale epidemiologic surveysmost of which were conducted in
South and Southeast Asiaranges from 0.02% to 0.83%.
The incidence is not known, but the average annual
incidence for microscopically proven oral carcinoma
in situ, which represents the great majority of erythroplakias, has been estimated to be 1.2 per 100,000
population (2.0 in males and 0.5 in females) in the
United States.
Erythroplakia also may occur in conjunction with
leukoplakia (see page 388) and has been found concurrently with a large proportion of early invasive oral
carcinomas. Although erythroplakia is less common
CLINICAL FEATURES
Erythroplakia is predominantly a disease of middleaged to older adults with no signicant gender predilection. In the United States, a peak prevalence of 65
to 74 years has been reported. In India, the peak prevalence is in a somewhat younger age range of 45 to 54
years. The oor of mouth, tongue, and soft palate are
the most common sites of involvement, and multiple
lesions may be present.
The altered mucosa appears as a well-demarcated
erythematous macule or plaque with a soft, velvety
texture (Figs. 10-76 and 10-77). It is usually asymptomatic and may be associated with an adjacent
leukoplakia (erythroleukoplakia) (see Fig. 10-67).
Nonspecic mucositis, candidiasis, psoriasis, or vascular lesions may clinically mimic erythroplakia, and
biopsy often is required to distinguish between them.
HISTOPATHOLOGIC FEATURES
According to one large clinicopathologic investigation,
90% of erythroplakic lesions histopathologically represent severe epithelial dysplasia (see page 394), carcinoma in situ (see page 394), or supercially invasive
squamous cell carcinoma (see page 419). The epithelium shows a lack of keratin production and often is
atrophic, but it may be hyperplastic. This lack of keratinization, especially when combined with epithelial
thinness, allows the underlying microvasculature to
show through, thereby explaining the red color. The
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CLINICAL FEATURES
Several health and addiction hazards may be associated with the use of smokeless tobacco because of the
ready absorption of nicotine and other molecules
through the oral mucosa. A variety of local oral alterations also are found in chronic users. One of the most
common local changes is a characteristic painless loss
of gingival tissues in the area of tobacco contact (Fig.
10-78). This gingival recession may be accompanied by
destruction of the facial surface of the alveolar bone
and correlates well with the quantity of daily use and
the duration of the smokeless tobacco habit. Although
the association between smokeless tobacco and gingival recession is well known, there is some variability
across studies regarding the association between
smokeless tobacco and periodontal bone loss. Researchers have suggested that this variability may be related
to the specic type of smokeless tobacco used or possible confounding by concurrent cigarette smoking.
Dental caries also has been reported to be more
prevalent in smokeless tobacco users, perhaps because
of the high sugar content of some brands; other reports
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HISTOPATHOLOGIC FEATURES
The histopathologic appearance of smokeless tobacco
keratosis is not specic. The squamous epithelium is
hyperkeratinized and acanthotic, with or without intracellular vacuolization or edema of glycogen-rich
supercial cells. Parakeratin chevrons may be seen as
pointed projections above or within supercial epithelial layers (Fig. 10-81). Increased subepithelial vascularity and vessel engorgement often are seen. In some
cases an unusual deposition of amorphous eosinophilic
material is noted within the subjacent connective tissue
and salivary glands (Fig. 10-82). Epithelial dysplasia is
uncommon in smokeless tobacco keratosis and, when
present, is typically mild. Occasionally, however, signicant dysplasia or squamous cell carcinoma may be
present.
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Fig. 10-83 Tobacco pouch keratosis. A, Moderately severe lesion of the lower anterior
vestibule and lip in a 15-year-old male subject, which demonstrates a gray-white surface
change and ssuring. The patient had been placing snuff in the area for several years. B, Two
weeks after cessation of the tobacco habit, the mucosa has returned to an almost normal
appearance.
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activity of the enzyme lysyl oxidase involved in collagen synthesis and cross-linking.
HISTOPATHOLOGIC FEATURES
CLINICAL FEATURES
Oral submucous brosis often is rst noted in young
adult betel quid users, whose chief complaint is an
inability to open the mouth (trismus), often accompanied by mucosal pain while eating spicy foods. An
interincisal distance of less than 20 mm is considered
severe; in advanced cases, the jaws may actually be
inseparable. Females are more susceptible to these
changes than males.
Vesicles, petechiae, melanosis, xerostomia, and a
generalized oral burning sensation (stomatopyrosis)
are usually the rst signs and symptoms. The buccal
mucosa, retromolar area, and soft palate are the most
commonly affected sites. The mucosa in these regions
develops a blotchy, marblelike pallor and a progressive
stiffness of subepithelial tissues (Fig. 10-84). When the
tongue is involved, it becomes rather immobile, is frequently diminished in size, and may be devoid of papillae. Submucosal brous bands are palpable on the
buccal mucosa, soft palate, and labial mucosa of fully
developed cases. Involvement may extend beyond the
oral cavity to involve the oropharynx and upper esophagus. Leukoplakia of the surface mucosa often is
noted.
Betel quid chewers also may exhibit a brown-red
discoloration of the mucosa with an irregular surface
that tends to desquamate. This particular change,
known as betel chewers mucosa, is not believed to
be precancerous. In addition, some authors have
reported betel quid lichenoid lesions, characterized
by white, parallel, wavy striae resembling oral lichen
planus (see page 782).
Oral submucous brosis is characterized by the submucosal deposition of dense and hypovascular collagenous connective tissue with variable numbers of
chronic inammatory cells (Fig. 10-85). Epithelial
changes include subepithelial vesicles in early lesions
and hyperkeratosis with marked epithelial atrophy in
older lesions. Epithelial dysplasia is found in 10% to
15% of cases submitted for biopsy, and carcinoma is
found in at least 6% of sampled cases.
The lesions of so-called betel chewers mucosa are
histopathologically similar to morsicatio buccarum
(see page 286), except that the ragged keratinaceous
surface is covered by encrustations of betel quid
ingredients.
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CLINICAL FEATURES
HISTOPATHOLOGIC FEATURES
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ACTINIC KERATOSIS
(SOLAR KERATOSIS)
Actinic keratosis is a common cutaneous premalignant lesion that is caused by cumulative ultraviolet
(UV) radiation to sun-exposed skin, especially in fairskinned people. A similar phenomenon, actinic cheilosis, is associated with sun damage to the lower lip
vermilion (see page 405). UV light exposure can
produce mutations in the p53 tumor suppressor gene,
an alteration found frequently in this and other precancers and cancers of the head and neck region. Mutations in the telomerase gene represent another early
event in lesion development, resulting in delayed apoptosis and immortalization of cells. Although UV light
exposure is the major etiologic factor, additional potential risk factors include immunosuppression, arsenic
exposure, and certain genetic abnormalities, such as
albinism, Rothmund-Thompson syndrome, Cockayne
syndrome, xeroderma pigmentosum (see page 747),
and Bloom syndrome.
The lesion will develop on the skin of more than 50%
of all white adults with signicant lifetime sun exposure, and in the U.S. white population the prevalence
rate is 15% for older men and 6% for older women. The
prevalence increases with advancing age. According to
the National Ambulatory Medical Care Survey, more
than 47 million physician ofce visits were conducted
in the United States over a 10-year period for the diagnosis of actinic keratosis.
CLINICAL FEATURES
Actinic keratosis seldom is found in persons younger
than 40 years of age. The face and neck, the dorsum of
the hands, the forearms, and the scalp of bald-headed
men are the most common sites of occurrence. Indi-
HISTOPATHOLOGIC FEATURES
Histopathologically, actinic keratosis is characterized
by hyperparakeratosis and acanthosis (Fig. 10-90).
Teardrop-shaped rete ridges typically extend down
from the epithelium; by denition, some degree of epithelial dysplasia is present. When full-thickness dysplasia is noted, this is termed bowenoid actinic keratosis.
Suprabasilar acantholysis may be seen, as may melanosis and a lichenoid inammatory inltrate. The dermis
exhibits a band of pale basophilic change, which represents sun-damaged collagen and elastic bers (solar
elastosis). In this band of sun-damaged connective
tissue, there is a fourfold increase in the amount of
elastic bers, and band thickness is increased with
increased exposure to actinic rays. Variable numbers
of chronic inammatory cells are typically present.
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sunlight exposure and compromised immunity, especially a transplant recipient, has an elevated risk of
developing a cancer of the lower lip vermilion.
Actinic cheilosis is similar to actinic keratosis of
the skin (see previous topic) in its pathophysiologic and
biologic behavior.
ACTINIC CHEILOSIS
(ACTINIC CHEILITIS)
Actinic cheilosis is a common premalignant alteration of the lower lip vermilion that results from longterm or excessive exposure to the ultraviolet component
of sunlight. It is a problem conned predominantly to
light-complexioned people with a tendency to sunburn
easily. Outdoor occupation obviously is associated with
this problem, leading to the popular use of terms such
as farmers lip and sailors lip. A person with chronic
CLINICAL FEATURES
Actinic cheilosis seldom occurs in persons younger
than 45 years of age. It has a strong male predilection,
with a male-to-female ratio as high as 10:1 in some
studies.
The lesion develops so slowly that patients often are
not aware of a change. The earliest clinical changes
include atrophy of the lower lip vermilion border,
characterized by a smooth surface and blotchy pale
areas. Blurring of the margin between the vermilion
zone and the cutaneous portion of the lip is typically
seen (Fig. 10-91). As the lesion progresses, rough, scaly
areas develop on the drier portions of the vermilion.
These areas thicken and may appear as leukoplakic
lesions, especially when they extend near the wet line
of the lip. The patient may report that the scaly material
can be peeled off with some difculty, only to reform
again within a few days.
With further progression, chronic focal ulceration
may develop in one or more sites (Fig. 10-92). Such
ulcerations may last for months and often suggest
progression to early squamous cell carcinoma
(Fig. 10-93).
HISTOPATHOLOGIC FEATURES
Actinic cheilosis is usually characterized by an atrophic
stratied squamous epithelium, often demonstrating
marked keratin production. Varying degrees of epithe-
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KERATOACANTHOMA
(SELF-HEALING CARCINOMA;
PSEUDOCARCINOMA;
KERATOCARCINOMA; SQUAMOUS
CELL CARCINOMA,
KERATOACANTHOMA TYPE)
Keratoacanthoma is a self-limiting, epithelial proliferation with a strong clinical and histopathologic similarity to well-differentiated squamous cell carcinoma.
In fact, some authorities consider it to represent an
extremely well-differentiated form of squamous cell
carcinoma. Cutaneous lesions presumably arise from
the infundibulum of hair follicles. Intraoral lesions
have been reported, but they are rare; in fact, some
authorities do not accept keratoacanthoma as an intraoral disease.
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Fig. 10-95 Keratoacanthoma. A nontender, welldemarcated nodule of the skin of the nose in an older
woman. The nodule demonstrates a central keratin plug.
CLINICAL FEATURES
Keratoacanthoma rarely occurs in patients before 45
years of age and shows a male predilection. Almost 95%
of solitary lesions are found on sun-exposed skin, and
8% of all cases are found on the outer edge of the vermilion border of the lips, with equal frequency on both
the upper and the lower lips.
Keratoacanthoma appears as a rm, nontender,
well-demarcated, sessile, dome-shaped nodule with a
central plug of keratin (Figs. 10-95 and 10-96), although
lesions reported as intraoral keratoacanthoma usually
HISTOPATHOLOGIC FEATURES
Keratoacanthoma of the skin and lip vermilion warrants excisional or large incisional biopsy with inclusion of adjacent, clinically normal epithelium for
proper histopathologic interpretation; this is because
the overall pattern of the tumor is diagnostically more
important than the appearance of individual cells. The
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cells appear mature, although considerable dyskeratosis (abnormal or premature keratin production) is typically seen in the form of deeply located individually
keratinizing lesional cells and keratin pearls similar
to those found in well-differentiated squamous cell
carcinoma.
The surface epithelium at the lateral edge of the
tumor appears normal; at the lip of the central crater,
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80
70
Black males
White males
Black females
White females
60
50
40
30
20
10
0
15
25
35
45
55
Age (in years)
65
75
85
Carcinoma of the lip vermilion is somewhat different from intraoral carcinoma. It has a pathophysiology
more akin to squamous cell carcinoma of the sunexposed skin. The average annual incidence rate for
white males in the United States is 4 per 100,000, but
the rate increases dramatically with age, to almost 30
per 100,000 for men older than 75 years of age. Once
the most common oral cancer, the cumulative lifetime
risk for developing lip cancer today is only 0.15% for
men and 0.07% for women. There was a considerable
decrease in the annual incidence rate of this cancer in
white males in the United States during the latter half
of the twentieth century, because fewer and fewer of
them held outdoor occupations. Few women or nonwhite men develop lip carcinoma; there has been little
change in the incidence over time for these groups.
Outside the United States, exceptionally wide differences in annual incidence and mortality rates for oral
carcinoma are found. These rates vary by as much as
twentyfold among different countries. Many of these
differences are undoubtedly caused by differing population habits, life expectancies, preventive education,
and the quality of medical records in various countries.
Despite the difculties involved in interpreting such
data, however, the data have been helpful in identifying potential causative factors.
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Disease Name
?
+/
From Speight PM, Farthing PM, Bouquot JE: The pathology of oral cancer and precancer, Curr Diag Pathol 3:165-176, 1997.
*PVL: High-risk, high-recurrence form of oral leukoplakia affecting multiple sites.
Reverse smoking: smoking with the lit end of the cigarette in ones mouth.
Precancer character is controversial.
such external agents as tobacco smoke, alcohol, syphilis, and (for vermilion cancers only) sunlight. Intrinsic
factors include systemic or generalized states, such as
general malnutrition or iron-deciency anemia. Heredity does not appear to play a major causative role in
oral carcinoma. Many oral squamous cell carcinomas
have been documented to be associated with or preceded by a precancerous lesion, especially leukoplakia (Table 10-1).
TOBACCO SMOKING
Tobacco smoking reached its greatest popularity in the
United States during the 1940s, when at least 65% of
white men smoked and other population subgroups
were beginning to smoke in large numbers. Today less
than 21% of U.S. adults, men and women alike, smoke
cigarettes. Unfortunately, the remaining smokers
appear to be the heavier users; therefore, the effects on
the mouth may be even greater than the typical effects
noted in the past.
Much indirect clinical evidence implicates the habit
of tobacco smoking in the development of oral squamous cell carcinoma. The proportion of smokers (80%)
among patients with oral carcinoma is two to three
times greater than the general population. The risk for
a second primary carcinoma of the upper aerodigestive
tract is two to six times greater for treated patients with
oral cancer who continue to smoke than for those who
quit after diagnosis.
In addition, case control studies have shown that
pipe and cigar smoking carries a greater oral cancer risk
than does cigarette smoking, and that the relative risk
(smokers risk for oral cancer compared with that of a
SMOKELESS TOBACCO
Smokeless tobacco use in Western cultures may increase a chronic users risk for oral carcinoma by a
factor ranging from less than two to as high as 26. This
variation in relative risk reported by different epidemiologic case control studies may be inuenced by
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ALCOHOL
Excessive alcohol consumption has been implicated
in oral cancer development. It is uncertain whether
alcohol alone can initiate carcinogenesis, although it is
well established that alcohol in combination with
tobacco is a signicant risk factor for oral cancer
development.
Case control studies have concluded that the risk is
dose dependent and time dependent, and the combination of alcohol and tobacco abuse over long periods
may increase a persons risk for oral cancer by a factor
of 15 or more (relative risk is 15). In this light, it may
be signicant that the lowest annual oral cancer incidence rate in the United States is found in Utah, where
75% of the population follows Mormon doctrines that
forbid the use of tobacco and alcohol.
Indirect evidence for alcohols role in oral cancer
production includes the fact that approximately one
third of male patients with oral cancer are heavy
alcohol users; less than 10% of the general population
can be classied as such. Cirrhosis of the liver, likewise,
is found in at least 20% of male patients with oral
cancer. Nutritional deciencies associated with heavy
alcohol consumption also may contribute to an
increased risk of oral cancer development.
PHENOLIC AGENTS
Recent evidence has pointed to an increased oral
cancer risk for workers in the wood products industry
chronically exposed to certain chemicals, such as phenoxyacetic acids. Moreover, it has long been known
RADIATION
The effects of ultraviolet (UV) radiation on the lips
are discussed elsewhere (actinic cheilosis, see page
405), but it is well known that another form of radiation, x-irradiation, decreases immune reactivity and
produces abnormalities in chromosomal material. It
should not seem surprising, then, that radiotherapy to
the head and neck area increases the risk of the later
development of a new primary oral malignancy, either
a carcinoma or a sarcoma. This effect is dose dependent, but even low-dose radiotherapy for benign entities may increase the local risk to some extent. However,
the small amount of radiation from routine diagnostic
dental radiographs has not been associated with oral
mucosal carcinomas.
IRON DEFICIENCY
Iron deciency, especially the severe, chronic form
known as the Plummer-Vinson or Paterson-Kelly
syndrome (see page 828), is associated with an
elevated risk for squamous cell carcinoma of the
esophagus, oropharynx, and posterior mouth. Malignancies develop at an earlier age than in patients
without iron deciency anemia. People who are decient in iron tend to have impaired cell-mediated
immunity, and iron is essential to the normal functioning of epithelial cells of the upper digestive tract. In
deciency states, these epithelial cells turn over more
rapidly and produce an atrophic or immature mucosa.
Intertwining brous bands of scar tissue also may
develop within the esophagus of severely affected
patients (esophageal webs). Patients with such esophageal webbing seem to be especially susceptible to
malignant transformation.
VITAMIN-A DEFICIENCY
Vitamin-A deciency produces excessive keratinization of the skin and mucous membranes, and researchers have suggested that the vitamin may play a
protective or preventive role in oral precancer and
cancer. Some believe that blood levels of retinol and
the amount of dietary betacarotene ingested are
inversely proportional to the risk of oral squamous cell
carcinoma and leukoplakia. Long-term therapy with
retinoic acids and betacarotene also has been associated with a regression of at least some leukoplakic
lesions and a concomitant reduction in the severity of
dysplasia within such lesions.
SYPHILIS
Syphilis (tertiary stage) has long been accepted as
having a strong association with the development of
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dorsal tongue carcinoma. The relative risk ratio approximates four. Conversely, a person with a lingual carcinoma is ve times more likely to have a positive serology
test for syphilis than someone without such a cancer.
The arsenical agents and heavy metals that were used
to treat syphilis before the advent of modern antibiotic
therapy have carcinogenic properties themselves and
may have been responsible for some of the earlier
cancer development in this disease. Regardless of the
pathophysiologic mechanism at work, however, syphilis-associated oral malignancies are rare today because
the infection is typically diagnosed and treated before
the onset of the tertiary stage.
CANDIDAL INFECTION
Hyperplastic candidiasis (see page 217) frequently is
cited as an oral precancerous condition. Because this
lesion appears as a white plaque that cannot be rubbed
off, it also has been called candidal leukoplakia. Unfortunately, it is difcult both clinically and histopathologically to distinguish between a true hyperplastic
candidiasis and a preexisting leukoplakia with superimposed candidiasis. Experimentally, some strains of
Candida albicans have produced hyperkeratotic lesions
of the dorsal rat tongue without any other contributing
factor. In other studies, certain strains have been shown
to produce nitrosamines, chemicals that have been
implicated in carcinogenesis. Some candidal strains
may have the potential to promote the development of
oral cancer; to date, however, the evidence to suggest
this role is largely circumstantial.
ONCOGENIC VIRUSES
Oncogenic (tumor producing) viruses may play a major
role in a wide variety of cancers, although no virus has
denitively been proven to cause oral cancer so far.
Viral agents capable of integration into the hosts
genetic material may be particularly dangerous and
potentially could commandeer the hosts ability to regulate normal growth and proliferation of the infected
cell. The oncogenic viruses may immortalize the host
cell, thereby facilitating malignant transformation. In
the past, retroviruses, adenoviruses, herpes simplex
viruses (HSVs), and human papillomaviruses (HPVs)
all have been suggested as playing a role in the development of oral carcinoma. It appears, however, that
HPV is the only one still implicated, not only in oral
cancer but also in carcinoma of the pharyngeal tonsil,
larynx, esophagus, uterine cervix, vulva, and penis.
HPV subtypes 16, 18, 31, and 33 are the strains most
closely associated with dysplasia and squamous cell
carcinoma. The underlying mechanisms by which
HPV is believed to contribute to oral carcinogenesis
primarily involve two virally encoded proteins: (1) E6
(which promotes degradation of the p53 tumor suppressor gene product) and (2) E7 (which promotes
IMMUNOSUPPRESSION
Immunosuppression may play a role in the development of at least some malignancies of the upper
aerodigestive tract. Without effective immunologic
surveillance and attack, it is thought that newly created
malignant cells cannot be recognized and destroyed at
an early stage. Persons with AIDS and those who are
undergoing immunosuppressive therapy for malignancy or organ transplantation are at increased risk for
oral squamous cell carcinoma and other head and
neck malignancies, especially when tobacco smoking
and alcohol abuse are present.
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The leukoplakic and erythroplakic examples are probably early cases that have not yet produced a mass or
ulceration, and the clinical features are identical to
those described for premalignant leukoplakia and
erythroplakia (see pages 388 and 397). These mucosal
surface changes typically are destroyed by the developing exophytic or endophytic carcinoma, but many cases
are diagnosed before their complete destruction and
show residual precancerous lesions involving adjacent
mucosa.
An exophytic lesion typically has a surface that is
irregular, fungating, papillary, or verruciform, and its
color may vary from normal to red to white, depending
on the amount of keratin and vascularity (Figs. 10-102
and 10-103). The surface is often ulcerated, and
the tumor feels hard (indurated) on palpation
(Fig. 10-104).
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for many centimeters along a nerve (perineural invasion) without breaking away to form a true
metastasis.
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INTRAORAL CARCINOMA
The most common site for intraoral carcinoma is the
tongue, usually the posterior lateral and ventral surfaces. The oral oor is affected almost as frequently in
men but is involved much less commonly in women.
Other sites of involvement (in descending order of frequency) are the soft palate, gingiva, buccal mucosa,
labial mucosa, and hard palate.
Carcinoma of the tongue accounts for more than
50% of intraoral cancers in population studies in the
United States (Figs. 10-110 and 10-111). Two thirds of
lingual carcinomas appear as painless, indurated
masses or ulcers of the posterior lateral border; 20%
occur on anterior lateral or ventral surfaces, and only
4% occur on the dorsum. The tongue especially is the
site of involvement in young patients and, in fact, is the
site of the only congenital oral squamous cell carcinoma reported.
Carcinoma of the oral oor represents 35% of all
intraoral cancers in epidemiologic surveys and appears
to be increasing in frequency among females. It occurs
a decade earlier in women than in men but is still
usually a disease of older adults. Of all intraoral carcinomas, oor of mouth lesions are the most likely to
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it may mimic periodontal disease or a pyogenic granuloma. Gingival carcinoma often destroys the underlying bone structure, causing tooth mobility. This lesion
may not become clinically evident until after tooth
extraction, when it proliferates out of the socket to
mimic the hyperplastic granulation tissue of epulis
granulomatosa. Of all the intraoral carcinomas, this
one is least associated with tobacco smoking and has
the greatest predilection for females.
OROPHARYNGEAL CARCINOMA
Carcinoma of the soft palate and oropharyngeal mucosa
has the same basic clinical appearance as more anterior carcinomas, except that, in this posterior location,
the patient often is unaware of its presence and the
diagnosis may be delayed. Tumor size is typically
greater than that of more anterior carcinomas, and the
proportion of cases with cervical and distant metastasis
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Jugulo-digastric
Preauricular
Submandibular
Tail of parotid
High jugular
Spinal accessory
Submental
Transverse cervical
Mid jugular
Low jugular
METASTASIS
The metastatic spread of oral squamous cell carcinoma
is largely through the lymphatics to the ipsilateral cervical lymph nodes (Fig. 10-117). A cervical lymph
node that contains a metastatic deposit of carcinoma is
usually rm to stony hard, nontender, and enlarged
(Fig. 10-118). If the malignant cells have perforated
the capsule of the node and invaded into surrounding
tissues, then the node will feel xed, or not easily
movable. Extracapsular spread (extension of metastatic
deposits outside of the lymph node capsule) is a microscopic feature associated with poor prognosis, including increased risk of locoregional recurrence, distant
metastasis, and lower survival rates.
Occasionally, contralateral or bilateral metastatic
deposits are seen, and at least 2% of patients have
distant (below the clavicles) metastasis at diagnosis;
in some studies this gure is as high as 22%. The most
common sites of distant metastasis are the lungs, liver,
and bones, but any part of the body may be affected.
Carcinoma of the lower lip and oral oor tends to
travel to the submental nodes; tumors from the poste-
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T4a
T4b
N2a
N2b
N2c
N3
From Tumor-node-metastasis (TNM) staging system for oral carcinoma. In Greene FL, Page DL, Fleming ID et al, editors, AJCC cancer staging manual, ed
4, New York, 2002, Springer.
population studies have positive cervical nodes at diagnosis, and one in 10 already have distant metastasis by
that time.
STAGING
Tumor size and the extent of metastatic spread of oral
squamous cell carcinoma are the best indicators of
the patients prognosis. Quantifying these clinical
parameters is called staging the disease. Table 10-2
summarizes the most popular staging protocol, the
tumor-node-metastasis (TNM) system. Individualized
TNM classications are used for most human cancers,
with each system pertaining exclusively to a specic
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Stage
Stage I
Stage II
Stage III
Stage IV
IVA
IVB
IVC
TNM Classication
Oral Cavity
Lip
68%
53%
41%
27%
83%
73%
62%
47%
T1 N0 M0
T2 N0 M0
T3 N0 M0, or T1, T2, or T3 N1 M0
T4a N0 or N1 M0, or T1, T2, T3, or T4a N2 M0
Any T N3 M0, or T4b any N M0
Any M1 lesion
HISTOPATHOLOGIC FEATURES
Squamous cell carcinoma arises from dysplastic surface epithelium and is characterized histopathologically by invasive islands and cords of malignant
squamous epithelial cells. When the tumor is sampled
fortuitously at the earliest moment of invasion, the
adjectives supercially invasive or microinvasive often are
used. The features of epithelial dysplasia are discussed
in more detail in the section pertaining to leukoplakia
(see page 394).
Invasion is represented by irregular extension of
lesional epithelium through the basement membrane
and into subepithelial connective tissue. Individual
squamous cells and sheets or islands of cells are seen
to be thriving as independent entities within the connective tissues, without attachment to the surface epithelium. Invading cells and cell masses may extend
deeply into underlying adipose tissue, muscle, or bone,
destroying the original tissue as they progress. Lesional
cells may surround and destroy blood vessels and may
invade into the lumina of veins or lymphatics. There is
often a strong inammatory or immune cell response
to invading epithelium, and focal areas of necrosis may
be present. The lesional epithelium is capable of inducing the formation of new small blood vessels (angiogenesis) and, occasionally, dense brosis (desmoplasia or scirrhous change).
Whether the tumor is supercially or deeply invasive, lesional cells generally show abundant eosinophilic cytoplasm with large, often darkly staining
(hyperchromatic) nuclei and an increased nuclearto-cytoplasmic ratio. Varying degrees of cellular and
nuclear pleomorphism are seen. The normal product of
squamous epithelium is keratin, and keratin pearls (a
round focus of concentrically layered keratinized cells)
may be produced within lesional epithelium. Single
cells also may undergo individual cell keratinization.
Histopathologic evaluation of the degree to which
these tumors resemble their parent tissue (squamous
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MULTIPLE CARCINOMAS
Patients with one carcinoma of the mouth or throat are
at increased risk for additional concurrent (synchronous) or later (metachronous) primary surface epithelial malignancies of the upper aerodigestive tract, the
esophagus, the stomach, the lungs, and other sites. This
risk has been estimated to be as low as 6% and as high
as 44% in affected individuals. The highest gures are
associated with male patients who continue to smoke
and abuse alcohol after therapy. Overall, in 9% to 25%
of patients with oral carcinoma, additional mouth or
throat malignancies develop.
In patients with more than one upper aerodigestive
tract malignancy, approximately one third of the
tumors arise simultaneously. Of the rest, the second
lesion usually develops within 3 years after the initial
cancer. This tendency toward the development of multiple mucosal cancers, sometimes called eld cancerization, may reect diffuse exposure to local carcinogens,
a process that increases the malignant transformation
potential of all exposed epithelial cells. Molecular
analyses of various markers, including loss of heterozygosity (LOH), microsatellite alterations, p53 tumor
suppressor gene mutations, and X-chromosome inactivation, have identied genetic alterations shared
between tumor tissue and adjacent clinically normalappearing tissue in one third to one half of cases examined. In addition, investigators have shown that a
signicant proportion of second primary tumors
develop from the same preneoplastic precursor lesion
or eld, with the remaining cases representing tumors
that develop independently. Furthermore, researchers
have proposed that patches of clonal cells can progress
to develop additional mutations and give rise to subclones in a process known as clonal divergence, which
would account for the genetic heterogeneity typically
seen among these tumors.
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VERRUCOUS CARCINOMA
(SNUFF DIPPERS CANCER;
ACKERMANS TUMOR)
Verrucous carcinoma is a low-grade variant of oral
squamous cell carcinoma. In 1948, Ackerman
described this lesion in detail, although the term verrucous carcinoma had been used in 1944 in a series of
cases reported by Burford, Ackerman, and Robinson.
Ackerman postulated that some of these lesions might
be associated with the use of smokeless tobacco,
because 11 of his 31 patients were tobacco chewers.
However, there was no mention of the type of smokeless tobacco used and no mention of whether any of
these patients also had smoked tobacco. In addition to
the oral mucosa, verrucous carcinoma has been identied at several extraoral sites, including laryngeal, vulvovaginal, penile, anorectal, sinonasal, and esophageal
mucosa, as well as the skin of the breast, axilla, ear
canal, and soles of the feet. Tumors at anatomic sites
other than the mouth are unrelated to tobacco use.
Several investigators have identied human papillomavirus (HPV) subtypes 16 and 18 in a minority of oral
verrucous carcinomas, but the signicance of this is
unclear because this virus often is associated with
otherwise normal oral mucosa.
Verrucous carcinoma represents less than 1% to 10%
of all oral squamous cell carcinomas, depending on the
local popularity of smokeless tobacco use. The only
epidemiologic assessment of this tumor in a Western
culture reported an average annual incidence rate of
one to three oral lesions per 1 million population each
year. Among 411,534 cases of head and neck carcinoma recorded in the National Cancer Database from
1985 to 1996, only 0.6% of cases were diagnosed as
verrucous carcinoma.
Some verrucous carcinomas arise from the oral
mucosa in people who chronically use chewing tobacco or snuff, typically in the area where the tobacco
is habitually placed. Cases also occur in nonusers, but
the exact gure is difcult to assess because patients
will often deny the tobacco habit. In smokeless tobacco
users, conventional squamous cell carcinoma is much
more likely to develop than this low-grade variant.
CLINICAL FEATURES
Verrucous carcinoma is found predominantly in men
older than 55 years of age (average age, 65 to 70 years).
In areas where women are frequent users of dry snuff,
however, older females may predominate. The most
common sites of oral mucosal involvement include the
mandibular vestibule, gingiva, buccal mucosa, tongue,
and hard palate. The site of occurrence often corresponds to the site of chronic tobacco placement. In
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gist must evaluate the overall histomorphologic conguration of the lesion to arrive at an appropriate
diagnosis. Adequate sampling also is important because
as many as 20% of these lesions have a routine squamous cell carcinoma developing concurrently within
the verrucous carcinoma.
HISTOPATHOLOGIC FEATURES
Verrucous carcinoma has a deceptively benign microscopic appearance; it is characterized by wide and
elongated rete ridges that appear to push into the
underlying connective tissue (Fig. 10-124). Lesions
usually show abundant keratin (usually parakeratin)
production and a papillary or verruciform surface.
Parakeratin typically lls the numerous clefts or crypts
(parakeratin plugs) between the surface projections.
These projections may be long and pointed or short
and blunted. The lesional epithelial cells generally
show a normal maturation pattern with no signicant
degree of cellular atypia. There is frequently an intense
inltrate of chronic inammatory cells in the subjacent
connective tissue.
The histopathologic diagnosis of verrucous carcinoma requires an adequate incisional biopsy. Because
the individual cells are not very dysplastic, the patholo-
Because metastasis is an extremely rare event in verrucous carcinoma, the treatment of choice is surgical
excision without radical neck dissection. The surgery
generally need not be as extensive as that required for
routine squamous cell carcinoma of a similar size.
With this treatment, 90% of patients are disease free
after 5 years, although some patients will require at
least one additional surgical procedure during that
time. The treatment failures usually occur in patients
with the most extensive involvement or in those unable
to tolerate extensive surgery because of unrelated systemic diseases. An additional cause of treatment failure
is the initial inability to identify a focal squamous cell
carcinoma arising concurrently within the less aggressive lesion. Verrucous carcinomas containing foci of
conventional squamous cell carcinoma should be
treated as conventional squamous cell carcinomas.
Radiotherapy is an alternative primary treatment
modality but provides poorer local control and thus is
considered less effective than surgery. In addition,
radiotherapy has been unpopular because of published
reports of poorly differentiated or anaplastic carcinoma
developing within the lesion after treatment. However,
more recent analysis suggests that this threat is seriously overexaggerated. Chemotherapy may temporarily reduce the size of verrucous carcinoma and may be
an option for inoperable cases, but it is not considered
a denitive, stand-alone treatment. In a limited number
of cases, tumor regression after radiochemotherapy or
photodynamic therapy has been reported, although
these treatment alternatives require further study.
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be simply an anaplastic type of carcinoma cell. Electron microscopy and immunohistochemical analysis
support the concept that these lesional cells are of epithelial origin, with the ability to produce mesenchymal
intermediate laments. Based on immunohistochemical studies, some investigators have hypothesized that
a dysfunctional cadherin-catenin complex important
for intercellular adhesion causes the tumor cells to
shift from a squamous to a spindled type, with increased
inltrative behavior. More than one third of all mucosal
cases develop as recurrences after radiotherapy for a
more differentiated squamous cell carcinoma, a phenomenon known as dedifferentiation.
CLINICAL FEATURES
The mean age at diagnosis for spindle cell carcinoma
is 57 years (range: 29 to 93 years). There is no sex
predilection. The neoplasm occurs predominantly in
the upper aerodigestive tract, especially the larynx, oral
cavity, and esophagus. Within the mouth, the lower lip,
lateral posterior tongue, and alveolar ridges are
common sites, but other areas may be involved.
In contrast to other oral cancers, the spindle cell
carcinoma typically appears as a pedunculated, polypoid mass, but it may occasionally appear as a sessile,
nodular or fungating mass or as an ulcer (Fig. 10-125).
Pain and paresthesia are prominent features. The
tumor grows rapidly, tends to metastasize early, and is
typically diagnosed in a late stage (stages III and IV).
Lower lip lesions seem to have a special propensity to
travel along nerves through the mental foramen and
into the mandibular canal.
HISTOPATHOLOGIC FEATURES
The spindle cell carcinoma is composed predominantly of fascicles of anaplastic spindle-shaped cells
(Fig. 10-126). Some spindle cells may appear as
obvious epithelial elements, but others strongly resemble atypical mesenchymal cells. On rare occasions,
bone, cartilage, or muscle differentiation may be seen.
Numerous mitotic gures often are present. The overall
picture is similar to that of an anaplastic brosarcoma
(see page 553), except for the often-inconspicuous
squamous element.
The squamous component usually consists of carcinoma in situ of the overlying surface epithelium but
may appear as islands of dysplastic squamous epithelium among the spindle cells. Direct transition between the two cell types may be seen. Metastatic lesions
may show only spindle cells, only squamous cells, or a
combination of spindle and squamous cells.
Serial sections may be needed to nd areas of
unequivocal squamous cell carcinoma, and immunohistochemical techniques can be particularly useful in
distinguishing this tumor from mesenchymal spindle
cell malignancies. The lesional cells of most mesenchymal tumors typically produce vimentin but not cytokeratin. Approximately two thirds of the cases of
spindle cell carcinoma react with antibodies directed
against cytokeratin, and an equivalent number show
vimentin immunoreactivity. Some cases also will be
positive for carcinoembryonic antigen (CEA).
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ADENOSQUAMOUS CARCINOMA
Adenosquamous carcinoma is a rare variant of squamous cell carcinoma that is characterized histopathologically by a combination of adenocarcinoma and
squamous cell carcinoma. The adenoid (glandular)
pattern, which includes mucus production, has been
demonstrated clearly in metastatic deposits. Some
authorities consider this carcinoma to be merely a
high-grade mucoepidermoid carcinoma (see page
487). The cause is unknown.
CLINICAL FEATURES
Cases of adenosquamous carcinoma have been
reported from the tongue, oral oor, and other mucosal
surfaces, usually in older adults. There is a slight male
predilection. The clinical appearance is that of a
nodular, broad-based, variably painful mass with or
without surface ulceration. Eighty percent of patients
have metastatic deposits within the neck nodes at
diagnosis.
HISTOPATHOLOGIC FEATURES
Adenosquamous carcinoma appears as an admixture
of a surface squamous cell carcinoma and an underlying ductal adenocarcinoma. The glandular component
tends to be most prominent in deeper portions of the
tumor. Intracytoplasmic mucin is noted by mucicarmine staining in most cases, making differentiation
from mucoepidermoid carcinoma difcult but helping
to distinguish adenosquamous carcinoma from forms
of squamous cell carcinoma that exhibit a pseudoglandular pattern of degeneration. Both squamous and
glandular components immunoreact with antibodies
directed against high molecularweight cytokeratin
(KL1).
BASALOID SQUAMOUS
CARCINOMA (BASALOID
SQUAMOUS CELL CARCINOMA)
Basaloid squamous carcinoma is a lesion found primarily in the upper aerodigestive tract mucosa and
represents the most recently described variant of squamous cell carcinoma. It has a tendency to develop in
the hypopharynx, but dozens of oral lesions have been
reported.
CLINICAL FEATURES
Basaloid squamous carcinoma of the head and neck
occurs predominantly in men, although no signicant
gender predilection exists among previously reported
oral cases. The neoplasm tends to occur in persons 40
to 85 years of age and in abusers of alcohol and smoked
tobacco. It most commonly involves the larynx, pyriform sinus, and tongue base, but any region of the
upper aerodigestive tract may be affected. The individual lesion clinically appears as a fungating mass or
ulcer and may be painful or interfere with swallowing
(dysphagia). Almost 80% of patients have cervical
metastases at the time of diagnosis of this high-grade,
aggressive cancer.
HISTOPATHOLOGIC FEATURES
As its name connotes, basaloid squamous carcinoma
has two microscopic components. The rst is a supercial, well-differentiated or moderately differentiated
squamous cell carcinoma, often with surface ulceration, multifocal origin, and areas of carcinoma in situ.
The second, deeper component is an invasive basaloid
epithelium arranged in islands, cords, and glandlike
lobules. This deeper tumor often shows palisading of
peripheral cells, necrosis of central regions, and occasional squamous differentiation (Fig. 10-127). This
component appears similar to basal cell carcinoma,
adenoid cystic carcinoma, basal cell adenocarcinoma,
or neuroendocrine carcinoma. The interface between
the two components is typically sharp and distinct, but
transition from squamous to basaloid cells may occasionally be seen. Basaloid cells and islands of cells often
are surrounded by mucoid stroma (basal lamina mate-
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CARCINOMA OF THE
MAXILLARY SINUS
Carcinoma of the maxillary sinus or antrum is an
uncommon malignancy of largely unknown cause. It
does not appear to be related to sinusitis or nasal polyps.
Unlike squamous cell carcinomas in other head and
neck sites, squamous cell carcinomas of the paranasal
sinuses have been associated only weakly with tobacco
use. A strong causal relationship to occupational wood
and leather dust exposure has been established for the
rarely occurring sinonasal intestinal type of adenocarcinoma. Maxillary sinus carcinomas comprise only 3%
of all head and neck carcinomas; however, among
paranasal sinus carcinomas, the maxillary sinus is the
most common site (accounting for 80% of lesions). Most
lesions remain asymptomatic or mimic sinusitis for
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HISTOPATHOLOGIC FEATURES
Although the antrum is lined by respiratory epithelium, the great majority of maxillary sinus carcinomas
are squamous cell carcinomas, usually moderately
or poorly differentiated.
SINONASAL UNDIFFERENTIATED
CARCINOMA
Sinonasal undifferentiated carcinoma (SNUC) is a
rare, highly aggressive, and clinicopathologically distinctive neoplasm of the nasal cavity and paranasal
sinuses. The tumor was rst described in 1986, and
since then fewer than 100 cases have been reported. In
the earlier literature, tumors of this type were probably
reported as anaplastic or undifferentiated carcinomas.
The histogenesis is uncertain; some investigators
have theorized that the cell of origin may be related to
the schneiderian membrane or olfactory epithelium.
The pathogenesis of SNUC is poorly understood. A few
cases have been associated with a history of smoking
or the presence of Epstein-Barr virus (EBV), although
a strong correlation with these factors has not been
established. In some instances, patients have developed SNUC secondary to radiation therapy for nasopharyngeal carcinoma or retinoblastoma.
HISTOPATHOLOGIC FEATURES
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NASOPHARYNGEAL CARCINOMA
Nasopharyngeal carcinoma refers to a group of
malignancies that arise from the lining epithelium of
the lymphoid tissuerich nasopharynx; similar tumors
are found in the palatine tonsil and base of tongue.
These three anatomic sites are collectively called
Waldeyers tonsillar tissue or Waldeyers ring.
Nasopharyngeal carcinoma is rare in most areas of
the world. The average annual incidence rate in the
United States is less than 1 case per 100,000 persons.
In southern Chinese men, however, the rate is a startling 20 to 55 cases per 100,000. Among southern
Chinese men who migrate to the United States, the rate
is intermediate, which suggests an environmental causative agent. Intermediate rates also are observed among
many indigenous people of Southeast Asia (including
Thais, Vietnamese, Malays, and Filipinos), Inuits of
Alaska and Greenland, and Arabs of North Africa.
Infection with Epstein-Barr virus, diets decient in
vitamin C, and consumption of salt sh that contains
potentially carcinogenic N-nitrosamines have been
implicated as contributory factors. Tobacco also has
been implicated as a risk factor; however, the magnitude of risk for carcinoma development for a given
level of tobacco exposure is lower in the nasopharynx
than in other parts of the upper aerodigestive tract.
HISTOPATHOLOGIC FEATURES
CLINICAL FEATURES
Nasopharyngeal carcinoma occurs in all age groups,
but most commonly affects those who are 40 to 60
years old. It also occurs three times more commonly in
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and diagnosis. Microscopic examination of a nasopharyngeal carcinoma typically shows one of three histopathologic patterns:
1. Squamous cell carcinoma (keratinizing squamous cell carcinoma)
2. Differentiated nonkeratinizing carcinoma (nonkeratinizing squamous cell carcinoma)
3. Undifferentiated nonkeratinizing carcinoma
(poorly differentiated carcinoma, anaplastic carcinoma, lymphoepithelioma)
More than one histopathologic type may be present in
the same biopsy sample, in which case the tumor is classied according to the predominant histologic type.
The histopathologic features of the keratinizing
squamous cell carcinoma are identical to those of
squamous cell carcinoma of other head and neck
regions (see page 419). Evidence of keratinization must
be seen at the light microscopic level.
The lesional cells of differentiated nonkeratinizing carcinoma are relatively mature and somewhat
squamous in nature, but they produce no keratin.
Broad interconnecting bands of oval or round cells are
organized in plexiform and papillary patterns.
Undifferentiated nonkeratinizing carcinoma
consists of sheets of lesional cells with less distinct
margins that show virtually no differentiation in most
instances (Fig. 10-131). They have very little cytoplasm
and large vesicular nuclei. These tumor cells are often
intermixed with the lymphoid cells normally found at
this anatomic site. The term lymphoepithelioma has
been used to describe this lesion because it was once
thought to be a malignancy that originated from both
epithelial and lymphoid tissues. This terminology
should be discouraged, however, because the lymphoid
tissue is not part of the neoplastic process. Such undifferentiated tumors may be difcult to distinguish from
lymphoma by light microscopy alone, and immunohistochemical studies often are used to demonstrate
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CLINICAL FEATURES
Basal cell carcinoma is a disease of adult whites, especially those with fair complexions. Although most
patients are older than 40 years of age at the time of
diagnosis, some lesions are detected as early as the
second decade of life, particularly in patients with red
or blonde hair and blue or green eyes. Approximately
80% of lesions occur on the head and neck, with the
remainder involving the trunk and limbs.
The most common form of this lesion, the nodular
(noduloulcerative) basal cell carcinoma, begins as a
rm, painless papule that slowly enlarges and gradually develops a central depression and an umbilicated
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HISTOPATHOLOGIC FEATURES
The basal cell carcinoma displays a considerable diversity of appearances under the microscope: nodulocystic (noduloulcerative), supercial, adenoid, pigmented,
inltrative, morpheaform, and keratotic. The noduloulcerative, pigmented, and syndrome-related basal cell
carcinomas are comprised of uniform ovoid, darkstaining basaloid cells with moderate-sized nuclei and
relatively little cytoplasm (Fig. 10-135). The cells are
arranged into well-demarcated islands and strands,
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CLINICAL FEATURES
Merkel cell carcinoma typically appears in older
people, with more than 76% of cases reported in individuals 65 years or older. The tumor exhibits a predilection for whites and a slight male predominance. It
occurs primarily on the sun-exposed areas of fairskinned individuals, most commonly (75%) on the skin
of the face. The vermilion border of the lower lip is also
a susceptible site. Merkel cell carcinoma only rarely
(4.5%) arises from mucosal sites, including the oral,
nasal, pharyngeal, laryngeal, and vaginal mucosa. The
tumor usually appears as a slowly enlarging, domeshaped nodule with a smooth surface and prominent
surface vessels (telangiectasias). It is red or violaceous
and ranges in size from 0.5 to 5.0 cm. Ulceration rarely
is seen. Occasional lesions grow rapidly, and 25% demonstrate local metastasis at diagnosis, belying its innocuous clinical appearance.
HISTOPATHOLOGIC FEATURES
Merkel cell carcinoma consists of inltrating sheets
and anastomosing strands of moderately sized, uniform,
undifferentiated basophilic cells in the dermis and subcutaneous fat (Fig. 10-136). Pseudoglandular, trabecular, cribriform (Swiss cheese), and sheetlike patterns
may be seen. The surface epithelium is usually intact
and otherwise unremarkable unless secondarily ulcerated by the tumor. Mitotic gures are abundant, and
tumor cells have prominent nuclei, scant cytoplasm,
and indistinct cell borders. Intracytoplasmic argyrophilic granules may be demonstrated by the Grimelius
stain, and lesional cells typically exhibit a perinuclear
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CLINICAL FEATURES
Most melanomas are seen in white adults. The average
age of affected persons is 50 to 55 years, but cases are
rather evenly distributed over the 30- to 80-year age
bracket. A few melanomas occur in the second and
third decades of life. Four clinicopathologic types of
melanoma have been described:
1. Supercial spreading melanoma
2. Nodular melanoma
3. Lentigo maligna melanoma
4. Acral lentiginous melanoma
Melanomas tend to exhibit two directional patterns
of growth: (1) the radial growth phase and (2) the
vertical growth phase. In the early stages of melanoma development, the radial growth phase tends to
predominate in lentigo maligna melanoma, supercial
spreading melanoma, and acral lentiginous melanoma.
In these lesions, the malignant melanocytes have a propensity to spread horizontally through the basal layer
Box 10-4
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NODULAR MELANOMA
Nodular melanoma represents 15% of cutaneous melanomas, and one third of such lesions develop in the
head and neck area. Nodular melanoma is thought to
begin almost immediately in the vertical growth phase;
therefore, it typically appears as a nodular elevation
that rapidly invades into the connective tissue. Nodular
melanoma is usually a deeply pigmented exophytic
lesion, although sometimes the melanoma cells are so
poorly differentiated that they no longer can produce
melanin, resulting in a nonpigmented amelanotic
melanoma.
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HISTOPATHOLOGIC FEATURES
With cutaneous and oral melanomas, atypical melanocytes are initially seen at the epithelial and connective
tissue junction. From here, they have the potential to
proliferate throughout the epithelium, laterally along
the basal cell layer, and downward into the connective
tissue. In the early stages of the neoplasm, atypical
melanocytes are seen either scattered singly among the
basal epithelial cells or as nests within the basal cell
layer. The atypical melanocytes are usually larger than
normal melanocytes and have varying degrees of
nuclear pleomorphism and hyperchromatism.
With supercial spreading melanoma, pagetoid
spread often is seen. Large melanoma cells inltrate
the surface epithelium singly or in nests (Fig. 10-142).
The resulting microscopic pattern is called pagetoid
because it resembles an intraepithelial adenocarcinoma known as Pagets disease of skin.
The spreading of the lesional cells along the basal
layer constitutes the radial growth phase of the neo-
plasm. Such lateral spread of cells within the epithelium, which occurs before invasion into the underlying
connective tissue, is characteristically seen in supercial spreading melanoma, lentigo maligna melanoma,
and acral lentiginous melanoma. In acral lentiginous
melanoma, many of the melanocytes have prominent
dendritic processes (Fig. 10-143).
When malignant melanocytes are observed invading the connective tissue, the vertical growth phase has
taken place. In nodular melanoma, this vertical growth
phase occurs early in the course of the tumor. No radial
growth of cells can be observed in the overlying epithelium beyond the edge of the invasive tumor (Fig.
10-144). The invasive melanoma cells usually appear
either spindle-shaped or epithelioid and inltrate the
connective tissue as loosely aggregated cords or sheets
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of pleomorphic cells. Oral lesions tend to show invasion of lymphatic and blood vessels more readily than
skin lesions. Several mucosal melanomas have been
reported to contain unequivocal bone and cartilage, a
feature that may cause diagnostic confusion with pleomorphic adenoma, sarcomatoid carcinoma, osteogenic
sarcoma, and mesenchymal chondrosarcoma.
In most instances, the lesional cells of melanoma
contain ne melanin granules, but they may demonstrate no melanin production (amelanotic melanoma).
A lack of melanin production may cause diagnostic
confusion at the light microscopic level because mela-
Clarks Classication
Level I
Level II
Level III
Level IV
Level V
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Table 10-5
T CLASSIFICATION
AND
MAXILLOFACIAL PATHOLOGY
T1
TUMOR THICKNESS
(BRESLOWS DEPTH OF INVASION)b
1.0 mm
T2
1.01-2.0 mm
T3
2.01-4.0 mm
T4
>4.0 mm
N CLASSIFICATION
N0
N1
ULCERATION STATUS
a: Without ulceration or Clarks level II/III
b: With ulceration or Clarks level IV/V
a: Without ulceration
b: With ulceration
a: Without ulceration
b: With ulceration
a: Without ulceration
b: With ulceration
NODAL METASTATIC MASS
a: Microscopicc
b: Macroscopicd
a: Microscopic
b: Macroscopic
c: In-transit metastasis/satellite(s) without
metastatic nodes
N2
N3
M CLASSIFICATION
M0
M1a
M1b
M1c
CLINICAL STAGE
GROUPING
Stage IA
Stage IB
TNM CLASSIFICATION
T1a N0 M0
T1b N0 M0
T2a N0 M0
T2b N0 M0
T3a N0 M0
T3b N0 M0
T4a N0 M0
T4b N0 M0
Any T N1 M0
Any T N2 M0
Any T N3 M0
Any M1
95%
91%
89%
77%
79%
63%
67%
45%
29%-70%
24%-63%
27%
10%-19%
Stage IIA
Stage IIB
Stage IIC
Stage III
Stage IV
a
Based on Greene FL, Page DL, Fleming ID et al, editors: AJCC cancer staging manual, ed 6, New York, 2002, Springer.
Breslows depth is measured from the top of the granular cell layer.
c
Microscopicclinically occult.
d
Macroscopicclinically apparent.
e
In-transitintralymphatic metastases occurring within 2 cm of the primary tumor.
f
Satellite metastasisintralymphatic metastases occurring >2 cm from the primary tumor but before the rst echelon of regional lymph nodes.
g
Survival data from Balch CM, Buzaid AC, Soong SJ et al: Final version of the American Joint Committee on Cancer staging system for cutaneous
melanoma, J Clin Oncol 19:3635-3648, 2001.
b
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Laryngoscope 97:905-908, 1987.
Righi PD, Francis F, Aron BS et al: Sinonasal undifferentiated
carcinoma: a 10-year experience, Am J Otolaryngol 17:167171, 1996.
Rischin D, Porceddu S, Peters L et al: Promising results with
chemoradiation in patients with sinonasal undifferentiated
carcinoma, Head Neck 26:435-441, 2004.
Sharara N, Muller S, Olson J et al: Sinonasal undifferentiated
carcinoma with orbital invasion: report of three cases, Ophthal
Plast Reconstr Surg 17:288-292, 2001.
Smith SR, Som P, Fahmy A et al: A clinicopathological study of
sinonasal neuroendocrine and sinonasal undifferentiated
carcinoma, Laryngoscope 110:1617-1622, 2000.
Nasopharyngeal Carcinoma
Agulnik M, Siu LL: State-of-the-art management of nasopharyngeal carcinoma: current and future directions, Br J Cancer
92:799-806, 2005.
August M, Dodson TB, Nastri A et al: Nasopharyngeal carcinoma:
clinical assessment and review of 176 cases, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 91:205-214, 2001.
Chen CL, Hsu MM: Second primary epithelial malignancy of
nasopharynx and nasal cavity after successful curative radiation therapy of nasopharyngeal carcinoma, Hum Pathol
31:227-232, 2000.
Epstein JB, Jones CK: Presenting signs and symptoms of nasopharyngeal carcinoma, Oral Surg Oral Med Oral Pathol 75:3236, 1993.
Farrow DC, Vaughan TL, Berwick M et al: Diet and nasopharyngeal cancer in a low-risk population, Int J Cancer 78:675-679,
1998.
Ma BBY, Chan ATC: Recent perspectives in the role of chemotherapy in the management of advanced nasopharyngeal
carcinoma, Cancer 103:22-31, 2005.
OMeara WP, Lee N: Advances in nasopharyngeal carcinoma,
Curr Opin Oncol 17:225-230, 2005.
Ou SHI, Zell JA, Ziogas A et al: Epidemiology of nasopharyngeal
carcinoma in the United States: improved survival of Chinese
patients within the keratinizing squamous cell carcinoma
histology, Ann Oncol 18:29-35, 2007.
Wei WI, Sham JST: Nasopharyngeal carcinoma, Lancet 365:20412052, 2005.
Wenig BM: Nasopharyngeal carcinoma, Ann Diagn Pathol 3:374385, 1999.
Yu MC, Yuan JM: Epidemiology of nasopharyngeal carcinoma,
Cancer Biol 12:421-429, 2002.
Basal Cell Carcinoma
Bath-Hextall FJ, Perkins W, Bong J et al: Interventions for basal
cell carcinoma of the skin, Cochrane Database Syst Rev 1:
CD003412, 2007.
Ceilley RI, Del Rosso JQ: Current modalities and new advances
in the treatment of basal cell carcinoma, Int J Dermatol
45:489-498, 2006.
Christenson LF, Borrowman TA, Vachon CM et al: Incidence of
basal cell and squamous cell carcinomas in a population
younger than 40 years, JAMA 294:681-690, 2005.
Crowson AN: Basal cell carcinoma: biology, morphology and
clinical implications, Mod Pathol 19:S127-S147, 2006.
Daya-Grosjean L, Couv-Privat S: Sonic hedgehog signaling in
basal cell carcinomas, Cancer Lett 225:181-192, 2005.
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Del Rosario RN, Barr RJ, Jensen JL et al: Basal cell carcinoma
of the buccal mucosa, Am J Dermatopathol 23:203-205,
2001.
Gutierrez MM, Mora RG: Nevoid basal cell carcinoma syndrome:
a review and case report of a patient with unilateral basal cell
nevus syndrome, J Am Acad Dermatol 15:1023-1030, 1986.
Kato N, Endo Y, Tamura G et al: Ameloblastoma with basal cell
carcinoma-like feature emerging as a nasal polyp, Pathol Int
49:747-751, 1999.
Kuijpers DIM, Thissen MRTM, Neumann MHA: Basal cell carcinoma. Treatment options and prognosis, a scientic approach
to a common malignancy, Am J Clin Dermatol 3:247-259,
2002.
Martin RC 2nd, Edwards MJ, Cawte TG et al: Basosquamous carcinoma: analysis of prognostic factors inuencing recurrence,
Cancer 88:1365-1369, 2000.
Niederhagen B, Lindern J, Berge S et al: Staged operations for
basal cell carcinoma of the face, Br J Oral Maxillofac Surg
38:477-479, 2000.
Rishiraj B, Epstein JB: Basal cell carcinoma: what dentists need
to know, J Am Dent Assoc 130:375-380, 1999.
Rubin AI, Chen EH, Ratner D: Basal-cell carcinoma, N Engl J Med
353:2262-2269, 2005.
Telfer NR, Colver GB, Bowers PW: Guidelines for the management of basal cell carcinoma, Br J Dermatol 141:415-423,
1999.
Merkel Cell Carcinoma
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2003.
Bickle K, Glass LF, Messina JF et al: Merkel cell carcinoma: a
clinical, histopathologic, and immunohistochemical review,
Semin Cutan Med Surg 23:46-53, 2004.
Chan JK, Suster S, Wenig BM et al: Cytokeratin 20 immunoreactivity distinguishes Merkel cell (primary cutaneous neuroendocrine) carcinomas and salivary gland small cell
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Surg Pathol 21:226-234, 1997.
Dancey AL, Rayatt SS, Soon C et al: Merkel cell carcinoma: a
report of 34 cases and literature review, J Plast Reconstr Aesthet
Surg 59:1294-1299, 2006.
Garneski KM, Nghiem P: Merkel cell carcinoma adjuvant
therapy: current data support radiation but not chemotherapy, J Am Acad Dermatol 57:166-169, 2007.
Gollard R, Weber R, Kosty MP et al: Merkel cell carcinoma.
Review of 22 cases with surgical, pathologic, and therapeutic
considerations, Cancer 8:1842-1851, 2000.
Hendrikx SMGA, de Wilde PCM, Kaanders JHAM et al: Merkel
cell carcinoma in the oral cavity: a case presentation and
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Jabbour J, Cumming R, Scolyer RA et al: Merkel cell carcinoma:
assessing the effect of wide local excision, lymph node dissection, and radiotherapy on recurrence and survival in earlystage diseaseresults from a review of 82 consecutive cases
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1943-1952, 2007.
Lewis KG, Weinstock MA, Weaver AL et al: Adjuvant local irradiation for Merkel cell carcinoma, Arch Dermatol 142:693700, 2006.
Longo F, Califano L, Mangone GM et al: Neuroendocrine (Merkel
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Mendenhall WM, Mendenhall CM, Mendenhall NP: Merkel cell
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Salivary Gland Pathology
CHAPTER OUTLINE
Salivary Gland Aplasia
Mucocele
Ranula
Salivary Duct Cyst
Sialolithiasis
Sialadenitis
Cheilitis Glandularis
Sialorrhea
Xerostomia
Benign Lymphoepithelial Lesion
Sjgren Syndrome
Sialadenosis
Adenomatoid Hyperplasia of the Minor Salivary
Glands
Necrotizing Sialometaplasia
Oncocytoma
Oncocytosis
Warthin Tumor
Monomorphic Adenoma
Canalicular Adenoma
Basal Cell Adenoma
Ductal Papillomas
Mucoepidermoid Carcinoma
Intraosseous Mucoepidermoid Carcinoma
Acinic Cell Adenocarcinoma
Malignant Mixed Tumors
Adenoid Cystic Carcinoma
Polymorphous Low-Grade Adenocarcinoma
Salivary Adenocarcinoma, Not Otherwise Specied
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CLINICAL FEATURES
Mucoceles typically appear as dome-shaped mucosal
swellings that can range from 1 or 2 mm to several
centimeters in size (Figs. 11-2 to 11-4). They are most
common in children and young adults, perhaps because
younger people are more likely to experience trauma
that induces mucin spillage. However, mucoceles have
been reported in patients of all ages, including infants
and older adults. The spilled mucin below the mucosal
surface often imparts a bluish translucent hue to the
swelling, although deeper mucoceles may be normal
in color. The lesion characteristically is uctuant, but
some mucoceles feel rmer to palpation. The reported
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Location of Mucoceles
Location
Lower lip
Floor of mouth
Ventral tongue
Buccal mucosa
Palate
Retromolar
Unknown
Upper lip
Total
Number of Cases
1477
106
106
87
26
10
12
0
1824
81.0
5.8
5.8
4.8
1.4
0.5
0.7
0.0
100
Data from Chi A, Lambert P, Richardson M et al: Oral mucoceles: a clinicopathologic review of 1,824 cases including unusual variants, Abstract No. 19. Paper
presented at the annual meeting of the American Academy of Oral and Maxillofacial Pathology, Kansas City, Mo, 2007.
HISTOPATHOLOGIC FEATURES
On microscopic examination, the mucocele shows an
area of spilled mucin surrounded by a granulation
tissue response (Figs. 11-6 and 11-7). The inamma-
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RANULA
CLINICAL FEATURES
The ranula usually appears as a blue, dome-shaped,
uctuant swelling in the oor of the mouth (Fig. 11-8),
but deeper lesions may be normal in color. Ranulas are
seen most frequently in children and young adults.
They tend to be larger than mucoceles in other oral
locations, often developing into large masses that ll
the oor of the mouth and elevate the tongue. The
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HISTOPATHOLOGIC FEATURES
The microscopic appearance of a ranula is similar to
that of a mucocele in other locations. The spilled mucin
elicits a granulation tissue response that typically contains foamy histiocytes.
CLINICAL FEATURES
Salivary duct cysts usually occur in adults and can arise
within either the major or minor glands. Cysts of the
major glands are most common within the parotid
gland, presenting as slowly growing, asymptomatic
swellings. Intraoral cysts can occur at any minor gland
site, but most frequently they develop in the oor of
the mouth, buccal mucosa, and lips (Fig. 11-10). They
often look like mucoceles and are characterized by a
soft, uctuant swelling that may appear bluish, depending on the depth of the cyst below the surface. Some
cysts may feel relatively rm to palpation. Cysts in the
oor of the mouth often arise adjacent to the submandibular duct and sometimes have an amber color.
On rare occasions, patients have been observed to
develop prominent ectasia of the excretory ducts of
many of the minor salivary glands throughout the
mouth. Such lesions have been termed mucus retention cysts, although they probably represent multifocal ductal dilatation. The individual lesions often
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HISTOPATHOLOGIC FEATURES
The lining of the salivary duct cyst is variable and may
consist of cuboidal, columnar, or atrophic squamous
epithelium surrounding thin or mucoid secretions in
the lumen (Fig. 11-11). In contrast, ductal ectasia secondary to salivary obstruction is characterized by oncocytic metaplasia of the epithelial lining. This epithelium
often demonstrates papillary folds into the cystic lumen,
somewhat reminiscent of a small Warthin tumor (see
page 482) but without the prominent lymphoid stroma
(Fig. 11-12). If this proliferation is extensive enough,
then these lesions sometimes are diagnosed as papillary cystadenoma, although it seems likely that most
are not true neoplasms. The individual lesions of
patients with multiple mucus retention cysts also
show prominent oncocytic metaplasia of the epithelial
lining.
Fig. 11-11 Salivary duct cyst. A, Low-power photomicrograph showing a cyst below the
mucosal surface. B, High-power view of cystic cavity (top) lined by thin cuboidal epithelium.
Adjacent to the cyst is an excretory salivary gland duct lined by columnar epithelium (bottom).
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however, surgical management does not appear feasible or advisable for all of the lesions, which may number
as many as 100. In one reported case, systemic erythromycin and chlorhexidine mouth rinses were helpful
in relieving pain and reducing drainage of pus. Sialagogue medications also may be helpful in stimulating
salivary ow, thereby preventing the accumulation of
inspissated mucus within the dilated excretory ducts.
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HISTOPATHOLOGIC FEATURES
On gross examination, sialoliths appear as hard masses
that are round, oval, or cylindrical. They are typically
yellow, although they may be a white or yellow-brown
color. Submandibular stones tend to be larger than
those of the parotid or minor glands. Sialoliths are
usually solitary, although occasionally two or more
stones may be discovered at surgery.
Microscopically, the calcied mass exhibits concentric laminations that may surround a nidus of
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SIALADENITIS
Inammation of the salivary glands (sialadenitis) can
arise from various infectious and noninfectious causes.
The most common viral infection is mumps (see page
263), although a number of other viruses also can
involve the salivary glands, including Coxsackie A,
ECHO, choriomeningitis, parainuenza, and cytomegalovirus (CMV) (in neonates). Most bacterial infections
arise as a result of ductal obstruction or decreased salivary ow, allowing retrograde spread of bacteria
throughout the ductal system. Blockage of the duct can
be caused by sialolithiasis (see page 459), congenital
strictures, or compression by an adjacent tumor.
Decreased ow can result from dehydration, debilitation, or medications that inhibit secretions.
One of the more common causes of sialadenitis is
recent surgery (especially abdominal surgery), after
which an acute parotitis (surgical mumps) may arise
because the patient has been kept without food or uids
(NPO) and has received atropine during the surgical
procedure. Other medications that produce xerostomia
as a side effect also can predispose patients to such an
infection. Most cases of acute bacterial sialadenitis are
caused by Staphylococcus aureus, but they also may arise
from streptococci or other organisms. Noninfectious
causes of salivary inammation include Sjgren syndrome (see page 466), sarcoidosis (see page 338), radiation therapy (see page 295), and various allergens.
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HISTOPATHOLOGIC FEATURES
In patients with acute sialadenitis, accumulation of
neutrophils is observed within the ductal system and
acini. Chronic sialadenitis is characterized by scattered
or patchy inltration of the salivary parenchyma by
lymphocytes and plasma cells. Atrophy of the acini is
common, as is ductal dilatation. If associated brosis is
present, then the term chronic sclerosing sialadenitis is used (Fig. 11-21).
Subacute necrotizing sialadenitis is characterized by
a heavy mixed inammatory inltrate consisting of
neutrophils, lymphocytes, histiocytes, and eosinophils.
The treatment of acute sialadenitis includes appropriate antibiotic therapy and rehydration of the patient
to stimulate salivary ow. Surgical drainage may be
needed if there is abscess formation. Although this
regimen is usually sufcient, a 20% to 50% mortality
rate has been reported in debilitated patients because
of the spread of the infection and sepsis.
The management of chronic sialadenitis depends
on the severity of the condition and ranges from
conservative therapy to surgical intervention. Initial
management often includes antibiotics, analgesics,
sialagogues, and glandular massage. Early cases that
develop secondary to ductal blockage may respond to
removal of the sialolith or other obstruction. However,
if sialectasia is present, then the dilated ducts can lead
to stasis of secretions and predispose the gland to
further sialolith formation. Sialadenoscopy and ductal
irrigation are newer techniques that can be used to
dilate ductal strictures and to eliminate sialoliths and
mucus plugs. Second-line treatment options for chronic
parotitis have included ligation of Stensens duct, but
this method has a high failure rate. Tympanic neurectomy, which results in decreased secretion by the
parotid gland via transection of the parasympathetic
secretory bers at the tympanic plexus, produces
improvement in 75% of patients with chronic parotitis.
If conservative methods cannot control chronic sialadenitis, then surgical removal of the affected gland may
be necessary.
Subacute necrotizing sialadenitis is a self-limiting
condition that usually resolves within 2 weeks of diagnosis without treatment.
CHEILITIS GLANDULARIS
Cheilitis glandularis is a rare inammatory condition
of the minor salivary glands. The cause is uncertain,
although several etiologic factors have been suggested,
including actinic damage, tobacco, syphilis, poor
hygiene, and heredity.
CLINICAL FEATURES
Cheilitis glandularis characteristically occurs on the
lower lip, although there are also purported cases
involving the upper lip and palate. Affected individuals
experience swelling and eversion of the lower lip as a
result of hypertrophy and inammation of the glands
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SIALORRHEA
HISTOPATHOLOGIC FEATURES
The microscopic ndings of cheilitis glandularis are
not specic and usually consist of chronic sialadenitis
and ductal dilatation. Concomitant dysplastic changes
may be observed in the overlying surface epithelium in
some cases.
CLINICAL FEATURES
The excess saliva production typically produces drooling and choking, which may cause social embarrassment. In children with mental retardation or cerebral
palsy, the uncontrolled salivary ow may lead to macerated sores around the mouth, chin, and neck that can
become secondarily infected. The constant soiling of
clothes and bed linens can be a signicant problem for
the parents and caretakers of these patients.
An interesting type of supersalivation of unknown
cause has been termed idiopathic paroxysmal sialorrhea. Individuals with this condition experience short
episodes of excessive salivation lasting from 2 to 5
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minutes. These episodes are associated with a prodrome of nausea or epigastric pain.
XEROSTOMIA
Xerostomia refers to a subjective sensation of a dry
mouth; it is frequently, but not always, associated with
salivary gland hypofunction. A number of factors may
play a role in the cause of xerostomia, and these are
listed in Box 11-1. Xerostomia is a common problem
that has been reported in 25% of older adults. In the
past, complaints of dry mouth in older patients often
were ascribed to the predictable result of aging.
However, it is now generally accepted that any reductions in salivary function associated with age are modest
and probably are not associated with any signicant
Box 11-1
Causes of Xerostomia
DEVELOPMENTAL ORIGIN
Salivary gland aplasia
WATER/METABOLITE LOSS
Impaired uid intake
Hemorrhage
Vomiting/diarrhea
IATROGENIC ORIGIN
Medications
Radiation therapy to the head and neck
Chemotherapy
SYSTEMIC DISEASES
Sjgren syndrome
Diabetes mellitus
Diabetes insipidus
Sarcoidosis
Human immunodeciency virus (HIV) infection
Hepatitis C infection
Graft-versus-host disease (GVHD)
Psychogenic disorders
LOCAL FACTORS
Decreased mastication
Smoking
Mouth breathing
CLINICAL FEATURES
Examination of the patient typically demonstrates a
reduction in salivary secretions, and the residual saliva
appears either foamy or thick and ropey. The mucosa
appears dry, and the clinician may notice that the
examining gloves stick to the mucosal surfaces. The
dorsal tongue often is ssured with atrophy of the liform papillae (see Fig. 11-1). The patient may complain of difculty with mastication and swallowing, and
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Table 11-2
Class of Drug
Antihistamine agents
Decongestant agents
Antidepressant agents
Antipsychotic agents
Sedatives and anxiolytic agents
Antihypertensive agents
Anticholinergic agents
Example
Diphenhydramine
Chlorpheniramine
Pseudoephedrine
Amitriptyline
Citalopram
Fluoxetine
Paroxetine
Sertraline
Bupropion
Phenothiazine derivatives
Haloperidol
Diazepam
Lorazepam
Alprazolam
Reserpine
Methyldopa
Chlorothiazide
Furosemide
Metoprolol
Calcium channel blockers
Atropine
Scopolamine
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CLINICAL FEATURES
Although the benign lymphoepithelial lesion frequently necessitates surgical removal of the involved
gland, the prognosis in most cases is good. However,
individuals with benign lymphoepithelial lesions have
an increased risk for lymphoma, either within the
affected gland or in an extrasalivary site. Although the
exact risk is uncertain, one study showed the risk in
patients with Sjgren syndrome to be more than 40
times higher than expected in the general population.
(The management of patients with Sjgren syndrome
is discussed on page 470.)
With the development of modern molecular techniques to assess for gene rearrangements and monoclonality within lymphoid inltrates, it is now
recognized that some lesions originally believed to represent benign lymphoepithelial lesions are actually
early-stage MALT lymphomas. Many experts now recognize a spectrum of salivary lymphoid proliferations,
which range from benign lymphoepithelial lesions to
borderline lesions to frank lymphomas. Because of this,
some authors have dropped the term benign from this
spectrum and refer to these proliferations only as lymphoepithelial lesions. Fortunately, most MALT lymphomas are low-grade tumors that tend to remain localized
with good survival rates. However, occasional tumors
transform to higher-grade lymphomas with more
aggressive behavior.
In addition, a rare malignant counterpart of this
lesion, called a malignant lymphoepithelial lesion
or lymphoepithelial carcinoma, represents a poorly
differentiated salivary carcinoma with a prominent
lymphoid stroma. Most of these lesions have occurred
in Inuit and Asian populations and appear to have
arisen de novo as carcinomas; however, some cases
(especially in non-Inuits) have been reported to develop
from a prior benign lymphoepithelial lesion. The
Epstein-Barr virus (EBV) has been strongly associated
in the cause of malignant lymphoepithelial lesions,
especially those cases arising in Inuit and Asian populations. The 5-year survival rate has been reported to
range from 70% to 85%.
HISTOPATHOLOGIC FEATURES
Microscopic examination of the benign lymphoepithelial lesion shows a heavy lymphocytic inltrate associated with the destruction of the salivary acini (Fig.
11-23). Germinal centers may or may not be seen.
Although the acini are destroyed, the ductal epithelium
persists. The ductal cells and surrounding myoepithelial cells become hyperplastic, forming highly characteristic groups of cells, known as epimyoepithelial islands,
throughout the lymphoid proliferation. The presence
of epimyoepithelial islands once was considered indicative of a benign process, but now it is recognized that
SJGREN SYNDROME
Fig. 11-23 Benign lymphoepithelial lesion. Lymphocytic
inltrate of the parotid gland with an associated
epimyoepithelial island.
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Box 11-2
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A simple means to conrm the decreased tear secretion is the Schirmer test. A standardized strip of sterile
lter paper is placed over the margin of the lower
eyelid, between the medial and lateral third of the lid
of the unanesthetized eye, so that the tabbed end rests
just inside the lower lid. By measuring the length of
wetting of the lter paper, tear production can be
assessed. Values less than 5 mm (after a 5-minute
period) are considered diagnostic of keratoconjunctivitis sicca.
Sjgren syndrome is a systemic disease, and the
inammatory process also can affect various other
body tissues. The skin is often dry, as are the nasal and
vaginal mucosae. Fatigue is fairly common, and depression sometimes can occur. Other possible associated
problems include lymphadenopathy, primary biliary
cirrhosis, Raynauds phenomenon, interstitial nephritis, interstitial lung brosis, vasculitis, and peripheral
neuropathies.
LABORATORY VALUES
In patients with Sjgren syndrome, the erythrocyte
sedimentation rate is high and serum immunoglobulin
(Ig) levels, especially IgG, typically are elevated. A
variety of autoantibodies can be produced, and although
none of these is specically diagnostic, their presence
can be another helpful clue to the diagnosis. A positive
rheumatoid factor (RF) is found in approximately 60%
of cases, regardless of whether the patient has rheumatoid arthritis. Antinuclear antibodies (ANAs) are also
present in 75% to 85% of patients. Two particular
nuclear autoantibodiesanti-SS-A (anti-Ro) and antiSS-B (anti-La)may be found, especially in patients
with primary Sjgren syndrome. Anti-SS-A antibodies
have been detected in approximately 40% of patients,
whereas anti-SS-B antibodies have been discovered in
HISTOPATHOLOGIC FEATURES
The basic microscopic nding in Sjgren syndrome
is a lymphocytic inltration of the salivary glands,
with destruction of the acinar units. If the major
glands are enlarged, then microscopic examination
usually shows progression to a lymphoepithelial lesion
(see page 466), with characteristic epimyoepithelial
islands in a background lymphoid stroma. Lymphocytic inltration of the minor glands also occurs,
although epimyoepithelial islands are rarely seen in
this location.
Biopsy of the minor salivary glands of the lower lip
has become a useful test in the diagnosis of Sjgren
syndrome. A 1.5- to 2.0-cm incision is made on clinically normal lower labial mucosa, parallel to the vermilion border and lateral to the midline, allowing the
harvest of ve or more accessory glands. These glands
then are examined histopathologically for the presence
of focal chronic inammatory aggregates (50 or more
lymphocytes and plasma cells). These aggregates should
be adjacent to normal-appearing acini and should be
found consistently in most of the glands in the specimen. The nding of more than one focus of 50 or more
cells within a 4-mm2 area of glandular tissue is considered supportive of the diagnosis of Sjgren syndrome
(Fig. 11-27). The greater the number of foci (up to 10
or conuent foci) is, the greater is the correlation with
this diagnosis. The focal nature of this chronic inammation among otherwise normal acini is a highly
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Box 11-3
Conditions Associated
with Sialadenosis
ENDOCRINE DISORDERS
Diabetes mellitus
Diabetes insipidus
Acromegaly
Hypothyroidism
Pregnancy
NUTRITIONAL CONDITIONS
General malnutrition
Alcoholism
Anorexia nervosa
Bulimia
NEUROGENIC MEDICATIONS
Antihypertensive drugs
Psychotropic drugs
Sympathomimetic drugs used for treating asthma
SIALADENOSIS (SIALOSIS)
Sialadenosis is an unusual noninammatory disorder
characterized by salivary gland enlargement, particularly involving the parotid glands. The condition frequently is associated with an underlying systemic
problem, which may be endocrine, nutritional, or neurogenic in origin (Box 11-3). The best known of these
conditions include diabetes mellitus, general malnutrition, alcoholism, and bulimia.
These conditions are believed to result in dysregulation of the autonomic innervation of the salivary acini,
causing an aberrant intracellular secretory cycle. This
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ADENOMATOID HYPERPLASIA OF
THE MINOR SALIVARY GLANDS
CLINICAL FEATURES
HISTOPATHOLOGIC FEATURES
leads to excessive accumulation of secretory granules,
with marked enlargement of the acinar cells.
Microscopic examination demonstrates lobular aggregates of relatively normal-appearing mucous acini that
are greater in number than normally would be found
in the area. These glands also sometimes appear to be
increased in size. In some instances, the glands are situated close to the mucosal surface. Chronic inammation occasionally is seen, but it usually is mild and
localized.
NECROTIZING SIALOMETAPLASIA
HISTOPATHOLOGIC FEATURES
Microscopic examination reveals hypertrophy of the
acinar cells, sometimes two to three times greater than
normal size. The nuclei are displaced to the cell base,
and the cytoplasm is engorged with zymogen granules.
In cases associated with long-standing diabetes or alcoholism, there may be acinar atrophy and fatty inltration. Signicant inammation is not observed.
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(From Allen CM, Camisa C: Diseases of the mouth and lips. In Sams WM,
Lynch P, editors: Principles of dermatology, New York, 1990, Churchill
Livingstone.)
CLINICAL FEATURES
Necrotizing sialometaplasia most frequently develops
in the palatal salivary glands; more than 75% of all
cases occur on the posterior palate. The hard palate is
affected more often than the soft palate. About two
thirds of palatal cases are unilateral, with the rest being
bilateral or midline in location. Necrotizing sialometaplasia also has been reported in other minor salivary
gland sites and, occasionally, in the parotid gland. The
submandibular and sublingual glands are rarely
affected. Although it can occur at almost any age, necrotizing sialometaplasia is most common in adults;
the mean age of onset is 46 years. Males are affected
nearly twice as often as females.
The condition appears initially as a nonulcerated
swelling, often associated with pain or paresthesia
(Fig. 11-29). Within 2 to 3 weeks, necrotic tissue
sloughs out, leaving a craterlike ulcer that can range
from less than 1 cm to more than 5 cm in diameter
(Fig. 11-30). The patient may report that a part of my
palate fell out. At this point, the pain often subsides.
HISTOPATHOLOGIC FEATURES
The microscopic appearance of necrotizing sialometaplasia is characterized by acinar necrosis in early
lesions, followed by associated squamous metaplasia of
the salivary ducts (Fig. 11-31). Although the mucous
acinar cells are necrotic, the overall lobular architecture of the involved glands is still preserveda helpful
histopathologic clue. There may be liberation of mucin,
with an associated inammatory response. The squamous metaplasia of the salivary ducts can be striking
and produce a pattern that is easily misdiagnosed as
squamous cell carcinoma or mucoepidermoid carcinoma. The frequent association of pseudoepitheliomatous hyperplasia of the overlying epithelium may
further compound this mistaken impression. In most
cases, however, the squamous proliferation has a bland
cytologic appearance.
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Box 11-4
Because of the worrisome clinical presentation of necrotizing sialometaplasia, biopsy usually is indicated to
rule out the possibility of malignant disease. Once the
diagnosis has been established, no specic treatment is
indicated or necessary. The lesion typically resolves on
its own accord, with an average healing time of 5 to 6
weeks.
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Table 11-3
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SITE
Author (Year)
Number of Cases
Table 11-4
Submandibular
2,410
2,579
2,807
73%
80%
70%
11%
10%
8%
13,749
64%
10%
Sublingual
Minor
0.3%
1.0%
(Included with
minor gland
tumors)
0.3%
14%
9%
22%
23%
Author (Year)
Number of Cases
Table 11-5
OCCURRENCE
Parotid
OF
OF
Parotid
Submandibular
2,410
2,579
2,807
15%
20%
25%
37%
45%
43%
13,749
32%
41%
Sublingual
Minor
86%
90%
(Included with
minor gland
tumors)
70%
46%
45%
82%
49%
Parotid Tumors
Ellis et al.
(United
States, 1991)
Thackray &
Lucas (Great
Britain, 1974)
Eneroth
(Sweden,
1971)
8222
1756
651
2158
764
BENIGN TUMORS
Pleomorphic adenoma
Warthin tumor
Oncocytoma
Basal cell adenoma
Other benign tumors
53.0%
7.7%
1.9%
1.4%
3.7%
63.3%
14.0%
0.9%
7.1%*
72.0%
9.0%
0.6%
1.8%
76.8%
4.7%
1.0%
58.5%
6.5%
0.1%
0.7%
TOTAL
67.7%
85.3%
83.4%
82.5%
65.8%
9.6%
8.6%
2.0%
2.5%
2.1%
7.5%
1.5%
2.5%
2.0%
3.2%
1.1%
4.4%
2.3%
1.2%
3.3%
4.1%
1.0%
4.7%
4.1%
3.1%
2.3%
1.5%
0.3%
6.3%
11.8%
2.7%
2.1%
6.0%
3.4%
8.1%
32.3%
14.7%
16.6%
17.5%
34.2%
MALIGNANT TUMORS
Mucoepidermoid carcinoma
Acinic cell adenocarcinoma
Adenoid cystic carcinoma
Malignant mixed tumor
Squamous cell carcinoma
Other malignant tumors
TOTAL
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Table 11-6
475
Submandibular Tumors
Ellis et al.
(United
States, 1991)
Thackray &
Lucas (Great
Britain, 1974)
Eneroth
(Sweden,
1971)
Foote &
Frazell (United
States, 1953)
1235
257
60
170
107
BENIGN TUMORS
Pleomorphic adenoma
Warthin tumor
Oncocytoma
Basal cell adenoma
Other benign tumors
53.3%
1.3%
1.5%
1.0%
1.7%
59.5%
0.8%
0.4%
1.9%*
68.0%
1.7%
0.0%
0.0%
60.0%
2.4%
0.6%
43.9%
0.0%
0.0%
0.0%
TOTAL
58.8%
62.6%
69.7%
62.9%
43.9%
MALIGNANT TUMORS
Mucoepidermoid carcinoma
Acinic cell adenocarcinoma
Adenoid cystic carcinoma
Malignant mixed tumor
Squamous cell carcinoma
Other malignant tumors
9.1%
2.7%
11.7%
3.5%
3.4%
10.8%
1.6%
0.4%
16.8%
7.8%
1.9%
8.9%
0.0%
0.0%
17.0%
1.7%
3.3%
8.3%
3.5%
0.6%
15.3%
1.8%
7.1%
8.8%
7.5%
0.0%
15.9%
10.3%
12.1%
10.3%
TOTAL
41.2%
37.4%
30.3%
37.1%
56.1%
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Table 11-7
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MAXILLOFACIAL PATHOLOGY
Pires et al.
(2006)
Yih et al.
(2005)
Ellis et al.
(1991)
Waldron et al.
(1988)
Eveson &
Cawson (1985)
546
213
3355
426
336
33.2%
9.2%
43.7%
11.7%
38.1%
4.5%
40.8%
10.8%
42.6%
11.0%
13.5%
0.5%
8.8%
5.9%
TOTAL
55.9%
55.9%
51.3%
57.5%
53.6%
MALIGNANT TUMORS
Mucoepidermoid carcinoma
Acinic cell adenocarcinoma
Adenoid cystic carcinoma
Malignant mixed tumor
Polymorphous low-grade
adenocarcinoma
Other malignant tumors
22.9%
3.8%
6.4%
0.4%
5.1%
21.1%
0.5%
10.3%
0.9%
8.4%
21.5%
3.5%
7.7%
1.7%
2.2%
15.3%
3.5%
9.4%
1.4%
11.0%
8.9%
1.8%
13.1%
7.1%
5.5%
2.8%
12.1%
1.9%
15.2%
TOTAL
44.1%
44.1%
48.7%
42.5%
46.4%
Table 11-8
Author (Year)
Eveson and Cawson (1985)
Waldron et al. (1988)
Ellis et al. (1991)
Yih et al. (2005)
Table 11-9
Number of
Cases
Palate
Lips
Buccal
Retromolar
Floor of
Mouth
Tongue
Other
336
426
3355
213
54%
42%
44%
48%
21%
22%
21%
25%
11%
15%
12%
14%
1%
5%
2%
4%
5%
3%
1%
4%
1%
5%
8%
9%
12%
8%
Yih et al.
(2005)
Ellis et al.
(1991)
Waldron et al.
(1988)
Eveson &
Cawson (1985)
181
102
1478
181
183
BENIGN TUMORS
Pleomorphic adenoma
Other benign tumors
39.8%
13.2%
49.0%
6.9%
48.2%
5.0%
51.9%
6.0%
47.0%
6.0%
TOTAL
53.0%
55.9%
53.2%
58.0%
53.0%
MALIGNANT TUMORS
Mucoepidermoid carcinoma
Acinic cell adenocarcinoma
Adenoid cystic carcinoma
Malignant mixed tumor
Polymorphous low-grade
adenocarcinoma
Other malignant tumors
23.8%
2.2%
7.7%
0.0%
6.1%
19.6%
1.0%
12.7%
0.0%
7.8%
20.7%
1.4%
8.3%
2.4%
3.0%
9.9%
1.7%
10.5%
2.2%
16.0%
9.3%
1.1%
15.3%
8.2%
7.2%
2.9%
11.0%
1.7%
13.1%
TOTAL
47.0%
44.1%
46.8%
42.0%
47.0%
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Table 11-10
Author (Year)
Number of Cases
Upper Lip
Lower Lip
71
93
103
536
53
89%
85%
84%
77%
81%
11%
15%
16%
23%
19%
Table 11-11
477
Author (Year)
Eveson and Cawson (1985)
Waldron et al. (1988)
Ellis et al. (1991)
Yih et al. (2005)
Palate
Upper Lip
Lower Lip
Buccal
Retromolar
Floor of Mouth
Tongue
47%
42%
47%
44%
25%
14%
22%
5%
50%
86%
60%
90%
50%
46%
50%
38%
60%
91%
90%
75%
80%
88%
100%
92%
75%
86%
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Fig. 11-35 Pleomorphic adenoma. T1-weighted, fatsuppressed, contrast-enhanced coronal magnetic resonance
image (MRI) of a tumor of the deep lobe of the parotid gland.
(Courtesy of Dr. Joel Cur.)
HISTOPATHOLOGIC FEATURES
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ONCOCYTOMA (OXYPHILIC
ADENOMA)
The oncocytoma is a benign salivary gland tumor
composed of large epithelial cells known as oncocytes.
The prex onco- is derived from the Greek word onkoustai, which means to swell. The swollen granular cytoplasm of oncocytes is due to excessive accumulation of
mitochondria. Focal oncocytic metaplasia of salivary
ductal and acinar cells is a common nding that is
related to patient age; oncocytes are uncommon in
persons younger than 50, but they can be found in
almost all individuals by age 70. In addition to salivary
glands, oncocytes have been identied in a number of
other organs, especially the thyroid, parathyroid, and
kidney. The oncocytoma is a rare neoplasm, representing approximately 1% of all salivary tumors.
CLINICAL FEATURES
Fig. 11-42 Pleomorphic adenoma. Many of the ducts and
myoepithelial cells are surrounded by a hyalinized,
eosinophilic background alteration.
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HISTOPATHOLOGIC FEATURES
The oncocytoma is usually a well-circumscribed tumor
that is composed of sheets of large polyhedral cells
(oncocytes), with abundant granular, eosinophilic cytoplasm (Fig. 11-43). Sometimes these cells form an
alveolar or glandular pattern. The cells have centrally
located nuclei that can vary from small and hyperchromatic to large and vesicular. Little stroma is present,
usually in the form of thin brovascular septa. An associated lymphocytic inltrate may be noted.
The granularity of the cells corresponds to an overabundance of mitochondria, which can be demonstrated by electron microscopy. These granules also
can be identied on light microscopic examination
with a phosphotungstic acid hematoxylin (PTAH) stain.
The cells also contain glycogen, as evidenced by their
positive staining with the periodic acid-Schiff (PAS)
technique but by negative PAS staining after digestion
with diastase.
Oncocytomas may contain variable numbers of cells
with a clear cytoplasm. In rare instances, these clear
cells may compose most of the lesion and create difculty in distinguishing the tumor from low-grade sali-
ONCOCYTOSIS (NODULAR
ONCOCYTIC HYPERPLASIA)
Oncocytic metaplasia is the transformation of ductal
and acinar cells to oncocytes. Such cells are uncommon before the age of 50; however, as people get older,
occasional oncocytes are common ndings in the salivary glands. Focal oncocytic metaplasia also may be a
feature of other salivary gland tumors. Oncocytosis
refers to both the proliferation and the accumulation
of oncocytes within salivary gland tissue. It may mimic
a tumor, both clinically and microscopically, but it also
is considered to be a metaplastic process rather than a
neoplastic one.
CLINICAL FEATURES
Oncocytosis is found primarily in the parotid gland;
however, in rare instances, it may involve the submandibular or minor salivary glands. It can be an incidental
nding in otherwise normal salivary gland tissue, but
it may be extensive enough to produce clinical swelling. Usually the proliferation is multifocal and nodular,
but sometimes the entire gland can be replaced by
oncocytes (diffuse hyperplastic oncocytosis). As
with other oncocytic proliferations, oncocytosis occurs
most frequently in older adults.
HISTOPATHOLOGIC FEATURES
Microscopic examination usually reveals focal nodular
collections of oncocytes within the salivary gland tissue.
These enlarged cells are polyhedral and demonstrate
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CLINICAL FEATURES
The Warthin tumor usually appears as a slowly growing,
painless, nodular mass of the parotid gland (Fig.
11-45). It may be rm or uctuant to palpation. The
tumor most frequently occurs in the tail of the parotid
near the angle of the mandible, and it may be noted for
many months before the patient seeks a diagnosis. One
unique feature is the tendency of Warthin tumor to
occur bilaterally, which has been noted in 5% to 17%
of reported cases. Most of these bilateral tumors do not
occur simultaneously but are metachronous (occurring
at different times).
In rare instances, the Warthin tumor has been
reported within the submandibular gland or minor
salivary glands. However, because the lymphoid component is often less pronounced in these extraparotid
sites, the pathologist should exercise caution to avoid
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HISTOPATHOLOGIC FEATURES
The Warthin tumor has one of the most distinctive
histopathologic patterns of any tumor in the body.
Although the term papillary cystadenoma lymphomatosum is cumbersome, it accurately describes the
salient microscopic features.
The tumor is composed of a mixture of ductal
epithelium and a lymphoid stroma (Figs. 11-46 and
11-47). The epithelium is oncocytic in nature, forming
uniform rows of cells surrounding cystic spaces. The
cells have abundant, nely granular eosinophilic cytoplasm and are arranged in two layers. The inner luminal
layer consists of tall columnar cells with centrally
placed, palisaded, and slightly hyperchromatic nuclei.
Beneath this is a second layer of cuboidal or polygonal
cells with more vesicular nuclei. The lining epithelium
demonstrates multiple papillary infoldings that pro-
MONOMORPHIC ADENOMA
The term monomorphic adenoma originally was
used to describe a group of benign salivary gland
tumors demonstrating a more uniform histopathologic
pattern than the common pleomorphic adenoma. In
some classication schemes, a variety of tumors were
included under the broad heading of monomorphic
adenoma, including Warthin tumor, oncocytoma, basal
cell adenoma, and canalicular adenoma. Other authors
have used this term more specically as a synonym just
for the basal cell adenoma or canalicular adenoma.
Because of its ambiguous nature, the term monomorphic
adenoma probably should be avoided, and each of the
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CANALICULAR ADENOMA
The canalicular adenoma is an uncommon tumor
that occurs almost exclusively in the minor salivary
glands. Because of its uniform microscopic pattern, the
canalicular adenoma also has been called a monomorphic adenoma. However, because this term also has
been applied to other tumors, its use probably should
be discontinued. Likewise, the term basal cell
adenoma sometimes has been used synonymously for
this tumor but should be avoided because it refers to a
separate tumor with different clinical features (see next
topic).
CLINICAL FEATURES
The canalicular adenoma shows a striking predilection
for the upper lip, with nearly 75% occurring in this
location. It represents the rst or second most common
tumor (along with pleomorphic adenoma) of the upper
lip. The buccal mucosa is the second most common
site. Occurrence in other minor salivary glands is
uncommon, and canalicular adenomas of the parotid
gland are rare.
The tumor nearly always occurs in older adults, with
a peak prevalence in the seventh decade of life. There
is a denite female predominance, ranging from 1.2 to
1.8 females for each male.
The canalicular adenoma appears as a slowly
growing, painless mass that usually ranges from several
millimeters to 2 cm (Fig. 11-48). It may be rm or
somewhat uctuant to palpation. The overlying mucosa
may be normal in color or bluish and can be mistaken
for a mucocele. However, mucoceles of the upper lip
are rare. In some instances, the lesion has been noted
to be multifocal, with multiple separate tumors discovered in the upper lip or buccal mucosa.
HISTOPATHOLOGIC FEATURES
The microscopic pattern of canalicular adenoma is
monomorphic in nature. This pattern is characterized
by single-layered cords of columnar or cuboidal epithelial cells with deeply basophilic nuclei (Fig. 11-49). In
some areas, adjacent parallel rows of cells may be seen,
resulting in a bilayered appearance of the tumor cords.
These cells enclose ductal structures, sometimes in the
form of long canals. Larger cystic spaces often are
created, and the epithelium may demonstrate papillary
projections into the cystic lumina. The tumor cells are
supported by a loose connective tissue stroma with
prominent vascularity. Unlike the appearance in pleo-
morphic adenomas, stromal alterations, such as chondroid metaplasia, do not occur. A thin, brous capsule
often surrounds the tumor, although satellite islands
are observed in the surrounding salivary gland tissue
in approximately 22% to 24% of cases, which explains
the tendency for multifocal tumors.
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should be avoided because of its imprecise and frequently confusing denition. In addition, ultrastructural and immunohistochemical studies have shown
that basal cell adenomas are not necessarily composed
of only one cell type but sometimes of a combination
of salivary ductal epithelium and myoepithelial cells.
The basal cell adenoma shows some histopathologic
similarity to the canalicular adenoma; in the past, these
two terms have been used synonymously. However,
histopathologic and clinical differences warrant that
they be considered as distinct entities.
CLINICAL FEATURES
Unlike the canalicular adenoma, the basal cell adenoma
is primarily a tumor of the parotid gland, with around
75% of all cases occurring there. However, the minor
glands represent the second most common site, specically the glands of the upper lip and buccal mucosa.
The tumor can occur at any age but is most common
in middle-aged and older adults, with a peak prevalence in the seventh decade of life. The tumor appears
to be more common in women, with some studies
showing as high as a 2:1 female-to-male ratio.
Clinically, the basal cell adenoma appears as a
slowly growing, freely movable mass similar to a pleomorphic adenoma. Most tumors are less than 3 cm in
diameter. Parotid tumors usually are located within the
supercial lobe of the gland.
One subtype, the membranous basal cell adenoma,
deserves separate mention. This form of the tumor
appears to be hereditary, often occurring in combination with skin appendage tumors, such as dermal cylindromas and trichoepitheliomas. Multiple bilateral
tumors may develop within the parotids. Because these
tumors often bear a histopathologic resemblance to the
skin tumors, they also have been called dermal analogue tumors.
HISTOPATHOLOGIC FEATURES
The basal cell adenoma is usually encapsulated or well
circumscribed. The most common subtype is the solid
variant, which consists of multiple islands and cords of
epithelial cells that are supported by a small amount of
brous stroma. The peripheral cells of these islands are
palisaded and cuboidal to columnar in shape, similar
to the microscopic appearance of basal cell carcinoma.
These peripheral cells are frequently hyperchromatic;
the central cells of the islands tend to have paler staining nuclei. The central cells occasionally form eddies
or keratin pearls.
The trabecular subtype demonstrates narrow cordlike epithelial strands (Fig. 11-50). The tubular subtype
is characterized by the formation of small, round, duct-
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enoma lymphomatosum). The sialadenoma papilliferum, intraductal papilloma, and inverted ductal
papilloma are three rare salivary tumors that also
show unique papillomatous features.
It also should be mentioned that, on occasion, the
common squamous papilloma (see page 362) of the
oral mucosa will arise at the site where a minor salivary
gland duct merges with the surface epithelium. Because
of this location, such squamous papillomas also contain
scattered mucous cells within the exophytic papillary
growth, and these lesions have sometimes been called
ductal papillomas. However, it should be emphasized
that these lesions are viral (human papillomavirus
[HPV]) surface papillomas and not primary salivary
gland tumors.
CLINICAL FEATURES
The sialadenoma papilliferum most commonly arises
from the minor salivary glands, especially on the
palate, although it also has been reported in the parotid
gland. It usually is seen in older adults and has a
1.5:1.0 male-to-female ratio. The tumor appears as an
exophytic, papillary surface growth that is clinically
similar to the common squamous papilloma (Fig.
11-51).
The intraductal papilloma is an ill-dened lesion
that often has been confused with other salivary gland
lesions, such as the papillary cystadenoma. It usually
occurs in adults and is most common in the minor
salivary glands, where it appears as a submucosal
swelling.
The inverted ductal papilloma is a rare tumor that
has been described only in the minor salivary glands
of adults. The lower lip and mandibular vestibule are
the most common locations. The lesion usually appears as an asymptomatic nodule, which sometimes
HISTOPATHOLOGIC FEATURES
At low-power magnication, the sialadenoma papilliferum is somewhat similar to the squamous papilloma,
exhibiting multiple exophytic papillary projections that
are covered by stratied squamous epithelium. This
epithelium is contiguous with a proliferation of papillomatous ductal epithelium found below the surface
and extending downward into the deeper connective
tissues (Fig. 11-53). Multiple ductal lumina are formed,
which characteristically are lined by a double-rowed
layer of cells consisting of a luminal layer of tall columnar cells and a basilar layer of smaller cuboidal cells.
These ductal cells often have an oncocytic appearance.
An inammatory inltrate of plasma cells, lymphocytes, and neutrophils is characteristically present.
Because of their microscopic similarity, this tumor has
been considered to be an analogue of the cutaneous
syringocystadenoma papilliferum.
The intraductal papilloma exhibits a dilated, unicystic structure that is located below the mucosal surface.
It is lined by a single or double row of cuboidal or
columnar epithelium, which has multiple arborizing
papillary projections into the cystic lumen. In contrast,
the inverted ductal papilloma is composed primarily of
a proliferation of squamoid epithelium with multiple
thick, bulbous papillary projections that ll the ductal
lumen (Fig. 11-54). This epithelium may be contiguous
with the overlying mucosal epithelium, communicating with the surface through a small porelike opening.
Although the tumor is primarily squamous in nature,
the luminal lining cells of the papillary projections are
often cuboidal or columnar in shape, with scattered
mucus-producing cells.
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MUCOEPIDERMOID CARCINOMA
A
CLINICAL FEATURES
Most studies show that the mucoepidermoid carcinoma is the most common malignant salivary gland
neoplasm. In the United States, it makes up 10% of all
major gland tumors and 15% to 23% of minor gland
tumors. However, British studies have shown a much
lower relative frequency, with mucoepidermoid carcinoma accounting for only 1% to 2% of major gland
neoplasms and 9% of minor gland tumors. Perhaps a
true geographic difference exists in the prevalence of
this lesion.
The tumor occurs fairly evenly over a wide age
range, extending from the second to seventh decades
of life. Rarely is it seen in the rst decade of life.
However, mucoepidermoid carcinoma is the most
common malignant salivary gland tumor in children.
Some tumors have been associated with a previous
history of radiation therapy to the head and neck
region.
The mucoepidermoid carcinoma is most common
in the parotid gland and usually appears as an asymptomatic swelling. Most patients are aware of the lesion
for 1 year or less, although some report a mass of many
years duration. Pain or facial nerve palsy may develop,
usually in association with high-grade tumors. The
minor glands constitute the second most common site,
especially the palate (Fig. 11-55). Minor gland tumors
also typically appear as asymptomatic swellings, which
are sometimes uctuant and have a blue or red color
that can be mistaken clinically for a mucocele. Although
the lower lip, oor of mouth, tongue, and retromolar
pad areas are uncommon locations for salivary gland
neoplasia, the mucoepidermoid carcinoma is the most
common salivary tumor in each of these sites (Fig.
11-56). Intraosseous tumors also may develop in the
jaws (see page 490).
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HISTOPATHOLOGIC FEATURES
As its name implies, the mucoepidermoid carcinoma is
composed of a mixture of mucus-producing cells and
squamous (epidermoid) cells (Figs. 11-57 to 11-59).
The mucous cells vary in shape but contain abundant
foamy cytoplasm that stains positively with mucin
stains. The epidermoid cells are characterized by
squamoid features, often demonstrating a polygonal
shape, intercellular bridges, and, rarely, keratinization.
In addition, a third type of cellthe intermediate cell
is typically present and is believed to be a progenitor
of both the mucous and the epidermoid cells. Intermediate cells vary in appearance from small, basaloid
(maternal) cells to slightly larger ovoid cells with
scant, pale eosinophilic cytoplasm. Some tumors also
show variable numbers of clear cells, which sometimes
can predominate the microscopic picture (Fig. 11-60).
An associated lymphoid inltrate is not unusual and
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Table 11-12
Parameter
AUCLAIR ET AL. (1992)
Intracystic component < 20%
Neural invasion present
Necrosis present
Four or more mitoses per 10 high-power
elds
Anaplasia present
Grade
Low
Intermediate
High
Point Value
2
2
3
3
4
Total Point Score
0-4
5-6
7-14
2
2
2
3
3
3
3
3
Total Point Score
0
2-3
4 or more
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INTRAOSSEOUS MUCOEPIDERMOID
CARCINOMA (CENTRAL
MUCOEPIDERMOID CARCINOMA)
On rare occasions, salivary gland tumors arise centrally
within the jaws. The most common and best-recognized
intrabony salivary tumor is the intraosseous mucoepidermoid carcinoma. However, other salivary
tumors have been reported to develop within the jaws,
including adenoid cystic carcinoma, benign and malignant mixed tumors, adenocarcinoma, acinic cell adenocarcinoma, epithelial-myoepithelial carcinoma, and
monomorphic adenoma.
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HISTOPATHOLOGIC FEATURES
The microscopic appearance of intraosseous mucoepidermoid carcinoma is similar to that of its soft tissue
counterpart. Most tumors are low-grade lesions,
although high-grade mucoepidermoid carcinomas also
have been reported within the jaws.
CLINICAL FEATURES
Around 85% of all acinic cell adenocarcinomas occur
in the parotid gland, a logical nding because this is
the largest gland and one that is composed entirely of
serous elements (Fig. 11-63). Most surveys have shown
that this neoplasm makes up 1% to 3% of all parotid
tumors, although one study showed it represented 8.6%
of all parotid tumors (see Table 11-4). It is much less
common in the submandibular gland, which is the site
for only 2.7% to 4% of these tumors. About 9% of all
acinic cell adenocarcinomas develop in the oral minor
salivary glands, with the buccal mucosa, lips, and palate
being the most common sites (Fig. 11-64). Overall,
around 2% to 6.5% of all minor salivary gland tumors
are acinic cell adenocarcinomas.
The tumor occurs over a broad age range, with a
relatively even peak prevalence stretching from the
second to the seventh decades of life; the mean age is
in the middle 40s. Approximately 60% of cases occur
HISTOPATHOLOGIC FEATURES
Acinic cell adenocarcinomas are highly variable in
their microscopic appearance. The tumor often is
well circumscribed and sometimes may even appear
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encapsulated; however, some tumors exhibit an inltrative growth pattern. The most characteristic cell is
one with features of the serous acinar cell, with abundant granular basophilic cytoplasm and a round, darkly
stained eccentric nucleus. These cells are fairly uniform
in appearance, and mitotic activity is uncommon.
Other cells may resemble intercalated duct cells, and
some tumors also have cells with a clear, vacuolated
cytoplasm.
Several growth patterns may be seen. The solid
variety consists of numerous well-differentiated acinar
cells arranged in a pattern that resembles normal
parotid gland tissue (Figs. 11-65 and 11-66). In the
microcystic variety, multiple small cystic spaces are
created that may contain some mucinous or eosinophilic material. In the papillary-cystic variety, larger
cystic areas are formed that are lined by epithelium
having papillary projections into the cystic spaces
(Fig. 11-67). The follicular variety has an appearance
Acinic cell adenocarcinomas conned to the supercial lobe of the parotid gland are best treated by lobectomy; for those in the deep lobe, total parotidectomy is
usually necessary. The facial nerve may need to be
sacriced if it is involved by tumor. Submandibular
tumors are managed by total removal of the gland, and
minor gland tumors are treated with assured surgical
excision. Lymph node dissection is not indicated unless
there is clinical evidence of metastatic disease. Adjunctive radiation therapy may be considered for uncontrolled local disease.
The acinic cell adenocarcinoma is associated with
one of the better prognoses of any of the malignant
salivary gland tumors. Approximately one third of
patients have recurrences locally, and metastases
develop in 10% to 15% of patients. From 6% to 26% of
patients die of their disease. The prognosis for minor
gland tumors is better than that for tumors arising in
the major glands.
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CLINICAL FEATURES
CARCINOMA EX PLEOMORPHIC ADENOMA
There is fairly convincing evidence that the carcinoma
ex pleomorphic adenoma represents a malignant transformation within what was previously a benign neoplasm. First of all, the mean age of patients with this
tumor is about 15 years older than that for the benign
pleomorphic adenoma. It is most common in middleaged and older adults, with a peak prevalence in the
sixth to eighth decades of life. In addition, patients may
report that a mass has been present for many years,
sometimes undergoing a recent rapid growth with
associated pain or ulceration. However, some tumors
may have a short duration. The histopathologic features, which are discussed later, also support malignant
transformation of a benign pleomorphic adenoma. It
has been noted that the risk for malignant change in a
pleomorphic adenoma increases with the duration of
the tumor.
More than 80% of cases of carcinoma ex pleomorphic adenoma are seen within the major glands, primarily the parotid gland (Fig. 11-68). Nearly two thirds
of minor salivary gland cases occur on the palate (Fig.
11-69). Although pain or recent rapid growth is not
unusual, many cases present as a painless mass that is
indistinguishable from a benign tumor. Parotid tumors
may produce facial nerve palsy.
CARCINOSARCOMA
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HISTOPATHOLOGIC FEATURES
nates the tumor and is usually in the form of chondrosarcoma but also may show characteristics of osteosarcoma, brosarcoma, liposarcoma, rhabdomyosarcoma,
or malignant brous histiocytoma. Some lesions have
evidence of an origin from a benign mixed tumor.
The carcinoma ex pleomorphic adenoma shows a variable microscopic appearance. Areas of typical benign
pleomorphic adenoma usually can be found and may
constitute most or only a small portion of the lesion.
Within the tumor are areas of malignant degeneration
of the epithelial component, characterized by cellular
pleomorphism and abnormal mitotic activity (Fig.
11-70). This change is most often in the form of a
poorly differentiated adenocarcinoma, but other patterns also can develop, including polymorphous lowgrade adenocarcinoma, salivary duct carcinoma,
mucoepidermoid carcinoma, and adenoid cystic carcinoma. The malignant component often has an aggressive growth pattern, with capsular invasion and
inltration into surrounding tissues. However, in rare
instances it is discovered as a small focus within the
center of an encapsulated mixed tumor. Because such
tumors have a markedly better prognosis than invasive
tumors, they have been designated as noninvasive
carcinoma ex mixed tumor or carcinoma in situ ex
mixed tumor.
The metastasizing mixed tumor has microscopic features of a benign pleomorphic adenoma, within both
the primary and the metastatic sites. Malignant histopathologic changes are not observed.
CARCINOSARCOMA
The carcinosarcoma is a biphasic tumor, demonstrating both carcinomatous and sarcomatous areas. The
epithelial component usually consists of a poorly differentiated adenocarcinoma or an undifferentiated
carcinoma. The sarcomatous portion often predomi-
CARCINOSARCOMA
Carcinosarcomas are treated by radical surgical excision, which may be combined with radiation therapy
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HISTOPATHOLOGIC FEATURES
The adenoid cystic carcinoma is composed of a mixture
of myoepithelial cells and ductal cells that can have a
varied arrangement (Fig. 11-73). Three major patterns
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POLYMORPHOUS LOW-GRADE
ADENOCARCINOMA (LOBULAR
CARCINOMA; TERMINAL
DUCT CARCINOMA)
The polymorphous low-grade adenocarcinoma is a
more recently recognized type of salivary malignancy
that was rst described in 1983. Before its identication as a distinct entity, examples of this tumor were
categorized as pleomorphic adenoma, an unspecied
form of adenocarcinoma, or sometimes as adenoid
cystic carcinoma. Once recognized as a specic entity,
however, it was realized that this tumor possesses distinct clinicopathologic features and is one of the more
common minor salivary gland malignancies.
CLINICAL FEATURES
The polymorphous low-grade adenocarcinoma is
almost exclusively a tumor of the minor salivary glands.
However, rare examples also have been reported in the
major glands, either arising de novo or as the malignant
component of a carcinoma ex pleomorphic adenoma.
497
HISTOPATHOLOGIC FEATURES
The tumor cells of polymorphous low-grade adenocarcinomas have a deceptively uniform appearance. They
are round to polygonal in shape, with indistinct cell
borders and pale to eosinophilic cytoplasm. The nuclei
may be round, ovoid, or spindled; these nuclei usually
are pale staining, although they can be more basophilic
in some areas. The cells can exhibit different growth
patterns, hence, the polymorphous term. The cells may
grow in a solid pattern or form cords, ducts, or larger
cystic spaces. In some tumors, a cribriform pattern can
be produced that mimics adenoid cystic carcinoma
(Fig. 11-77). Mitotic gures are uncommon.
At low power, the tumor sometimes appears well
circumscribed. However, the peripheral cells are
usually inltrative, invading the adjacent tissue in a
single-le fashion (Fig. 11-78). Extension into underlying bone or skeletal muscle may be observed. The
stroma is often mucoid in nature, or it may demonstrate hyalinization. Perineural invasion is common
another feature that may cause the tumor to be
mistaken for adenoid cystic carcinoma (Fig. 11-79).
However, a distinction between these two tumors is
important because of their vastly different prognoses.
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In spite of the wide variety of salivary gland malignancies that have been specically identied and categorized, some tumors still defy the existing classication
schemes. These tumors usually are designated as
salivary adenocarcinomas, not otherwise specied
(NOS).
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better for tumors of the oral cavity than for those in the
major salivary glands. The reported 10-year survival
rate for parotid tumors ranges from 26% to 55%; in
contrast, one study reported a 10-year survival rate of
76% for intraoral tumors.
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Sialadenosis
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Canalicular Adenoma
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Soft Tissue Tumors
CHAPTER OUTLINE
Fibroma
Giant Cell Fibroma
Epulis Fissuratum
Inammatory Papillary Hyperplasia
Fibrous Histiocytoma
Fibromatosis
Myobroma
Oral Focal Mucinosis
Pyogenic Granuloma
Peripheral Giant Cell Granuloma
Peripheral Ossifying Fibroma
Lipoma
Traumatic Neuroma
Palisaded Encapsulated Neuroma
Neurilemoma
Neurobroma
Neurobromatosis Type I
Multiple Endocrine Neoplasia Type 2B
Melanotic Neuroectodermal Tumor of Infancy
Paraganglioma
Granular Cell Tumor
Congenital Epulis
CLINICAL FEATURES
Although the irritation broma can occur anywhere in
the mouth, the most common location is the buccal
mucosa along the bite line. Presumably, this is a consequence of trauma from biting the cheek (Figs. 12-1
and 12-2). The labial mucosa, tongue, and gingiva also
are common sites (Figs. 12-3 and 12-4). It is likely
that many gingival bromas represent brous maturation of a preexisting pyogenic granuloma. The lesion
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HISTOPATHOLOGIC FEATURES
Microscopic examination of the irritation broma
shows a nodular mass of brous connective tissue
covered by stratied squamous epithelium (Figs. 12-6
and 12-7). This connective tissue is usually dense and
collagenized, although in some cases it is looser in
nature. The lesion is not encapsulated; the brous
tissue instead blends gradually into the surrounding
connective tissues. The collagen bundles may be
arranged in a radiating, circular, or haphazard fashion.
The covering epithelium often demonstrates atrophy of
the rete ridges because of the underlying brous mass.
However, the surface may exhibit hyperkeratosis from
secondary trauma. Scattered inammation may be
The giant cell broma is a brous tumor with distinctive clinicopathologic features. Unlike the traumatic
broma, it does not appear to be associated with
chronic irritation. The giant cell broma represents
approximately 2% to 5% of all oral brous proliferations
submitted for biopsy.
CLINICAL FEATURES
The giant cell broma is typically an asymptomatic
sessile or pedunculated nodule, usually less than 1 cm
in size (Fig. 12-8). The surface of the mass often appears
papillary; therefore, the lesion may be clinically mistaken for a papilloma. Compared with the common
irritation broma, the lesion usually occurs at a younger
age. In about 60% of cases, the lesion is diagnosed
during the rst 3 decades of life. Some studies have
suggested a slight female predilection. Approximately
50% of all cases occur on the gingiva. The mandibular
gingiva is affected twice as often as the maxillary
gingiva. The tongue and palate also are common sites.
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HISTOPATHOLOGIC FEATURES
Microscopic examination of the giant cell broma
reveals a mass of vascular brous connective tissue,
which is usually loosely arranged (Fig. 12-10). The hallmark is the presence of numerous large, stellate broblasts within the supercial connective tissue. These
cells may contain several nuclei. Frequently, the surface
of the lesion is pebbly. The covering epithelium often
is thin and atrophic, although the rete ridges may
appear narrow and elongated.
used synonymously for epulis ssuratum, epulis is actually a generic term that can be applied to any tumor of
the gingiva or alveolar mucosa. Therefore, some authors
have advocated not using this term, preferring to call
these lesions inammatory brous hyperplasia or other
descriptive names. However, the term epulis ssuratum
is still widely used today and is well understood by
virtually all clinicians. Other examples of epulides
include the giant cell epulis (peripheral giant cell
granuloma) (see page 520), ossifying broid epulis
(peripheral ossifying broma) (see page 521), and
congenital epulis (see page 537).
CLINICAL FEATURES
The epulis ssuratum typically appears as a single or
multiple fold or folds of hyperplastic tissue in the alveolar vestibule (Figs. 12-11 and 12-12). Most often, there
are two folds of tissue, and the ange of the associated
denture ts conveniently into the ssure between the
folds. The redundant tissue is usually rm and brous,
although some lesions appear erythematous and ulcer-
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ated, similar to the appearance of a pyogenic granuloma. Occasional examples of epulis ssuratum
demonstrate surface areas of inammatory papillary
hyperplasia (see page 512). The size of the lesion can
vary from localized hyperplasias less than 1 cm in size
to massive lesions that involve most of the length of the
HISTOPATHOLOGIC FEATURES
Microscopic examination of the epulis ssuratum
reveals hyperplasia of the brous connective tissue.
Often multiple folds and grooves occur where the
denture impinges on the tissue (Fig. 12-15). The overlying epithelium is frequently hyperparakeratotic and
demonstrates irregular hyperplasia of the rete ridges.
In some instances, the epithelium shows inammatory
papillary hyperplasia (see page 513) or pseudoepitheliomatous (pseudocarcinomatous) hyperplasia. Focal
areas of ulceration are not unusual, especially at the
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In rare instances, the formation of osteoid or chondroid is observed. This unusual-appearing product,
known as osseous and chondromatous metaplasia,
is a reactive phenomenon caused by chronic irritation
by the ill-tting denture (see page 318). The irregular
nature of this bone or cartilage can be microscopically
disturbing, and the pathologist should not mistake it for
a sarcoma.
The denture-related broepithelial polyp has a
narrow core of dense brous connective tissue
covered by stratied squamous epithelium. Like the
epulis ssuratum, the overlying epithelium may be
hyperplastic.
INFLAMMATORY PAPILLARY
HYPERPLASIA (DENTURE
PAPILLOMATOSIS)
Inammatory papillary hyperplasia is a reactive
tissue growth that usually, although not always, develops beneath a denture. Some investigators classify this
lesion as part of the spectrum of denture stomatitis (see
page 216). Although the exact pathogenesis is unknown,
the condition most often appears to be related to the
following:
An ill-tting denture
Poor denture hygiene
Wearing the denture 24 hours a day
Approximately 20% of patients who wear their dentures 24 hours a day have inammatory papillary hyperplasia. Candida organisms also have been suggested as a
cause, but any possible role appears uncertain.
CLINICAL FEATURES
Fig. 12-15 Epulis ssuratum. Low-power photomicrograph
demonstrating folds of hyperplastic brovascular connective
tissue covered by stratied squamous epithelium.
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HISTOPATHOLOGIC FEATURES
The mucosa in inammatory papillary hyperplasia
exhibits numerous papillary growths on the surface
that are covered by hyperplastic, stratied squamous
epithelium (Fig. 12-18). In advanced cases, this hyperplasia is pseudoepitheliomatous in appearance, and
the pathologist should not mistake it for carcinoma
(Fig. 12-19). The connective tissue can vary from loose
and edematous to densely collagenized. A chronic
inammatory cell inltrate is usually seen, which consists of lymphocytes and plasma cells. Less frequently,
Fig. 12-18 Inammatory papillary hyperplasia. Mediumpower view showing brous and epithelial hyperplasia
resulting in papillary surface projections. Heavy chronic
inammation is present.
Fig. 12-19 Inammatory papillary hyperplasia. Higherpower view showing pseudoepitheliomatous hyperplasia of
the epithelium. This epithelium has a bland appearance that
should not be mistaken for carcinoma.
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FIBROUS HISTIOCYTOMA
Fibrous histiocytomas are a diverse group of tumors
that exhibit broblastic and histiocytic differentiation. Although the cell of origin is still uncertain, it
may arise from the tissue histiocyte, which then
assumes broblastic properties. Because of the variable
nature of these lesions, an array of terms has been used
for them, including dermatobroma, sclerosing
hemangioma, broxanthoma, and nodular subepidermal brosis. Unlike other brous growths
discussed previously in this chapter, the brous
histiocytoma is generally considered to represent a
true neoplasm.
CLINICAL FEATURES
The brous histiocytoma can develop almost anywhere
in the body. The most common site is the skin of the
extremities, where the lesion is called a dermatobroma.
Tumors of the oral and perioral region are uncommon.
Although oral tumors can occur at any site, the most
frequent location is the buccal mucosa and vestibule.
Rare intrabony lesions of the jaws have also been
reported. Oral brous histiocytomas tend to occur in
middle-aged and older adults; cutaneous examples are
most frequent in young adults. The tumor is usually
a painless nodular mass and can vary in size from a
few millimeters to several centimeters in diameter
(Fig. 12-20). Deeper tumors tend to be larger.
HISTOPATHOLOGIC FEATURES
Microscopically, the brous histiocytoma is characterized by a cellular proliferation of spindle-shaped broblastic cells with vesicular nuclei (Figs. 12-21 and
12-22). The margins of the tumor often are not sharply
dened. The tumor cells are arranged in short, intersecting fascicles, known as a storiform pattern because
of its resemblance to the irregular, whorled appearance of a straw mat. Rounded histiocyte-like cells,
lipid-containing xanthoma cells, or multinucleated
giant cells can be seen occasionally, as may scattered
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FIBROMATOSIS
The bromatoses are a broad group of brous proliferations that have a biologic behavior and histopathologic pattern that is intermediate between those of
benign brous lesions and brosarcoma. A number of
different forms of bromatosis are recognized throughout the body, and they often are named based on their
particular clinicopathologic features. In the soft tissues
of the head and neck, these lesions are frequently
called juvenile aggressive bromatoses or extraabdominal desmoids. Similar lesions within the bone
have been called desmoplastic bromas (see page
658). Individuals with familial adenomatous polyposis
and Gardner syndrome (see page 651) have a greatly
increased risk for developing aggressive bromatosis.
HISTOPATHOLOGIC FEATURES
Soft tissue bromatosis is characterized by a cellular
proliferation of spindle-shaped cells that are arranged
in streaming fascicles and are associated with a variable amount of collagen (Fig. 12-24). The lesion is
usually poorly circumscribed and inltrates the adjacent tissues. Hyperchromatism and pleomorphism of
the cells should not be observed.
MYOFIBROMA (MYOFIBROMATOSIS)
Myobroma is a rare spindle cell neoplasm that consists of myobroblasts (i.e., cells with both smooth
muscle and broblastic features). Such cells are not
specic for this lesion, however, because they also can
be identied in other brous proliferations. Most myobromas occur as solitary lesions, but some patients
develop a multicentric tumor process known as
myobromatosis.
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Fig. 12-26 Myobromatosis. Proliferation of spindleshaped cells with both broblastic and smooth muscle
features.
HISTOPATHOLOGIC FEATURES
Myobromas are composed of interlacing bundles of
spindle cells with tapered or blunt-ended nuclei and
eosinophilic cytoplasm (Fig. 12-26). Nodular fascicles
may alternate with more cellular zones, imparting a
biphasic appearance to the tumor. Scattered mitoses
are not uncommon. Centrally, the lesion is often more
vascular with a hemangiopericytoma-like appearance.
The tumor cells are positive for smooth muscle actin
and muscle-specic actin with immunohistochemistry,
but they are negative for desmin.
CLINICAL FEATURES
Oral focal mucinosis is most common in young adults
and shows a 2:1 female-to-male predilection. The
gingiva is the most common site; two thirds to three
fourths of all cases are found there. The hard palate is
the second most common location. The mass rarely
appears at other oral sites. The lesion usually presents
as a sessile or pedunculated, painless nodular mass that
is the same color as the surrounding mucosa (Fig.
12-27). The surface is typically smooth and nonulcerated, although occasional cases exhibit a lobulated
appearance. The size varies from a few millimeters up
to 2 cm in diameter. The patient often has been aware
of the mass for many months or years before the diagnosis is made.
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HISTOPATHOLOGIC FEATURES
Microscopic examination of oral focal mucinosis shows
a well-localized but nonencapsulated area of loose,
myxomatous connective tissue surrounded by denser,
normal collagenous connective tissue (Figs. 12-28 and
12-29). The lesion is usually found just beneath the
surface epithelium and often causes attening of the
rete ridges. The broblasts within the mucinous area
can be ovoid, fusiform, or stellate, and they may demonstrate delicate, brillar processes. Few capillaries
are seen within the lesion, especially compared with
the surrounding denser collagen. Similarly, no signicant inammation is observed, although a perivascular
lymphocytic inltrate often is noted within the surrounding collagenous connective tissue. No appreciable reticulin is evident within the lesion, and special
stains suggest that the mucinous product is hyaluronic
acid.
PYOGENIC GRANULOMA
The pyogenic granuloma is a common tumorlike
growth of the oral cavity that traditionally has been
considered to be nonneoplastic in nature.* Although it
was originally thought to be caused by pyogenic organisms, it is now believed to be unrelated to infection.
*However, some pyogenic granulomas (also known as lobular capillary
hemangiomas) currently are categorized as vascular tumors under the classication scheme of the International Society for the Study of Vascular
Anomalies (see Box 12-2, page 539).
Instead, the pyogenic granuloma is thought to represent an exuberant tissue response to local irritation
or trauma. In spite of its name, it is not a true
granuloma.
CLINICAL FEATURES
The pyogenic granuloma is a smooth or lobulated mass
that is usually pedunculated, although some lesions are
sessile (Figs. 12-30 to 12-32). The surface is characteristically ulcerated and ranges from pink to red to
purple, depending on the age of the lesion. Young pyogenic granulomas are highly vascular in appearance;
older lesions tend to become more collagenized and
pink. They vary from small growths only a few millimeters in size to larger lesions that may measure several
centimeters in diameter. Typically, the mass is painless,
although it often bleeds easily because of its extreme
vascularity. Pyogenic granulomas may exhibit rapid
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HISTOPATHOLOGIC FEATURES
Microscopic examination of a peripheral giant cell
granuloma shows a proliferation of multinucleated
giant cells within a background of plump ovoid and
spindle-shaped mesenchymal cells (Figs. 12-39 and
12-40). The giant cells may contain only a few nuclei
or up to several dozen. Some of these cells may have
large, vesicular nuclei; others demonstrate small, pyknotic nuclei. Mitotic gures are fairly common in the
background mesenchymal cells. Abundant hemorrhage is characteristically found throughout the mass,
which often results in deposits of hemosiderin pigment,
especially at the periphery of the lesion.
The overlying mucosal surface is ulcerated in about
50% of cases. A zone of dense brous connective tissue
usually separates the giant cell proliferation from the
mucosal surface. Adjacent acute and chronic inammatory cells are frequently present. Areas of reactive
bone formation or dystrophic calcications are not
unusual.
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CLINICAL FEATURES
The peripheral ossifying broma occurs exclusively on
the gingiva. It appears as a nodular mass, either pedunculated or sessile, that usually emanates from the interdental papilla (Figs. 12-41 and 12-42). The color ranges
from red to pink, and the surface is frequently, but not
always, ulcerated. The growth probably begins as an
ulcerated lesion; older ones are more likely to demonstrate healing of the ulcer and an intact surface. Red,
ulcerated lesions often are mistaken for pyogenic granulomas; the pink, nonulcerated ones are clinically
similar to irritation bromas. Most lesions are less than
2 cm in size, although larger ones occasionally occur.
The lesion often has been present for many weeks or
months before the diagnosis is made.
The peripheral ossifying broma is predominantly a
lesion of teenagers and young adults, with peak prevalence between the ages of 10 and 19. Almost two thirds
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of all cases occur in females. There is a slight predilection for the maxillary arch, and more than 50% of all
cases occur in the incisor-cuspid region. Usually, the
teeth are unaffected; rarely, there can be migration and
loosening of adjacent teeth.
HISTOPATHOLOGIC FEATURES
The basic microscopic pattern of the peripheral ossifying broma is one of a brous proliferation associated
with the formation of a mineralized product (Figs.
12-43 and 12-44). If the epithelium is ulcerated, then
the surface is covered by a brinopurulent membrane
with a subjacent zone of granulation tissue. The deeper
broblastic component often is cellular, especially in
areas of mineralization. In some cases, the broblastic
proliferation and associated mineralization is only a
small component of a larger mass that resembles a
broma or pyogenic granuloma.
The type of mineralized component is variable and
may consist of bone, cementum-like material, or dystrophic calcications. Frequently, a combination of
products is formed. Usually, the bone is woven and
trabecular in type, although older lesions may demonstrate mature lamellar bone. Trabeculae of unmineralized osteoid are not unusual. Less frequently, ovoid
droplets of basophilic cementum-like material are
formed. Dystrophic calcications are characterized
by multiple granules, tiny globules, or large, irregular
masses of basophilic mineralized material. Such dystrophic calcications are more common in early, ulcerated lesions; older, nonulcerated examples are more
likely to demonstrate well-formed bone or cementum.
In some cases, multinucleated giant cells may be found,
usually in association with the mineralized product.
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LIPOMA
The lipoma is a benign tumor of fat. Although it represents by far the most common mesenchymal neoplasm, most examples occur on the trunk and proximal
portions of the extremities. Lipomas of the oral and
maxillofacial region are much less frequent. The pathogenesis of lipomas is uncertain, but they appear to be
more common in obese people. However, the metabolism of lipomas is completely independent of the
normal body fat. If the caloric intake is reduced, then
lipomas do not decrease in size, although normal body
fat may be lost.
CLINICAL FEATURES
Oral lipomas are usually soft, smooth-surfaced nodular
masses that can be sessile or pedunculated (Figs. 12-45
and 12-46). Typically, the tumor is asymptomatic and
often has been noted for many months or years before
diagnosis. Most are less than 3 cm in size, but occasional lesions can become much larger. Although a
subtle or more obvious yellow hue often is detected
clinically, deeper examples may appear pink. The
buccal mucosa and buccal vestibule are the most
common intraoral sites and account for 50% of all
cases. Some buccal cases may not represent true
tumors, but rather herniation of the buccal fat pad
through the buccinator muscle, which may occur after
local trauma in young children or subsequent to surgical removal of third molars in older patients. Less
common sites include the tongue, oor of the mouth,
and lips. Most patients are 40 years of age or older;
lipomas are uncommon in children. Lipomas of the
oral and maxillofacial region have shown a fairly balanced sex distribution in some studies, although one
recent large series demonstrated a marked male
predilection.
HISTOPATHOLOGIC FEATURES
Most oral lipomas are composed of mature fat cells that
differ little in microscopic appearance from the surrounding normal fat (Figs. 12-47 and 12-48). The
tumor is usually well circumscribed and may demonstrate a thin brous capsule. A distinct lobular arrange-
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TRAUMATIC NEUROMA
(AMPUTATION NEUROMA)
The traumatic neuroma is not a true neoplasm but a
reactive proliferation of neural tissue after transection
or other damage of a nerve bundle. After a nerve has
been damaged or severed, the proximal portion
attempts to regenerate and reestablish innervation of
the distal segment by the growth of axons through
tubes of proliferating Schwann cells. If these regenerating elements encounter scar tissue or otherwise cannot
reestablish innervation, then a tumorlike mass may
develop at the site of injury.
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HISTOPATHOLOGIC FEATURES
Microscopic examination of traumatic neuromas shows
a haphazard proliferation of mature, myelinated and
unmyelinated nerve bundles within a brous connective tissue stroma that ranges from densely collagenized to myxomatous in nature (Figs. 12-51 and 12-52).
An associated mild chronic inammatory cell inltrate
may be present. Traumatic neuromas with inammation are more likely to be painful than those without
signicant inammation.
PALISADED ENCAPSULATED
NEUROMA (SOLITARY
CIRCUMSCRIBED NEUROMA)
The palisaded encapsulated neuroma is a benign
neural tumor with distinctive clinical and histopathologic features. Although it was rst recognized only
as recently as 1972, it represents one of the more
common supercial nerve tumors, especially in the
head and neck region. The cause is uncertain, but some
authors have speculated that trauma may play an etiologic role; the tumor is generally considered to represent a reactive lesion rather than a true neoplasm.
CLINICAL FEATURES
The palisaded encapsulated neuroma shows a striking
predilection for the face, which accounts for approximately 90% of reported cases. The nose and cheek are
the most common specic sites. The lesion is most frequently diagnosed between the fth and seventh
decades of life, although the tumor often has been
present for many months or years. It is a smoothsurfaced, painless, dome-shaped papule or nodule that
is usually less than 1 cm in diameter. There is no sex
predilection.
Oral palisaded encapsulated neuromas are not
uncommon, although many are probably diagnosed
microscopically as neurobromas or neurilemomas.
The lesion appears most frequently on the hard palate
(Fig. 12-53) and maxillary labial mucosa, although it
also may occur in other oral locations.
HISTOPATHOLOGIC FEATURES
Palisaded encapsulated neuromas appear well circumscribed and often encapsulated (Fig. 12-54), although
this capsule may be incomplete, especially along the
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NEURILEMOMA (SCHWANNOMA)
Fig. 12-54 Palisaded encapsulated neuroma. A, Lowpower view showing a well-circumscribed, nodular
proliferation of neural tissue. B, Higher-power view
demonstrating spindle cells with wavy nuclei.
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Usually, the mass is asymptomatic, although tenderness or pain may occur in some instances. The lesion
is most common in young and middle-aged adults and
can range from a few millimeters to several centimeters in size.
The tongue is the most common location for oral
neurilemomas, although the tumor can occur almost
anywhere in the mouth (Fig. 12-56). On occasion, the
tumor arises centrally within bone and may produce
bony expansion. Intraosseous examples are most
common in the posterior mandible and usually appear
as either unilocular or multilocular radiolucencies on
radiographs. Pain and paresthesia are not unusual for
intrabony tumors.
NF2 is an autosomal dominant condition caused by
a mutation of a tumor suppressor gene on chromosome
22, which codes for a protein known as merlin. In addition to bilateral neurilemomas (acoustic neuromas)
of the vestibular nerve, patients also develop neurilemomas of peripheral nerves, plus meningiomas and
ependymomas of the central nervous system (CNS).
Characteristic symptoms include progressive sensorineural deafness, dizziness, and tinnitus.
HISTOPATHOLOGIC FEATURES
The neurilemoma is usually an encapsulated tumor
that demonstrates two microscopic patterns in varying
amounts: (1) Antoni A and (2) Antoni B. Streaming
fascicles of spindle-shaped Schwann cells characterize
Antoni A tissue. These cells often form a palisaded
arrangement around central acellular, eosinophilic
areas known as Verocay bodies (Fig. 12-57). These
Verocay bodies consist of reduplicated basement
membrane and cytoplasmic processes. Antoni B tissue
is less cellular and less organized; the spindle cells
are randomly arranged within a loose, myxomatous
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NEUROFIBROMA
The neurobroma is the most common type of peripheral nerve neoplasm. It arises from a mixture of cell
types, including Schwann cells and perineural
broblasts.
HISTOPATHOLOGIC FEATURES
The treatment for solitary neurobromas is local surgical excision, and recurrence is rare. Any patient with a
lesion that is diagnosed as a neurobroma should be
evaluated clinically for the possibility of neurobromatosis (see next topic). Malignant transformation of
solitary neurobromas can occur, although the risk
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Box 12-1
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CLINICAL FEATURES
Patients with MEN type 2B usually have a marfanoid
body build characterized by thin, elongated limbs with
muscle wasting. The face is narrow, but the lips are
characteristically thick and protuberant because of the
diffuse proliferation of nerve bundles. The upper eyelid
sometimes is everted because of thickening of the tarsal
plate (Fig. 12-70). Small, pedunculated neuromas may
be observable on the conjunctiva, eyelid margin, or
cornea.
Oral mucosal neuromas are usually the rst sign of
the condition. These neuromas appear as soft, painless
papules or nodules that principally affect the lips and
anterior tongue but also may be seen on the buccal
mucosa, gingiva, and palate (Fig. 12-71). Bilateral
neuromas of the commissural mucosa are highly
characteristic.
Pheochromocytomas of the adrenal glands develop
in at least 50% of all patients and become more prevalent with increasing age. These neuroendocrine tumors
are frequently bilateral or multifocal. The tumor cells
secrete catecholamines, which result in symptoms
such as profuse sweating, intractable diarrhea, headaches, ushing, heart palpitations, and severe
hypertension.
The most signicant aspect of this condition is the
development of medullary carcinoma of the thyroid
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LABORATORY VALUES
If medullary carcinoma of the thyroid gland is present,
then serum or urinary levels of calcitonin are elevated.
An increase in calcitonin levels may herald the onset
of the tumor, and calcitonin also can be monitored to
detect local recurrences or metastases after treatment.
Pheochromocytomas may result in increased levels of
urinary vanillylmandelic acid (VMA) and increased
epinephrine-to-norepinephrine ratios.
HISTOPATHOLOGIC FEATURES
The mucosal neuromas are characterized by marked
hyperplasia of nerve bundles in an otherwise normal
or loose connective tissue background (Figs. 12-72 and
12-73). Prominent thickening of the perineurium is
typically seen.
MELANOTIC NEUROECTODERMAL
TUMOR OF INFANCY
The melanotic neuroectodermal tumor of infancy
is a rare pigmented neoplasm that usually occurs
during the rst year of life. It is generally accepted that
this lesion is of neural crest origin. In the past, however,
a number of tissues were suggested as possible sources
of this tumor. These included odontogenic epithelium
and retina, which resulted in various older terms for
this entity, such as pigmented ameloblastoma,
retinal anlage tumor, and melanotic progonoma.
Because these names are inaccurate, however, they
should no longer be used. Melanotic (pigmented) neuroectodermal tumor of infancy is the preferred term.
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LABORATORY VALUES
High urinary levels of vanillylmandelic acid (VMA)
often are found in patients with melanotic neuroectodermal tumor of infancy. These levels may return to
normal once the tumor has been resected. This nding
supports the hypothesis of neural crest origin because
other tumors from this tissue (e.g., pheochromocytoma,
neuroblastoma) often secrete norepinephrine-like hormones that are metabolized to VMA and excreted in
the urine.
HISTOPATHOLOGIC FEATURES
The tumor consists of a biphasic population of cells that
form nests, tubules, or alveolar structures within a
dense, collagenous stroma (Figs. 12-76 and 12-77).
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in middle-aged adults. Most often it is a slowly enlarging, painless mass of the upper lateral neck below the
angle of the jaw. It is seen more frequently in patients
who live at high altitudes, indicating that some cases
may arise from chronic hyperplasia of the carotid body
in response to lower oxygen levels. Angiography can
help to localize the tumor and demonstrate its characteristic vascular nature.
Jugulotympanic paragangliomas are the second most
common type of these tumors. They also are most
frequent in middle-aged individuals but show a 2:1
female predilection. The most common symptoms
include dizziness, tinnitus (a ringing or other noise in
the ear), hearing loss, and cranial nerve palsies. Imaging
studies, especially three-dimensional (3D) time-of-ight
magnetic resonance angiography, can help to detect
and characterize such lesions. Other less common paragangliomas of the head and neck include vagal, nasopharyngeal, laryngeal, and orbital paragangliomas.
Approximately 10% to 20% of affected patients have
multifocal tumors. In 10% of all cases, there is a family
history of such tumors, with an autosomal dominant
pattern of inheritance that is modied by genomic
imprinting. The gene responsible for familial paragangliomas has been mapped to chromosome 11q23. In
genomic imprinting, the gene is transmitted in a mendelian manner, but expression of that gene is determined by the sex of the transmitting parent. Paternal
transmission results in development of tumors in the
offspring, even if the father is clinically unaffected.
Maternal transmission does not result in development
of tumors in the offspring, although these children will
carry the gene and have the ability to pass it down to
subsequent generations. Hereditary cases have an even
greater chance of being multicentric; about one third
of affected patients have more than one tumor.
HISTOPATHOLOGIC FEATURES
The paraganglioma is characterized by round or polygonal epithelioid cells that are organized into nests
or zellballen (Fig. 12-78). The overall architecture is
similar to that of the normal paraganglia, except the
zellballen are usually larger and more irregular in shape.
These nests consist primarily of chief cells, which
demonstrate centrally located, vesicular nuclei and
somewhat granular, eosinophilic cytoplasm. The tumor
is typically vascular and may be surrounded by a thin
brous capsule.
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CLINICAL FEATURES
Granular cell tumors are most common in the oral
cavity and on the skin. The single most common site is
the tongue, which accounts for one third to half of all
reported cases. Tongue lesions most often occur on the
dorsal surface. The buccal mucosa is the second most
common intraoral location. The tumor most frequently
occurs in the fourth to sixth decades of life and is rare
in children. There is a 2:1 female predilection.
The granular cell tumor is typically an asymptomatic sessile nodule that is usually 2 cm or less in size
(Figs. 12-79 and 12-80). The lesion often has been
noted for many months or years, although sometimes
the patient is unaware of its presence. The mass is typically pink, but occasional granular cell tumors appear
yellow. The granular cell tumor is usually solitary,
although multiple, separate tumors sometimes occur,
especially in black patients.
HISTOPATHOLOGIC FEATURES
The granular cell tumor is composed of large, polygonal cells with abundant pale eosinophilic, granular
cytoplasm and small, vesicular nuclei (Fig. 12-81). The
cells are usually arranged in sheets, but they also may
be found in cords and nests. The cell borders often are
indistinct, which results in a syncytial appearance. The
lesion is not encapsulated and sometimes appears to
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Fig. 12-82 Granular cell tumor. Marked pseudoepitheliomatous hyperplasia overlying a granular cell tumor. Such
cases may easily be mistaken for squamous cell carcinoma.
CLINICAL FEATURES
The congenital epulis typically appears as a pink-tored, smooth-surfaced, polypoid mass on the alveolar
ridge of a newborn (Fig. 12-83). Most examples are
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Fig. 12-84 Congenital epulis. Low-power photomicrograph showing a nodular tumor mass. Note the atrophy of
the rete ridges.
HISTOPATHOLOGIC FEATURES
The congenital epulis is characterized by large, rounded
cells with abundant granular, eosinophilic cytoplasm
and round to oval, lightly basophilic nuclei (Figs. 12-84
and 12-85). In older tumors, these cells may become
elongated and separated by brous connective tissue.
In contrast to the granular cell tumor, the overlying
epithelium never shows pseudoepitheliomatous hyperplasia but typically demonstrates atrophy of the rete
ridges. In addition, in contradistinction to the granular
cell tumor, immunohistochemical analysis shows the
tumor cells to be negative for S-100 protein.
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Fig. 12-86 Congenital epulis. A, Nodular mass on the maxillary alveolar ridge. Instead of
being excised, the lesion was monitored clinically. B, Clinical appearance of the child at 1 year
of age. The mass has disappeared without treatment. (Courtesy of Dr. Erwin Turner.)
Box 12-2
HEMANGIOMA OF INFANCY
Hemangiomas are the most common tumors of infancy,
occurring in 5% to 10% of 1-year-old children. They are
much more common in females than in males (ratio:
3:1 to 5:1), and they occur more frequently in whites
than in other racial groups. The most common location
is the head and neck, which accounts for 60% of all
cases. Eighty percent of hemangiomas occur as single
lesions, but 20% of affected patients will have multiple
tumors.
Fully developed hemangiomas are rarely present at
birth, although a pale macule with threadlike telangiectasias may be noted on the skin. During the rst few
weeks of life, the tumor will demonstrate rapid development that occurs at a faster pace than the infants
overall growth. Supercial tumors of the skin appear
raised and bosselated with a bright-red color (strawberry hemangioma) (Fig. 12-87). They are rm and
rubbery to palpation, and the blood cannot be evacuated by applying pressure. Deeper tumors may appear
only slightly raised with a bluish hue.
The proliferative phase usually lasts for 6 to 10
months, after which the tumor slows in growth and
begins to involute. The color gradually changes to a
Kaposiform Hemangioendothelioma
Tufted Angioma
Pyogenic Granuloma (lobular capillary hemangioma)
VASCULAR MALFORMATIONS
Simple
Capillary malformation
Venous malformation
Lymphatic malformation
Arteriovenous malformation
Combined Malformations
dull-purple hue and the lesion feels less rm to palpation. By age 5, most of the red color is usually gone.
About half of all hemangiomas will show complete
resolution by 5 years of age, with 90% resolving by
age 9. After tumor regression is complete, normal
skin will be restored in about 50% of patients; however,
up to 40% of affected individuals will show permanent changes such as atrophy, scarring, wrinkling, or
telangiectasias.
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VASCULAR MALFORMATIONS
In contrast to hemangiomas, vascular malformations
are present at birth and persist throughout life. Port
wine stains are relatively common capillary malforma-
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HISTOPATHOLOGIC FEATURES
Early hemangiomas of infancy are characterized by
numerous plump endothelial cells and often-indistinct
vascular lumina (Figs. 12-92 and 12-93). At this stage,
such lesions often are known microscopically as juvenile or cellular hemangiomas. Because of their cellular
nature, these lesions also have been called juvenile
Fig. 12-89 Intrabony venous malformation. Wellcircumscribed radiolucency that contains ne trabeculations.
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problematic or life-threatening hemangiomas, pharmacologic therapy may be indicated. Systemic corticosteroids may help to reduce the size of the lesion and
are associated with a 70% to 90% response rate. Intralesional and topical corticosteroids also have been
used for smaller localized, problematic lesions. Intravenous (IV) vincristine is currently the drug of
choice for complicated tumors that are unresponsive
to systemic corticosteroid therapy. Interferon -2a is
no longer widely used because of the reported risk of
permanent spastic diplegia.
Flashlamp pulsed dye lasers can be effective in the
treatment of port wine stains. The management of
venous malformations depends on the size, location,
and associated complications of the lesion. Small, stable
malformations may not require treatment. Larger,
problematic lesions may be treated with a combination
of sclerotherapy and surgical excision. Sclerotherapy
involves the injection of sclerosing agents, such as 95%
ethanol, directly into the lesion to induce brosis.
Sclerotherapy alone may be sufcient for smaller
lesions; for larger lesions, subsequent surgical resection can be accomplished with less risk of bleeding
after sclerotherapy.
The treatment of arteriovenous malformations is
more challenging and also depends on the size of the
lesion and degree of involvement of vital structures.
For cases that require resection, radiographic embolization often is performed 24 to 48 hours before surgery
to minimize blood loss.
Vascular malformations of the jaws are potentially
dangerous lesions because of the risk of severe bleeding, which may occur spontaneously or during surgical
manipulation. Needle aspiration of any undiagnosed
intrabony lesion before biopsy is a wise precaution to
rule out the possibility of a vascular malformation.
Severe and even fatal hemorrhages have occurred after
incisional biopsy or extraction of teeth in the area of
such lesions.
STURGE-WEBER ANGIOMATOSIS
(ENCEPHALOTRIGEMINAL
ANGIOMATOSIS; STURGEWEBER SYNDROME)
Sturge-Weber angiomatosis is a rare, nonhereditary
developmental condition that is characterized by a
hamartomatous vascular proliferation involving the
tissues of the brain and face. It is believed to be caused
by the persistence of a vascular plexus around the
cephalic portion of the neural tube. This plexus develops during the sixth week of intrauterine development
but normally undergoes regression during the ninth
week.
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HISTOPATHOLOGIC FEATURES
NASOPHARYNGEAL ANGIOFIBROMA
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HISTOPATHOLOGIC FEATURES
The nasopharyngeal angiobroma consists of dense
brous connective tissue that contains numerous
dilated, thin-walled blood vessels of variable size (Fig.
12-103). Typically, the vascular component is more
prominent at the periphery of the tumor, especially in
lesions from younger patients.
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HEMANGIOPERICYTOMASOLITARY
FIBROUS TUMOR
As originally described, the hemangiopericytoma
(HPC) was a rare neoplasm that presumably was
derived from pericytes (i.e., cells with processes that
encircled endothelial cells of capillaries). However, in
many examples it was difcult to conrm pericytic differentiation, making diagnostic reproducibility among
pathologists difcult. The solitary brous tumor (SFT)
was initially described as a pleural neoplasm that was
believed to be derived from either mesothelial cells or
submesothelial broblasts. However, examples of this
tumor were later identied in a number of other anatomic sites, including the head and neck region. Many
of these lesions exhibit microscopic features that
overlap those of HPC. In recent years, experts have
questioned the concept of the HPC, suggesting that
many purported examples should be reclassied as
SFTs or designated by the combined name, hemangiopericytomasolitary brous tumor (HPC-SFT).
As more knowledge is gained, it appears likely that the
classication and nomenclature of this spectrum of
tumors will undergo further revision.
In addition, a microscopically similar neoplasm
(hemangiopericytoma-like tumor) of the sinonasal
region is recognized, which is felt to represent a distinct, separate entity.
CLINICAL FEATURES
HPC-SFTs have been reported primarily in adults and
are rare in children. The tumor is usually described as
a slow-growing, painless, submucosal, or deep soft
tissue mass that is easily removed from the surrounding tissues. One of the most common oral locations is
the buccal mucosa, which accounts for 75% of cases
reported under the designation of SFT.
Hemangiopericytoma-like tumors of the nasal cavity
and paranasal sinuses primarily occur in middle-aged
and older adults. Common presenting symptoms
include nasal obstruction and epistaxis.
HISTOPATHOLOGIC FEATURES
HPC-SFTs are usually well-circumscribed lesions
that exhibit a variable microscopic appearance. At the
traditional HPC end of the spectrum, the tumor exhibits tightly packed cells that surround endotheliumlined vascular channels. The cells are haphazardly
arranged and demonstrate round to ovoid nuclei
and indistinct cytoplasmic borders. The blood vessels
often show irregular branching, which results in a
characteristic staghorn and antlerlike appearance
(Fig. 12-104, A).
At the SFT end of the spectrum, the cells are more
spindled and arranged in either short fascicles or in
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LYMPHANGIOMA
Lymphangiomas are benign, hamartomatous tumors
of lymphatic vessels. It is doubtful that they are true
neoplasms; instead, they most likely represent developmental malformations that arise from sequestrations of
lymphatic tissue that do not communicate normally
with the rest of the lymphatic system.
There are three types of lymphangioma:
1. Lymphangioma simplex (capillary lymphangioma), which consists of small, capillary-sized
vessels
2. Cavernous lymphangioma, which is composed
of larger, dilated lymphatic vessels
3. Cystic lymphangioma (cystic hygroma), which
exhibits large, macroscopic cystic spaces
However, this classication system is rather arbitrary
because all three sizes of vessels often can be found
within the same lesion.
CLINICAL FEATURES
Lymphangiomas have a marked predilection for the
head and neck, which accounts for 50% to 75% of all
cases (Fig. 12-105). About half of all lesions are noted
at birth, and around 90% develop by 2 years of age.
Cervical lymphangiomas are more common in the
posterior triangle and are typically soft, uctuant
masses. They occur less frequently in the anterior triangle, although lesions in this location are more likely
to result in respiratory difculties or dysphagia if they
grow large. Occasionally, cervical lymphangiomas
extend into the mediastinum or upward into the oral
cavity. Such tumors can become massive and can
measure 15 cm or greater in size. Rapid tumor enlargement may occur secondary to an upper respiratory
tract infection, presumably because of increased lymph
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HISTOPATHOLOGIC FEATURES
Lymphangiomas are composed of lymphatic vessels
that may show marked dilatation (cavernous lymphangioma) (Figs. 12-108 and 12-109) or macroscopic cystlike structures (cystic hygroma) (Fig. 12-110). The
vessels often diffusely inltrate the adjacent soft tissues
and may demonstrate lymphoid aggregates in their
walls. The lining endothelium is typically thin, and the
spaces contain proteinaceous uid and occasional lymphocytes. Some channels also may contain red blood
cells, which creates uncertainty as to whether they are
lymphatic or blood vessels. Although many of these
likely represent secondary hemorrhage into a lymphatic vessel, some actually may be examples of mixed
lymphangioma and hemangioma.
In intraoral tumors, the lymphatic vessels are characteristically located just beneath the epithelial surface
and often replace the connective tissue papillae. This
supercial location results in the translucent, vesicle-
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LEIOMYOMA
Leiomyomas are benign tumors of smooth muscle that
most commonly occur in the uterus, gastrointestinal
tract, and skin. Leiomyomas of the oral cavity are rare.
Most of these probably have their origin from vascular
smooth muscle.
HISTOPATHOLOGIC FEATURES
Solid leiomyomas are well-circumscribed tumors that
consist of interlacing bundles of spindle-shaped smooth
muscle cells (Figs. 12-112 and 12-113). The nuclei are
elongated, pale staining, and blunt ended. Mitotic
gures are uncommon. Angiomyomas also are wellcircumscribed lesions that demonstrate multiple tortuous blood vessels with thickened walls caused by
hyperplasia of their smooth muscle coats (Fig. 12-114).
Intertwining bundles of smooth muscle may be found
between the vessels, sometimes with intermixed
adipose tissue. As its name implies, the epithelioid leiomyoma is composed primarily of epithelioid cells
rather than spindle cells.
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Fig. 12-112 Leiomyoma. Low-power view showing a wellcircumscribed cellular mass of spindle-shaped smooth muscle
cells.
RHABDOMYOMA
Benign neoplasms of skeletal muscle are called rhabdomyomas. The term rhabdomyoma also is used to
describe a hamartomatous lesion of the heart that often
is associated with tuberous sclerosis (see page 757).
Despite the great amount of skeletal muscle throughout the body, benign skeletal muscle tumors are
extremely rare. However, these extracardiac rhabdomyomas show a striking predilection for the head and
neck. Rhabdomyomas of the head and neck can be
subclassied into two major categories: (1) adult rhabdomyomas and (2) fetal rhabdomyomas.
CLINICAL FEATURES
ADULT RHABDOMYOMAS
Adult rhabdomyomas of the head and neck occur primarily in middle-aged and older patients, with about
70% of cases found in men. The most frequent sites are
the pharynx, oral cavity, and larynx; intraoral lesions
are most common in the oor of the mouth, soft palate,
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HISTOPATHOLOGIC FEATURES
ADULT RHABDOMYOMAS
The adult rhabdomyoma is composed of well-circumscribed lobules of large, polygonal cells, which exhibit
abundant granular, eosinophilic cytoplasm (Fig.
12-118). These cells often demonstrate peripheral
vacuolization that results in a spider web appearance
of the cytoplasm. Focal cells with cross striations can
be identied in most cases (Fig. 12-119). Although
rarely necessary for the diagnosis, immunohistochemical examination will show the tumor cells to be positive
for myoglobin, desmin, and muscle-specic actin.
FETAL RHABDOMYOMAS
FETAL RHABDOMYOMAS
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HISTOPATHOLOGIC FEATURES
CLINICAL FEATURES
Osseous and cartilaginous choristomas show a striking
predilection for the tongue, which accounts for 85% of
cases. The most common location is the posterior
tongue near the foramen cecum, although rare examples also have been reported elsewhere on the tongue
and at other oral locations. The lesion is usually a rm,
smooth-surfaced, sessile or pedunculated nodule
between 0.5 and 2.0 cm in diameter (Fig. 12-120).
Many patients are unaware of the lesion, although
Microscopic examination of choristomas shows a wellcircumscribed mass of dense lamellar bone or mature
cartilage that is surrounded by dense brous connective tissue (Fig. 12-121). Sometimes a combination of
bone and cartilage is formed. The bone has a welldeveloped haversian canal system and occasionally
demonstrates central fatty or hematopoietic marrow.
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FIBROSARCOMA
The brosarcoma is a malignant tumor of broblasts.
At one time, it was considered one of the most common
soft tissue sarcomas. However, the diagnosis of brosarcoma is made much less frequently today because
of the recognition and separate classication of other
spindle cell lesions that have similar microscopic features. The tumor is most common in the extremities;
only 10% occur in the head and neck region.
CLINICAL FEATURES
Fibrosarcomas most often present as slow-growing
masses that may reach considerable size before they
produce pain (Fig. 12-122). They can occur anywhere
in the head and neck region. A number of cases have
been reported in the nose and paranasal sinuses, where
they often result in obstructive symptoms. They can
occur at any age but are most common in young adults
and children.
HISTOPATHOLOGIC FEATURES
Well-differentiated brosarcomas consist of fascicles
of spindle-shaped cells that classically form a herringbone pattern (Fig. 12-123). The cells often show little
variation in size and shape, although variable numbers
of mitotic gures can usually be identied. In poorly
CLINICAL FEATURES
The malignant brous histiocytoma is primarily considered to be a tumor of older age groups. The most
common complaint is an expanding mass that may or
Fig. 12-123 Fibrosarcoma. Cellular mass of spindleshaped cells demonstrating mild pleomorphism.
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may appear normal in color or yellow. Pain or tenderness is uncommon; when present, it is usually a late
feature. The neck is the most common site for liposarcomas of the head and neck region. The most frequent
oral locations are the tongue and cheek.
HISTOPATHOLOGIC FEATURES
Several histopathologic subtypes have been described.
The storiform-pleomorphic type is the most common.
This pattern is characterized by short fascicles of plump
spindle cells arranged in a storiform pattern, admixed
with areas of pleomorphic giant cells (Fig. 12-124).
Myxoid, giant cell, inammatory, and angiomatoid subtypes also have been recognized.
HISTOPATHOLOGIC FEATURES
CLINICAL FEATURES
LIPOSARCOMA
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survival rate ranges from 59% to 70%. There is a 10year survival rate of approximately 50%. The histopathologic subtype is extremely important in predicting the
prognosis; the outlook for pleomorphic liposarcomas is
much worse than for myxoid and well-differentiated
tumors.
In contrast, the prognosis for oral liposarcoma is
more favorable because of the predominance of welldifferentiated subtypes and because most tumors are
small when diagnosed. Local recurrence has been
reported in 15% to 20% of cases, but metastasis and
death as a result of tumor is rare.
HISTOPATHOLOGIC FEATURES
The malignant peripheral nerve sheath tumor shows
fascicles of atypical spindle-shaped cells, which often
resemble the cells of brosarcoma (see Fig. 12-69,
page 531). However, these cells are frequently more
irregular in shape with wavy or comma-shaped nuclei.
In addition to streaming fascicles, less cellular myxoid
areas also may be present. With some tumors, there
can be heterologous elements, which include skeletal
OLFACTORY NEUROBLASTOMA
(ESTHESIONEUROBLASTOMA)
The olfactory neuroblastoma is a rare neuroectodermal neoplasm of the upper nasal vault that shows some
similarities to neuroblastomas seen elsewhere in the
body. Traditionally, it is believed to arise from the olfactory epithelium.
HISTOPATHOLOGIC FEATURES
Olfactory neuroblastomas consist of small, round to
ovoid basophilic cells that are arranged in sheets and
lobules (Fig. 12-127). Rosette and pseudorosette formation and areas of delicate neurobrillary material
may be seen.
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ANGIOSARCOMA
Angiosarcoma is a rare malignancy of vascular endothelium, which may arise from either blood or lymphatic vessels. More than 50% of all cases occur in the
head and neck region, with the scalp and forehead
being the most common sites. Oral lesions are quite
rare.
The term hemangioendothelioma is used to
describe vascular tumors with microscopic features
intermediate between those of hemangiomas and
angiosarcomas. Such tumors also are rare and are considered to be of intermediate malignancy.
CLINICAL FEATURES
Cutaneous angiosarcomas of the head and neck are
most common in older adult patients. Early lesions
often resemble a simple bruise, which may lead to a
delay in diagnosis. However, the lesion continues to
enlarge, which results in an elevated, nodular, or ulcerated surface. Many examples appear multifocal in
nature. Oral angiosarcomas have been reported in
various locations; the tongue and mandible are two of
the more common sites (Fig. 12-128).
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HISTOPATHOLOGIC FEATURES
Angiosarcoma is characterized by an inltrative proliferation of endothelium-lined blood vessels that form
an anastomosing network (Fig. 12-129). The endothelial cells appear hyperchromatic and atypical; they
often tend to pile up within the vascular lumina.
Increased mitotic activity may be seen. Immunohistochemical studies show the tumor cells to be positive for
CD31 and factor VIIIrelated antigen in most cases,
whereas CD34 positivity is observed less consistently.
CLINICAL FEATURES
CLASSIC TYPE
KAPOSIS SARCOMA
Kaposis sarcoma is an unusual vascular neoplasm
that was rst described in 1872 by Moritz Kaposi, a
Hungarian dermatologist. Before the advent of the
acquired immunodeciency syndrome (AIDS) epidemic, it was a rare tumor; however, beginning in the
early 1980s, Kaposis sarcoma became quite common
because of its propensity to develop in individuals
infected by the human immunodeciency virus (HIV).
Since the introduction of highly active antiretroviral
therapy (HAART) in the mid- to late 1990s, the preva-
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ENDEMIC TYPE
Endemic Kaposis sarcoma in Africa has been divided
into four subtypes:
1. A benign nodular type, similar to classic
Kaposis sarcoma
2. An aggressive or inltrative type, characterized
by progressive development of locally invasive
lesions that involve the underlying soft tissues
and bone
3. A orid form, characterized by rapidly progressive and widely disseminated, aggressive lesions
with frequent visceral involvement
4. A unique lymphadenopathic type, occurring
primarily in young black children and exhibiting
generalized, rapidly growing tumors of the lymph
nodes, occasional visceral organ lesions, and
sparse skin involvement
IATROGENIC TYPE
Iatrogenic immunosuppression-associated Kaposis sarcoma most often occurs in recipients of organ
transplants. It affects 0.5% of renal transplant patients,
usually several months to a few years after the transplant. It is probably related to the loss of cellular immunity, which occurs as a result of immunosuppressive
drugs. Like classic Kaposis sarcoma, iatrogenic immunosuppression-associated cases are most common in
individuals of Italian, Jewish, and Slavic ancestry;
however, the disease may run a more aggressive
course.
HISTOPATHOLOGIC FEATURES
Kaposis sarcoma typically evolves through three
stages:
1. Patch (macular)
2. Plaque
3. Nodular
A proliferation of miniature vessels characterizes
the patch stage. This results in an irregular, jagged
vascular network that surrounds preexisting vessels.
Sometimes normal structures, such as hair follicles or
preexisting blood vessels, may appear to protrude into
these new vessels (promontory sign). The lesional
endothelial cells have a bland appearance and may be
associated with scattered lymphocytes and plasma
cells.
The plaque stage demonstrates further proliferation of these vascular channels along with the development of a signicant spindle cell component.
In the nodular stage, the spindle cells increase to
form a nodular tumorlike mass that may resemble a
brosarcoma or other spindle cell sarcomas (Figs.
12-131 and 12-132). However, numerous extrava-
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LEIOMYOSARCOMA
The leiomyosarcoma is a malignant neoplasm of
smooth muscle differentiation, which accounts for 5%
to 10% of all soft tissue sarcomas. The most common
sites are the uterine wall and gastrointestinal tract.
Leiomyosarcomas of the oral cavity are rare.
CLINICAL FEATURES
In general, leiomyosarcomas are most common in
middle-aged and older adults. However, tumors in the
oral and maxillofacial region occur over a wide age
range without a predilection for any age group. They
have been reported at various sites, but half of all oral
cases occur in the jawbones. The clinical appearance
is nonspecic; there is usually an enlarging mass that
may or may not be painful (Fig. 12-133). Secondary
ulceration of the mucosal surface may occur.
HISTOPATHOLOGIC FEATURES
The microscopic examination of a leiomyosarcoma
shows fascicles of spindle-shaped cells with abundant
eosinophilic cytoplasm and blunt-ended, cigar-shaped
RHABDOMYOSARCOMA
Rhabdomyosarcoma is a malignant neoplasm that is
characterized by skeletal muscle differentiation. These
tumors are much more common in young children,
accounting for 60% of soft tissue sarcomas in childhood. In contrast, rhabdomyosarcoma comprises only
2% to 5% of soft tissue sarcomas in adults. The most
frequent site is the head and neck, which accounts for
35% of all cases. The genitourinary tract is the second
most common location. Several microscopic patterns
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Table 12-1
Pediatric Rhabdomyosarcomas
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MAXILLOFACIAL PATHOLOGY
Major Types
Embryonal rhabdomyosarcoma
NOS
Botryoid
Spindle
Alveolar rhabdomyosarcoma
Undifferentiated sarcoma
Anaplastic rhabdomyosarcoma
Distribution
Five-Year Survival
49%
6%
3%
31%
3%
2%
66%
95%
88%
53%
44%
45%
Relative Prognosis
Intermediate
Excellent
Excellent
Poor
Poor
Poor
Adapted from Hicks J, Flaitz C: Rhabdomyosarcoma of the head and neck in children, Oral Oncol 38:450-459, 2002.
NOS, Not otherwise specied.
CLINICAL FEATURES
Rhabdomyosarcoma primarily occurs during the rst
decade of life but also may occur in teenagers
and young adults. It is rare in people older than 45
years, and approximately 60% of all cases occur in
males. Embryonal rhabdomyosarcomas are most
common in the rst 10 years of life and account for
about 60% of all cases. Alveolar rhabdomyosarcomas
occur most often in persons between 10 and 25 years
of age; they account for 20% to 30% of all tumors.
Pleomorphic rhabdomyosarcomas represent less
than 5% of all cases and show a peak prevalence in
patients older than 40 years of age. Most head and
neck lesions are embryonal or alveolar types; pleomorphic rhabdomyosarcomas primarily occur on the
extremities.
HISTOPATHOLOGIC FEATURES
EMBRYONAL TYPE
The embryonal rhabdomyosarcoma resembles various
stages in the embryogenesis of skeletal muscle. Poorly
differentiated examples may be difcult to diagnose
and consist of small round or oval cells with hyperchromatic nuclei and indistinct cytoplasm (Fig. 12-137).
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Fig. 12-137 Embryonal rhabdomyosarcoma. Mediumpower view showing a sheet of small, round cells with
hyperchromatic nuclei.
ALVEOLAR TYPE
Both classic and solid variants of alveolar rhabdomyosarcoma are recognized. The classic pattern is characterized by aggregates of poorly differentiated round to
oval cells separated by brous septa. These cells demonstrate a central loss of cohesiveness, which results in
an alveolar pattern. The peripheral cells of these aggregates adhere to the septal walls in a single layer. The
central cells appear to oat freely within the alveolar
spaces. Mitoses are common, and multinucleated giant
cells also may be seen. In contrast, solid alveolar rhabdomyosarcoma demonstrates cellular elds of small
round basophilic cells without brovascular septa.
Cytogenetic and molecular studies play an important role in the diagnosis of rhabdomyosarcoma. Two
distinct translocations have been identied in alveolar
rhabdomyosarcoma (PAX3-FKHR and PAX7-FKHR).
Embryonal rhabdomyosarcoma is characterized by a
Before 1960 the prognosis for a patient with rhabdomyosarcoma was extremely poor, with more than 90%
of patients dying. With the advent of multimodal
therapy during the past several decades, the prognosis
has improved dramatically.
Treatment typically consists of local surgical excision followed by multiagent chemotherapy (vincristine,
actinomycin D, and cyclophosphamide). Postoperative
radiation therapy also is used, except for localized
tumors that have been completely resected at initial
surgery. The 5-year survival rate for embryonal rhabdomyosarcoma (not otherwise specied [NOS]) is
around 66%, although the gures for botryoid (95%)
and spindle cell variants (88%) are much better. The
5-year survival rate for alveolar rhabdomyosarcoma is
only 53%, and survival drops to slightly less than 50%
for anaplastic rhabdomyosarcoma and undifferentiated sarcomas.
SYNOVIAL SARCOMA
Synovial sarcoma is an uncommon malignancy that
represents 5% to 10% of all soft tissue sarcomas. The
tumor occurs primarily near large joints and bursae,
especially in the extremities, but most authorities now
agree that this lesion probably does not arise from the
synovium. Although it is often para-articular in location, the tumor rarely occurs within the joint capsule.
In some instances, it arises in areas without any obvious
relationship to synovial structures. Synovial sarcomas
of the head and neck are rare (only 4% to 9% of all
cases), and many of these apparently are unrelated to
joint areas.
Over 90% of synovial sarcomas exhibit a specic
balanced reciprocal translocation between the X chromosome and chromosome 18: t(X;18)(p11.2;q11.2).
Detection of this translocation can be helpful in making
the diagnosis, evaluating tumor margins, and conrming the presence of metastatic disease.
CLINICAL FEATURES
Synovial sarcomas most frequently occur in teenagers
and young adults, and there is a slight male predilection. The most common presentation is a gradually
enlarging mass that often is associated with pain or
tenderness. Tumors in the head and neck region are
most common in the paravertebral and parapharyngeal areas. Often, they produce symptoms of dysphagia, dyspnea, or hoarseness. Oral tumors most often
have been reported in the tongue and cheek.
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CLINICAL FEATURES
HISTOPATHOLOGIC FEATURES
Classic synovial sarcoma is a biphasic tumor that consists of a combination of spindle cells and epithelial
cells (Fig. 12-138). The spindle cells usually predominate and produce a pattern that is similar to brosarcoma. Within this spindle cell background are groups
of cuboidal to columnar epithelial cells that surround
glandlike spaces or form nests, cords, or whorls. Calcications are seen in around 30% of cases.
Less frequently, the tumor is monophasic and consists primarily or entirely of spindle cells. The diagnosis
of these tumors is difcult, but most lesions demonstrate at least focal positive immunostaining of spindle
cells for cytokeratin or epithelial membrane antigen.
Rare examples of monophasic epithelial synovial sarcomas also have been reported.
HISTOPATHOLOGIC FEATURES
Alveolar soft-part sarcomas are composed of groups of
large, polygonal cells that are arranged around central
alveolar spaces (Fig. 12-139). These cells have abundant granular, eosinophilic cytoplasm and one to
several vesicular nuclei. Mitoses are rare. Special stains
will reveal PAS-positive, diastase-resistant crystals that
are highly characteristic for this tumor. Under the electron microscope, these crystals appear as rhomboid,
polygonal, or rod-shaped structures with a regular latticework pattern.
Immunohistochemistry has played a limited role in
the specic diagnosis of alveolar soft-part sarcoma,
except to rule out other tumors with more characteristic staining patterns. However, molecular analysis of
fresh tissue may be helpful in difcult cases because
the tumor shows a characteristic genetic translocation,
der(17)t(X;17)(p11.2;q25), which results in an ASPLTFE3 fusion gene. Recently, an antibody against the
C-terminus of the ASPL-TFE3 fusion protein has been
created, allowing the development of a sensitive immunohistochemical marker for this tumor.
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CLINICAL FEATURES
The most common site for oral soft tissue metastases is
the gingiva, which accounts for slightly more than 50%
of all cases. The next most common site is the tongue,
which accounts for 25% of cases. The lesion usually
appears as a nodular mass that often resembles a
hyperplastic or reactive growth, such as a pyogenic
granuloma (Figs. 12-140 to 12-142). Occasionally, the
lesion appears as a surface ulceration. Adjacent teeth
may become loosened by an underlying destruction of
the alveolar bone. The presence of teeth may play an
important role in the preference of metastases for the
gingiva. Once malignant cells reach the oral cavity, the
rich vascular network of inamed gingival tissues may
serve as a fertile site for further growth.
Oral soft tissue metastases are more common in
males and are seen most frequently in middle-aged
and older adults. Almost any malignancy from any
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Fig. 12-142 Metastatic adenocarcinoma of the colon. A, Focal swelling of the left
retromolar pad area. B, Same patient 4 weeks later. Note the marked enlargement of the
lesion. (Courtesy of Dr. George Blozis.)
BIBLIOGRAPHY
however, the oral lesion is the rst sign of the malignant disease.
HISTOPATHOLOGIC FEATURES
The microscopic appearance of the metastatic neoplasm should resemble the tumor of origin (Fig.
12-143). Most cases represent carcinomas; metastatic
sarcomas to the oral region are rare.
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Nikitakis NG, Lopes MA, Bailey JS et al: Oral leiomyosarcoma:
review of the literature and report of two cases with assessment of the prognostic and diagnostic signicance of immunohistochemical and molecular markers, Oral Oncol
38:201-208, 2002.
Sedghizadeh PP, Angiero F, Allen CM et al: Post-irradiation leiomyosarcoma of the maxilla: report of a case in a patient with
prior radiation treatment for retinoblastoma, Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 97:726-731, 2004.
Vilos GA, Rapidis AD, Lagogiannis GD et al: Leiomyosarcomas
of the oral tissues: clinicopathologic analysis of 50 cases,
J Oral Maxillofac Surg 63:1461-1477, 2005.
Rhabdomyosarcoma
Bras J, Batsakis JG, Luna MA: Rhabdomyosarcoma of the oral soft
tissues, Oral Surg Oral Med Oral Pathol 64:585-596, 1987.
Dagher R, Helman L: Rhabdomyosarcoma: an overview, Oncologist 4:34-44, 1999.
Hicks J, Flaitz C: Rhabdomyosarcoma of the head and neck in
children, Oral Oncol 38:450-459, 2002.
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Hematologic Disorders
CHAPTER OUTLINE
Lymphoid Hyperplasia
Hemophilia
Plasminogen Deciency
Anemia
Sickle Cell Anemia
Thalassemia
Aplastic Anemia
Neutropenia
Agranulocytosis
Cyclic Neutropenia
Thrombocytopenia
Polycythemia Vera
Leukemia
Langerhans Cell Histiocytosis
Hodgkins Lymphoma
Non-Hodgkins Lymphoma
Mycosis Fungoides
Burkitts Lymphoma
Extranodal NK/T-Cell Lymphoma, Nasal-type
Multiple Myeloma
Plasmacytoma
LYMPHOID HYPERPLASIA
The lymphoid tissue of the body plays an important
role in the recognition and processing of foreign antigens, such as viruses, fungi, and bacteria. In addition,
the lymphoid tissue has a protective function through
a variety of direct and indirect mechanisms. In responding to antigenic challenges, lymphoid cells proliferate,
thus increasing their numbers, to combat the offending
agent more effectively. This proliferation results in
enlargement of the lymphoid tissue, which is seen
clinically as lymphoid hyperplasia.
CLINICAL FEATURES
Lymphoid hyperplasia may affect the lymph nodes, the
lymphoid tissue of Waldeyers ring, or the aggregates
of lymphoid tissue that are normally scattered throughout the oral cavity, particularly in the oropharynx,
the soft palate, the lateral tongue, and the oor of
the mouth. When lymphoid hyperplasia affects the
lymph nodes, usually the site that the lymph node
drains can be identied as a source of active or recent
infection. In the head and neck region, the anterior
cervical chain of lymph nodes is most commonly
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Fig. 13-2 Lymphoid hyperplasia. The smooth-surfaced
papule of the posterior lateral tongue represents an enlarged
lymphoid aggregate. The lesion exhibits a lighter color as a
result of the accumulation of lymphocytes, which are white
blood cells. (Courtesy of Dr. Dean White.)
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Type
Hemophilia A (classic hemophilia)
Hemophilia B (Christmas disease)
von Willebrands disease
Defect
Inheritance
Findings
X-linked recessive
X-linked recessive
Autosomal dominant
Abnormal PTT
Abnormal PTT
Abnormal BT, abnormal PTT
HEMOPHILIA
Hemophilia (hemo = blood; philia = loving) represents
a variety of bleeding disorders associated with a genetic
deciency of any one of the clotting factors of the blood
(Table 13-1). This condition was common in certain
European royal families, many of whom carried an
X-linked hereditary deciency of either factor VIII or
factor IX. Consequently, as a result of inbreeding, a
signicant proportion of the male members of these
families had hemophilia. In the days before blood
transfusions and clotting factor replacement therapy,
many of these patients died as a direct result of, or from
the complications of, uncontrolled hemorrhage. It is
not known whether these people had factor VIII or
factor IX deciency, because all of the affected individuals died before the denitive diagnostic studies
were developed to determine precisely which deciency was present. Because hemophilia A (factor VIII
deciency) is the most signicant and widely recognized form of hemophilia and accounts for 80% to 85%
of the bleeding diatheses associated with a specic
clotting factor deciency, most of this discussion
centers on that entity. Its estimated prevalence in the
United States is 1 in 10,000 persons (or 1 in 5000
males).
As previously mentioned, a deciency of factor IX
or hemophilia B (Christmas disease) also may be
encountered. Hemophilia B is similar to hemophilia A
in its presentation, being transmitted in an X-linked
fashion. Hemophilia B is much less common than
hemophilia A, occurring with a prevalence of 1 in
60,000 (or 1 in 30,000 males). The term Christmas
disease was obtained from the surname of the rst
person, a Canadian boy, who was identied as having
hemophilia B in 1952.
Another clotting disorder that is sometimes seen,
von Willebrands disease, is the result of a genetic
deciency of a plasma glycoprotein called von Willebrands factor. This glycoprotein aids in the adhesion
of platelets at a site of bleeding, and it also binds to
factor VIII, acting as a transport molecule. Von Willebrands disease is a genetically heterogeneous condi-
CLINICAL FEATURES
Hemophilia A is an X-linked disorder. Females typically carry the trait, but it is expressed primarily in
males. Approximately 1 in 5000 males is born with
this genetic disease, with about 30% of the cases representing new mutations. Failure of normal hemostasis
after circumcision is typically one of the rst signs that
a bleeding disorder is present.
The severity of the bleeding disorder depends on the
extent of the clotting factor deciency. Hemophilia A
is a heterogeneous disorder that is caused by any one
of a variety of mutations associated with the gene for
factor VIII. Because the mutations occur at different
sites in the factor VIII gene (more than 900 different
mutations have been identied), a clinical spectrum of
deciency of factor VIII is seen. This results in varying
degrees of disease expression, with those mutations
affecting more signicant or larger portions of the
factor VIII gene causing more severe clinical disease.
Not all patients have an absolute lack of the particular
clotting factor; rather, the deciency may be a percentage of the normal value in a given patient. For example,
a patient with only 25% of normal factor VIII levels
may be able to function normally under most circumstances; one with less than 5% commonly manifests a
marked tendency to bruise with only minor trauma.
In infants, oral lacerations and ecchymoses that
involve the lips and tongue are a frequent occurrence
as a result of the common falls and bumps experienced
by this age group. If not treated appropriately, then
such lacerations may result in signicant blood loss in
more severely affected patients. Sometimes deep hemorrhage occurs during normal activity and may involve
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for many of these patients. Cryoprecipitation, the traditional method of concentrating clotting factors from the
serum, also resulted in the concentration of several
viruses, including the hepatitis viruses and human
immunodeciency virus (HIV). Currently more than
40% of hemophilia A and B patients in the United States
are estimated to be infected with hepatitis C virus. In
addition, as many as 80% to 90% of hemophiliac patients
treated with multiple doses of factor VIII cryoprecipitate were infected with HIV. The methods of preparing
the clotting factors have been modied to eliminate the
risk of acquiring HIV from the preparation; however,
many hemophiliac patients who were infected developed acquired immunodeciency syndrome (AIDS).
Recombinant DNA technology now provides a source
of factor VIII that is manufactured by inserting the
human factor VIII gene into bacteria that then synthesize the protein. Therefore, this product can now be
manufactured without contamination by any viral
organisms, and young people affected by hemophilia
have minimal risk of contracting these infections.
Other problems must occasionally be confronted,
however. Approximately 6% of patients with hemophilia A may develop antibodies directed against factor
VIII, and this is a very serious complication. Because
the antibodies react with the factor VIII molecule, the
result is an inhibition of the activity of the clotting
factor, and these patients are once more faced with the
prospect of uncontrolled bleeding. Patients with factor
IX deciency can develop similar inhibitory antibodies
to factor IX, but this appears to occur much less frequently. Attempts to induce immune tolerance may
help some individuals, although more immediate care
has generally centered on bypassing the factor VIII
related portion of the clotting cascade by administration of recombinant factor VIIa. Research has shown
this approach to be effective, although costly.
PLASMINOGEN DEFICIENCY
(LIGNEOUS CONJUNCTIVITIS;
HYPOPLASMINOGENEMIA)
Plasminogen deciency is a rare autosomal recessive
condition that is caused by any one of several mutations of the gene responsible for the production of plasminogen, the precursor to plasmin. In the clotting
cascade, factors are activated that lead to the development of a clot; however, simultaneously serum proteins
such as plasminogen are converted to plasmin, which
is responsible for degrading the clot. Without the formation of plasmin, the clot tends to grow and persist
despite having performed its original hemostatic function. The result of plasminogen deciency is a buildup
of brin, deposited as irregular plaques and nodules
that primarily affect mucosal surfaces. Involvement of
the conjunctival mucosa is characterized by the formation of thick, rm plaques, for which the term ligneous
conjunctivitis has been used (ligneous means woodlike).
Even though this condition was initially described in
the nineteenth century, it was during the late 1990s
that an explanation for the majority of these cases was
provided. Similar lesions have been produced in mice
that have been genetically manipulated to create
knock-out mutations of the plasminogen gene.
CLINICAL FEATURES
The most striking aspect of plasminogen deciency is
the development of thick, creamy yellow to erythematous, rm plaques and nodules involving primarily the
conjunctival mucosa of the upper eyelid. Typically the
condition is detected during the rst decade of life, but
lesions can develop later as well. Even though this is an
autosomal recessive condition, there is a tendency for
the disease to present more often in women, although
the reason for this is unknown.
In addition to the conjunctival lesions, other mucosal
surfaces can be affected, including the oral mucosa,
laryngeal mucosa, and vaginal mucosa. In a recent
series of 50 patients with this condition, ocular lesions
were documented in 80%, gingival lesions in 34%,
respiratory tract lesions in 16%, and vaginal lesions in
8%. Laryngeal mucosal involvement often includes the
vocal cords, which will typically cause a raspy, hoarse
voice.
Oral lesions of plasminogen deciency primarily
involve the gingivae, presenting as patchy ulcerated
papules and nodules with a very irregular surface (Fig.
13-6). These lesions may be few in number or distributed diffusely in all quadrants, and they tend to wax
and wane in severity.
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ANEMIA
HISTOPATHOLOGIC FEATURES
The microscopic features of the lesions associated with
this condition can be very confusing for the pathologist
who is not familiar with the disease. The accumulation
of brin appears as diffuse sheets of acellular eosinophilic material that bears a close resemblance to
amyloid (Fig. 13-7). Special stains for amyloid (such
as Congo red) are negative, however, because this
material represents brin. Conrmation that the
eosinophilic material is brin can be done using the
Fraser-Lendrum histochemical staining method. Variable numbers of inammatory cells are seen, and
granulation tissue is usually seen adjacent to the brin
deposits.
CLINICAL FEATURES
The symptoms of anemia are typically related to the
reduced oxygen-carrying capacity of the blood, which
is a result of the reduced numbers of erythrocytes.
Symptoms such as tiredness, headache, or lightheadedness are often present.
Pallor of the mucous membranes may be observed
in severe cases of anemia. The palpebral conjunctiva is
often the site where this paleness is most easily appreciated, but the oral mucosa may show similar signs.
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Box 13-1
Causes of Anemia
ANEMIAS WITH DISTURBED IRON METABOLISM
Iron deciency anemia
Sideroblastic anemias
MEGALOBLASTIC ANEMIAS
Cobalamin (B
12) deciency (pernicious anemia)
Folic acid deciency
ANEMIA ASSOCIATED WITH CHRONIC DISORDERS
Anemia of chronic infection (infective endocarditis,
tuberculosis, osteomyelitis, lung abscess,
pyelonephritis)
Anemia of inammatory connective tissue disorders
(rheumatoid arthritis, lupus erythematosus, sarcoidosis, temporal arteritis, regional enteritis)
Anemia associated with malignancy
Secondary to chronic bleeding
Myelophthisic anemia
Anemia of uremia
Anemia of endocrine failure
Anemia of liver disease
HEMOLYTIC ANEMIAS
Extrinsic causes
Splenomegaly
Red cell antibodies
Trauma in the circulation
Direct toxic effects (various microorganisms,
copper salts, venom of certain snakes)
Membrane abnormalities
Spur cell anemia
Paroxysmal nocturnal hemoglobinuria
Hereditary spherocytosis
Hereditary elliptocytosis
Disorders of the interior of the red cell
Defects in the Embden-Meyerhof pathway
Defects in the hexose monophosphate shunt
DISORDERS OF HEMOGLOBIN
Sickle cell anemia
Thalassemias
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HISTOPATHOLOGIC FEATURES
In homozygous sickle cell disease, a peripheral blood
smear shows a peculiar curved distortion of the erythrocytes, resembling a sickle or boomerang shape.
THALASSEMIA
Thalassemia represents a group of disorders of hemoglobin synthesis that are characterized by reduced synthesis of either the -globin or -globin chains of the
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a-THALASSEMIA
Because four -globin genes may be affected, a-thalassemia has a broader spectrum of involvement than
does -thalassemia.
With the alteration of only one gene, no disease can
be detected. With the inheritance of two altered genes,
the condition is known as a-thalassemia trait. These
patients have a mild degree of anemia and microcytosis that is usually not clinically signicant. With three
altered genes, the term hemoglobin H (HbH) disease
is applied. Patients have problems with hemolytic
anemia and splenomegaly. For patients with severe
hemolysis, splenectomy may be indicated.
The homozygous state, in which all four genes are
abnormal, causes severe generalized fetal edema, a
condition that has been termed hydrops fetalis.
Hydrops fetalis is not specic for -thalassemia and
can be seen as a manifestation of other diseases, such
as severe Rh incompatibility. Infants with -thalassemia who are affected by this problem typically die
within a few hours of birth.
APLASTIC ANEMIA
Aplastic anemia is a rare, life-threatening hematologic disorder that is characterized by failure of the
hematopoietic precursor cells in the bone marrow to
produce adequate numbers of all types of blood cells.
A signicant amount of evidence supports the concept
that most cases of aplastic anemia represent an
immune-mediated disease caused by cytotoxic T lymphocytes that target differentiating hematopoietic cells
in the marrow. As a result, the hematopoietic stem cells
do not seem to undergo normal maturation despite
normal or increased levels of cytokines, such as granulocyte-macrophage colony-stimulating factor (GMCSF), which normally induce the production and
maturation of several types of white blood cells.
Although the underlying trigger for the immunemediated destruction of the hematopoietic cells is
unknown, some cases of aplastic anemia are associated
with exposure to certain environmental toxins (e.g.,
benzene), treatment with certain drugs (especially the
antibiotic chloramphenicol), or infection with certain
viruses (particularly non-A, non-B, non-C, non-G
hepatitis). It is possible that the abnormal immune
response is perhaps initiated by such exogenous stimuli
in certain instances. A few genetic disorders, such as
Fanconis anemia and dyskeratosis congenita (see
page 746), also are associated with an increased frequency of aplastic anemia.
CLINICAL FEATURES
Because all of the formed elements of the blood are
decreased in patients with aplastic anemia, the initial
symptoms may be related to any one or several of the
deciencies. The erythrocyte deciency produces signs
and symptoms related to a decreased oxygen-carrying
capacity of the blood; therefore, patients may experience fatigue, lightheadedness, tachycardia, or weakness. The platelet deciency (thrombocytopenia) is
seen as a marked tendency for bruising and bleeding,
which affects a variety of sites. Retinal and cerebral
hemorrhages are some of the more devastating manifestations of this bleeding tendency. Deciency of
white blood cells (neutropenia, leukopenia, or granulo-
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HISTOPATHOLOGIC FEATURES
A bone marrow biopsy specimen usually demonstrates
a relatively acellular marrow with extensive fatty inltration. The histopathologic features of an oral ulceration in a patient with aplastic anemia show numerous
microorganisms in addition to a remarkable lack of
inammatory cells in the ulcer bed.
DIAGNOSIS
The diagnosis of aplastic anemia is usually established
by laboratory studies. A pancytopenia is characterized
by at least two of the following ndings:
Fewer than 500 granulocytes/L
Fewer than 20,000 platelets/L
Fewer than 20,000 reticulocytes/L
NEUTROPENIA
Neutropenia refers to a decrease in the number of the
circulating neutrophils below 1500/mm3 in an adult.
It is often associated with an increased susceptibility of
the patient to bacterial infections. Clinicians must be
aware of this disorder because infection of the oral
mucosa may be the initial sign of the disease. Interestingly, several ethnic groups, including patients of
African and Middle Eastern background, will consistently have neutrophil counts that would qualify as
neutropenia (as low as 1200/mm3), yet these individuals are otherwise healthy. This nding has been termed
benign ethnic neutropenia, and it appears to have no
effect on the health of the patient because neutrophil
counts respond to bacterial challenge.
A decrease in neutrophils may be precipitated by
several mechanisms, most of which involve decreased
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CLINICAL FEATURES
Most patients with neutropenia have some form of bacterial infection rather than a viral or fungal infection,
particularly if the other elements of the immune system
(lymphocytes, plasma cells, and monocytes) are still
intact. Staphylococcus aureus and gram-negative organisms seem to cause the most problems for patients
with neutropenia. The suppuration and abscess formation normally associated with such infections may be
markedly reduced because of the lack of neutrophils.
The most common sites of infection include the middle
ear, the oral cavity, and the perirectal area. When
neutrophil counts drop below 500/mm3, however, pulmonary infections often develop.
The oral lesions of neutropenia consist of ulcerations
that usually involve the gingival mucosa, probably
because of the heavy bacterial colonization of this
area and the chronic trauma that it receives. These
ulcers characteristically lack an erythematous periphery, although this nding has been variable. Premature
periodontal bone loss with exfoliation of the deciduous
dentition has been described.
HISTOPATHOLOGIC FEATURES
A biopsy specimen of a neutropenic ulceration usually
shows a reduced number or the absence of neutrophils. Bacterial invasion of the host tissue may be
apparent in some instances.
AGRANULOCYTOSIS
Agranulocytosis is a condition in which the cells of
the granulocytic series, particularly neutrophils, are
absent. As in other disorders of the formed elements of
the blood, agranulocytosis may occur as a result of
decreased production or increased destruction or use
of these cells. Although some cases are idiopathic, most
are induced by exposure to one of several drugs. Some
drugs, such as the anticancer chemotherapeutic agents,
induce agranulocytosis by inhibiting the normal mitotic
division and maturation of the hematopoietic stem
cells. In other instances, the drugs trigger an immuno-
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logic reaction that results in the destruction of granulocytes. Rarely, agranulocytosis may be a congenital
syndrome (congenital agranulocytosis, Kostmann
syndrome) that results from a decreased level of
the cytokine granulocyte colony-stimulating factor
(G-CSF).
CLINICAL FEATURES
Agranulocytosis typically develops within a few days
after a person ingests the offending drug. Because of
the lack of granulocytes (especially neutrophils), bacterial infections often develop and patients may show
signs and symptoms of malaise, sore throat, swelling,
fever, chills, bone pain, pneumonia, and shock. The
erythrocyte and platelet counts are usually normal or
only slightly depressed.
Oral lesions are common and include necrotizing,
deep, punched-out ulcerations of the buccal mucosa,
tongue, and palate. The gingivae are especially susceptible to infection, often resembling the pattern of necrotizing ulcerative gingivitis (NUG) (see page 157).
HISTOPATHOLOGIC FEATURES
Microscopic examination of a biopsy specimen from
one of the oral ulcerations in agranulocytosis characteristically shows abundant bacterial organisms, both
on the surface and within the tissue. The host inammatory response is relatively sparse, with few granulocytes, particularly neutrophils, seen in the ulcer bed.
DIAGNOSIS
The diagnosis of cyclic neutropenia should be established by sequential complete blood counts (typically
two to three times per week for 8 weeks) to determine
whether cycling of the neutrophil levels occurs. The
neutrophil count should be less than 500/mm3 for 3 to
5 days during each of at least three successive cycles to
make this diagnosis.
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THROMBOCYTOPENIA
Thrombocytopenia is a hematologic disorder that is
characterized by a markedly decreased number of circulating blood platelets (formed elements derived from
megakaryocyte precursors in the bone marrow). Platelets are necessary for hemostasis and clot formation. A
platelet count of 200,000 to 400,000/mm3 is considered normal. The decrease in platelets may be the
result of the following:
Reduced production
Increased destruction
Sequestration in the spleen
HISTOPATHOLOGIC FEATURES
The histopathologic features of cyclic neutropenia are
similar to those of the other neutropenic and granulocytopenic ulcerations if the biopsy is performed during
the nadir of the neutrophil count.
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CLINICAL FEATURES
Clinical evidence of thrombocytopenia is not usually
seen until the platelet levels drop below 100,000/mm3.
The severity of involvement is directly related to the
extent of platelet reduction. The condition often is initially detected because of the presence of oral lesions.
Minor traumatic events are continuously inicted on
the oral mucosa during chewing and swallowing of
food. The small capillaries that are damaged during
this process are normally sealed off with microscopic
thrombi. In a patient with thrombocytopenia, however,
the thrombi do not form properly. This results in a
leakage of blood from the small vessels. Clinically, this
usually produces pinpoint hemorrhagic lesions known
as petechiae. If a larger quantity of blood is extravasated, then an ecchymosis or bruise results (Fig.
13-14). With even larger amounts of extravasated
blood, a hematoma (hemat = blood; oma = tumor) will
develop (Fig. 13-15). Spontaneous gingival hemorrhage often occurs in these patients, as does bleeding
from sites of minor trauma.
Similar hemorrhagic events occur throughout the
body. With severe thrombocytopenia (<10,000 plate-
HISTOPATHOLOGIC FEATURES
Gingival biopsy may be performed for diagnostic purposes in patients with suspected TTP. Approximately
30% to 40% of such biopsy specimens show the presence of brin deposits in the small vessels. These
deposits are more readily appreciated after staining the
tissue section using the periodic acid-Schiff (PAS)
method.
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corticosteroid therapy may be necessary if life-threatening hemorrhage occurs. As mentioned earlier, ITP
often resolves spontaneously, but those cases that are
more severe may require corticosteroid therapy or
intravenous immunoglobulin (IVIG) therapy. For some
forms of thrombocytopenia, such as TTP, the patients
prognosis is relatively guarded. In the past, the condition was almost uniformly fatal, although the outlook
has improved since therapy with plasmapheresis or
plasma exchange transfusions became available. More
than 70% of these patients now survive with proper
treatment.
CLINICAL FEATURES
Polycythemia vera typically affects older adults. The
median age at diagnosis is 60 years. Only 5% of cases
are diagnosed before the age of 40 years. No sex predilection is seen, and the annual incidence estimates
of the condition have ranged widely, from 0.2 to 28.0
cases per million population. Recent evidence suggests
that an acquired mutation of one of the tyrosine kinase
genes, Janus kinase 2 (JAK2), may play a signicant
role in the development of this disorder, because more
than 95% of patients with polycythemia vera have
been shown to have this mutation.
The initial symptoms of the disease are nonspecic
and include the following:
Headache
Weakness
Dizziness
Drowsiness
Visual disturbances
Sweating
Weight loss
Dyspnea
Epigastric pain
A ruddy complexion may be evident on physical
examination. One relatively characteristic complaint,
described in about 40% of affected patients, is that of
generalized pruritus (itching), particularly after bathing,
without evidence of a rash.
The problems caused by thrombus formation, which
would be expected with the increased viscosity of the
blood and the increased platelet numbers, include
transient ischemic attacks, cerebrovascular accidents,
and myocardial infarctions. Hypertension and splenomegaly are also common.
A peculiar peripheral vascular event called erythromelalgia affects the hands and feet. Patients experience a painful burning sensation accompanied by
erythema and warmth. This may eventually lead to
thrombotic occlusion of the vessels that supply the
digits. Digital gangrene and necrosis may result. Erythromelalgia is probably caused by excessive platelets,
and its onset seems to be precipitated by exercise,
standing, or warm temperatures.
Strangely enough, these patients may also have
problems with excess hemorrhage. Epistaxis and ecchymoses are often a problem, and gingival hemorrhage
has been described.
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LEUKEMIA
Leukemia represents several types of malignancies of
hematopoietic stem cell derivation. The disease begins
with the malignant transformation of one of the stem
cells, which initially proliferates in the bone marrow
and eventually overows into the peripheral blood of
the affected patient. Problems arise when the leukemic
cells crowd out the normal defense cell and erythrocyte precursors. In the United States, approximately
2.5% of all cancers are leukemia, and 3.9% of deaths
from cancer can be attributed to this disease.
Leukemias are usually classied according to their
histogenesis and clinical behavior. Therefore, the broad
categories would be acute or chronic (referring to the
clinical course) and myeloid or lymphocytic/lymphoblastic (referring to the histogenetic origin).
Myeloid leukemias can differentiate along several different pathways; thus they produce malignant cells that
usually show features of granulocytes or monocytes,
and less frequently, erythrocytes or megakaryocytes.
Acute leukemias, if untreated, run an aggressive
course and often result in the death of the patient
within a few months. Chronic leukemias tend to follow
a more indolent course, although the end result is the
same. One of the greatest successes in cancer treatment has been achieved in acute lymphoblastic leukemia of childhood, a condition that used to be uniformly
fatal but now is often capable of being controlled.
Leukemias are probably the result of a combination
of environmental and genetic factors. Certain syndromes are associated with an increased risk. These
genetic disorders include the following:
Down syndrome
Bloom syndrome
Neurobromatosis type I
Schwachman syndrome
Ataxia-telangiectasia syndrome
Klinefelter syndrome
Fanconis anemia
Wiskott-Aldrich syndrome
In addition, certain types of leukemia show specic
chromosomal abnormalities. The rst chromosomal
abnormality to be detected was found in patients with
chronic myeloid leukemia, and this malignancy was
characterized by a genetic alteration called the Philadelphia chromosome. This abnormality represents a
translocation of the chromosomal material between
the long arms of chromosomes 22 and 9. This rearrangement of the genetic material occurs in such a
CLINICAL FEATURES
If all types of leukemia are considered, this condition
occurs at a rate of 13 cases per 100,000 population
annually. Slightly more males than females are affected.
The myeloid leukemias generally affect an adult population; acute myeloid leukemia affects a broader
age range, which includes children. Chronic myeloid
leukemia shows a peak incidence during the third
and fourth decades of life. Acute lymphoblastic
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leukemia, in contrast, occurs predominantly in children and represents one of the more common childhood malignancies. Chronic lymphocytic leukemia,
the most common type of leukemia, primarily affects
older adults.
Many of the clinical signs and symptoms of leukemia
are related to the marked reduction in the numbers of
normal white and red blood cells, a phenomenon that
results from the crowding out of the normal hematopoietic stem cells by the malignant proliferation (myelophthisic anemia). Because of the reduced red blood
cell count and subsequent reduction in oxygen-carrying
capacity of the blood, patients complain of fatigue, easy
tiring, and dyspnea on mild exertion. The malignant
cells may also inltrate other organs and often cause
splenomegaly, hepatomegaly, and lymphadenopathy.
Leukemic patients may also complain of easy bruising and bleeding, problems that are caused by a lack
of blood platelets (thrombocytopenia), the result of
megakaryocytes being crowded out of the marrow.
Petechial hemorrhages of the posterior hard palate and
the soft palate may be observed, and these may be
accompanied by spontaneous gingival hemorrhage,
especially with platelet counts less than 10,000 to
20,000/mm3. Because disturbances in stem cell differentiation accompany the myelodysplasia syndromes,
thrombocytopenia is often present in these patients,
and gingival hemorrhage has been reported in this
setting. Serious hemorrhagic complications may result
from bleeding into the central nervous system or the
lungs.
A fever associated with infection may be the initial
sign of the leukemic process. Perirectal infections,
pneumonia, urinary tract infections, and septicemia
are common infectious complications. The microorganisms that are typically involved include gramnegative bacteria, gram-positive cocci, and certain
Candida species.
Ulceration of the oral mucosa is often present as a
result of the impaired ability of the host to combat the
normal microbial ora. Usually, the gingival mucosa is
the most severely affected because of the abundant
bacteria normally present around the teeth. The neutropenic ulcers that are produced are typically deep,
punched-out lesions with a gray-white necrotic base.
Oral candidiasis is often a complication of leukemia,
involving the oral mucosa diffusely. Herpetic infections
are the most common viral lesions, and these may
involve any area of the oral mucosa rather than being
conned to the keratinized mucosa, as in immunocompetent patients.
Occasionally, the leukemic cells inltrate the oral
soft tissues and produce a diffuse, boggy, nontender
swelling that may or may not be ulcerated. This occurs
most frequently with the myelomonocytic types of leu-
kemia, and it may result in diffuse gingival enlargement (Figs. 13-16 and 13-17) or a prominent tumorlike
growth (Fig. 13-18). The tumorlike collection of leukemic cells is known as granulocytic sarcoma or extramedullary myeloid tumor, and historically the term
chloroma has been used because it is often greenish
(chlor = green; oma = tumor) on fresh-cut sections.
Other oral manifestations include inltration of the
periapical tissues, simulating periapical inammatory
disease both clinically and radiographically.
HISTOPATHOLOGIC FEATURES
Microscopic examination of leukemia-affected tissue
shows diffuse inltration and destruction of the normal
host tissue by sheets of poorly differentiated cells with
either myelomonocytic characteristics or lymphoid
features.
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DIAGNOSIS
The diagnosis is usually established by conrming the
presence of poorly differentiated leukemic cells in the
peripheral blood and bone marrow. Bone marrow
biopsy is normally performed in conjunction with the
peripheral blood studies because some patients may go
through an aleukemic phase in which the atypical cells
are absent from the circulation. Classifying the type of
leukemia requires establishing the immunophenotype
by using immunohistochemical markers to identify cell
surface antigens expressed by the tumor cells. Immunohistochemical conrmation of certain characteristic
enzymes (e.g., myeloperoxidase, lysozyme) is necessary
to identify and classify the myeloid leukemias. In addition, cytogenetic and molecular characterization of the
lesional cells is typically necessary. In many cases, the
results of these various studies will be signicant
because the patients prognosis is directly affected.
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HISTOPATHOLOGIC FEATURES
The bone lesions of patients with Langerhans cell histiocytosis show a diffuse inltration of large, pale-staining mononuclear cells that resemble histiocytes. These
cells have indistinct cytoplasmic borders and rounded
or indented vesicular nuclei. Varying numbers of
eosinophils are typically interspersed among the histiocyte-like cells (Fig. 13-22). Plasma cells, lymphocytes,
and multinucleated giant cells are often seen, and areas
of necrosis and hemorrhage may be present.
The identication of lesional Langerhans cells is
necessary to conrm the diagnosis. Because Langerhans cells cannot be differentiated from other histiocytes by routine histologic staining, additional diagnostic
methods are required. Electron microscopic evaluation of lesional tissue has been the gold standard for
many years because, ultrastructurally, Langerhans cells
contain rod-shaped cytoplasmic structures known as
Birbeck granules, which differentiate them from
other mononuclear phagocytes (Fig. 13-23). Most laboratories now rely on immunohistochemical procedures
to identify the lesional Langerhans cells because of
their immunoreactivity with antibodies directed against
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the apparent spontaneous regression of localized Langerhans cell histiocytosis has been reported. The prognosis for bone lesions in the absence of signicant
visceral involvement is generally good; however, progression or dissemination of the disease may occur,
particularly for patients who have three or more bones
affected.
Chronic disseminated disease is often associated
with considerable morbidity, but few patients die as a
result of the disease. Because of the relative rarity of
disseminated cases, the ideal treatment has yet to be
identied. Single-agent chemotherapy using prednisolone, etoposide, vincristine, or cyclosporine has produced a good response in a signicant percentage of
such patients, although recurrence is typically seen in
over half of the cases. A combination of vincristine and
prednisone seems to reduce this risk of recurrence.
The acute disseminated form of the disease seen in
infants and young children may not respond to these
more conservative approaches, and multiple chemotherapeutic agents are given in that situation. Diffuse
involvement with compromise of multiple organs is
associated with a poor prognosis and is often fatal. In
general, the prognosis is poorer for patients in whom
the rst sign of the disease develops at a very young age
and somewhat better for patients who are older at the
time of onset.
HODGKINS LYMPHOMA
(HODGKINS DISEASE)
Fig. 13-23 Langerhans cell histiocytosis. Electron
micrograph showing rod-shaped Birbeck bodies (black arrows)
in the cytoplasm of a Langerhans cell. (Courtesy of Richard
Geissler.)
Hodgkins lymphoma represents a malignant lymphoproliferative disorder, although for many years the
exact nature of the process was poorly understood. The
difculty in comprehending the character of the condition is reected in the relatively noncommittal term
Hodgkins disease, which was used for decades and still
may be heard today. Perhaps one reason why Hodgkins lymphoma was not easily understood is that,
unlike most malignancies, the neoplastic cells (ReedSternberg cells) make up only about 1% to 3% of the
cells in the enlarged lymph nodes that characterize this
condition. Current evidence regarding the histogenesis
of the Reed-Sternberg cell points to a B-lymphocyte
origin. Certainly, the disease can cause death if appropriate therapy is not instituted, although the treatment
of this malignancy is one of the few major success
stories in cancer therapy during the past 20 years. In
the United States, Hodgkins lymphoma is about one
sixth as common as non-Hodgkins lymphoma; approximately 8000 cases are diagnosed annually. Although
the cause of this disease is unknown, epidemiologic
and molecular studies have linked Epstein-Barr virus
(EBV) infection to a signicant percentage of these
lesions.
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CLINICAL FEATURES
Hodgkins lymphoma almost always begins in the
lymph nodes, and any lymph node group is susceptible.
The most common sites of initial presentation are the
cervical and supraclavicular nodes (70% to 75%) or the
axillary and mediastinal nodes (5% to 10% each).
The disease initially appears less than 5% of the time in
the abdominal and inguinal lymph nodes.
Overall, a male predilection is observed, and a
bimodal pattern is noted with respect to the patients
age at diagnosis. One peak is observed between 15 and
35 years of age; another peak is seen after the age of
50.
The usual presenting sign is the identication by the
patient of a persistently enlarging, nontender, discrete
mass or masses in one lymph node region (Fig. 13-24).
In the early stages, the involved lymph nodes are often
rather movable; as the condition progresses, the nodes
become more matted and xed to the surrounding
tissues. If it is untreated, then the condition spreads to
other lymph node groups and eventually involves the
spleen and other extralymphatic tissues, such as bone,
liver, and lung. Oral involvement has been reported,
but it is rare. In about 30% of patients with Hodgkins
disease, other systemic signs and symptoms may be
HISTOPATHOLOGIC FEATURES
Hodgkins lymphoma is recognized to comprise two
main forms, (1) nodular lymphocytepredominant
Hodgkins lymphoma and (2) classical Hodgkins lymphoma, the latter of which is divided into ve subtypes.
Although this group of diseases has certain features in
common, current immunohistochemical and molecular biologic techniques have allowed distinctions to be
made among the various types. The common features
include effacement of the normal nodal architecture
by a diffuse, often mixed, inltrate of inammatory
cells that is interspersed with large, atypical neoplastic
lymphoid cells. In the case of classical Hodgkins
lymphoma, this atypical cell is known as a ReedSternberg cell (Fig. 13-25). The Reed-Sternberg cell
is typically binucleated (owl-eye nuclei), although it
may be multinucleated (pennies on a plate), with
prominent nucleoli. The malignant cell in nodular lymphocytepredominant Hodgkins lymphoma is the
popcorn cell, which is so-named because of the
resemblance of the nucleus to a kernel of popped corn.
The pathologist must see one of these types of distinctive atypical cells to make a diagnosis of Hodgkins
lymphoma, although their presence does not automatically imply that diagnosis, because similar cells may be
seen in certain viral infections, especially infectious
mononucleosis. To summarize, Hodgkins lymphoma
is currently classied in the following manner:
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Stage
Dening Features
I
II
Involvement of a single lymph node region (I) or a single extralymphatic organ or site (IE)
Involvement of two or more lymph node regions on the same side of the diaphragm (II) or one or more lymph
node regions with an extralymphatic site (IIE)
Involvement of lymph node regions on both sides of the diaphragm (III), possibly with an extralymphatic organ
or site (IIIE), the spleen (IIIS), or both (IIISE)
Diffuse or disseminated involvement of one or more extralymphatic organs (identied by symbols), with or
without associated lymph node involvement
A: Absence of systemic signs
B: Presence of fever, night sweats, and/or unexplained loss of 10% or more of body weight during the 6month period before diagnosis
III
IV
Adapted from DeVita VT, Hubbard SM: Hodgkins disease, N Engl J Med 328:560-565, 1993.
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NON-HODGKINS LYMPHOMA
The non-Hodgkins lymphomas include a diverse
and complex group of malignancies of lymphoreticular
histogenesis and differentiation. In most instances,
they initially arise within lymph nodes and tend to
grow as solid masses. This is in contrast to lymphocytic
leukemias (see page 587), which begin in the bone
marrow and are characterized by a large proportion of
malignant cells that circulate in the peripheral blood.
The non-Hodgkins lymphomas most commonly originate from cells of the B-lymphocyte series, with an
estimated 85% of European and American lymphoid
neoplasms having this derivation. Tumors with a T-
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Box 13-2
REAL, Revised European-American Lymphoma; WHO, World Health Organization; NK, natural killer.
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Lymphoma of bone may cause vague pain or discomfort, which might be mistaken for a toothache. The
patient may complain of paresthesia, particularly with
a mandibular lesion (so-called numb chin syndrome).
Radiographs usually show an ill-dened or ragged
radiolucency, although in the early stages, the radiographic changes may be subtle or nonexistent. If
untreated, then the process typically causes expansion
of the bone, eventually perforating the cortical plate
and producing a soft tissue swelling. Such lesions have
been mistaken for a dental abscess, although a signicant amount of pain is not present in most cases.
Clinical staging to determine the extent to which the
disease has spread is an important factor in assessing
the prognosis for a particular patient. The staging evaluation should include a history, physical examination,
complete blood count, liver function studies, routine
chest radiographs, CT scans of the pelvic and abdominal regions, lymphangiography, and bone marrow
biopsy. The staging system for Hodgkins lymphoma
(see Table 13-2) has been widely adopted for use with
the non-Hodgkins lymphomas.
HISTOPATHOLOGIC FEATURES
Fig. 13-27 Non-Hodgkins lymphoma. One of the
frequent locations of extranodal lymphoma in the head and
neck area is the palate, where the tumor appears as a
nontender, boggy swelling. Note the overlying telangiectatic
blood vessels, a feature often seen with malignancy.
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sidered incurable, new treatments are being investigated. Most of these lesions are of B-cell differentiation,
so treatment strategies using monoclonal antibodies
directed against CD20, a B-cell surface antigen, are
now being evaluated. Rituximab is one of the agents
being examined in clinical trials.
For the intermediate-grade and high-grade lymphomas, the treatment of localized disease consists of
radiation plus chemotherapy. With more advanced
and disseminated disease, chemotherapy alone usually
is implemented. Multiagent chemotherapy is used routinely, and new combinations are being evaluated continuously. Unfortunately, although the response rate of
many lesions is good and much progress has been
made in this area, the cure rate is not high. For intermediate-grade lesions, a failure rate of 30% to 50% can
be expected. High-grade lymphomas are associated
with a 60% mortality rate at 5 years after diagnosis and
treatment.
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CLINICAL FEATURES
Mycosis fungoides is a condition that usually affects
middle-aged adult men; there is a 2:1 male-to-female
ratio and a mean age at diagnosis of 55 to 60 years. The
disease progresses through three stages, usually over
the course of several years.
The rst stage, known as the eczematous (erythematous) stage, is often mistaken for psoriasis of the
skin because of the well-demarcated, scaly, erythematous patches that characterize these lesions. Patients
may complain of pruritus. With time, the erythematous
patches evolve into slightly elevated, red lesions
(plaque stage). These plaques tend to grow and
become distinct papules and nodules. At this time, the
disease has entered the tumor stage (Fig. 13-31). Visceral involvement is also seen at this point.
Approximately 35 cases of mycosis fungoides with
oral involvement have been reported. The most commonly affected sites are the tongue, hard and soft
palates, and gingiva (Fig. 13-32). The buccal mucosa,
tonsils, lips, sinuses, and nasopharynx may also be
affected. The oral lesions present as erythematous,
indurated plaques or nodules that are typically ulcerated. Generally, these lesions appear late in the course
of the disease and develop after the cutaneous lesions.
Szary syndrome is an aggressive expression of
mycosis fungoides that essentially represents a derma-
HISTOPATHOLOGIC FEATURES
ECZEMATOUS STAGE
The early stages of mycosis fungoides may be difcult
to diagnose histopathologically because of the subtle
changes that characterize the initial lesions. A psoriasiform pattern of epithelial alteration is seen, with
parakeratin production and elongation of the epithelial
rete ridges. Scattered, slightly atypical lymphocytic
cells may be seen in the connective tissue papillae, but
such features are often mistaken for an inammatory
process.
PLAQUE STAGE
With the development of the plaque stage, a more
readily identiable microscopic pattern emerges.
Examination of the surface epithelium reveals inltration by atypical lymphocytic cells, which are sometimes referred to as mycosis cells or Szary cells. These
atypical lymphocytes classically form small intraepithelial aggregates termed Pautriers microabscesses (Fig.
13-33). The lesional cells have an extremely unusual
nucleus because of the marked infolding of the nuclear
membrane, which results in what is termed a cerebriform nucleus. This feature can best be appreciated when
viewed in special semithin, plastic-embedded microscopic sections (Fig. 13-34). The diagnosis of mycosis
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fungoides can be conrmed by demonstrating positivity for CD4 (a cell surface marker for T-helper cells) in
the lesional cell population. In addition, T-cell receptor
gene rearrangement analysis should identify a monoclonal population of T lymphocytes. A mixed inltrate
of eosinophils, histiocytes, and plasma cells may be
observed in the subepithelial connective tissue.
TUMOR STAGE
As the condition progresses to the tumor stage, the
diffuse inltration of the dermis and epidermis by
atypical lymphocytic cells makes it easier to identify as
a malignant process. Other types of lymphoma would
enter into the histopathologic differential diagnosis.
Immunohistochemical studies demonstrating a
T-helper phenotype, combined with the T-cell receptor
gene rearrangement studies, would help to distinguish
Topical nitrogen mustard, topical carmustine, superpotent topical corticosteroids, electron beam therapy, or
photochemotherapy (PUVA [8-methoxy-psoralen +
ultraviolet A]) are effective in controlling mycosis
fungoides during the early stages. Ultimately, the
topical forms of therapy fail, and aggressive chemotherapy is necessary, particularly if there is visceral
involvement. Newer agents that may be added to the
chemotherapy regimen include monoclonal antibodies directed against the cell surface marker CD52,
certain retinoid compounds, and specic interferon
compounds. Another new agent that may be used for
advanced disease is known as denileukin diftitox, which
is derived from diphtheria toxin and targets the interleukin-2 receptor on the neoplastic lymphocytes. If
Szary syndrome develops, then extracorporeal photopheresis or chemotherapy is used as a treatment modality. Extracorporeal photopheresis involves the ingestion
of the photoactive drug 8-methoxypsoralen, followed
by the removal of a portion of the patients blood and
a separation of red and white blood cells. The red blood
cells are returned to the patient immediately. The
white blood cells are irradiated outside the body (extracorporeal) with ultraviolet A. These altered white cells
are then infused back into the patient. Their altered
state may help generate an immunologic response to
the patients own abnormal lymphocytes.
Although mycosis fungoides is not considered to be
curable, the disease is usually slowly progressive. As a
result, there is a median survival time of 8 to 10 years,
and patients may die of causes unrelated to their lymphoma. Once the disease progresses beyond the cutaneous involvement, the course becomes much worse.
The patient usually dies of organ failure or sepsis within
1 year.
BURKITTS LYMPHOMA
Burkitts lymphoma is a malignancy of B-lymphocyte
origin that represents an undifferentiated lymphoma.
It was named after the missionary doctor, Denis Burkitt,
who rst documented the process. In the original
report, this type of lymphoma was described in young
African children, and it seemed to have a predilection
for the jaws. Because it was seen frequently in subSaharan Africa, the term African Burkitts lymphoma
has been applied to the disease. In addition, there is
increased prevalence in other areas of the world, such
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HISTOPATHOLOGIC FEATURES
Burkitts lymphoma histopathologically represents an
undifferentiated, small, noncleaved B-cell lymphoma.
The lesion invades as broad sheets of tumor cells that
exhibit round nuclei with minimal cytoplasm. Each
tumor nucleus often has several prominent nucleoli,
and numerous mitoses are seen. Immunohistochemical studies using markers that identify proliferating
cells (e.g., Ki-67) typically indicate that almost 100% of
the tumor cells are in the process of replicating. On
viewing the lesion on low-power magnication, a
classic starry-sky pattern is often appreciateda
phenomenon that is caused by the presence of
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drives
the
neoplastic
EXTRANODAL NK/T-CELL
LYMPHOMA, NASAL-TYPE
(ANGIOCENTRIC T-CELL LYMPHOMA;
MIDLINE LETHAL GRANULOMA;
IDIOPATHIC MIDLINE DESTRUCTIVE
DISEASE; POLYMORPHIC
RETICULOSIS; MIDLINE MALIGNANT
RETICULOSIS; ANGIOCENTRIC
IMMUNOPROLIFERATIVE LESION)
Fig. 13-38 Burkitts lymphoma. This high-power
photomicrograph demonstrates the undifferentiated, small,
dark lesional cells with numerous histiocytes.
Also known as angiocentric T-cell lymphoma, extranodal NK/T-cell lymphoma, nasal-type is a rare
process that is characterized clinically by aggressive,
nonrelenting destruction of the midline structures of
the palate and nasal fossa. For many decades, the
nature of this process has been controversial, a fact that
can readily be appreciated by the wide variety of terms
by which it has been called. In actuality, many of the
cases reported as midline lethal granuloma in the
past represented a wide variety of immunologic (e.g.,
Wegeners granulomatosis) and infectious (e.g., tertiary
syphilis) diseases. The term midline lethal granuloma should be used only as a descriptive designation
of a destructive midline condition, and thorough diagnostic evaluation, including biopsy and culture, is necessary to make a denitive diagnosis. Once the other
causes of midline destruction have been eliminated,
the consensus among most investigators is that this
disorder should be classied as a natural killer (NK)
T-cell lymphoma, based on modern cytogenetic, immunologic, and molecular studies. The difculty in distinguishing among these destructive disorders can be
appreciated by the fact that lymphomatoid granulo-
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Fig. 13-39 Extranodal NK/T-cell lymphoma, nasal-type. A, This 62-year-old man had a
destructive palatal lesion that proved to be a T-cell lymphoma, and evaluation showed cervical
lymph node involvement as well. B, Resolution of the lesion 1 month later, after multiagent
chemotherapy.
CLINICAL FEATURES
Extranodal NK/T-cell lymphoma is typically observed
in adults. The initial signs and symptoms are often
localized to the nasal region and include nasal stufness or epistaxis. Pain may accompany the nasal symptoms. Swelling of the soft palate or posterior hard palate
may precede the formation of a deep, necrotic ulceration, which usually occupies a midline position. This
ulceration enlarges and destroys the palatal tissues,
which typically creates an oronasal stula (Fig. 13-39).
Secondary infection may complicate the course of the
disease, and life-threatening hemorrhage is a potential
problem in some instances.
HISTOPATHOLOGIC FEATURES
Histopathologic examination of one of these lesions
shows a mixed inltrate of a variety of inammatory
cells, often arranged around blood vessels (angiocentric) (Fig. 13-40). The lesional process appears to invade
and destroy the normal tissue in the area. Necrosis is
often present in some areas of the lesion, presumably
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MULTIPLE MYELOMA
Multiple myeloma is a relatively uncommon malignancy of plasma cell origin that often appears to have
a multicentric origin within bone. The cause of the
condition is unknown, although sometimes a plasmacytoma (see page 606) may evolve into multiple
myeloma. This disease makes up about 1% of all malignancies and 10% to 15% of hematologic malignancies.
If metastatic disease is excluded, then multiple
myeloma accounts for nearly 50% of all malignancies
that involve the bone. Nearly 20,000 cases are diagnosed annually in the United States.
The abnormal plasma cells that compose this tumor
are typically monoclonal. The abnormal cells probably
arise from a single malignant precursor that has undergone uncontrolled mitotic division and has spread
throughout the body. Because the neoplasm develops
from a single cell, all the daughter cells that comprise
the lesional tissue have the same genetic makeup and
produce the same proteins. These proteins are the
immunoglobulin components that the plasma cell
would normally produce, although in the case of this
malignant tumor the immunoglobulins are not normal
or functional. The signs and symptoms of this disease
result from the uncontrolled proliferation of the tumor
cells and the uncontrolled manufacture of their protein
products.
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HISTOPATHOLOGIC FEATURES
Histopathologic examination of the lesional tissue in
multiple myeloma shows diffuse, monotonous sheets of
neoplastic, variably differentiated, plasmacytoid cells
that invade and replace the normal host tissue (Fig.
13-42). Mitotic activity may be seen with some frequency. The monoclonality of the plasma cell population can be demonstrated using antibodies directed
against the lambda and kappa light chain components
of the immunoglobulin molecule. In a neoplastic proliferation of plasma cells, virtually all of the lesional
cells will mark with only one of these antibodies. In
contrast, a reactive plasma cell inltrate will show a
mixture of lambda- and kappa-producing plasma cells.
Occasionally, deposition of amyloid may be observed
in association with the neoplastic cells. Like other types
of amyloid, this material appears homogeneous, eosinophilic, and relatively acellular. It stains metachromatically with crystal violet and shows an afnity for Congo
red, demonstrating apple-green birefringence on
viewing with polarized light. A biopsy specimen of
bone marrow from a patient with multiple myeloma
should show at least 10% atypical plasma cells making
up the marrow cell population.
DIAGNOSIS
Although the histopathologic and radiographic ndings strongly suggest a diagnosis of multiple myeloma,
screening of the serum or urine by protein electrophoresis should be performed. If an abnormality is
detected, then this should be conrmed by protein
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PLASMACYTOMA
The plasmacytoma is a unifocal, monoclonal, neoplastic proliferation of plasma cells that usually arises
within bone. Infrequently, it is seen in soft tissue, in
which case, the term extramedullary plasmacytoma
is used. Some investigators believe that this lesion represents the least aggressive part of a spectrum of plasma
cell neoplasms that extends to multiple myeloma.
Therefore, the plasmacytoma is important because it
may ultimately give rise to the more serious problem
of multiple myeloma.
HISTOPATHOLOGIC FEATURES
The histopathologic features of the plasmacytoma are
identical to those of multiple myeloma. Sheets of
plasma cells show varying degrees of differentiation.
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BIBLIOGRAPHY
Lymphoid Hyperplasia
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Lofqvist T, Nilsson IM, Berntorp E et al: Haemophilia prophylaxis
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Mannucci PM: Treatment of von Willebrands disease, N Engl J
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Pisciotta AV: Drug-induced agranulocytosis: peripheral destruction of polymorphonuclear leukocytes and their marrow precursors, Blood Rev 4:226-237, 1990.
Salama A, Mueller-Eckhardt C: Immune-mediated blood cell
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Aprikyan AAG, Liles WC, Boxer LA et al: Mutant elastase in
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Baer PN, Iacono VJ: Cyclic neutropenia: report of a case with a
15-year follow-up, Periodontal Clin Investig 16:14-19, 1994.
Boxer LA, Hutchinson R, Emerson S: Recombinant human granulocyte-colony-stimulating factor in the treatment of patients
with neutropenia, Clin Immunol Immunopathol 62:S39-S46,
1992.
Dale DC, Bolyard AA, Aprikyan A: Cyclic neutropenia, Semin
Hematol 39:89-94, 2002.
Haurie C, Dale DC, Mackey MC: Cyclical neutropenia and other
periodic hematological disorders: a review of mechanisms
and mathematical models, Blood 92:2629-2640, 1998.
Kinane D: Blood and lymphoreticular disorders, Periodontol
2000 21:84-93, 1999.
Nakai Y, Ishihara C, Ogata S et al: Oral manifestations of cyclic
neutropenia in a Japanese child: case report with a 5-year
follow-up, Pediatr Dent 25:383-388, 2003.
Pernu HE, Pajari UH, Lanning M: The importance of regular
dental treatment in patients with cyclic neutropenia. Followup of 2 cases, J Periodontol 67:454-459, 1996.
Thrombocytopenia
Bolton-Maggs PHB: Idiopathic thrombocytopenic purpura, Arch
Dis Child 83:220-222, 2000.
Chong BH: Clinical aspects of thrombocytopenias, Aust Fam Physician 23:1463-1464, 1468-1470, 1473, 1994.
George JN: Thrombotic thrombocytopenic purpura, N Engl J Med
354:1927-1935, 2006.
Lusher JM: Screening and diagnosis of coagulation disorders, Am
J Obstet Gynecol 175:778-783, 1996.
Medeiros D, Buchanan GR: Idiopathic thrombocytopenic
purpura: beyond consensus, Curr Opin Pediatr 12:4-9,
2000.
Murrin RJA, Murray JA: Thrombotic thrombocytopenic purpura:
aetiology, pathophysiology and treatment, Blood Rev 20:5160, 2006.
Rogers GM: Overview of platelet physiology and laboratory evaluation of platelet function, Clin Obstet Gynecol 42:349-359,
1999.
Thompson CC, Tacke RB, Woolley LH et al: Purpuric oral and
cutaneous lesions in a case of drug-induced thrombocytopenia, J Am Dent Assoc 105:465-467, 1982.
Wazny LD, Ariano RE: Evaluation and management of druginduced thrombocytopenia in the acutely ill patient, Pharmacotherapy 20:292-307, 2000.
Polycythemia Vera
Campbell PJ, Green AR: The myeloproliferative disorders, N Engl
J Med 355:2452-2466, 2006.
Cao M, Olsen RJ, Zu Y: Polycythemia vera: new clinicopathologic perspectives, Arch Pathol Lab Med 130:1126-1132,
2006.
Johansson P: Epidemiology of the myeloproliferative disorders
polycythemia vera and essential thrombocythemia, Semin
Thromb Hemost 32:171-173, 2006.
Lengfelder E, Merx K, Hehlmann R: Diagnosis and therapy of
polycythemia vera, Semin Thromb Hemost 32:267-275, 2006.
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Bone Pathology*
Revised by ANGELA C. CHI
CHAPTER OUTLINE
Ossifying Fibroma
Juvenile Ossifying Fibroma
Osteoma
Gardner Syndrome
Osteoblastoma and Osteoid Osteoma
Cementoblastoma
Chondroma
Chondromyxoid Fibroma
Synovial Chondromatosis
Desmoplastic Fibroma
Osteosarcoma
Chondrosarcoma
Ewing Sarcoma
Metastatic Tumors to the Jaws
Osteogenesis Imperfecta
Osteopetrosis
Cleidocranial Dysplasia
Focal Osteoporotic Marrow Defect
Idiopathic Osteosclerosis
Massive Osteolysis
Pagets Disease of Bone
Central Giant Cell Granuloma
Cherubism
Simple Bone Cyst
Aneurysmal Bone Cyst
Fibrous Dysplasia
Cemento-Osseous Dysplasias
Familial Gigantiform Cementoma
OSTEOGENESIS IMPERFECTA
Osteogenesis imperfecta comprises a heterogeneous
group of heritable disorders characterized by impairment of collagen maturation. Except on rare occasions,
the disorder arises from heterozygosity for mutations
in one of two genes that guide the formation of type I
collagen: the COL1A1 gene on chromosome 17 and
the COL1A2 gene on chromosome 7. Collagen forms
a major portion of bone, dentin, sclerae, ligaments, and
skin; osteogenesis imperfecta demonstrates a variety of
changes that involve these sites. Several different forms
of osteogenesis imperfecta are seen, and they represent
*Dr. Charles A. Waldron wrote the original version of this chapter in the
rst edition of this book.
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HISTOPATHOLOGIC FEATURES
On histopathologic examination, cortical bone appears
attenuated. Osteoblasts are present, but bone matrix
production is reduced markedly. The bone architecture remains immature throughout life, and there is a
failure of woven bone to become transformed to lamellar bone.
Histopathologically, teeth from affected patients can
exhibit abnormalities of dentin similar to those
described for patients with dentinogenesis imperfecta
(see page 108). These microscopic ndings tend to be
most pronounced in teeth that clinically appear opal-
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endochondral ossication, results in thickening of cortical bone and sclerosis of the cancellous bone.
Although genetic defects have yet to be identied in
a substantial percentage of patients with osteopetrosis,
mutations discovered thus far have been found to cause
defects in key elements necessary for osteoclast function, including the H+-ATPase proton pump, chloride
channel, and carbonic anhydrase II. These proteins are
necessary for acidication of resorption lacunae, regulation of ionic charge across the osteoclast cell membrane, and subsequent resorption of the bone matrix.
Although a number of types have been identied,
these pathoses group into two major clinical patterns:
(1) infantile and (2) adult osteopetrosis. The infantile
form has an estimated incidence of 1:200,000 to
1:300,000, and the adult form has an estimated incidence of 1 in 100,000 to 1:500,000. The clinical
severity of the disease varies widely, even within the
same pattern of osteopetrosis.
ADULT OSTEOPETROSIS
Adult osteopetrosis is usually discovered later in life
and exhibits less severe manifestations. In most patients,
this pattern is inherited as an autosomal dominant trait
and has been termed benign osteopetrosis. The axial
skeleton usually reveals signicant sclerosis, whereas
the long bones demonstrate little or no defects. Approximately 40% of affected patients are asymptomatic, and
marrow failure is rare. Occasionally, the diagnosis is
discovered initially on review of dental radiographs
that reveal a diffuse increased radiopacity of the medullary portions of the bone. In symptomatic patients,
bone pain is frequent.
Two major variants of adult osteopetrosis are seen.
In one form, cranial nerve compression is common,
although fractures occur rarely. In contrast, the second
pattern demonstrates frequent fractures, but nerve
compression is uncommon. When the mandible is
involved, fracture and osteomyelitis after tooth extraction are signicant complications.
Although distinctly uncommon, other causes of
widespread osteosclerosis exist and should be considered during evaluation of patients with osteopetrosis.
Such diseases include autosomal dominant osteosclerosis (endosteal hyperostosis, Worth type), sclerosteosis, and Van Buchem disease.
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HISTOPATHOLOGIC FEATURES
Several patterns of abnormal endosteal bone formation
have been described. These include the following:
Tortuous lamellar trabeculae replacing the cancellous portion of the bone
Globular amorphous bone deposition in the
marrow spaces (Fig. 14-5)
Osteophytic bone formation
Numerous osteoclasts may be seen, but there is no
evidence that they function because Howships lacunae
are not visible.
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CLEIDOCRANIAL DYSPLASIA
Best known for its dental and clavicular abnormalities,
cleidocranial dysplasia is a disorder of bone caused
by a defect in the CBFA1 gene (also known as the
RUNX2 gene) of chromosome 6p21. This gene normally guides osteoblastic differentiation and appropriate bone formation. This condition initially was thought
to involve only membranous bones (e.g., clavicles, skull,
at bones), but it is now known to affect endochondral
ossication and to represent a generalized disorder
of skeletal structures. Recent evidence suggests that
the CBFA1 gene additionally plays an important role
in odontogenesis via participation in odontoblast
differentiation, enamel organ formation, and dental
lamina proliferation. Disruption of these functions
might explain the distinct dental anomalies found in
patients with this disorder. The disease has an estimated prevalence of 1:1,000,000 and shows an
autosomal dominant inheritance pattern, but as many
as 40% of cases appear to represent spontaneous
mutations. This condition formerly was known as
cleidocranial dysostosis.
The gnathic and dental manifestations are distinctive and may lead to the initial diagnosis. The patients
often have a narrow, high-arched palate, and there is
an increased prevalence of cleft palate. Prolonged
retention of deciduous teeth and delay or complete
failure of eruption of permanent teeth are characteristic features. There may be abnormal spacing in
the mandibular incisor area because of widening of
the alveolar bone. On review of dental radiographs, the
most dramatic nding is the presence of numerous
unerupted permanent and supernumerary teeth, many
of which frequently exhibit distorted crown and root
shapes (Fig. 14-7). The number of supernumerary teeth
can be impressive, with reports of some patients demonstrating more than 60 such teeth.
In addition to the dental alterations, review of
panoramic radiographs reveals an increased prevalence of a number of additional osseous malformations.
The mandible often demonstrates coarse trabeculation
with areas of increased density. The mandibular rami
are often narrow with nearly parallel-sided anterior
and posterior borders, and the coronoid processes may
be slender and pointed with a distal curvature. In some
cases the mandibular symphysis remains patent. The
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HISTOPATHOLOGIC FEATURES
The reason for failure of permanent tooth eruption in
patients with cleidocranial dysplasia is not understood
well. Microscopic studies of unerupted permanent
teeth have shown that these teeth lack secondary
cementum. However, a recent histomorphometric
study demonstrated no statistically signicant difference in the percentage of root surface covered by
cementum between teeth extracted from a patient with
cleidocranial dysplasia and teeth from control patients.
Some investigators alternatively have proposed that
insufcient alveolar bone resorption is the reason for
impaired tooth eruption; this theory is based on obser-
FOCAL OSTEOPOROTIC
MARROW DEFECT
The focal osteoporotic marrow defect is an area of
hematopoietic marrow that is sufcient in size to
produce an area of radiolucency that may be confused
with an intraosseous neoplasm. The area does not
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Jones.)
represent a pathologic process, but its radiographic features may be confused with a variety of pathoses. The
pathogenesis of this condition is unknown. Various
theories include the following:
Aberrant bone regeneration after tooth extraction
Persistence of fetal marrow
Marrow hyperplasia in response to increased
demand for erythrocytes
HISTOPATHOLOGIC FEATURES
Microscopically, the defects contain cellular hematopoietic and/or fatty marrow. Lymphoid aggregates may
be present. Bone trabeculae included in the biopsy
IDIOPATHIC OSTEOSCLEROSIS
Idiopathic osteosclerosis refers to a focal area of
increased radiodensity that is of unknown cause and
cannot be attributed to any inammatory, dysplastic,
neoplastic, or systemic disorder. Idiopathic osteosclerosis also has been termed dense bone island, bone eburnation, bone whorl, bone scar, enostosis, and focal periapical
osteopetrosis. These sclerotic areas are not restricted to
the jaws, and radiographically similar lesions may be
found in other bones.
Similar radiopaque foci may develop in the periapical areas of teeth with nonvital or signicantly inamed
pulps; these lesions most likely represent a response to
a low-grade inammatory stimulus. Such reactive foci
should be designated as condensing osteitis or focal
chronic sclerosing osteomyelitis (see page 147) and
should not be included under the designation of idio-
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pathic osteosclerosis. Because past studies did not distinguish the idiopathic lesions from those of inammatory
origin, confusion in terminology has resulted.
multiple areas of involvement, the possibility of multiple osteomas within the setting of Gardner syndrome
(see page 651) should be excluded.
Radiographically, the lesions are characterized by a
well-dened, rounded, or elliptic radiodense mass.
Although the majority is uniformly radiopaque, occasional large lesions demonstrate a nonhomogeneous
mixture of increased and reduced radiopacity. This
is most likely because of variation in the threedimensional (3D) shape of the lesion and is unrelated
to differences in the mineral content of the mass. The
lesions vary from 3.0 mm to more than 2.0 cm in greatest extent. A radiolucent rim does not surround the
radiodense area. Most examples of idiopathic osteosclerosis are associated with a root apex. In a lesser
number of cases, the sclerotic area may extend into or
be located only in the interradicular area (Fig. 14-10).
In about 20% of cases, the sclerotic area is located in
the jaw, with no apparent relationship to a tooth. Rarely,
the sclerotic bone may surround all or portions of an
impacted tooth. Root resorption and movement of
teeth have been noted but are uncommon.
HISTOPATHOLOGIC FEATURES
In the few microscopic studies that have been reported,
the lesion consists of dense lamellar bone with scant
brofatty marrow. Inammatory cells are inconspicuous or absent.
DIAGNOSIS
Usually a diagnosis of idiopathic osteosclerosis may
be made with condence, based on history, clinical
features, and radiographic ndings. Biopsy is consid-
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In approximately 30% of affected patients, maxillofacial involvement is noted, with the mandible being
affected most frequently. Simultaneous involvement of
the maxilla and mandible may occur. Signs and symptoms include mobile teeth, pain, malocclusion, deviation of the mandible, and clinically obvious deformity.
Obstructive sleep apnea syndrome has been noted
secondary to posterior mandibular displacement
after extensive osteolysis. Pathologic fracture of the
mandible may occur. Temporomandibular joint (TMJ)
involvement may be confused with other conditions
that can cause TMJ dysfunction.
Radiographically, the earliest changes consist of
intramedullary radiolucent foci of varying size with
indistinct margins (Fig. 14-11). These coalesce to
become larger and involve the cortical bone. Eventually, large portions of the involved bone disappear
(Fig. 14-12). As the process proceeds, newly involved
areas often demonstrate loss of the lamina dura and
thinning of the cortical plates before development of
obvious radiolucency. In some cases the bone destruction may mimic periodontitis or periapical inammatory disease.
HISTOPATHOLOGIC FEATURES
The microscopic ndings in massive osteolysis contrast
sharply with the striking clinical and radiographic ndings. In the early stages of disease, specimens removed
from the radiolucent defects consist of a nonspecic
vascular proliferation intermixed with brous connective and a chronic inammatory inltrate of lymphocytes and plasma cells. The vascular proliferation varies
in intensity and is characterized by thin-walled channels that may be capillary or cavernous in nature
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Fig. 14-12 Massive osteolysis. Panoramic radiograph of the same patient shown in
Fig. 14-11, showing extensive bone loss and a pathologic fracture of the left mandible. This
destruction occurred over an 8-month period. (Courtesy of Dr. John R. Cramer.)
Mortality from massive osteolysis is relatively uncommon and usually the result of severe chest cage involvement or destruction of vertebral bodies with spinal
cord compression.
Treatment is not particularly satisfactory. Previous
reported therapies include estrogens, magnesium,
calcium, vitamin D, uoride, calcitonin, alpha-2b interferon, and chemotherapeutic agents (e.g., cisplatin,
actinomycin D, etoposide). Surgical intervention has
met with limited success. When surgical removal is
combined with bone grafting, the newly placed bone
often undergoes osteolysis. Radiation therapy is the
most successful and widely accepted mode of therapy,
but failures may occur. In addition, this therapy places
the patient at risk for postirradiation sarcoma. In a
limited number of patients, stabilization of disease
after bisphosphonate therapy has been reported,
although longer-term studies on a greater number of
patients are needed to assess this proposed treatment
modality. The effectiveness of any therapeutic intervention is difcult to evaluate, not only because the
disease is so rare but also because the condition may
arrest spontaneously in some patients.
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DIAGNOSIS
HISTOPATHOLOGIC FEATURES
Microscopic examination shows an apparent uncontrolled alternating resorption and formation of bone. In
the active resorptive stages, numerous osteoclasts surround bone trabeculae and show evidence of resorptive activity. Simultaneously, osteoblastic activity is
seen with formation of osteoid rims around bone trabeculae. A highly vascular brous connective tissue
replaces the marrow. A characteristic microscopic
feature is the presence of basophilic reversal lines in
the bone. These lines indicate the junction between
alternating resorptive and formative phases of the bone
and result in a jigsaw puzzle, or mosaic, appearance
of the bone (Fig. 14-16). In the less active phases, large
Although Pagets disease is chronic and slowly progressive, it is seldom the cause of death. In patients with
more limited involvement and no symptoms, treatment often is not required. In asymptomatic patients,
systemic therapy is usually not initiated unless the
alkaline phosphatase is more than 25% to 50%
above normal. When symptomatic, bone pain is noted
most frequently and often may be controlled by acetaminophen or nonsteroidal antiinammatory drugs
(NSAIDs). Neurologic complications, such as deafness
or visual disturbances, may result from bony encroachment on cranial nerves passing through skull
foramina.
Pharmacologic antiresorptive therapy is recommended for patients with the following signs or
symptoms: considerable bone pain, headache related
to skull involvement, deafness or visual disturbances
because of narrowing of the skull foramina, back pain
because of pagetic radiculopathy or arthropathy, bone
fractures, and hypercalcemia resulting from immobilization. Use of parathyroid hormone (PTH) antagonists,
such as calcitonin and bisphosphonates, can reduce
bone turnover and improve the biochemical abnormalities. For several decades, the mainstays of therapy
were calcitonin and the bisphosphonate etidronate.
However, these agents have been largely supplanted by
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the newer bisphosphonates, alendronate and risedronate, which provide enhanced control of bone turnover. Bisphosphonates are typically administered orally
for a period of 2 to 6 months. Intravenous pamidronate
can be an alternative for those patients who cannot
tolerate oral bisphosphonates because of gastrointestinal irritation or who require treatment before surgery
in an area of pagetic bone. A recently reported regimen
of notable efcacy is single-infusion therapy with the
potent bisphosphonate, zoledronic acid. In mild cases,
a single infusion of a bisphosphonate often is associated
with yearlong remissions. Patients with more severe
disease usually require higher doses or more frequent
courses of a particular bisphosphonate. The goal of
therapy is to achieve midrange normal levels of serum
alkaline phosphatase, with retreatment occurring when
values rise 25% higher than normal. Plicamycin, a cytotoxic antibiotic, is known to inhibit osteoclastic activity,
but its use is restricted to patients with severe disease
that is refractory to calcitonin and bisphosphonate
medications.
Case reports of osteonecrosis of the jaw as a complication of bisphosphonate therapy for Pagets disease of
bone have raised some safety concerns. Long-term
data are needed to fully assess the potential risks and
benets of bisphosphonate therapy; thus the merits
of aggressive preventive or prolonged maintenance
therapy remain uncertain at this time.
Edentulous patients may require new and larger
dentures periodically to compensate for progressive
enlargement of the alveolar processes. Dental complications include difculties in extraction of teeth
exhibiting signicant hypercementosis. During active
disease, pagetoid bone is extremely vascular with
multiple arteriovenous shunts. Oral surgical procedures during this time can result in extensive hemorrhage. During the later sclerotic phase, the bone is
hypersensitive to inammation and can develop osteomyelitis with minimal provocation. In one recent
report, long-term correction of maxillary deformity
was achieved by removal, reshaping, and reinsertion
of the maxillomalar complex in a patient who had
received no prior medical treatment for his disease.
Development of a malignant bone tumor, usually an
osteosarcoma, is a recognized complication of Pagets
disease. Osteosarcoma in adults older than 40 years is
quite uncommon in individuals who do not have
Pagets disease. The frequency of bone sarcoma complicating Pagets disease ranges from 0.9% to 13.0% in
various studies. The true frequency is probably in the
range of 1% or less. Most of the osteosarcomas develop
in the pelvis and long bones of the lower extremities.
The skull and jaws are very rare sites for sarcomas
associated with Pagets disease. Clinical signs and
symptoms that should raise suspicion of possible under-
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Fig. 14-17 Central giant cell granuloma. A, A blue-purple mass is present on the anterior
alveolar ridge of this 4-year-old white boy. B, The occlusal radiograph shows a radiolucent
lesion with cortical expansion.
14-19). Multilocular giant cell lesions cannot be distinguished radiographically from ameloblastomas or
other multilocular lesions.
Areas histopathologically identical to giant cell granuloma have been noted in aneurysmal bone cysts (see
page 634) and intermixed with central odontogenic
bromas (see page 727). Because giant cell granulomas are also histopathologically identical to brown
tumors, hyperparathyroidism (see page 838) should
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HISTOPATHOLOGIC FEATURES
Giant cell lesions of the jaw show a variety of features.
Common to all is the presence of few to many multinucleated giant cells in a background of ovoid to
spindle-shaped mesenchymal cells and round monocyte-macrophages (Fig. 14-20). There is evidence that
these giant cells represent osteoclasts, although others
suggest the cells may be aligned more closely with
macrophages. The spindle-shaped cells appear to be
broblast related. It has been proposed that the spindle
cell component is the proliferating cell population and
recruits monocyte-macrophage precursors, inducing
them to differentiate into osteoclastic giant cells by
activation of the receptor activator of the nuclear factorB (RANK)/RANK ligand signaling pathway. The giant
cells may be aggregated focally in the lesional tissue or
may be present diffusely throughout the lesion. These
cells vary considerably in size and shape from case to
case. Some are small and irregular in shape and contain
only a few nuclei. In other cases, the giant cells are
large and round and contain 20 or more nuclei.
In some cases the stroma is loosely arranged and
edematous; in other cases it may be quite cellular.
Areas of erythrocyte extravasation and hemosiderin
deposition often are prominent. Older lesions may
show considerable brosis of the stroma. Foci of osteoid
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In spite of the reported recurrence rate, the longterm prognosis of giant cell granulomas is good and
metastases do not develop.
CHERUBISM
Cherubism is a rare developmental jaw condition that
is generally inherited as an autosomal dominant trait
with high penetrance but variable expressivity. Several
investigators have reported a higher disease penetrance
in males than in females. Sporadic cases also can occur
and are thought to represent spontaneous mutations.
In two reports published simultaneously by laboratories on different continents, the gene for cherubism
was mapped to chromosome 4p16. Mutations subsequently were identied in the SH3BP2 gene within this
locus. The protein encoded by this gene is believed
to function in signal transduction pathways and to
increase the activity of osteoclasts and osteoblasts
during normal tooth eruption. It has been suggested
that mutations in the SH3BP2 gene may lead to pathologic activation of osteoclasts and disruption of jaw
morphogenesis. However, the molecular pathogenesis
of cherubism remains poorly understood.
The name cherubism was applied to this condition
because the facial appearance is similar to that of the
plump-cheeked little angels (cherubs) depicted in
Renaissance paintings. Although cherubism also has
been called familial brous dysplasia, this term should be
avoided because cherubism has no relationship to
brous dysplasia of bone (see page 635).
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B
Fig. 14-25 Simple bone cyst. Periapical radiograph
showing a radiolucent area in the apical region of the
anterior mandible. The incisor teeth responded normally to
vitality testing, and no restorations are present.
Fig. 14-24 Cherubism. A, Photomicrograph showing
scattered giant cells within a background of cellular,
hemorrhagic mesenchymal tissue. B, High-power view
showing perivascular eosinophilic cufng.
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HISTOPATHOLOGIC FEATURES
The walls of the defect may be lined by a thin band of
vascular brous connective tissue or demonstrate a
thickened myxobromatous proliferation that often is
intermixed with trabeculae of cellular and reactive
bone. This lining may exhibit areas of vascularity, brin,
erythrocytes, and occasional giant cells adjacent to the
bone surface (Fig. 14-28). Stringy lacelike dystrophic
calcications occasionally are noted (Fig. 14-29). There
is never any evidence of an epithelial lining. The bony
surface next to the cavity often shows resorptive areas
(Howships lacunae) indicative of past osteoclastic
activity.
DIAGNOSIS
The radiographic features of the simple bone cyst,
although often suggestive of the diagnosis, are not
diagnostic and may be confused with a wide variety
of odontogenic and nonodontogenic radiolucent jaw
lesions. Surgical exploration is necessary to establish
the diagnosis.
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Fibro-Osseous Lesions
of the Jaws
HISTOPATHOLOGIC FEATURES
Microscopically, the aneurysmal bone cyst is characterized by spaces of varying size, lled with unclotted
blood surrounded by cellular broblastic tissue containing multinucleated giant cells and trabeculae of
osteoid and woven bone. On occasion, the wall contains an unusual lacelike pattern of calcication that is
uncommon in other intraosseous lesions. The bloodlled spaces are not lined by endothelium (Fig. 14-31).
In approximately 20% of the cases, aneurysmal bone
cyst is associated with another pathosis, most commonly a bro-osseous lesion or giant cell granuloma.
FIBROUS DYSPLASIA
Fibrous dysplasia is a developmental tumorlike condition that is characterized by replacement of normal
bone by an excessive proliferation of cellular brous
connective tissue intermixed with irregular bony trabeculae. Although considerable confusion has existed
regarding the nature of brous dysplasia, much has
been learned about the genetics of this group of disorders, and this knowledge makes the wide variety of
clinical patterns more understandable.
Fibrous dysplasia is a sporadic condition that results
from a postzygotic mutation in the GNAS1 (guanine
nucleotidebinding protein, -stimulating activity polypeptide 1) gene. Clinically, brous dysplasia may manifest as a localized process involving only one bone, as
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Fig. 14-33 Fibrous dysplasia. Panoramic radiograph of the patient shown in Fig. 14-32.
A diffuse ground-glass radiopacity is evident. (Courtesy of Dr. Richard Brock.)
brous dysplasia is Mazabraud syndrome, characterized by brous dysplasia in combination with intramuscular myxomas.
Although the skull and jaws may be affected with
resultant facial asymmetry, the clinical picture in
patients with polyostotic brous dysplasia is usually
dominated by symptoms related to the long bone
lesions (Fig. 14-37). Pathologic fracture with resulting
pain and deformity is frequently noted. Leg length discrepancy is very common as a result of involvement
of the upper portion of the femur (hockey stick
deformity).
Hypophosphatemia caused by renal phosphate
wasting is another fairly common nding among
patients with polyostotic brous dysplasia. The mechanism for this nding appears to be related to the renal
inuences of circulating broblast growth factor 23
CA, Giansanti JS: Benign bro-osseous lesions of the jaws: a clinicalradiologic-histologic review of 65 cases. I. Fibrous dysplasia of the jaws, Oral
Surg Oral Med Oral Pathol 35:190-201, 1973.)
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HISTOPATHOLOGIC FEATURES
The typical microscopic ndings of brous dysplasia
consist of irregularly shaped trabeculae of immature
(woven) bone in a cellular, loosely arranged brous
stroma. The bone trabeculae are not connected to each
other. They often assume curvilinear shapes, which
have been likened to Chinese script writing. The bone
trabeculae are considered to arise by metaplasia and
are not surrounded by plump appositional osteoblasts
(Fig. 14-39). Tiny calcied spherules may be seen
rarely but are never numerous. In contrast to ossifying
broma and cemento-osseous dysplasia, brous dysplasia typically demonstrates a rather monotonous
pattern throughout the lesion rather than being a haphazard mixture of woven bone, lamellar bone, and
spheroid particles. The lesional bone fuses directly to
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CEMENTO-OSSEOUS DYSPLASIAS
(OSSEOUS DYSPLASIA)
Cemento-osseous dysplasia occurs in the toothbearing areas of the jaws and is probably the most
common bro-osseous lesion encountered in clinical
practice. In spite of its frequency, the associated nomenclature and diagnostic criteria remain an area of debate.
Because the pathologic features share many similarities with brous dysplasia and ossifying broma, correct
diagnosis can be problematic but is critical to appropriate management.
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Fig. 14-41 Focal cemento-osseous dysplasia. A, A radiolucent area involves the edentulous
rst molar area and the apical area of the second molar. B, Radiograph of the same patient
taken 9 years later showing a mixed radiolucent and radiopaque pattern.
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Fig. 14-45 Florid cemento-osseous dysplasia. Multiple mixed radiolucent and radiopaque
lesions involving the anterior and posterior regions of the mandible.
series, more than 90% of patients), with a marked predilection for middle-aged to older adults. An intermediate frequency among East Asian populations also has
been described.
The lesions show a marked tendency for bilateral
and often quite symmetrical involvement, and it is not
unusual to encounter extensive lesions in all four pos-
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HISTOPATHOLOGIC FEATURES
All three patterns of cemento-osseous dysplasia demonstrate similar histopathologic features. The tissue
consists of fragments of cellular mesenchymal tissue
composed of spindle-shaped broblasts and collagen
bers with numerous small blood vessels (Fig. 14-48).
Free hemorrhage is typically noted interspersed
throughout the lesion.
Fig. 14-47 Florid cemento-osseous dysplasia. Multifocal radiopaque lesions of the posterior
areas of the jaws. (Courtesy of Dr. Solomon Israel.)
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multiquadrant involvement or multiple lesions involving vital lower incisor teeth) allow a strong presumptive diagnosis without the necessity of biopsy. The
features of focal cemento-osseous dysplasia are less
specic and often mandate surgical investigation. Even
on histopathologic review, distinguishing focal cemento-osseous dysplasia from ossifying broma often can
be difcult. The ndings at surgery are very helpful in
discriminating between these two lesions. Before the
nal sclerotic stage, cemento-osseous dysplasia consists of easily fragmented and gritty tissue that can be
curetted easily from the defect but does not separate
cleanly from the adjacent normal bone. In contrast,
ossifying bromas tend to separate cleanly from the
bone and are removed in one or several large masses.
Several histopathologic features also can help to
conrm the impression obtained from the surgical and
gross descriptions. Although cemento-osseous dysplasia and ossifying broma demonstrate a mixture of
bone and cementum-like particles, the trabeculae in
ossifying broma tend to be more delicate and often
demonstrate osteoblastic rimming. The cementum-like
particles in cemento-osseous dysplasia are irregularly
shaped and often exhibit retraction from the adjacent
stroma, whereas those in ossifying broma are more
ovoid and often demonstrate brush borders in intimate
association with the adjacent stroma. Although ossifying broma can exhibit hemorrhage along the margins
of the specimen, cemento-osseous dysplasia typically
reveals free hemorrhage throughout the lesion and a
sinusoidal vascularity in close association with the bony
trabeculae.
DIAGNOSIS
In most instances of periapical or orid cementoosseous dysplasia, the distinctive clinical and radiographic patterns (e.g., a black female patient with
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Fig. 14-51 Familial gigantiform cementoma. Young woman with massive lesions involving
all four quadrants of the jaws. (A from Abdelsayed RA, Eversole LR, Singh BS et al: Gigantiform cementoma:
clinicopathologic presentation of 3 cases, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 91:438-444, 2001;
B courtesy of Dr. Rak Abdelsayed.)
HISTOPATHOLOGIC FEATURES
Histopathologically, familial gigantiform cementoma
shows the same spectrum of changes seen in orid
cemento-osseous dysplasia, and the two cannot be distinguished microscopically.
OSSIFYING FIBROMA
(CEMENTIFYING FIBROMA;
CEMENTO-OSSIFYING FIBROMA)
Although it can resemble focal cemento-osseous dysplasia radiographically and, to a lesser extent, histopathologically, ossifying broma is a true neoplasm
with a signicant growth potential. Before the rening
of the concept of focal cemento-osseous dysplasia in
the mid 1990s, ossifying broma was thought to be a
common neoplasm. In reality, true ossifying bromas
are relatively rare, with many previously reported
examples actually being focal cemento-osseous
dysplasia.
The neoplasm is composed of brous tissue that
contains a variable mixture of bony trabeculae,
cementum-like spherules, or both. Although the lesions
do contain a variety of mineralized structures, most
authorities agree the same progenitor cell produces the
different materials. It has been suggested that the origin
of these tumors is odontogenic or from periodontal
ligament, but microscopically identical neoplasms with
cementum-like differentiation also have been reported
in the orbital, frontal, ethmoid, sphenoid, and temporal
bones, leaving these prior theories of origin open to
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Fig. 14-52 Ossifying broma. A, Enlargement of the posterior maxilla caused by a large
ossifying broma. B, Note the mixed radiolucent and radiopaque lesion expanding the
posterior maxilla.
HISTOPATHOLOGIC FEATURES
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HISTOPATHOLOGIC FEATURES
Both patterns are typically nonencapsulated but well
demarcated from the surrounding bone. The tumor
consists of cellular brous connective tissue that exhibits areas that are loose and other zones that are so cellular that the cytoplasm of individual cells is hard to
discern because of nuclear crowding. Myxomatous foci
are not rare and often are associated with pseudocystic
degeneration. Mitotic gures can be found but are not
numerous. Areas of hemorrhage and small clusters of
multinucleated giant cells are usually seen.
The mineralized component in the two patterns is
very different. The trabecular variant shows irregular
strands of highly cellular osteoid encasing plump and
irregular osteocytes (Fig. 14-57). These strands often
are lined by plump osteoblasts and in other areas
by multinucleated osteoclasts. In contrast, the psammomatoid pattern forms concentric lamellated and
spherical ossicles that vary in shape and typically have
basophilic centers with peripheral eosinophilic osteoid
rims (Fig. 14-58). A peripheral brush border blending
into the surrounding stroma is noted in many of
the ossicles. Occasionally, individual ossicles undergo
remodeling and form crescentic shapes.
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OSTEOMA
Osteomas are benign tumors composed of mature
compact or cancellous bone. Osteomas are essentially
restricted to the craniofacial skeleton and rarely, if
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Because of the frequency of associated symptoms, osteomas arising in the condyle are usually removed surgically. Large lesions mandate condylectomy, whereas
peripheral osteomas are treated by local resection.
Paranasal sinus osteomas may not require removal
unless they become large or symptomatic; small, periosteal lesions may be removed endoscopically, whereas
larger lesions typically require an open surgical
approach. Osteomas are completely benign, and
patients do not experience malignant change. Recurrence after excision is extremely rare.
HISTOPATHOLOGIC FEATURES
Compact osteomas are composed of normal-appearing
dense bone showing minimal marrow tissue (Fig.
14-60). Cancellous osteomas are composed of trabeculae of bone and brofatty marrow. Osteoblastic activity may be fairly prominent.
GARDNER SYNDROME
Gardner syndrome is a rare disorder that is inherited
as an autosomal dominant trait with near 100% penetrance; approximately one third of cases occur spontaneously and appear to represent new gene mutations.
The responsible gene has been mapped to the long arm
of chromosome 5 and has been identied as the adenomatous polyposis coli (APC) tumor suppressor gene.
Gardner syndrome is considered to be part of a spectrum of diseases characterized by familial colorectal
polyposis. In addition to the colonic manifestations,
other gastrointestinal abnormalities are seen along
with a variety of ndings that may involve the skin, soft
tissues, retina, skeletal system, and teeth. The presence
of extracolonic manifestations and the severity of gastrointestinal disease correlate with the specic position
of mutations within the APC gene. However, the possibility that additional mutations in undiscovered modier genes also may inuence the severity and pattern
of disease cannot be excluded. Several of the extracolonic manifestations are distinctive and have led to the
discovery of the syndrome.
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Fig. 14-61 Gardner syndrome. Panoramic radiograph showing multiple osteomas of the
mandible.
HISTOPATHOLOGIC FEATURES
Histopathologically, the osteomas are generally of the
compact type. An individual lesion cannot be differentiated microscopically from a solitary osteoma.
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OSTEOBLASTOMA AND
OSTEOID OSTEOMA
Osteoblastoma and osteoid osteoma are closely
related benign bone tumors that arise from osteoblasts.
There is general agreement that the histopathologic
features of these two lesions are identical, but it has
been shown that the tumor nidus in osteoid osteomas
contains a concentration of peripheral nerves not seen
in other bro-osseous neoplasms. In addition, the
tumor produces prostaglandins that result in signicant pain that is relieved by prostaglandin inhibitors
such as aspirin. Classically, the distinction depends on
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cases, pain may be misinterpreted as evidence of odontogenic infection. Lesions adjacent to teeth may lead to
tooth mobility, root resorption, or tooth displacement.
Radiographically, the osteoblastoma may appear as a
well-dened or ill-dened radiolucent lesion often
with patchy areas of mineralization (Fig. 14-64). Other
lesions demonstrate considerable mineralization.
Although frequently noted in osteoid osteomas, reactive sclerosis surrounding the lesion is not a constant
feature. Most osteoblastomas arise within medullary
bone; however, in some instances, an osteoblastoma
may present as a bony outgrowth projecting from
the periosteum without evidence of a more central
destructive process. Such lesions are termed periosteal
osteoblastomas.
A small group of osteoblastomas (aggressive osteoblastomas) is characterized by more atypical histopathologic features and locally aggressive behavior.
These tumors usually occur in older patients, with most
being older than 30 years of age. A variety of bones,
including the mandible, may be involved. Aggressive
osteoblastomas tend to be larger than conventional
osteoblastomas and typically measure greater than 4
cm in diameter. Pain is a common symptom and may
be severe. Radiographically, these lesions show the features of conventional osteoblastomas but tend to be
larger.
OSTEOID OSTEOMA
Osteoid osteomas occur most often in the femur, tibia,
and phalanges. They are very rare in the jaws. Pain is
the most common presenting symptom. It is usually
nocturnal in nature and alleviated by salicylates.
However, nocturnal pain relieved by aspirin has been
HISTOPATHOLOGIC FEATURES
The lesions reveal mineralized material that demonstrates prominent reversal lines. The material may be
present in large sheets or irregular trabeculae. At the
periphery of the large masses and surrounding the
trabeculae are scattered multinucleated osteoclast-like
cells and numerous osteoblasts that have ample cytoplasm and hyperchromatic nuclei (Fig. 14-66). The
supporting stroma consists of loose brous connective
tissue that contains scattered dilated vascular channels. Focal areas of hemorrhage are not rare, and
osteoblastomas occasionally exhibit a central zone of
increased vascularity.
Microscopically, aggressive osteoblastomas are characterized by the presence of large (epithelioid) osteoblasts with increased mitotic activity and nontrabecular
sheets or lacelike areas of osteoid production. On occasion, osteoblastomas may demonstrate a rich cellularity that has led to erroneous diagnoses of osteosarcoma.
Differentiation between some osteoblastomas and
low-grade osteosarcomas may be very difcult. Some
low-grade osteosarcomas may closely resemble the
microscopic appearance of osteoblastomas, and some
lesions may have microscopic features intermediate
between osteoblastoma and osteosarcoma.
Eisenberg.)
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CEMENTOBLASTOMA
(TRUE CEMENTOMA)
HISTOPATHOLOGIC FEATURES
Fig. 14-67 Cementoblastoma. A, A densely mineralized mass is seen at the apex of the
distal root of the rst molar. The root is partially resorbed. B, The surgical specimen shows
that the mass is attached to the root. (Courtesy of Dr. John Wright.)
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CHONDROMA
Chondromas are benign tumors composed of mature
hyaline cartilage. Chondromas are one of the more
common bone tumors and are located most often in
the short tubular bones of the hands and feet. However,
a diagnosis of chondroma in the jaws, facial bones, and
base of the skull should be viewed with great skepticism because many so-called benign chondromas of
the craniofacial complex have recurred and acted in a
malignant manner. No major series has reported
enchondromas arising in the craniofacial bones. In
spite of this, individual reports and small series of
gnathic chondromas can be found, with most examples
thought to arise from vestigial cartilaginous rests. Such
rests are located in the anterior maxilla, symphysis,
coronoid process, and condyle.
Fig. 14-68 Cementoblastoma. Low-power photomicrograph showing the tumor attached to the roots of the tooth.
HISTOPATHOLOGIC FEATURES
Histopathologically, a chondroma appears as a circumscribed mass of mature hyaline cartilage that typically
demonstrates well-formed lacunae containing small
chondrocytes with pale cytoplasm and small, round
nuclei. On occasion, the microscopic distinction
between a benign chondroma and a low-grade chondrosarcoma of the jaws is difcult (see page 664).
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CHONDROMYXOID FIBROMA
The chondromyxoid broma is an uncommon
benign neoplasm accounting for less than 1% of all
primary bone tumors. It is located most commonly in
the metaphyseal region of the long bones. Chondromyxoid bromas rarely involve the jaws. Cytogenetic
analysis in several cases has demonstrated the presence
of nonrandom, clonal abnormalities of chromosome 6,
where a number of candidate genes important in cartilage development are located. Further characterization
of these chromosomal abnormalities may aid in differentiating chondromyxoid broma from chondrosarcoma, a distinction that at times can be difcult.
HISTOPATHOLOGIC FEATURES
The tumor consists of lobulated areas of spindle-shaped
or stellate cells with abundant myxoid or chondroid
intercellular substance. The lobules characteristically
are separated by zones of a more cellular tissue composed of spindle-shaped or round cells with varying
numbers of multinucleated giant cells (Fig. 14-70).
Large pleomorphic cells that may cause confusion
with chondrosarcoma may be seen. Focal areas of calcication and spicules of residual bone also may be
present within the tumor.
ommend block excision as the initial treatment. Generally, chondromyxoid bromas of the jaws have been
small and treated by curettage; recurrence is uncommon. Because of the lobular growth and associated
scalloped margins, larger gnathic lesions appear to
justify resection in an attempt to prevent recurrence.
Radiation therapy is contraindicated because of
the risk of inducing malignant transformation or
osteoradionecrosis.
Distinguishing between a chondromyxoid broma
and myxoid chondrosarcoma histopathologically may
be difcult. Examples of both underdiagnosis and
overdiagnosis, with resultant improper treatment, have
been described.
SYNOVIAL CHONDROMATOSIS
(CHONDROMETAPLASIA)
Synovial chondromatosis is a rare, benign, nonneoplastic arthropathy characterized by the metaplastic
development of cartilaginous nodules within the synovial membrane. The exact cause is unknown. In many
cases an association with other joint conditions (e.g.,
inammatory joint disease, noninammatory arthropathy, joint overuse or other trauma) has been described,
and thus the development of synovial chondromatosis
appears to represent a secondary reactive phenomenon. Less commonly, no identiable etiologic factors
are identied, and such cases have been designated as
primary synovial chondromatosis.
The process typically proceeds through three stages.
In the rst stage, foci of metaplastic cartilage arise in
the synovial lining. With time, these foci increase in
size and begin to detach, with cartilaginous material
present in both the synovial membrane and the joint.
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HISTOPATHOLOGIC FEATURES
Nodules of cartilage are present within the synovium and
lie loose in the joint space. As many as 100 nodules may
be present. These cartilaginous nodules often become
calcied and may ossify. The cartilage may appear atypical with hyperchromatic and binucleated chondrocytes,
particularly in primary lesions (Fig. 14-71). In another
clinical situation, these features would suggest a diagnosis
of chondrosarcoma, but these changes are not considered
signicant in synovial chondromatosis.
DESMOPLASTIC FIBROMA
The desmoplastic broma of bone is an uncommon
tumor of broblastic origin. It is thought to be the
osseous counterpart of the soft tissue bromatosis
(desmoid tumor) (see page 515). In a few cases, desmoplastic broma-like lesions of the jaws have been
reported in association with tuberous sclerosis.
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HISTOPATHOLOGIC FINDINGS
The tumor is composed of small elongated broblasts
and abundant collagen bers (Fig. 14-73). The degree
of cellularity may vary from area to area in a given
lesion, and the cellular areas may show plumper broblasts and less collagen. The broblasts are not atypical,
however, and mitoses are essentially absent. Bone
spicules may be present at the interface between the
tumor and adjacent bone but are never an integral part
of the lesion.
Some authors have recommended that diagnostic
biopsies be sampled generously from the center rather
than the periphery of the lesion, because reactive bone
at the periphery may be mistaken for osteoid production, which may lead to a mistaken diagnosis of a
benign bro-osseous lesion or osteosarcoma.
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Some authorities suggest that all desmoplastic bromas of bone be considered potentially malignant.
OSTEOSARCOMA (OSTEOGENIC
SARCOMA)
Osteosarcoma is a malignancy of mesenchymal cells
that have the ability to produce osteoid or immature
bone. Excluding hematopoietic neoplasms, osteosarcoma is the most common type of malignancy to
originate within bone. The majority of osteosarcomas
demonstrate intramedullary origin, but a small number
may be juxtacortical (discussed in the following section)
or rarely, extraskeletal.
Fig. 14-74 Osteosarcoma. A, This patient shows a rm, painful swelling of the left maxilla
of recent onset. B, The periapical radiograph shows a dense sclerotic change in the bone
pattern. (Courtesy of Dr. Len Morrow.)
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Fig. 14-75 Osteosarcoma. A, This massive tumor had been present for many months before
the patient sought treatment. B, Intraoral photograph of the tumor mass. C, The panoramic
radiograph shows a sunburst pattern of trabeculation within the tumor.
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HISTOPATHOLOGIC FEATURES
Osteosarcomas of the jaws display considerable histopathologic variability. The essential microscopic criterion is the direct production of osteoid by malignant
mesenchymal cells (Fig. 14-78). In addition to osteoid,
the cells of the tumor may produce chondroid material
and brous connective tissue. The tumor cells may vary
from relatively uniform round or spindle-shaped cells
to highly pleomorphic cells with bizarre nuclear and
cytoplasmic shapes. The amount of matrix material
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Parosteal
Periosteal
Elevated
periosteum with
new bone formation
No
elevation of
periosteum
No new
bone
formation
sarcoma treated by neoadjuvant chemotherapy followed by surgical removal and adjuvant chemotherapy
are necessary in an attempt to conrm the most appropriate approach.
PERIPHERAL (JUXTACORTICAL)
OSTEOSARCOMA
In contrast to the usual forms of intramedullary osteosarcoma, several varieties originate adjacent to the
cortex of the bone, initially grow outward from the
surface, and do not involve the underlying medullary
cavity. The terminology used for these lesions by different authors is somewhat confusing. These peripheral
(juxtacortical) osteosarcomas usually occur in the
long bones, but examples involving the jaws have been
reported.
The parosteal type of osteosarcoma is a lobulated
nodule attached to the cortex by a short stalk (Fig.
14-80). There is no elevation of the periosteum and no
peripheral periosteal reaction. Histopathologically, the
exophytic mass demonstrates a spindle cell broblastlike proliferation that contains well-developed trabeculae of bone. With time, the trabeculae often coalesce
and form a large mass of solid bone. Parosteal osteosarcoma is a low-grade sarcoma that has a small risk
of recurrence and metastasis if treated by radical
excision. With inadequate surgery, the tumor may
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CHONDROSARCOMA
Chondrosarcoma is a malignant tumor characterized
by the formation of cartilage, but not bone, by the
tumor cells. Chondrosarcomas comprise about 10% of
all primary tumors of the skeleton but are considered
by most authorities to involve the jaws only rarely.
Chondrosarcoma is about half as common as osteosarcoma and about twice as common as Ewing sarcoma.
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HISTOPATHOLOGIC FEATURES
Chondrosarcomas are composed of cartilage showing
varying degrees of maturation and cellularity. In most
cases, typical lacunar formation within the chondroid
matrix is visible, although this feature may be scarce in
poorly differentiated tumors. The tumor often shows a
lobular growth pattern, with tumor lobules separated
GRADES
Grade I chondrosarcomas closely mimic the appearance of a chondroma, composed of chondroid matrix
and chondroblasts that show only subtle variation from
the appearance of normal cartilage. The distinction
between benign and well-differentiated malignant cartilaginous tumors is notoriously difcult. Many believe
that a tumor should be considered malignant when
large, plump chondroblasts and binucleated chondrocytes are present, even in only scattered microscopic
elds. Calcication or ossication of the cartilaginous
matrix often is prominent, and mitoses are rare.
Grade II chondrosarcomas show a greater proportion of moderately sized nuclei and increased cellularity, particularly about the periphery of the lobules.
The cartilaginous matrix tends to be more myxoid,
with a less prominent hyaline matrix. The mitotic rate,
however, is low (Fig. 14-82).
Grade III chondrosarcomas are highly cellular
and may show a prominent spindle cell proliferation.
Mitoses may be prominent. Easily recognizable cartilaginous matrix containing cells within lacunae may be
scarce.
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VARIANTS
Several uncommon microscopic variants of chondrosarcoma are also recognized.
The clear cell chondrosarcoma shows cells with
abundant clear cytoplasm; this may lead to problems
in differentiation from a metastatic clear cell carcinoma. The clear cell chondrosarcoma is considered to
be a low-grade lesion.
Dedifferentiated chondrosarcoma is a highgrade malignancy that shows an admixture of welldifferentiated chondrosarcoma and a malignant
mesenchymal tumor resembling brosarcoma. If these
variants occur in the jaws, then they are exceedingly
rare.
Myxoid chondrosarcoma classically is described
as a soft tissue tumor, although intraosseous lesions
have been reported within the head and neck and elsewhere. This variant is characterized by a proliferation
of cells with clear, vacuolated, or eosinophilic cytoplasm within a background of mucoid material.
Mesenchymal chondrosarcoma is discussed in
the next section.
sinonasal lesions. The overall 5- and 10-year diseasespecic survival rates in this series were 87.2% and
70.6%, respectively. Survival was greater for patients
with conventional chondrosarcoma than for those with
the myxoid or mesenchymal variants. In the Mayo
Clinic review, no distant metastases occurred in the 56
reported patients; the 5-, 10-, and 15-year survivals
were 67.6%, 53.7%, and 43.9%, respectively. As is
obvious from these data, the importance of 5-year survival is minimal because recurrence often is a late
sequela. Patients must be followed for their lifetime.
Although these two large series suggest that the prognosis of gnathic and craniofacial chondrosarcoma is
better than that associated with osteosarcoma, previous studies have suggested that the prognosis of chondrosarcoma is worse. This disagreement may be related
to differences in the diagnostic categorization of many
cartilage-producing tumors (chondrosarcoma versus
chondroblastic osteosarcoma).
MESENCHYMAL CHONDROSARCOMA
The mesenchymal chondrosarcoma, an uncommon
and distinctive tumor of bone and soft tissue, shows a
biphasic histopathologic pattern. This aggressive form
of chondrosarcoma represents only 3% to 9% of all
chondrosarcomas.
HISTOPATHOLOGIC FEATURES
Microscopically, the mesenchymal chondrosarcoma
reveals sheets or patternless masses of small, undifferentiated spindle or round cells surrounding discrete
nodules of cartilage (Fig. 14-84). The chondroid tissue
is well differentiated, and its degree of cellularity and
atypia may vary from that of a benign chondroma to
a low-grade chondrosarcoma. The noncartilaginous
component of the tumor is difcult to differentiate
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EWING SARCOMA
Fig. 14-84 Mesenchymal chondrosarcoma. Mediumpower photomicrograph showing sheets of small basophilic
cells with focal areas of cartilaginous differentiation (right).
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HISTOPATHOLOGIC FEATURES
Ewing sarcoma is composed of small round cells with
well-delineated nuclear outlines and ill-dened cellular borders (Fig. 14-86). The tumor cells often are
arranged in broad sheets without any distinct pattern.
In some cases, variable-sized nests of tumor cells are
separated by brovascular septa, creating a lobular
pattern. Large areas of necrosis and hemorrhage are
commonly present. Ewing sarcomas are not as mor-
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which the tooth was recently removed because of complaints of local pain or signicant mobility.
Of particular interest are those cases in which diagnosis of a jaw metastasis is the rst indication that the
patient has a primary malignancy at some other anatomic site. On occasion, the oral lesion is the rst indication of an undiscovered and distant malignancy.
Location of the occult primary tumor may be difcult,
requiring extensive evaluation.
Radiographically, metastatic deposits in the jaws
usually appear as radiolucent defects. The defect may
be well circumscribed, resembling a cyst, but more
often it is ill dened with a moth-eaten appearance.
Involvement of the alveolus may resemble periodontal
disease clinically and radiographically (Fig. 14-87). On
occasion, a metastatic tumor may cause widening of
the periodontal ligament (Fig. 14-88). Some carcinomas, particularly from the prostate and breast, may
stimulate new bone formation in the metastatic site,
resulting in radiopaque or mixed radiolucent and radiopaque lesions.
Not uncommonly, patients with gnathic metastases
will have symptoms at a time when conventional radiographs fail to demonstrate detectable alterations. In
these instances, bone scintigraphy is occasionally used
because it has a higher sensitivity and a greater ability
to detect subtle osseous metastases. Some investigators
recommend this technique for patients with prolonged,
unexplained pain who have a history of cancer that is
frequently associated with osseous metastases.
HISTOPATHOLOGIC FEATURES
The microscopic appearance of metastatic carcinoma
in bone varies. In some instances, the metastatic tumor
is well differentiated and closely resembles a carci-
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sarcomas, malignant lymphomas, and malignant melanoma. Immunohistochemical reactions are usually
necessary in such cases to establish the diagnosis.
Although the diagnosis of metastatic carcinoma can
usually be determined by microscopic examination,
the nal diagnosis depends mostly on a careful medical
history and complete physical examination, with appropriate laboratory studies.
BIBLIOGRAPHY
Fig. 14-88 Carcinoma metastatic to the jaws. Periapical
radiograph showing widening of the periodontal ligament
spaces.
Osteogenesis Imperfecta
Ablin DS: Osteogenesis imperfecta: a review, Can Assoc Radiol J
49:110-123, 1998.
Binger T, Rcker M, Spitzer WJ: Dentofacial rehabilitation by
osteodistraction, augmentation and implantation despite
osteogenesis imperfecta, Int J Oral Maxillofac Surg 35:559562, 2006.
Gorlin RJ, Cohen MM Jr, Hennekam RCM: Syndromes affecting
bone: the osteogenesis imperfectas. In Syndromes of the head
and neck, ed 4, pp 178-191, New York, 2001, Oxford University Press.
Lee CYS, Ertel SK: Bone graft augmentation and dental implant
treatment in a patient with osteogenesis imperfecta: review
of the literature with a case report, Implant Dent 12:291-295,
2003.
Levin LS, Wright JM, Byrd DL et al: Osteogenesis imperfecta
with unusual skeletal lesions: report of three families, Am J
Med Genet 21:257-269, 1985.
OConnell AC, Marini JC: Evaluation of oral problems in an
osteogenesis imperfecta population, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 87:189-196, 1999.
Ormiston IW, Tideman H: Orthognathic surgery in osteogenesis
imperfecta: a case report with management considerations,
J Craniomaxillofac Surg 23:261-265, 1995.
Rauch F, Glorieux FH: Osteogenesis imperfecta, Lancet 363:13771385, 2004.
Schwartz S, Tsipouras P: Oral ndings in osteogenesis
imperfecta, Oral Surg Oral Med Oral Pathol 57:161-167,
1984.
Sillence DO, Senn A, Danks PM: Genetic heterogeneity in osteogenesis imperfecta, J Med Genet 16:101-116, 1979.
Osteopetrosis
Albuquerque MA, Melo ES, Jorge WA et al: Osteomyelitis of the
mandible associated with autosomal dominant osteopetrosis:
a case report, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
102:94-98, 2006.
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Pagets Disease
Ankrom MA, Shapiro JR: Pagets disease of bone (osteitis deformans), J Am Geriatr Soc 46:1025-1033, 1998.
Carrillo R, Morales A, Rodriguez-Peralto JL et al: Benign broosseous lesions in Pagets disease of the jaws, Oral Surg Oral
Med Oral Pathol 71:588-592, 1991.
Cheng YSL, Wright JM, Walstad WR et al: Osteosarcoma arising
in Pagets disease of the mandible, Oral Oncol 38:785-792,
2002.
Daroszewska A, Ralston SH: Mechanisms of disease: genetics of
Pagets disease of bone and related disorders, Nat Clin Pract
Rheumatol 2:270-277, 2006.
Drake WM, Kendler DL, Brown JP: Consensus statement on the
modern therapy of Pagets disease of bone from a Western
Osteoporosis Alliance Symposium, Clin Ther 23:620-626,
2001.
Gleich LL, Eberle RC, Shaha AR et al: Pagets sarcoma of the
mandible, Head Neck 17:425-430, 1995.
Mailander JC: The black beard sign of monostotic Pagets
disease of the mandible, Clin Nucl Med 11:325-327, 1986.
Mankin HJ, Hornicek FJ: Pagets sarcoma: a historical and
outcome review, Clin Orthop Relat Res 438:97-102, 2005.
Selby PL, Davie MW, Ralston SH et al: Guidelines on the management of Pagets disease of bone, Bone 31:10-19, 2002.
Siris ES: Pagets disease of bone, J Bone Miner Res 13:1061-1065,
1998.
Smith J, Eveson J: Pagets disease of bone with particular reference to dentistry, J Oral Pathol 10:233-247, 1981.
Takata S, Yasui N, Nakatsuka K et al: Evolution of understanding
of genetics of Pagets disease of bone and related diseases,
J Bone Miner Metab 22:519-523, 2004.
Tillman H: Pagets disease of bone: a clinical, radiographic and
histopathologic study of 24 cases involving the jaws, Oral Surg
Oral Med Oral Pathol 15:1225-1234, 1962.
Whyte MP: Pagets disease of bone, N Engl J Med 355:593-600,
2006.
Central Giant Cell Granuloma
Adornato MC, Paticoff KA: Intralesional corticosteroid injection
for treatment of central giant-cell granuloma, J Am Dent Assoc
132:186-190, 2001.
Auclair PL, Cuenin P, Kratochvil FJ et al: A clinical and histomorphologic comparison of the central giant cell granuloma
and the giant cell tumor, Oral Surg Oral Med Oral Pathol
66:197-208, 1988.
DeLange J, van den Akker HP: Clinical and radiological features
of central giant-cell lesions of the jaw, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 99:464-470, 2005.
DeLange J, van den Akker HP, Klip H: Incidence and diseasefree survival after surgical therapy of central giant cell granulomas of the jaw in the Netherlands: 1990-1995, Head Neck
26:792-795, 2004.
DeLange J, van der Akker HP, van Zanten GOV et al: Calcitonin
therapy in central giant cell granuloma of the jaw: a randomized double-blind placebo-controlled study, Int J Oral Maxillofac Surg 35:791-795, 2006.
DeLange J, Rosenberg AJWP, van den Akker HP et al: Treatment
of central giant cell granuloma of the jaw with calcitonin,
Int J Oral Maxillofac Surg 28:372-376, 1999.
Ficarra G, Kaban LB, Hansen LS: Giant cell lesions of the jaws:
a clinicopathologic and cytometric study, Oral Surg Oral Med
Oral Pathol 64:44-49, 1987.
Goldman KE, Marshall MK, Alessandrini E et al: Complications
of alpha-interferon therapy for aggressive central giant cell
lesion of the maxilla, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 100:285-291, 2005.
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pathologic entities, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 93:296-304, 2002.
Johnson LC, Youse M, Vinh TN et al: Juvenile active ossifying
broma: its nature, dynamics and origin, Acta Otolaryngol
Suppl 488:1-40, 1991.
Makek MS: So-called broosseous lesions of tumorous origin:
biology confronts terminology, J Craniomaxillofac Surg 15:154168, 1987.
Margo C, Ragsdale BD, Perman KI et al: Psammomatoid
(juvenile) ossifying broma of the orbit, Ophthalmology
92:150-159, 1985.
Slootweg PJ, Panders AK, Koopmans R et al: Juvenile ossifying
broma. An analysis of 33 cases with emphasis on histopathological aspects, J Oral Pathol Med 23:385-388, 1994.
Williams HK, Mangham C, Speight PM: Juvenile ossifying
broma. An analysis of eight cases and a comparison with
other bro-osseous lesions, J Oral Pathol Med 29:13-18,
2000.
Osteoma
Cutilli BJ, Quinn PD: Traumatically induced peripheral osteoma:
report of case, Oral Surg Oral Med Oral Pathol 73:667-669,
1992.
Johann AC, de Freitas JB, de Aguiar MC et al: Peripheral osteoma
of the mandible: case report and review of the literature,
J Craniomaxillofac Surg 33:276-281, 2005.
Kondoh T, Seto K, Kobayashi K: Osteoma of the mandibular
condyle: report of a case with a review of the literature, J Oral
Maxillofac Surg 56:972-979, 1998.
Ortakoglu K, Gunaydin Y, Aydintug YS et al: Osteoma of the
mandibular condyle: report of a case with 5-year follow-up,
Mil Med 170:117-120, 2005.
Richards HE, Strider JW Jr, Short SG et al: Large peripheral
osteoma arising from the genial tubercle area, Oral Surg Oral
Med Oral Pathol 61:268-271, 1986.
Schneider LC, Dolinski HB, Grodjesk JE: Solitary peripheral
osteoma of the jaws: report of a case and review of the literature, Oral Surg Oral Med Oral Pathol 38:452-455, 1980.
Woldenberg Y, Nash M, Bodner L: Peripheral osteoma of the
maxillofacial region. Diagnosis and management: a study of
14 cases, Med Oral Patol Oral Cir Bucal 10(suppl 2):E139E142, 2005.
Yassin OM, Bataineh AB, Mansour MJ: An unusual osteoma of
the mandible, J Clin Pediatr Dent 21:337-340, 1997.
Gardner Syndrome
Baykul T, Heybeli N, Oyar O et al: Multiple huge osteomas of the
mandible causing disgurement related with Gardners syndrome: case report, Auris Nasus Larynx 30:447-451, 2003.
Bilkay U, Erdem O, Ozek C et al: Benign osteoma with Gardner
syndrome: review of the literature and report of a case,
J Craniofac Surg 15:506-509, 2004.
Butler J, Healy C, Toner M et al: Gardner syndromereview and
report of a case, Oral Oncol Extra 41:89-92, 2005.
Chimenos-Kstner E, Pascual M, Blanco I et al: Hereditary
familial polyposis and Gardners syndrome: contribution
of the odontostomatology examination in its diagnosis and
a case description, Med Oral Patol Oral Cir Bucal 10:402-409,
2005.
Fotiadis C, Tsekouras DK, Antonakis P et al: A case report and
review of the literature, World J Gastroenterol 11:5408-5411,
2005.
Galiatsatos P, Foulkes WD: Familial adenomatous polyposis,
Am J Gastroenterol 101:385-398, 2006.
Gorlin RJ, Cohen MM Jr, Hennekam RCM: Gardner syndrome.
In Syndromes of the head and neck, ed 4, pp 437-444, New York,
2001, Oxford University Press.
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Lustman J, Zeltzer R: Synovial chondromatosis of the temporomandibular joint: review of the literature and case report,
Int J Oral Maxillofac Surg 18:90-94, 1989.
Miyamoto H, Sakashita H, Wilson DF et al: Synovial chondromatosis of the temporomandibular joint, Br J Oral Maxillofac Surg
38:205-208, 2000.
Petito AR, Bennett J, Assael LA et al: Synovial chondromatosis of
the temporomandibular joint: varying presentation in 4 cases,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 90:758-764,
2000.
Von Lindern JJ, Theuerkauf I, Niederhagen B et al: Synovial
chondromatosis of the temporomandibular joint: clinical,
diagnostic, and histomorphologic ndings, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 94:31-38, 2002.
Yu Q, Yang Y, Wang P et al: CT features of synovial chondromatosis in the temporomandibular joint, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 97:524-528, 2004.
Desmoplastic Fibroma
Bakaeen G, Rajab LD: Desmoplastic broma of the mandible:
report of a case, Int J Paediatr Dent 9:117-121, 1999.
Bertoni F, Present D, Marchetti C et al: Desmoplastic broma of
the jaw: the experience of the Istituto Beretta, Oral Surg Oral
Med Oral Pathol 61:179-184, 1986.
Fletcher CDM, Uni KK, Mertens F: WHO classication of tumors:
pathology and genetics of tumors of soft tissue and bone, p 288,
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Freedman PD, Cardo VA, Kerpel SM et al: Desmoplastic broma
(bromatosis) of the jaw-bones: report of a case and review
of the literature, Oral Surg Oral Med Oral Pathol 46:386-395,
1978.
Said-Al-Naief N, Fernandes R, Louis P et al: Desmoplastic broma
of the jaw: a case report and review of literature, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 101:82-94,
2006.
Templeton K, Glass N, Young SK: Desmoplastic broma of the
mandible in a child: report of a case, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 84:620-623, 1997.
Vargas-Gonzalez R, San Martin-Brieke W, Gil-Orduna C et al:
Desmoplastic broma-like tumor of maxillofacial region associated with tuberous sclerosis, Pathol Oncol Res10:237-239,
2004.
Osteosarcoma
August M, Magennis P, Dewitt D: Osteogenic sarcoma of the
jaws: factors inuencing prognosis, Int J Oral Maxillofac Surg
26:198-204, 1997.
Bennett JH, Thomas G, Evans AW et al: Osteosarcoma of the
jaws: a 30-year retrospective review, Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 90:323-333, 2000.
Canadian Society of Otolaryngology-Head and Neck Surgery
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and maxilla: a Canadian review (1980-2000), J Otolaryngol
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Fernandes R, Nikitakis NG, Pazoki A et al: Osteogenic sarcoma
of the jaw: a 10-year experience, J Oral Maxillofac Surg
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Garrington GE, Scoeld HH, Cornyn J et al: Osteosarcoma of the
jaws: analysis of 56 cases, Cancer 20:377-391, 1967.
Givol N, Buchner A, Taicher S et al: Radiological features of
osteogenic sarcoma of the jaws. A comparative study of different radiographic modalities, Dentomaxillofac Radiol 27:313320, 1998.
Huvos AG, Woodard HQ, Cahan WG et al: Postradiation
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Ewing Sarcoma
Arafat A, Ellis G, Adrian JC: Ewings sarcoma of the jaws, Oral
Surg Oral Med Oral Pathol 55:589-596, 1983.
Berk R, Heller A, Heller D et al: Ewings sarcoma of the mandible: a case report, Oral Surg Oral Med Oral Pathol Oral Radiol
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Infante-Cassio P, Gutierrez-Perez JL, Garcia-Perla A et al:
Primary Ewings sarcoma of the maxilla and zygoma: report
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Ewings sarcoma study, Hum Pathol 14:773-779, 1983.
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sarcoma of the mandible in a child: interdisciplinary treat-
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Odontogenic Cysts and Tumors*
CHAPTER OUTLINE
ODONTOGENIC CYSTS
Dentigerous Cyst
Eruption Cyst
Primordial Cyst
Odontogenic Keratocyst
Orthokeratinized Odontogenic Cyst
Nevoid Basal Cell Carcinoma Syndrome
Gingival (Alveolar) Cyst of the Newborn
Gingival Cyst of the Adult
Lateral Periodontal Cyst
Calcifying Odontogenic Cyst
Glandular Odontogenic Cyst
Buccal Bifurcation Cyst
Carcinoma Arising in Odontogenic Cysts
ODONTOGENIC TUMORS
TUMORS OF ODONTOGENIC EPITHELIUM
Ameloblastoma
*Dr. Charles A. Waldron wrote the original version of this chapter in the
rst edition of this book.
Odontogenic Cysts
With rare exceptions, epithelium-lined cysts in bone
are seen only in the jaws. Other than a few cysts that
may result from the inclusion of epithelium along
embryonic lines of fusion, most jaw cysts are lined by
epithelium that is derived from odontogenic epithelium. These are referred to as odontogenic cysts. (Nonodontogenic jaw cysts are discussed in Chapter 1.)
Odontogenic cysts are subclassied as developmental or inammatory in origin. The inciting factors that
initiate the formation of developmental cysts are
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Box 15-1
DENTIGEROUS CYST
(FOLLICULAR CYST)
The dentigerous cyst is dened as a cyst that originates by the separation of the follicle from around the
crown of an unerupted tooth. This is the most common
type of developmental odontogenic cyst, making up
about 20% of all epithelium-lined cysts of the jaws. The
dentigerous cyst encloses the crown of an unerupted
tooth and is attached to the tooth at the cementoenamel junction (Fig. 15-1). The pathogenesis of this
cyst is uncertain, but apparently it develops by accumulation of uid between the reduced enamel epithelium and the tooth crown.
Although most dentigerous cysts are considered to
be developmental in origin, there are some examples
that appear to have an inammatory pathogenesis. For
example, it has been suggested that, on occasion, a
dentigerous cyst may develop around the crown of an
unerupted permanent tooth as a result of periapical
inammation from an overlying primary tooth. Another
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in facial asymmetry. Large dentigerous cysts are uncommon, and most lesions that are considered to be large
dentigerous cysts on radiographic examination will
prove to be odontogenic keratocysts or ameloblastomas. Dentigerous cysts may become infected and be
associated with pain and swelling. Such infections may
arise in a dentigerous cyst that is associated with a
partially erupted tooth or by extension from a periapical or periodontal lesion that affects an adjacent
tooth.
Radiographically, the dentigerous cyst typically
shows a unilocular radiolucent area that is associated
with the crown of an unerupted tooth. The radiolucency usually has a well-dened and often sclerotic
border, but an infected cyst may show ill-dened
borders. A large dentigerous cyst may give the impression of a multilocular process because of the persistence of bone trabeculae within the radiolucency.
Dentigerous cysts, however, are grossly and histopathologically unilocular processes and probably never are
truly multilocular lesions.
The cyst-to-crown relationship shows several radiographic variations. In the central variety, which is the
most common, the cyst surrounds the crown of the
tooth and the crown projects into the cyst (Fig. 15-2).
The lateral variety is usually associated with mesioangular impacted mandibular third molars that are partially erupted. The cyst grows laterally along the root
surface and partially surrounds the crown (Fig. 15-3).
In the circumferential variant, the cyst surrounds the
crown and extends for some distance along the root so
that a signicant portion of the root appears to lie
within the cyst (Fig. 15-4). Rarely, a third molar may
be displaced to the lower border of the mandible or
higher up into the ascending ramus. Maxillary anterior
teeth may be displaced into the oor of the nose, and
other maxillary teeth may be moved through the maxillary sinus to the oor of the orbit. Dentigerous cysts
may displace the involved tooth for a considerable distance. Root resorption of adjacent erupted teeth can
occur.
Radiographic distinction between a small dentigerous cyst and an enlarged follicle about the crown of an
unerupted tooth is difcult and may be largely an academic exercise (Fig. 15-5). For the lesion to be considered a dentigerous cyst, some investigators believe that
the radiolucent space surrounding the tooth crown
should be at least 3 to 4 mm in diameter. Radiographic
ndings are not diagnostic for a dentigerous cyst,
however, because odontogenic keratocysts, unilocular
ameloblastomas, and many other odontogenic and
nonodontogenic tumors may have radiographic features that are essentially identical to those of a dentigerous cyst.
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HISTOPATHOLOGIC FEATURES
The histopathologic features of dentigerous cysts vary,
depending on whether the cyst is inamed or not
inamed. In the noninamed dentigerous cyst, the
brous connective tissue wall is loosely arranged and
contains considerable glycosaminoglycan ground substance. Small islands or cords of inactive-appearing
odontogenic epithelial rests may be present in the
brous wall. Occasionally these rests may be numerous, and at times pathologists who are not familiar with
oral lesions have misinterpreted this nding as ameloblastoma. The epithelial lining consists of two to four
layers of attened nonkeratinizing cells, and the epithelium and connective tissue interface is at (Fig.
15-6).
In the fairly common inamed dentigerous cyst,
the brous wall is more collagenized, with a variable
inltration of chronic inammatory cells. The epithelial lining may show varying amounts of hyperplasia
with the development of rete ridges and more denite
squamous features (Fig. 15-7). A keratinized surface is
sometimes seen, but these changes must be differentiated from those observed in the odontogenic keratocyst. Focal areas of mucous cells may be found in the
epithelial lining of dentigerous cysts (Fig. 15-8). Rarely,
ciliated columnar cells are present. Small nests of sebaceous cells rarely may be noted within the brous cyst
wall. These mucous, ciliated, and sebaceous elements
are believed to represent the multipotentiality of the
odontogenic epithelial lining in a dentigerous cyst.
Gross examination of the wall of a dentigerous cyst
may reveal one or several areas of nodular thickening
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CLINICAL FEATURES
The eruption cyst appears as a soft, often translucent
swelling in the gingival mucosa overlying the crown of
an erupting deciduous or permanent tooth. Most examples are seen in children younger than age 10. Although
the cyst may occur with any erupting tooth, the lesion
is most commonly associated with the deciduous mandibular central incisors, the rst permanent molars,
and the deciduous maxillary incisors. Surface trauma
may result in a considerable amount of blood in the
cystic uid, which imparts a blue to purple-brown
color. Such lesions sometimes are referred to as eruption hematomas (Fig. 15-9).
HISTOPATHOLOGIC FEATURES
Intact eruption cysts seldom are submitted to the oral
and maxillofacial pathology laboratory, and most
examples consist of the excised roof of the cyst, which
has been removed to facilitate tooth eruption. These
show surface oral epithelium on the superior aspect.
The underlying lamina propria shows a variable inammatory cell inltrate. The deep portion of the specimen, which represents the roof of the cyst, shows a thin
layer of nonkeratinizing squamous epithelium (Fig.
15-10).
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PRIMORDIAL CYST
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ODONTOGENIC KERATOCYST
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20%
49%
2%
13%
7%
9%
that include large series of cysts indicate that odontogenic keratocysts make up 3% to 11% of all odontogenic
cysts.
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nearly 70 years. Rare examples of peripheral odontogenic keratocysts within the gingival soft tissues have
been reported.
Fig. 15-15 Odontogenic keratocyst. Computed
tomography (CT) scan showing a large cyst involving the
crown of an unerupted maxillary third molar. The cyst largely
lls the maxillary sinus. (Courtesy of Dr. E.B. Bass.)
HISTOPATHOLOGIC FEATURES
The odontogenic keratocyst typically shows a thin,
friable wall, which is often difcult to enucleate from
the bone in one piece. The cystic lumen may contain a
clear liquid that is similar to a transudate of serum, or
it may be lled with a cheesy material that, on microscopic examination, consists of keratinaceous debris.
Microscopically, the thin brous wall is essentially
devoid of any inammatory inltrate. The epithelial
lining is composed of a uniform layer of stratied squamous epithelium, usually six to eight cells in thickness.
The epithelium and connective tissue interface is
usually at, and rete ridge formation is inconspicuous.
Detachment of portions of the cyst-lining epithelium
from the brous wall is commonly observed. The
luminal surface shows attened parakeratotic epithelial cells, which exhibit a wavy or corrugated appearance (Fig. 15-17). The basal epithelial layer is composed
of a palisaded layer of cuboidal or columnar epithelial
cells, which are often hyperchromatic. Small satellite
cysts, cords, or islands of odontogenic epithelium may
be seen within the brous wall. These structures have
been present in 7% to 26% of cases in various reported
series. In rare instances, cartilage has been observed in
the wall of an odontogenic keratocyst.
In the presence of inammatory changes, the typical
features of the odontogenic keratocyst may be altered.
The parakeratinized luminal surface may disappear,
and the epithelium may proliferate to form rete ridges
with the loss of the characteristic palisaded basal layer
(Fig. 15-18). When these changes involve most of the
cyst lining, the diagnosis of odontogenic keratocyst
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ORTHOKERATINIZED
ODONTOGENIC CYST
The designation orthokeratinized odontogenic cyst
does not denote a specic clinical type of odontogenic
cyst but refers only to an odontogenic cyst that microscopically has an orthokeratinized epithelial lining.
Although such lesions were originally called the orthokeratinized variant of odontogenic keratocyst, it is generally
accepted that they are clinicopathologically different
from the more common parakeratinized odontogenic
keratocyst and should be placed into a different category. Orthokeratinized odontogenic cysts represent 7%
to 17% of all keratinizing jaw cysts.
HISTOPATHOLOGIC FEATURES
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Box 15-2
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HISTOPATHOLOGIC FEATURES
Fig. 15-28 Nevoid basal cell carcinoma syndrome. Large cysts are present in the right and
left mandibular molar regions, together with a smaller cyst involving the right maxillary canine
in the same patient shown in Fig. 15-23. (Courtesy of Dr. Richard DeChamplain.)
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CLINICAL FEATURES
Gingival cysts of the newborn appear as small, usually
multiple whitish papules on the mucosa overlying the
alveolar processes of neonates (Fig. 15-32). The individual cysts are usually no more than 2 to 3 mm in
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HISTOPATHOLOGIC FEATURES
Examination of an intact gingival cyst of the newborn
shows a thin, attened epithelial lining with a parakeratotic luminal surface. The lumen contains keratinaceous debris.
CLINICAL FEATURES
Like the lateral periodontal cyst, the gingival cyst of the
adult shows a striking predilection to occur in the mandibular canine and premolar area (60% to 75% of cases).
Gingival cysts of the adult are most commonly found
HISTOPATHOLOGIC FEATURES
The histopathologic features of the gingival cyst of the
adult are similar to those of the lateral periodontal cyst,
consisting of a thin, attened epithelial lining with or
without focal plaques that contain clear cells (Figs. 1534 and 15-35). Small nests of these glycogen-rich clear
cells, which represent rests of the dental lamina, also
may be seen in the surrounding connective tissue. Sometimes the cystic lining is so thin that it is easily mistaken
for the endothelial lining of a dilated blood vessel.
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1%
1%
15%
4%
66% 14%
to arise from rests of the dental lamina, and it represents the intrabony counterpart of the gingival cyst of
the adult. The lateral periodontal cyst accounts for less
than 2% of all epithelium-lined jaw cysts.
In the past, the term lateral periodontal cyst was used
to describe any cyst that developed along the lateral
root surface, including lateral radicular cysts (see page
131) and odontogenic keratocysts (see page 683).
However, the lateral periodontal cyst has distinctive
clinical and microscopic features that distinguish it
from other lesions that sometimes develop in the same
location.
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B
Fig. 15-38 Lateral periodontal cyst. A larger lesion
causing root divergence.
HISTOPATHOLOGIC FEATURES
represent a variant of the lateral periodontal cyst, possibly the result of cystic degeneration and subsequent
fusion of adjacent foci of dental lamina rests. The botryoid variant often shows a multilocular radiographic
appearance, but it also may appear unilocular.
The radiographic features of the lateral periodontal
cyst are not diagnostic; an odontogenic keratocyst that
develops between the roots of adjacent teeth may show
identical radiographic ndings. An inammatory
radicular cyst that occurs laterally to a root in relation
to an accessory foramen or a cyst that arises from
periodontal inammation also may simulate a lateral
The lateral periodontal cyst has a thin, generally noninamed, brous wall, with an epithelial lining that is
only one to three cells thick in most areas. This epithelium usually consists of attened squamous cells,
but sometimes the cells are cuboidal in shape. Foci of
glycogen-rich clear cells may be interspersed among
the lining epithelial cells. Some cysts show focal nodular
thickenings of the lining epithelium, which are composed chiey of clear cells (Fig. 15-40). Clear cell epithelial rests sometimes are seen within the brous wall.
Rarely, botryoid odontogenic cysts exhibit focal areas
that histopathologically are suggestive of the glandular
odontogenic cyst (see page 697).
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2%
12% 38%
11%
10% 27%
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Fig. 15-43 Calcifying odontogenic cyst. A, Expansion of the posterior maxillary alveolus
caused by a large calcifying odontogenic cyst. B, Panoramic radiograph of the same patient
showing a large radiolucency in the posterior maxilla. A small calcied structure is seen in the
lower portion of the cyst. (Courtesy of Dr. Tom Brock.)
HISTOPATHOLOGIC FEATURES
The cystic (nonneoplastic) forms comprise 86% to 98%
of all calcifying odontogenic cysts in various reported
series. These may occur both intraosseously and
extraosseously. Most commonly, a well-dened cystic
lesion is found with a brous capsule and a lining of
odontogenic epithelium of 4 to 10 cells in thickness.
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Fig. 15-47 Glandular odontogenic cyst. A, Expansile lesion of the anterior mandible. B, The
panoramic radiograph shows a large multilocular radiolucency. (Courtesy of Dr. Cheng-Chung Lin.)
HISTOPATHOLOGIC FEATURES
The glandular odontogenic cyst is lined by squamous
epithelium of varying thickness. The interface between
the epithelium and the brous connective tissue wall
is generally at. The brous cyst wall is usually devoid
of any inammatory cell inltrate. The supercial epithelial cells that line the cyst cavity tend to be cuboidal
to columnar, resulting in an uneven hobnail and sometimes papillary surface (Fig. 15-48). Occasionally, cilia
may be noted. Pools of mucicarminophilic material are
often present within the epithelium. Cuboidal cells
usually line these pools. Mucous cells may or may not
be present within the epithelium. In focal areas, the
epithelial lining cells may form spherical nodules,
similar to those seen in lateral periodontal cysts.
There is some histopathologic overlap between the
features of the glandular odontogenic cyst and those
of some intraosseous, low-grade, predominantly cystic
mucoepidermoid carcinomas (see page 490). In
selected microscopic elds, the microscopic features
may be identical. Examination of multiple sections,
however, usually permits the differentiation of these
lesions.
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Pharoah.)
HISTOPATHOLOGIC FEATURES
The microscopic features are nonspecic and show a
cyst that is lined by nonkeratinizing stratied squamous epithelium with areas of hyperplasia. A prominent chronic inammatory cell inltrate is present in
the surrounding connective tissue wall.
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CARCINOMA ARISING IN
ODONTOGENIC CYSTS
Carcinoma arising within bone is a rare lesion that is
essentially limited to the jaws. Because the putative
source of the epithelium giving rise to the carcinoma is
odontogenic, these intraosseous jaw carcinomas are
collectively known as odontogenic carcinomas.
Odontogenic carcinomas may arise in an ameloblastoma, rarely from other odontogenic tumors, de novo
(without evidence of a preexisting lesion), or from the
epithelial lining of odontogenic cysts. Some intraosseous mucoepidermoid carcinomas (see page 490) also
may arise from mucous cells lining a dentigerous cyst.
Most intraosseous carcinomas apparently arise in
odontogenic cysts. Although infrequently documented
in the literature, carcinomatous transformation of the
lining of an odontogenic cyst may be more common
than is generally appreciated. Several studies have
shown that 1% to 2% of all oral cavity carcinomas seen
in some oral and maxillofacial pathology services may
originate from odontogenic cysts. The pathogenesis of
carcinomas arising in odontogenic cysts is unknown.
Occasionally, areas within the lining of odontogenic
cysts histopathologically demonstrate varying degrees
of epithelial dysplasia, and such changes likely give rise
to the carcinoma.
tomography of the lesion may demonstrate a destructive pattern that is not appreciated on viewing plain
radiographs. A lesion considered to be a residual periapical cyst is apparently the most common type associated with carcinomatous transformation, although
routine periapical cysts can also exhibit malignant
change. In about 25% of reported cases, the carcinoma
appeared to have arisen in a dentigerous cyst (Fig.
15-51). In one patient, the carcinoma appeared to
originate in a lateral periodontal cyst.
A few examples of carcinoma arising in an odontogenic keratocyst also have been documented (Fig.
15-52). However, some reported examples do not
appear to have arisen in true parakeratinized odontogenic keratocysts, but rather in orthokeratinized
odontogenic cysts.
HISTOPATHOLOGIC FEATURES
Most carcinomas arising in cysts have histopathologically been well-differentiated squamous cell carcinomas. It is sometimes possible to identify a transition
from a normal-appearing cyst lining to invasive squamous cell carcinoma (Figs. 15-53 and 15-54).
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Odontogenic Tumors
Odontogenic tumors comprise a complex group of
lesions of diverse histopathologic types and clinical
behavior. Some of these lesions are true neoplasms and
may rarely exhibit malignant behavior. Others may
represent tumorlike malformations (hamartomas).
Odontogenic tumors, like normal odontogenesis,
demonstrate varying inductive interactions between
odontogenic epithelium and odontogenic ectomesenchyme. This ectomesenchyme was formerly referred to
as mesenchyme because it was thought to be derived
from the mesodermal layer of the embryo. It is now
accepted that this tissue differentiates from the ectodermal layer in the cephalic portion of the embryo.
Tumors of odontogenic epithelium are composed
only of odontogenic epithelium without any participation of odontogenic ectomesenchyme.
Other odontogenic neoplasms, sometimes referred
to as mixed odontogenic tumors, are composed of
odontogenic epithelium and ectomesenchymal elements. Dental hard tissue may or may not be formed
in these lesions.
A third group, tumors of odontogenic ectomesenchyme, is composed principally of ectomesenchymal
elements. Although odontogenic epithelium may be
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Box 15-3
6%
1%
6%
66%
11%
10%
Tumors of Odontogenic
Epithelium
Epithelial odontogenic tumors are composed of odontogenic epithelium without participation of odontogenic ectomesenchyme. Several distinctly different
tumors are included in the group; ameloblastoma is the
most important and common of them.
AMELOBLASTOMA
The ameloblastoma is the most common clinically
signicant odontogenic tumor. Its relative frequency
equals the combined frequency of all other odontogenic tumors, excluding odontomas. Ameloblastomas
are tumors of odontogenic epithelial origin. Theoretically, they may arise from rests of dental lamina, from
a developing enamel organ, from the epithelial lining
of an odontogenic cyst, or from the basal cells of the
oral mucosa. Ameloblastomas are slow-growing, locally
invasive tumors that run a benign course in most cases.
They occur in three different clinicoradiographic situ-
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the radiolucent loculations are large) or as being honeycombed (when the loculations are small) (Figs.
15-59 to 15-61). Buccal and lingual cortical expansion
is frequently present. Resorption of the roots of teeth
adjacent to the tumor is common. In many cases an
unerupted tooth, most often a mandibular third molar,
is associated with the radiolucent defect. Solid amelo-
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HISTOPATHOLOGIC FEATURES
Conventional solid or multicystic intraosseous ameloblastomas show a remarkable tendency to undergo
cystic change; grossly, most tumors have varying combinations of cystic and solid features. The cysts may be
seen only at the microscopic level or may be present
as multiple large cysts that include most of the tumor.
Several microscopic subtypes of conventional ameloblastoma are recognized, but these microscopic patterns generally have little bearing on the behavior of
the tumor. Large tumors often show a combination of
microscopic patterns.
The follicular and plexiform patterns are the
most common. Less common histopathologic patterns
include the acanthomatous, granular cell, desmoplastic, and basal cell types.
FOLLICULAR PATTERN
The follicular histopathologic pattern is the most
common and recognizable. Islands of epithelium
resemble enamel organ epithelium in a mature brous
connective tissue stroma. The epithelial nests consist of
a core of loosely arranged angular cells resembling the
stellate reticulum of an enamel organ. A single layer
of tall columnar ameloblast-like cells surrounds this
central core. The nuclei of these cells are located at the
opposite pole to the basement membrane (reversed
polarity). In other areas, the peripheral cells may be
more cuboidal and resemble basal cells. Cyst formation is common and may vary from microcysts, which
form within the epithelial islands, to large macroscopic
cysts, which may be several centimeters in diameter
(Figs. 15-64 and 15-65).
Fig. 15-65 Ameloblastoma (follicular pattern). This highpower photomicrograph highlights the peripheral columnar
cells exhibiting reverse polarization.
PLEXIFORM PATTERN
The plexiform type of ameloblastoma consists of
long, anastomosing cords or larger sheets of odontogenic epithelium. The cords or sheets of epithelium are
bounded by columnar or cuboidal ameloblast-like cells
surrounding more loosely arranged epithelial cells.
The supporting stroma tends to be loosely arranged
and vascular. Cyst formation is relatively uncommon
in this variety. When it occurs, it is more often associated with stromal degeneration rather than cystic
change within the epithelium (Fig. 15-66).
ACANTHOMATOUS PATTERN
When extensive squamous metaplasia, often associated with keratin formation, occurs in the central
portions of the epithelial islands of a follicular
ameloblastoma, the term acanthomatous ameloblas-
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DESMOPLASTIC PATTERN
This type of ameloblastoma contains small islands and
cords of odontogenic epithelium in a densely collagenized stroma. Immunohistochemical studies have
shown increased production of the cytokine known as
transforming growth factor-b (TGF-) in association with
this lesion, suggesting that this may be responsible for
the desmoplasia. Peripheral columnar ameloblast-like
cells are inconspicuous about the epithelial islands
(Fig. 15-69).
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Chewning.)
UNICYSTIC AMELOBLASTOMA
The unicystic ameloblastoma has for several decades
been given separate consideration based on its clinical,
radiographic, and pathologic features. Although its
response to treatment in reports from the 1970s and
1980s suggested that this lesion might behave in a less
aggressive fashion, recent reports have disputed this
concept. Unicystic ameloblastomas account for 10% to
46% of all intraosseous ameloblastomas in various
studies. Whether the unicystic ameloblastoma originates de novo as a neoplasm or whether it is the result
of neoplastic transformation of nonneoplastic cyst epithelium has been long debated. Both mechanisms
probably occur, but proof of which is involved in an
individual patient is virtually impossible to obtain.
HISTOPATHOLOGIC FEATURES
Three histopathologic variants of unicystic ameloblastoma have been described. In the rst type (luminal
unicystic ameloblastoma), the tumor is conned to
the luminal surface of the cyst. The lesion consists of a
brous cyst wall with a lining that consists totally or
partially of ameloblastic epithelium. This demonstrates
a basal layer of columnar or cuboidal cells with hyperchromatic nuclei that show reverse polarity and basilar
cytoplasmic vacuolization (Fig. 15-74). The overlying
epithelial cells are loosely cohesive and resemble stellate reticulum. This nding does not seem to be related
to inammatory edema.
In the second microscopic variant, one or more
nodules of ameloblastoma project from the cystic lining
into the lumen of the cyst. This type is called an intraluminal unicystic ameloblastoma. These nodules
may be relatively small or largely ll the cystic lumen.
In some cases, the nodule of tumor that projects into
the lumen demonstrates an edematous, plexiform
pattern that resembles the plexiform pattern seen
in conventional ameloblastomas (Fig. 15-75). These
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lesions are sometimes referred to as plexiform unicystic ameloblastomas. The intraluminal cellular
proliferation does not always meet the strict histopathologic criteria for ameloblastoma, and this may be secondary to inammation that nearly always accompanies
this pattern. Typical ameloblastoma, however, may be
found in other, less inamed parts of the specimen.
In the third variant, known as mural unicystic
ameloblastoma, the brous wall of the cyst is inltrated by typical follicular or plexiform ameloblastoma.
The extent and depth of the ameloblastic inltration
may vary considerably. With any presumed unicystic
ameloblastoma, multiple sections through many levels
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PERIPHERAL (EXTRAOSSEOUS)
AMELOBLASTOMA
The peripheral ameloblastoma is uncommon and
accounts for about 1% to 10% of all ameloblastomas.
This tumor probably arises from rests of dental lamina
beneath the oral mucosa or from the basal epithelial
cells of the surface epithelium. Histopathologically,
these lesions have the same features as the intraosseous
form of the tumor.
CLINICAL FEATURES
The peripheral ameloblastoma is usually a painless,
nonulcerated sessile or pedunculated gingival or alveolar mucosal lesion. The clinical features are nonspecic, and most lesions are clinically considered
to represent a broma or pyogenic granuloma. Most
examples are smaller than 1.5 cm, but larger lesions
have been reported (Fig. 15-77). The tumor has been
found in patients across a wide age range, but most are
seen in middle-aged persons, with an average reported
age of 52 years.
Peripheral ameloblastomas are most commonly
found on the posterior gingival and alveolar mucosa,
and they are somewhat more common in mandibular
than in maxillary areas. In some cases, the supercial
alveolar bone becomes slightly eroded, but signicant
bone involvement does not occur. A few examples of a
HISTOPATHOLOGIC FEATURES
Peripheral ameloblastomas have islands of ameloblastic epithelium that occupy the lamina propria
underneath the surface epithelium (Fig. 15-78). The
proliferating epithelium may show any of the features
described for the intraosseous ameloblastoma; plexiform or follicular patterns are the most common. Connection of the tumor with the basal layer of the surface
epithelium is seen in about 50% of cases. Whether this
represents origin of the tumor from the basal layer of
the epithelium or merging of the tumor with the surface
epithelium has not been ascertained.
Basal cell carcinomas of the oral mucosa have
been reported, but most of these would be designated
best as peripheral ameloblastomas. A peripheral
odontogenic broma may be confused microscopically with a peripheral ameloblastoma, particularly if a
prominent epithelial component is present in the
former. The presence of dysplastic dentin or cementum-like elements in the peripheral odontogenic
broma and the lack of peripheral columnar epithelial
cells showing reverse polarity of their nuclei should
serve to distinguish the two lesions.
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HISTOPATHOLOGIC FEATURES
With malignant ameloblastomas, the primary jaw
tumor and the metastatic deposits show no microscopic
features that differ from those of ameloblastomas with
a completely benign local course. With ameloblastic
carcinomas, the metastatic deposits or primary tumor
shows the microscopic pattern of ameloblastoma in
addition to cytologic features of malignancy. These
include an increased nuclear-to-cytoplasmic ratio,
nuclear hyperchromatism, and the presence of mitoses
(Fig. 15-80). Necrosis in tumor islands and areas of
dystrophic calcication may also be present.
Fig. 15-79 Ameloblastic carcinoma. A, Rapidly growing tumor showing prominent labial
expansion of the mandible in the incisor and premolar area. B, The panoramic radiograph
shows irregular destruction of the mandible. (From Neville BW, Damm DD, White DK: Color atlas of
clinical oral pathology, ed 2, Hamilton, 1999, BC Decker.)
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HISTOPATHOLOGIC FEATURES
The clear cell odontogenic carcinoma exhibits a variable clinical pattern. A wide age range (from 14 to 89
years of age) has been described, but most cases are
diagnosed in patients older than age 50. More than
80% of the lesions develop in the mandible. Some
patients complain of pain and bony swelling; others are
relatively symptom free. Approximately 60% of patients
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2%
2%
9%
7%
53%
27%
ADENOMATOID ODONTOGENIC
TUMOR
The adenomatoid odontogenic tumor represents 3%
to 7% of all odontogenic tumors, and more than 750
examples have been reported in the literature. Although
this lesion was formerly considered to be a variant of
the ameloblastoma and was designated as adenoameloblastoma, its clinical features and biologic behavior
indicate that it is a separate entity. Although there
is evidence that the tumor cells are derived from
enamel organ epithelium, investigators have also suggested that the lesion arises from remnants of dental
lamina.
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HISTOPATHOLOGIC FEATURES
The adenomatoid odontogenic tumor is a well-dened
lesion that is usually surrounded by a thick, brous
capsule. When the lesion is bisected, the central portion
Fig. 15-87 Adenomatoid odontogenic tumor. Welldened pericoronal radiolucency enveloping the maxillary
right rst bicuspid. Note the prominent snowake
calcications. (Courtesy of Dr. William Dobbins.)
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B
Fig. 15-88 Adenomatoid odontogenic tumor. A wellcircumscribed cystlike mass can be seen enveloping the
crown of a maxillary cuspid. Note the intraluminal
vegetations, which represent nodular tumor growth.
Fig. 15-89 Adenomatoid odontogenic tumor. A, Lowpower view demonstrating a thick capsule surrounding the
tumor. B, Higher magnication showing the ductlike
epithelial structures. The nuclei of the columnar calls are
polarized away from the central spaces.
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21%
8%
57%
14%
CALCIFYING EPITHELIAL
ODONTOGENIC TUMOR
(PINDBORG TUMOR)
The calcifying epithelial odontogenic tumor, also
widely known as the Pindborg tumor, is an uncommon lesion that accounts for less than 1% of all odontogenic tumors. Approximately 200 cases have been
reported to date. Although the tumor is clearly of odontogenic origin, its histogenesis is uncertain. The tumor
cells bear a close morphologic resemblance to the cells
of the stratum intermedium of the enamel organ;
however, some investigators have recently suggested
that the tumor arises from dental lamina remnants
based on its anatomic distribution in the jaws.
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HISTOPATHOLOGIC FEATURES
The calcifying epithelial odontogenic tumor has discrete islands, strands, or sheets of polyhedral epithelial
cells in a brous stroma (Fig. 15-93). The cellular
outlines of the epithelial cells are distinct, and intercellular bridges may be noted. The nuclei show considerable variation, and giant nuclei may be seen. Some
tumors show considerable nuclear pleomorphism, but
this feature is not considered to indicate malignancy.
Large areas of amorphous, eosinophilic, hyalinized
(amyloid-like) extracellular material are also often
present. The tumor islands frequently enclose masses
of this hyaline material; this results in a cribriform
appearance. Calcications, which are a distinctive
feature of the tumor, develop within the amyloid-like
material and form concentric rings (Liesegang ring
calcications) (Fig. 15-94). These tend to fuse and
form large, complex masses.
Several microscopic variations may be encountered.
Some tumors consist of large sheets of epithelial cells
with minimal production of amyloid-like material and
calcications. Others show large diffuse masses of
amyloid-like material that contain only small nests or
islands of epithelium. A clear cell variant has been
described, in which clear cells constitute a signicant
portion of the epithelial component, and this tumor also
has been reported to have a cystic growth pattern.
The amyloid-like material in the Pindborg tumor
has been extensively investigated by histochemical,
immunohistochemical, and biochemical methods, as
well as by electron microscopy. The material generally
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HISTOPATHOLOGIC FEATURES
The microscopic ndings of squamous odontogenic
tumor are distinctive and consist of varying-shaped
islands of bland-appearing squamous epithelium in a
mature brous connective tissue stroma. The peripheral cells of the epithelial islands do not show the characteristic polarization seen in ameloblastomas (Fig.
15-97). Microcystic vacuolization and individual cell
keratinization within the epithelial islands are common
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719
23%
69%
4%
4%
AMELOBLASTIC FIBROMA
The ameloblastic broma is considered to be a true
mixed tumor in which the epithelial and mesenchymal
tissues are both neoplastic. It is an uncommon tumor,
but the data regarding its frequency are difcult to
evaluate because (particularly in earlier reports) some
lesions that were diagnosed as ameloblastic broma
may actually have represented the early developing
stage of an odontoma.
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HISTOPATHOLOGIC FEATURES
The ameloblastic broma appears as a solid, soft tissue
mass with a smooth outer surface. A denite capsule
may or may not be present. Microscopically, the tumor
is composed of a cell-rich mesenchymal tissue resembling the primitive dental papilla admixed with proliferating odontogenic epithelium. The latter may have
one of two patterns, both of which are usually present
in any given case. The most common epithelial pattern
consists of long, narrow cords of odontogenic epithelium, often in an anastomosing arrangement. These
cords are usually only two cells in thickness and are
composed of cuboidal or columnar cells (Fig. 15-100).
In the other pattern, the epithelial cells form small,
discrete islands that resemble the follicular stage of
the developing enamel organ. These show peripheral
columnar cells, which surround a mass of loosely
arranged epithelial cells that resemble stellate reticulum. In contrast to the follicular type of ameloblastoma,
these follicular islands in the ameloblastic broma
seldom demonstrate microcyst formation.
The mesenchymal portion of the ameloblastic
broma consists of plump stellate and ovoid cells in a
loose matrix, which closely resembles the developing
dental papilla. Collagen formation is generally inconspicuous. Juxtaepithelial hyalinization of the mesenchymal portion of the tumor is sometimes seen,
and occasionally diffuse areas of hyalinized acellular
lesional tissue are evident.
In recent years, a few examples of ameloblastic
broma occurring in conjunction with calcifying odontogenic cyst have been reported.
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AMELOBLASTIC FIBRO-ODONTOMA
The ameloblastic bro-odontoma is dened as a
tumor with the general features of an ameloblastic
broma but that also contains enamel and dentin.
Some investigators believe that the ameloblastic broodontoma is only a stage in the development of an
odontoma and do not consider it to be a separate entity.
Certainly the histopathologic features of a developing
odontoma may overlap somewhat with ameloblastic
bro-odontoma. There are well-documented examples,
however, of this tumor exhibiting progressive growth
and causing considerable deformity and bone destruction. Such lesions appear to be true neoplasms.
However, distinguishing between a developing odontoma and an ameloblastic bro-odontoma may be difcult based on histopathologic grounds alone.
721
21%
54%
14%
11%
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HISTOPATHOLOGIC FEATURES
The soft tissue component of the ameloblastic broodontoma is microscopically identical to the ameloblastic broma and has narrow cords and small
islands of odontogenic epithelium in a loose primitiveappearing connective tissue that resembles the dental
papilla. The calcifying element consists of foci of
enamel and dentin matrix formation in close relationship to the epithelial structures (Fig. 15-104). The more
calcied lesions show mature dental structures in the
form of rudimentary small teeth or conglomerate
masses of enamel and dentin. Some researchers have
designated a similar tumor in which the calcifying
component consists only of dentin matrix and dentinoid material as ameloblastic bro-dentinoma. It is
questionable whether this lesion represents a separate
entity, and it is probably best considered as only a
variant of the ameloblastic bro-odontoma.
AMELOBLASTIC FIBROSARCOMA
(AMELOBLASTIC SARCOMA)
The rare ameloblastic brosarcoma is considered
to be the malignant counterpart of the ameloblastic
broma, and slightly more than 60 cases have been
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HISTOPATHOLOGIC FEATURES
Ameloblastic brosarcomas contain an epithelial component similar to that seen in the ameloblastic broma,
although it is frequently less prominent than that
present in the typical ameloblastic broma. The epithelial component appears histopathologically benign and
does not demonstrate any cytologic atypia. The mesenchymal portion of the tumor, however, is highly cellular and shows hyperchromatic and often-bizarre
pleomorphic cells (Fig. 15-106). Mitoses are usually
prominent. In some cases with multiple recurrences,
the epithelial component becomes progressively less
conspicuous so that the tumor eventually shows only a
poorly differentiated brosarcoma.
In a few instances, dysplastic dentin or small
amounts of enamel may be formed. Some have called
such lesions ameloblastic dentinosarcomas or ameloblastic bro-odontosarcomas. This additional subclassication, however, appears unnecessary. Another
rare event that actually may be overrepresented in the
literature is concurrent malignant transformation of
both the epithelial and mesenchymal elements of an
ameloblastic broma, resulting in an ameloblastic
carcinosarcoma.
ODONTOAMELOBLASTOMA
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than 20 cases have been reported with sufcient documentation to support this diagnosis. This tumor was
formerly called ameloblastic odontoma and was confused
with the more common (though still relatively rare)
lesion currently designated as ameloblastic broodontoma. Because the clinical behavior of these two
tumors is quite different, they should be distinguished
from one another. This neoplasm is also frequently
confused with an odontoma that is in its early stages of
development.
HISTOPATHOLOGIC FEATURES
The histopathologic features of the odontoameloblastoma are complex. The proliferating epithelial portion
of the tumor has features of an ameloblastoma, most
often of the plexiform or follicular pattern. The ameloblastic component is intermingled with immature or
more mature dental tissue in the form of developing
rudimentary teeth, which is similar to the appearance
of a compound odontoma, or conglomerate masses
of enamel, dentin, and cementum, as seen in a complex
odontoma.
ODONTOMA
Odontomas are the most common types of odontogenic tumors. Their prevalence exceeds that of all other
odontogenic tumors combined. Odontomas are considered to be developmental anomalies (hamartomas),
rather than true neoplasms. When fully developed,
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lesion. A complex odontoma, however, may be radiographically confused with an osteoma or some other
highly calcied bone lesion.
HISTOPATHOLOGIC FEATURES
The compound odontoma consists of multiple structures resembling small, single-rooted teeth, contained
in a loose brous matrix (Fig. 15-110). The mature
enamel caps of the toothlike structures are lost during
decalcication for preparation of the microscopic
section, but varying amounts of enamel matrix are
often present. Pulp tissue may be seen in the coronal
and root portions of the toothlike structures. In patients
with developing odontomas, structures that resemble
tooth germs are present.
Complex odontomas consist largely of mature
tubular dentin. This dentin encloses clefts or hollow
circular structures that contained the mature enamel
725
Fig. 15-109 Complex odontoma. A large radiopaque mass is overlying the crown of the
mandibular right second molar, which has been displaced to the inferior border of the
mandible.
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10%
29%
6%
18%
29%
8%
Tumors of Odontogenic
Ectomesenchyme
CENTRAL ODONTOGENIC FIBROMA
The central odontogenic broma is an uncommon
and somewhat controversial lesion. Approximately
70 examples have been reported. Formerly, some oral
and maxillofacial pathologists designated solid brous
masses that were almost always associated with the
crown of an unerupted tooth as odontogenic bromas.
Most oral and maxillofacial pathologists today consider
HISTOPATHOLOGIC FEATURES
Lesions reported as central odontogenic broma have
shown considerable histopathologic diversity; this
has led some authors to describe two separate types,
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although this concept has been questioned. The socalled simple odontogenic broma is composed of
stellate broblasts, often arranged in a whorled pattern
with ne collagen brils and considerable ground substance (Fig. 15-114). Small foci of odontogenic epithelial rests may or may not be present. Occasional foci of
dystrophic calcication may be seen. Some investigators have suggested that this lesion actually belongs
with the spectrum of odontogenic myxoma and should
be designated as a myxobroma. A more collagenized
odontogenic broma needs to be differentiated from a
desmoplastic broma, which is a more aggressive
lesion. The desmoplastic broma, however, does not
have an epithelial component.
The central odontogenic broma, World Health
Organization (WHO) type, has a more complex
pattern, which often consists of a fairly cellular brous
727
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HISTOPATHOLOGIC FEATURES
The peripheral odontogenic broma shows similar
histopathologic features to the central odontogenic
broma (WHO type). The tumor consists of interwoven fascicles of cellular brous connective tissue, which
may be interspersed with areas of less cellular, myxoid
connective tissue. A granular cell change has been
rarely identied in the connective tissue component,
and giant cell granulomalike areas have been described
in a few lesions. Islands or strands of odontogenic epithelium are scattered throughout the connective tissue.
These may be prominent or scarce. The epithelial cells
may show vacuolization. Dysplastic dentin, amorphous
ovoid cementum-like calcications, and trabeculae of
osteoid may also be present.
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HISTOPATHOLOGIC FEATURES
The granular cell odontogenic tumor is composed of
large eosinophilic granular cells, which closely resemble the granular cells seen in the soft tissue granular
cell tumor (see page 536) or the granular cells seen in
the granular cell variant of the ameloblastoma (see
page 709). Narrow cords or small islands of odontogenic epithelium are scattered among the granular
cells (Fig. 15-119). Small cementum-like or dystrophic
calcications associated with the granular cells have
been seen in some lesions.
The nature of the granular cells is controversial.
Ultrastructural studies reveal the features of mesenchymal cells, and bodies consistent with lysosomal
structures have been identied within the lesional cell
cytoplasm. Immunohistochemically, the granular cells
in the granular cell odontogenic tumor do not react
with antibodies directed against S-100 protein, in contrast to the positive S-100 reactivity of the granular cell
tumor.
ODONTOGENIC MYXOMA
Myxomas of the jaws are believed to arise from odontogenic ectomesenchyme. They bear a close microscopic resemblance to the mesenchymal portion of a
developing tooth. Formerly, some investigators made a
distinction between odontogenic myxomas (derived
from odontogenic mesenchyme) and osteogenic
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16%
28%
9%
9%
20% 18%
HISTOPATHOLOGIC FEATURES
At the time of surgery or gross examination of the specimen, the gelatinous, loose structure of the myxoma is
obvious (Fig. 15-124). Microscopically, the tumor is
composed of haphazardly arranged stellate, spindleshaped, and round cells in an abundant, loose myxoid
stroma that contains only a few collagen brils (Fig.
15-125). Histochemical study shows that the ground
substance is composed of glycosaminoglycans, chiey
hyaluronic acid and chondroitin sulfate. Immunohistochemically, the myxoma cells show diffuse immunoreactivity with antibodies directed against vimentin, with
focal reactivity for muscle-specic actin. Small islands
of inactive-appearing odontogenic epithelial rests may
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CEMENTOBLASTOMA (TRUE
CEMENTOMA)
Fig. 15-125 Odontogenic myxoma. A loose, myxomatous
tumor can be seen lling the marrow spaces between the
bony trabeculae. The inset shows stellate-shaped cells and
ne collagen brils.
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Akrish S, Buchner JA, Shoshani Y et al: Ameloblastic carcinoma:
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ameloblastoma, J Oral Maxillofac Surg 65:777-783, 2007.
Corio RL, Goldblatt LI, Edwards PA et al: Ameloblastic carcinoma: a clinicopathologic assessment of eight cases, Oral Surg
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Eliasson A, Moser RJ III, Tenholder MF: Diagnosis and treatment
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1989.
Eversole LR: Malignant epithelial odontogenic tumors, Semin
Diagn Pathol 16:317-324, 1999.
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Adenomatoid Odontogenic Tumor
Courtney RM, Kerr DA: The odontogenic adenomatoid tumor:
a comprehensive review of 21 cases, Oral Surg Oral Med Oral
Pathol 39:424-435, 1975.
Damm DD, White DK, Drummond JF et al: Combined epithelial
odontogenic tumor: adenomatoid odontogenic tumor and
calcifying epithelial odontogenic tumor, Oral Surg Oral Med
Oral Pathol 55:487-496, 1983.
Giansanti JS, Someren A, Waldron CA: Odontogenic adenomatoid tumor (adenoameloblastoma), Oral Surg Oral Med Oral
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Leon JE, Mata GM, Fregnani ER et al: Clinicopathological and
immunohistochemical study of 39 cases of adenomatoid
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Miyake M, Nagahata S, Nishihara J et al: Combined adenomatoid
odontogenic tumor and calcifying epithelial odontogenic
tumor: report of a case and ultrastructural study, J Oral Maxillofac Surg 54:788-793, 1996.
Philipsen HP, Reichart PA: Adenomatoid odontogenic tumour:
facts and gures, Oral Oncol 35:125-131, 1999.
Philipsen HP, Srisuwan T, Reichart PA: Adenomatoid odontogenic tumor mimicking a periapical (radicular) cyst: a case
report, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
94:246-248, 2002.
Poulson TC, Greer RO: Adenomatoid odontogenic tumor: clinicopathologic and ultrastructural concepts, J Oral Maxillofac
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Calcifying Epithelial Odontogenic Tumor
Anavi Y, Kaplan I, Citir M et al: Clear-cell variant of calcifying
epithelial odontogenic tumor: clinical and radiographic characteristics, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
95:332-339, 2003.
Aviel-Ronen S, Liokumovich P, Rahima D et al: The amyloid
deposit in calcifying epithelial odontogenic tumor is immunoreactive for cytokeratins, Arch Pathol Lab Med 124:872876, 2000.
Basu MK, Matthews JB, Sear AJ et al: Calcifying epithelial odontogenic tumour: a case showing features of malignancy, J Oral
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Bridle C, Visram K, Piper K et al: Maxillary calcifying epithelial
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Oral Pathol Oral Radiol Endod 102:e12-e15, 2006.
Cheng Y-SL, Wright JM, Walstad WR et al: Calcifying epithelial
odontogenic tumor showing microscopic features of potential
malignant behavior, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 93:287-295, 2002.
Dantas da Silveira EJ, Gordn-Nez MA, Guerra Seabra FR
et al: Peripheral calcifying epithelial odontogenic tumor associated with generalized drug-induced gingival growth: a case
report, J Oral Maxillofac Surg 65:341-345, 2007.
Franklin CD, Pindborg JJ: The calcifying epithelial odontogenic
tumor: a review and analysis of 113 cases, Oral Surg Oral Med
Oral Pathol 42:753-765, 1976.
Germanier Y, Bornstein MM, Stauffer E et al: Calcifying epithelial odontogenic (Pindborg) tumor of the mandible with clear
cell component treated by conservative surgery: report of a
case, J Oral Maxillofac Surg 63:1377-1382, 2005.
Gopalakrishnan R, Simonton S, Rohrer MD et al: Cystic variant
of calcifying epithelial odontogenic tumor, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 102:773-777, 2006.
Houston GD, Fowler CB: Extraosseous calcifying epithelial
odontogenic tumor: report of two cases and review of the
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literature, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
83:577-583, 1997.
Kaplan I, Buchner A, Calderon S et al: Radiological and clinical
features of calcifying epithelial odontogenic tumour, Dentomaxillofac Radiol 30:22-28, 2001.
Kawano K, Ono K, Yada N et al: Malignant calcifying epithelial
odontogenic tumor of the mandible: report of a case with
pulmonary metastasis showing remarkable response to platinum derivatives, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 104:76-81, 2007.
Kumamoto H, Sato I, Tateno H et al: Clear cell variant of calcifying epithelial odontogenic tumor (CEOT) in the maxilla:
report of a case with immunohistochemical and ultrastructural investigations, J Oral Pathol Med 28:187-191, 1999.
Philipsen HP, Reichart PA: Calcifying epithelial odontogenic
tumour: biological prole based on 181 cases from the literature, Oral Oncol 36:17-26, 2000.
Pindborg JJ: A calcifying epithelial odontogenic tumor, Cancer
11:838-843, 1958.
Seim P, Regezi JA, ORyan F: Hybrid ameloblastoma and calcifying epithelial odontogenic tumor: case report, J Oral Maxillofac
Surg 63:852-855, 2005.
Solomon A, Murphy CL, Weaver K et al: Calcifying epithelial
odontogenic (Pindborg) tumor-associated amyloid consists of
a novel human protein, J Lab Clin Med 142:348-355, 2003.
Veness MJ, Morgan G, Collins AP et al: Calcifying epithelial
odontogenic (Pindborg) tumor with malignant transformation and metastatic spread, Head Neck 23:692-696, 2001.
Squamous Odontogenic Tumor
Baden E, Doyle J, Mesa M et al: Squamous odontogenic tumor:
report of three cases including the rst extraosseous case,
Oral Surg Oral Med Oral Pathol 75:733-738, 1993.
Goldblatt LI, Brannon RB, Ellis GL: Squamous odontogenic
tumor: report of ve cases and review of the literature, Oral
Surg Oral Med Oral Pathol 54:187-196, 1982.
Haghighat K, Kalmar JR, Mariotti AJ: Squamous odontogenic
tumor: diagnosis and management, J Periodontol 73:653-656,
2002.
Ide F, Shimoyama T, Horie N et al: Intraosseous squamous cell
carcinoma arising in association with a squamous odontogenic tumour of the mandible, Oral Oncol 35:431-434,
1999.
Kim K, Mintz SM, Stevens J: Squamous odontogenic tumor
causing erosion of the lingual cortical plate in the mandible:
a report of 2 cases, J Oral Maxillofac Surg 65:1227-1231,
2007.
Krithika C, Vardhan BG, Saraswathy K et al: Radiolucency in
the anterior maxilla associated with an impacted tooth, Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 103:164-168,
2007.
Kusama K, Kawashima A, Nagai H et al: Squamous odontogenic
tumor of the maxilla: report of a case, J Oral Sci 40:119-122,
1998.
Leider AS, Jonker A, Cook HE: Multicentric familial squamous
odontogenic tumor, Oral Surg Oral Med Oral Pathol 68:175181, 1989.
Mills WP, Davilla MA, Beattenmuller EA et al: Squamous odontogenic tumor: report of a case with lesions in three quadrants, Oral Surg Oral Med Oral Pathol 61:557-563, 1986.
Philipsen HP, Reichart PA: Squamous odontogenic tumor (SOT):
a benign neoplasm of the periodontium. A review of 36
reported cases, J Clin Periodontol 23:922-926, 1996.
Pullon PA, Shafer WG, Elzay RP et al: Squamous odontogenic
tumor: report of six cases of a previously undescribed lesion,
Oral Surg Oral Med Oral Pathol 40:616-630, 1975.
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Oral Surg Oral Med Oral Pathol 71:371-373, 1991.
LaBriola JD, Steiner M, Bernstein ML et al: Odontoameloblastoma, J Oral Surg 38:139-143, 1980.
Odontoma
Ashkenazi M, Greenberg BP, Chodik G et al: Postoperative prognosis of unerupted teeth after removal of supernumerary
teeth or odontomas, Am J Orthod Dentofacial Orthop 131:614619, 2007.
Budnick SD: Compound and complex odontomas, Oral Surg Oral
Med Oral Pathol 42:501-506, 1976.
Cohen DM, Bhattacharyya I: Ameloblastic broma, ameloblastic
bro-odontoma, and odontoma, Oral Maxillofac Surg Clin North
Am 16:375-384, 2004.
Ide F, Shimoyama T, Horie N: Gingival peripheral odontoma in
an adult: case report, J Periodontol 71:830-832, 2000.
Kaugars GE, Miller ME, Abbey LM: Odontomas, Oral Surg Oral
Med Oral Pathol 67:172-176, 1989.
Miki Y, Oda Y, Iwaya N et al: Clinicopathological studies of
odontoma in 47 patients, J Oral Sci 41:173-176, 1999.
Owens BM, Schuman NJ, Mincer HH et al: Dental odontomas:
a retrospective study of 104 cases, J Clin Pediatr Dent 21:261264, 1997.
Sapp JP, Gardner DG: An ultrastructural study of the calcications in calcifying odontogenic cysts and odontomas, Oral
Surg Oral Med Oral Pathol 44:754-766, 1977.
Sedano HO, Pindborg JJ: Ghost cell epithelium in odontomas,
J Oral Pathol 4:27-30, 1975.
Tomizawa M, Otsuka Y, Noda T: Clinical observations of odontomas in Japanese children: 39 cases including one recurrent
case, Int J Paediatr Dent 15:37-43, 2005.
Central Odontogenic Fibroma
Allen CM, Hammond HL, Stimson PG: Central odontogenic
broma WHO type: a report of 3 cases with an unusual associated giant cell reaction, Oral Surg Oral Med Oral Pathol
73:62-66, 1992.
Daniels JSM: Central odontogenic broma of the mandible: a
case report and review of the literature, Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 98:295-300, 2004.
Dunlap CL: Odontogenic broma, Semin Diagn Pathol 16:293296, 1999.
Gardner DG: The central odontogenic broma: an attempt at
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1980.
Gardner DG: Central odontogenic broma current concepts,
J Oral Pathol Med 25:556-561, 1996.
Handlers JP, Abrams AM, Melrose RJ et al: Central odontogenic
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the literature, J Oral Maxillofac Surg 49:46-54, 1991.
Ide F, Sakashita H, Kusama K: Ameloblastomatoid, central odontogenic broma: an epithelium-rich variant, J Oral Pathol Med
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Kaffe I, Buchner A: Radiologic features of central odontogenic
broma, Oral Surg Oral Med Oral Pathol 78:811-818, 1994.
Mosqueda Taylor A, Bermudez Flores V, Diaz Franco MA: Combined central odontogenic broma and giant cell granulomalike lesion of the mandible: report of a case and review of the
literature, J Oral Maxillofac Surg 57:1258-1262, 1999.
Odell EW, Lombardi T, Barrett AW et al: Hybrid central giant
cell granuloma and central odontogenic broma-like lesions
of the jaws, Histopathology 30:165-171, 1997.
Ramer M, Buonocore P, Krost B: Central odontogenic broma
report of a case and review of the literature, Periodontal Clin
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Waldron CA, Thompson CW, Conner WA: Granular cell ameloblastic broma, Oral Surg Oral Med Oral Pathol 16:1202-1213,
1963.
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broma), Oral Surg Oral Med Oral Pathol 45:396-405, 1978.
Yih W-Y, Thompson C, Meshul CK et al: Central odontogenic
granular cell tumor of the jaw: report of case and immunohistochemical and electron microscopic study, J Oral Maxillofac Surg 53:453-459, 1995.
Myxoma
Barker BF: Odontogenic myxoma, Semin Diagn Pathol 16:297301, 1999.
Barros RE, Domingnez PV, Cabrini RL: Myxoma of the jaws, Oral
Surg Oral Med Oral Pathol 27:225-236, 1969.
Chiodo AA, Strumas N, Gilbert RW et al: Management of odontogenic myxoma of the maxilla, Otolaryngol Head Neck Surg
117:S73-76, 1997.
Goldblatt LI: Ultrastructural study of an odontogenic myxoma,
Oral Surg Oral Med Oral Pathol 42:206-220, 1976.
Gosh BC, Huvos AG, Gerald FP et al: Myxoma of the jaw bones,
Cancer 31:237-240, 1973.
Kaffe I, Naor H, Buchner A: Clinical and radiological features
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26:299-303, 1997.
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myxoma (myxosarcoma) of the maxilla, Scan J Dent Res
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Noffke CEE, Raubenheimer EJ, Chabikuli NJ et al: Odontogenic
myxoma: review of the literature and report of 30 cases from
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104:101-109, 2007.
Pahl S, Henn W, Binger T et al: Malignant odontogenic myxoma
of the maxilla: case with cytogenetic conrmation, J Laryngol
Otol 114:533-535, 2000.
Peltola J, Magnusson B, Happonen R-P et al: Odontogenic
myxomaa radiographic study of 21 tumours, Br J Oral Maxillofac Surg 32:298-302, 1994.
Schmidt-Westhausen A, Becker J, Schuppan D et al: Odontogenic myxomacharacterisation of the extracellular matrix
(ECM) of the tumour stroma, Eur J Cancer B Oral Oncol
30B:377-380, 1994.
Simon ENM, Merkx MAW, Vuhahula E et al: Odontogenic
myxomas: a clinicopathologic study of 33 cases, Int J Oral
Maxillofac Surg 33:333-337, 2004.
White DK, Chen SY, Mohnae AM et al: Odontogenic myxoma:
a clinical and ultrastructural study, Oral Surg Oral Med Oral
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Zhao M, Lu Y, Takata T et al: Immunohistochemical and histochemical characterisation of the mucosubstances of odontogenic myxoma: histogenesis and differential diagnosis, Pathol
Res Pract 195:391-397, 1999.
Zimmerman DC, Dahlin DC: Myxomatous tumors of the jaws,
Oral Surg Oral Med Oral Pathol 11:1069-1080, 1958.
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Dermatologic Diseases
CHAPTER OUTLINE
Ectodermal Dysplasia
White Sponge Nevus
Hereditary Benign Intraepithelial
Dyskeratosis
Pachyonychia Congenita
Dyskeratosis Congenita
Xeroderma Pigmentosum
Hereditary Mucoepithelial Dysplasia
Incontinentia Pigmenti
Dariers Disease
Warty Dyskeratoma
Peutz-Jeghers Syndrome
Hereditary Hemorrhagic Telangiectasia
Ehlers-Danlos Syndromes
Tuberous Sclerosis
Multiple Hamartoma Syndrome
Epidermolysis Bullosa
ECTODERMAL DYSPLASIA
Ectodermal dysplasia represents a group of inherited
conditions in which two or more ectodermally derived
anatomic structures fail to develop. Thus depending on
the type of ectodermal dysplasia, hypoplasia or aplasia
of tissues (e.g., skin, hair, nails, teeth, sweat glands) may
be seen. The various types of this disorder may be
inherited in any one of several genetic patterns, including autosomal dominant, autosomal recessive, and
X-linked patterns. Even though by some accounts more
than 170 different subtypes of ectodermal dysplasia
can be dened, these disorders are considered to be
relatively rare, with an estimated frequency of seven
cases occurring in every 10,000 births. For fewer than
20% of these conditions, the specic genetic mutations
CLINICAL FEATURES
Perhaps the best known of the ectodermal dysplasia
syndromes is hypohidrotic ectodermal dysplasia.
In most instances, this disorder seems to show an
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HISTOPATHOLOGIC FEATURES
Histopathologic examination of the skin from a patient
with hypohidrotic ectodermal dysplasia shows a
decreased number of sweat glands and hair follicles.
The adnexal structures that are present are hypoplastic
and malformed.
CLINICAL FEATURES
The lesions of white sponge nevus usually appear at
birth or in early childhood, but sometimes the condition develops during adolescence. Symmetrical, thickened, white, corrugated or velvety, diffuse plaques
affect the buccal mucosa bilaterally in most instances
(Fig. 16-4). Other common intraoral sites of involvement include the ventral tongue, labial mucosa, soft
palate, alveolar mucosa, and oor of the mouth,
although the extent of involvement can vary from
patient to patient. Extraoral mucosal sites, such as the
nasal, esophageal, laryngeal, and anogenital mucosa,
appear to be less commonly affected. Patients are
usually asymptomatic.
HISTOPATHOLOGIC FEATURES
The microscopic features of white sponge nevus are
characteristic but not necessarily pathognomonic.
Prominent hyperparakeratosis and marked acanthosis
with clearing of the cytoplasm of the cells in the spinous
layer are common features (Figs. 16-5 and 16-6);
however, similar microscopic ndings may be associated with leukoedema and hereditary benign intraepithelial dyskeratosis (HBID). In some instances, an
eosinophilic condensation is noted in the perinuclear
region of the cells in the supercial layers of the epithelium, a feature that is unique to white sponge nevus.
Ultrastructurally, this condensed material can be identied as tangled masses of keratin tonolaments.
Exfoliative cytologic studies may provide more
denitive diagnostic information. A cytologic preparation stained with the Papanicolaou method often shows
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CLINICAL FEATURES
the eosinophilic perinuclear condensation of the epithelial cell cytoplasm to a greater extent than does the
histopathologic section (Fig. 16-7).
HEREDITARY BENIGN
INTRAEPITHELIAL
DYSKERATOSIS (WITKOPVON SALLMANN SYNDROME)
Hereditary benign intraepithelial dyskeratosis
(HBID) is a rare autosomal dominant genodermatosis
primarily affecting descendants of a triracial isolate
HISTOPATHOLOGIC FEATURES
The histopathologic features of HBID include prominent parakeratin production in addition to marked
acanthosis. A peculiar dyskeratotic process, similar to
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PACHYONYCHIA CONGENITA
(JADASSOHN-LEWANDOWSKY TYPE;
JACKSON-LAWLER TYPE)
Pachyonychia congenita is a group of rare genodermatoses that are usually inherited as an autosomal
dominant trait. The nails are dramatically affected in
most patients, but oral lesions are seen only in patients
affected by the Jadassohn-Lewandowsky form of the
disease (pachyonychia congenita type 1). Fewer than
500 cases have been reported. Specic mutations in
either the keratin 6a or keratin 16 gene have been
detected for the Jadassohn-Lewandowsky type of
pachyonychia congenita, whereas mutations of either
the keratin 6b or keratin 17 gene are associated with
the Jackson-Lawler form (pachyonychia congenita
type 2).
CLINICAL FEATURES
Virtually all patients with pachyonychia congenita
exhibit characteristic nail changes, either at birth or in
the early neonatal period. The free margins of the nails
are lifted up because of an accumulation of keratinaceous material in the nail beds. This results in a
pinched, tubular conguration. Ultimately, nail loss
may occur (Fig. 16-11).
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HISTOPATHOLOGIC FEATURES
Microscopic examination of lesional oral mucosa
shows marked hyperparakeratosis and acanthosis with
perinuclear clearing of the epithelial cells.
DYSKERATOSIS CONGENITA
(COLE-ENGMAN SYNDROME;
ZINSSER-COLE-ENGMAN SYNDROME)
Dyskeratosis congenita is a rare genodermatosis that
is usually inherited as an X-linked recessive trait, resulting in a striking male predilection. Autosomal dominant and autosomal recessive forms, although less
common, have been reported. Mutations in the DKC1
gene have been determined to cause the X-linked form
of dyskeratosis congenita. The mutated gene appears
to disrupt the normal maintenance of telomerase, an
enzyme that is critical in determining normal cellular
longevity. The clinician should be aware of the condition because the oral lesions may undergo malignant
transformation, and patients are susceptible to aplastic
anemia.
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HISTOPATHOLOGIC FEATURES
Biopsy specimens of the early oral mucosal lesions
show hyperorthokeratosis with epithelial atrophy. As
the lesions progress, epithelial dysplasia develops until
frank squamous cell carcinoma evolves.
Fig. 16-14 Dyskeratosis congenita. Dysplastic nail
changes.
CLINICAL FEATURES
Dyskeratosis congenita usually becomes evident during
the rst 10 years of life. A reticular pattern of skin
hyperpigmentation develops, affecting the face, neck,
and upper chest. In addition, abnormal, dysplastic
changes of the nails are evident at this time (Fig.
16-14).
Intraorally, the tongue and buccal mucosa develop
bullae; these are followed by erosions and, eventually,
leukoplakic lesions (Fig. 16-15). The leukoplakic lesions
are considered to be premalignant, and approximately
one third of them become malignant in a 10- to 30year period. The actual rate of transformation may be
higher, but this may not be appreciated because of
the shortened life span of these patients. Rapidly
progressive periodontal disease has been reported
sporadically.
Thrombocytopenia is usually the rst hematologic
problem that develops, typically during the second
decade of life, followed by anemia. Ultimately, aplastic
XERODERMA PIGMENTOSUM
Xeroderma pigmentosum is a rare genodermatosis
in which numerous cutaneous malignancies develop
at a very early age. The prevalence of the condition in
the United States is estimated to be 1 in 250,000 to
500,000. The condition is inherited as an autosomal
recessive trait and is caused by one of several defects
in the excision repair and/or postreplication repair
mechanism of DNA. As a result of the inability of the
epithelial cells to repair ultraviolet (UV) light-induced
damage, mutations in the epithelial cells occur, leading
to the development of skin cancer at a rate 1000 to
4000 times what would normally be expected in people
younger than 20 years of age.
CLINICAL FEATURES
During the rst few years of life, patients affected by
xeroderma pigmentosum show a markedly increased
tendency to sunburn. Skin changes, such as atrophy,
freckled pigmentation, and patchy depigmentation,
soon follow (Fig. 16-16). In early childhood, actinic
keratoses begin developing, a process that normally
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HISTOPATHOLOGIC FEATURES
The histopathologic features of xeroderma pigmentosum are relatively nonspecic, in that the cutaneous
premalignant lesions and malignancies that occur are
microscopically indistinguishable from those observed
in unaffected patients.
HEREDITARY MUCOEPITHELIAL
DYSPLASIA
Hereditary mucoepithelial dysplasia is a rare disorder that may occur sporadically or may be inherited as
an autosomal dominant trait. Approximately 30 cases
have been reported. For reasons that are not entirely
understood, the mucosal epithelial cells do not develop
in a normal fashion, and for this reason the designation
of dysplasia has been given. However, in this situation,
no increased risk of malignant transformation is seen.
When a cervical exfoliative cytologic preparation (Pap
smear) is done, the epithelial cells that are harvested
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CLINICAL FEATURES
Hereditary mucoepithelial dysplasia is characterized
by both cutaneous and mucosal abnormalities. Patients
typically have sparse, coarse hair with nonscarring alopecia. Eyelashes and eyebrows are generally affected
(Fig. 16-17). Severe photophobia develops at an early
age, and most of these patients will have evidence of
cataracts beginning in childhood or early adult life.
Corneal vascularization, keratitis, and nystagmus are
also commonly described. As would be expected, vision
is usually markedly impaired for these patients. Other
skin manifestations include a prominent perineal rash
that appears during infancy, as well as a widespread
rough, dry texture because of follicular keratosis.
Pulmonary complications related to mucoepithelial
dysplasia can range in severity, presumably because of
the degree of gene expression. In one family, cavitary
bullae were reported to form within the lung parenchyma, and these led to recurrent bouts of pneumonia,
often resulting in life-threatening complications.
The oral manifestations of hereditary mucoepithelial dysplasia are usually quite striking, appearing as
demarcated ery-red erythema of the hard palate (Fig.
16-18), with generally less involvement of the attached
gingivae and tongue mucosa. These mucosal alterations are typically asymptomatic, despite their remarkable clinical appearance. The nasal, conjunctival,
vaginal, cervical, urethral, and bladder mucosa may
have the same unusual erythematous features.
HISTOPATHOLOGIC FEATURES
Biopsies of the mucosal lesions of hereditary mucoepithelial dysplasia show epithelium with minimal keratinization and a disorganized maturation pattern. The
squamous epithelial cells may have a relatively high
nuclear/cytoplasmic ratio, but signicant nuclear or
cellular pleomorphism is not observed. Cytoplasmic
vacuoles have been described and may appear as
grayish inclusions (Fig. 16-19). These vacuoles also
may be observed in exfoliative cytology samples. Ultrastructurally, the lesional cells have been described as
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CLINICAL FEATURES
The clinical manifestations of incontinentia pigmenti
usually begin in the rst few weeks of infancy. There
are four stages:
1. Vesicular stageVesiculobullous lesions appear on
the skin of the trunk and limbs. Spontaneous resolution occurs within 4 months.
2. Verrucous stageVerrucous cutaneous plaques
develop, affecting the limbs. These clear by 6 months
of age, evolving into the third stage.
3. Hyperpigmentation stageMacular, brown skin
lesions appear, characterized by a strange swirling
pattern (Fig. 16-20), although these tend to fade
around the time of puberty.
4. Atrophy and depigmentation stageAtrophy and
depigmentation of the skin ultimately occur.
CNS abnormalities occur in approximately 30% of
affected patients. The most common problems are
mental retardation, seizure disorders, and motor difculties. Ocular problems (e.g., strabismus, nystagmus,
cataracts, retinal vascular abnormalities, optic nerve
atrophy) may also be identied in nearly 35% of these
patients.
HISTOPATHOLOGIC FEATURES
The microscopic ndings in incontinentia pigmenti
vary, depending on when a biopsy of the skin lesions is
performed.
In the initial vesicular stage, intraepithelial clefts
lled with eosinophils are observed. During the verrucous stage, hyperkeratosis, acanthosis, and papillomatosis are noted. The hyperpigmentation stage shows
numerous melanin-containing macrophages (melanin
incontinence) in the subepithelial connective tissue,
the feature from which the disorder derives its name.
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CLINICAL FEATURES
Patients with Dariers disease have numerous erythematous, often pruritic, papules on the skin of the trunk
and the scalp that develop during the rst or second
decade of life (Fig. 16-22). An accumulation of keratin,
producing a rough texture, may be seen in association
with the lesions, and a foul odor may be present as a
result of bacterial degradation of the keratin. The
process generally becomes worse during the summer
HISTOPATHOLOGIC FEATURES
Microscopic examination of the cutaneous or mucosal
lesions shows a dyskeratotic process characterized by
a central keratin plug that overlies epithelium exhibiting a suprabasilar cleft (Fig. 16-24). This intraepithelial
clefting phenomenon, also known as acantholysis, is
not unique to Dariers disease and may be seen in conditions such as pemphigus vulgaris (see page 765). In
addition, the epithelial rete ridges associated with the
lesions appear narrow, elongated, and test tube
shaped. Closer inspection of the epithelium reveals
varying numbers of two types of dyskeratotic cells,
called corps ronds (round bodies) or grains (because
they resemble cereal grains).
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HISTOPATHOLOGIC FEATURES
CLINICAL FEATURES
The cutaneous warty dyskeratoma typically appears as
a solitary, asymptomatic, umbilicated papule on the
skin of the head or neck of an older adult. The intraoral
lesion also develops in patients older than age 40, and
a slight male predilection has been identied. The
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PEUTZ-JEGHERS SYNDROME
Peutz-Jeghers syndrome is a relatively rare but wellrecognized condition, having a prevalence of approximately 1 in 100,000 to 200,000 births. It is characterized by freckle-like lesions of the hands, perioral skin,
and oral mucosa, in conjunction with intestinal polyposis and predisposition for affected patients to develop
cancer. The syndrome is generally inherited as an autosomal dominant trait, although as many as 35% of cases
represent new mutations. Mutation of the STK11 gene
(also known as LKB1) on chromosome 19p13.3, which
encodes for a serine/threonine kinase, is responsible
for most cases of Peutz-Jeghers syndrome.
CLINICAL FEATURES
The skin lesions of Peutz-Jeghers syndrome usually
develop early in childhood and involve the perioricial
areas (e.g., mouth, nose, anus, genital region). The skin
of the extremities is affected in about 50% of patients
(Fig. 16-27). The lesions resemble freckles, but they do
not wax and wane with sun exposure, as do true
freckles.
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HISTOPATHOLOGIC FEATURES
The gastrointestinal polyps of Peutz-Jeghers syndrome
histopathologically represent benign overgrowths of
intestinal glandular epithelium supported by a core of
smooth muscle. Epithelial atypia is not usually a prominent feature, unlike the polyps of Gardner syndrome
(see page 651).
Microscopic evaluation of the pigmented cutaneous
lesions shows slight acanthosis of the epithelium with
elongation of the rete ridges. No apparent increase in
melanocyte number is detected by electron microscopy, but the dendritic processes of the melanocytes
are elongated. Furthermore, the melanin pigment
appears to be retained in the melanocytes rather than
being transferred to adjacent keratinocytes.
HEREDITARY HEMORRHAGIC
TELANGIECTASIA (OSLER-WEBERRENDU SYNDROME)
Hereditary hemorrhagic telangiectasia (HHT) is an
uncommon mucocutaneous disorder that is inherited
as an autosomal dominant trait, and recent epidemiologic studies suggest a prevalence of at least 1 in 10,000
people. Mutation of either one of two different genes
at two separate loci is responsible for the condition.
HHT1 is caused by a mutation of the ENG (endoglin)
gene on chromosome 9, whereas mutation of ALK1
(activin receptor-like kinase-1; ACVRL1), a gene located
on chromosome 12, produces HHT2. The proteins
produced by these genes may play a role in blood vessel
wall integrity. With both types of HHT, numerous vascular hamartomas develop, affecting the skin and
mucosa; however, other vascular problems, such as
arteriovenous stulas, may also be seen. Patients
affected with HHT1 tend to have more pulmonary
involvement, whereas those with HHT2 generally have
a later onset of their telangiectasias and a greater
degree of hepatic involvement. The clinician should be
familiar with HHT because the oral lesions are often
the most dramatic and most easily identied component of this syndrome.
CLINICAL FEATURES
Patients with HHT are often diagnosed initially because
of frequent episodes of epistaxis. On further examination, the nasal and oropharyngeal mucosae exhibit
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telangiectatic vessels. Laser ablation of the telangiectatic lesions has also been used, although this approach
appears to be most successful for patients with mild
to moderate disease. More severely affected patients,
particularly those troubled by repeated episodes of
epistaxis, may require a surgical procedure of the nasal
septum (septal dermoplasty). The involved nasal
mucosa is removed and replaced by a skin graft;
however, some long-term follow-up studies suggest
that the grafts eventually become revascularized,
resulting in recurrence of the problem. Nasal closure
is another surgical technique that has been performed
for patients with severe epistaxis in whom other
methods have failed.
Combined progesterone and estrogen therapy may
benet some patients, but because of the potentially
serious side effects, this should be limited to the most
severely affected individuals. Iron replacement therapy
is indicated for the iron-decient patient, and occasionally blood transfusions may be necessary to compensate for blood loss.
From a dental standpoint, some authors recommend the use of prophylactic antibiotics before dental
procedures that might cause bacteremia in patients
with HHT and evidence of a pulmonary arteriovenous
malformation. For patients with a history of HHT, such
antibiotics are advocated until a pulmonary arteriovenous malformation is ruled out because of the 1% prevalence of brain abscesses in affected individuals.
Researchers believe that antibiotic coverage, similar to
that for endocarditis prophylaxis, may prevent this
serious complication. Patients with a history of HHT
should be screened for arteriovenous malformations,
which can be eliminated by embolization or other
vasodestructive techniques using interventional radiologic methods.
The prognosis is generally good, although a 1% to 2%
mortality rate is reported from complications related
to blood loss. For patients with brain abscesses, the
mortality rate is 10%, even with early diagnosis and
appropriate therapy.
EHLERS-DANLOS SYNDROMES
HISTOPATHOLOGIC FEATURES
If one of the telangiectasias is submitted for biopsy, the
microscopic features essentially show a supercially
located collection of thin-walled vascular spaces that
contain erythrocytes (Fig. 16-31).
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Table 16-1
Ehlers-Danlos Syndromes
AND
MAXILLOFACIAL PATHOLOGY
Type
Classical (severe)
Classical (mild)
Hypermobility
Vascular
Kyphoscoliosis
Arthrochalasis
Dermatosparaxis
Other (includes X-linked,
periodontal, and
bronectin types)
Clinical Features
Inheritance
Defect
AD
AD
AD
AD, AR
AR
AD
AR
XLR, AD, AR
CLINICAL FEATURES
The pattern of inheritance and the clinical manifestations vary with the type of Ehlers-Danlos syndrome
being examined. About 80% of patients have the classical type in either the mild or severe form. Classical
Ehlers-Danlos syndrome is inherited as an autosomal
dominant trait, and defects of type I collagen have been
reported in some families, whereas problems with type
V collagen have been identied in others, suggesting
genetic heterogeneity. Hyperelasticity of the skin (Fig.
16-32) and cutaneous fragility can be observed. An
unusual healing response that often occurs with rela-
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CLINICAL FEATURES
Several clinical features characterize tuberous sclerosis. The rst of these, facial angiobromas, used to be
called adenoma sebaceum. Because these lesions are
neither adenomas nor sebaceous, the use of that term
should be discontinued. Facial angiobromas appear
as multiple, smooth-surfaced papules and occur primarily in the nasolabial fold area (Fig. 16-34). Similar
lesions, called ungual or periungual bromas, are seen
around or under the margins of the nails (Fig. 16-35).
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HISTOPATHOLOGIC FEATURES
Microscopic examination of the brous papules of the
oral mucosa or the enlarged gingivae shows a nonspecic brous hyperplasia. Similarly, the radiolucent jaw
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CLINICAL FEATURES
Cutaneous manifestations are present in almost all
patients with multiple hamartoma syndrome, usually
developing during the second decade of life. The majority of the skin lesions appear as multiple, small (less
than 1 mm) papules, primarily on the facial skin, especially around the mouth, nose, and ears (Fig. 16-39).
Microscopically, most of these papules represent hair
follicle hamartomas called trichilemmomas. Other
commonly noted skin lesions are acral keratosis, a
warty-appearing growth that develops on the dorsal
HISTOPATHOLOGIC FEATURES
The histopathologic features of the oral lesions are
rather nonspecic, essentially representing broepithelial hyperplasia. Other lesions associated with this
syndrome have their own characteristic histopathologic ndings, depending on the hamartomatous or
neoplastic tissue origin.
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DIAGNOSIS
The diagnosis can be based on the nding of two of the
following three pathognomonic signs:
1. Multiple facial trichilemmomas
2. Multiple oral papules
3. Acral keratoses
A variety of other major and minor diagnostic criteria, as well as a positive family history, are also helpful
in conrming the diagnosis. Genetic testing for mutations of the PTEN gene are clinically available, but 20%
of patients who otherwise have characteristic multiple
hamartoma syndrome will not demonstrate a genetic
abnormality; therefore, a negative test does not necessarily preclude the diagnosis of multiple hamartoma
syndrome.
CLINICAL FEATURES
EPIDERMOLYSIS BULLOSA
The term epidermolysis bullosa describes a heterogeneous group of inherited blistering mucocutaneous
disorders. Each has a specic defect in the attachment
mechanisms of the epithelial cells, either to each other
or to the underlying connective tissue. Recent advances
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Table 16-2
AND
Form
MAXILLOFACIAL PATHOLOGY
Inheritance
Clinical Features
Defect
EB simplex
AD
Junctional EB,
generalized gravis
variant
AR
AD
AD
AR
AR
Defects of hemidesmosomes
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HISTOPATHOLOGIC FEATURES
The histopathologic features of epidermolysis bullosa
vary with the type being examined. The simplex form
shows intraepithelial clefting by light microscopy.
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with the recessive dystrophic forms are also predisposed to development of cutaneous squamous cell
carcinoma. This malignancy often develops in areas of
chronic ulceration during the second through third
decades of life and represents a signicant cause of
death for these patients. Infrequently, the lingual
mucosa of affected patients has been reported to
undergo malignant transformation as well.
Management of the oral manifestations also depends
on the type of the disease. For patients who are susceptible to mucosal bulla formation, dental manipulation
should be kept to a minimum. To achieve this, topical
1% neutral sodium uoride solution should be administered daily to prevent dental caries. A soft diet that is
as noncariogenic as possible, as well as atraumatic oral
hygiene procedures, should be encouraged. Maintaining adequate nutrition for affected patients is critical to
ensure optimal wound healing.
If dental restorative care is required, the lips should
be lubricated to minimize trauma. Injections for local
anesthesia can usually be accomplished by depositing
the anesthetic slowly and deeply within the tissues. For
extensive dental care, endotracheal anesthesia may
be performed without signicant problems in most
cases.
Unfortunately, because of the genetic nature of these
diseases, no cure exists. Genetic counseling of affected
families is indicated. Both prenatal diagnosis and preimplantation diagnosis are available as adjuncts to
family planning.
Immune-Mediated Diseases
and Their Evaluation
Several conditions discussed in this chapter are the
result of inappropriate production of antibodies by
the patient (autoantibodies). These autoantibodies are
directed against various constituents of the molecular
apparatus that hold epithelial cells together or that
bind the surface epithelium to the underlying connective tissue. The ensuing damage produced by the interaction of these autoantibodies with the host tissue is
seen clinically as a disease process, often termed an
immunobullous disease. Because each disease is
characterized by production of specic types of autoantibodies, identication of the antibodies and the
tissues against which they are targeted is important
diagnostically. The two techniques that are widely used
to investigate the immunobullous diseases are (1)
direct immunouorescence and (2) indirect immunouorescence studies. Following is a brief overview of
how they work.
Direct
immunofluorescence
Indirect
immunofluorescence
Apply
fluorescein-conjugated
anti-human Ig
antibodies
Apply patient's
serum, antibodies
bind to homologous
structures
Patient's
tissue
specimen
Wash off excess
Section of
monkey
esophagus
Wash off excess
Apply
fluorescein-conjugated
anti-human Ig
antibodies
View with UV
microscope
View with UV
microscope
Direct immunouorescence is used to detect autoantibodies that are bound to the patients tissue. Before
testing can take place, several procedures must occur.
Inoculating human immunoglobulins into a goat
creates antibodies directed against these human immunoglobulins. The antibodies raised in response to the
human immunoglobulins are harvested from the
animal and tagged with uorescein, a dye that glows
when viewed with ultraviolet (UV) light. As illustrated
on the left side of Fig. 16-47, a frozen section of the
patients tissue is placed on a slide, and this is incubated with uorescein-conjugated goat antihuman
antibodies. These antibodies bind to the tissue at any
site where human immunoglobulin is present. The
excess antibody suspension is washed off, and the
section is then viewed with a microscope having a UV
light source.
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Normal structures
Targeted structures
for immune-mediated
diseases
Pemphigus (desmoglein 3
of desmosome)
Desmosome
Basal cell layer
Hemidesmosome
Pemphigoid (various components
of BMZ or hemidesmosome)
Basement membrane
Anchoring fibrils
Connective tissue
PEMPHIGUS
The condition known as pemphigus represents four
related diseases of an autoimmune origin:
1. Pemphigus vulgaris
2. Pemphigus vegetans
3. Pemphigus erythematosus
4. Pemphigus foliaceus
Only the rst two of these affect the oral mucosa,
and the discussion is limited to pemphigus vulgaris.
Pemphigus vegetans is rare; most authorities now
feel it represents simply a variant of pemphigus
vulgaris.
Pemphigus vulgaris is the most common of these
disorders (vulgaris is Latin for common). Even so, it is not
seen very often. The estimated incidence is one to ve
cases per million people diagnosed each year in the
general population. Nevertheless, pemphigus vulgaris
is an important condition because, if untreated, it often
results in the patients death. Furthermore, the oral
lesions are often the rst sign of the disease, and they
are the most difcult to resolve with therapy. This has
prompted the description of the oral lesions as the rst
to show, and the last to go.
The blistering that typies this disease is due to an
abnormal production, for unknown reasons, of autoantibodies that are directed against the epidermal cell
surface glycoproteins, desmoglein 3 and desmoglein 1.
These desmogleins are components of desmosomes
(structures that bond epithelial cells to each other), and
the autoantibodies attach to these desmosomal components, effectively inhibiting the molecular interaction
that is responsible for adherence. As a result of this
immunologic attack on the desmosomes, a split develops within the epithelium, causing a blister to form.
Desmoglein 3 is preferentially expressed in the parabasal region of the epidermis and oral epithelium,
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Table 16-3
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Mean
Age
Sex
Predilection
Clinical
Features
Histopathologic
Features
Direct
Immunouorescence
Indirect
Immunouorescence
Pemphigus
vulgaris
Fourth to
sixth
decade
Equal
Intraepithelial
clefting
Positive intercellular
Positive
Paraneoplastic
pemphigus
Sixth to
seventh
decade
Equal
Subepithelial and
intraepithelial
clefting
Positive, intercellular
and basement
membrane zone
Mucous
membrane
pemphigoid
Bullous
pemphigoid
Sixth to
seventh
decade
Seventh to
eighth
decade
Third to
fourth
decade
Female
Vesicles,
erosions, and
ulcerations
on any oral
mucosal or
skin surface
Vesicles,
erosions, and
ulcerations
on any
mucosal or
skin surface
Primarily
mucosal
lesions
Primarily skin
lesions
Subepithelial
clefting
Positive, basement
membrane zone
Negative
Subepithelial
clefting
Positive, basement
membrane zone
Positive
Subepithelial
edema and
perivascular
inammations
Nondiagnostic
Negative
Hyperkeratosis,
saw-toothed
rete ridges,
bandlike
inltrate of
lymphocytes
Fibrinogen, basement
membrane zone
Negative
Condition
Erythema
multiforme
Lichen planus
Fifth to
sixth
decade
Equal
Male
Female
Skin and
mucosa
involved;
target lesions
on skin
Oral and/or
skin lesions;
may or may
not be
erosive
whereas desmoglein 1 is found primarily in the supercial portion of the epidermis, with minimal expression in oral epithelium. Patients who have developed
autoantibodies directed against desmoglein 3, with or
without desmoglein 1, will histopathologically show
intraepithelial clefting just above the basal layer, and
clinically oral mucosal blisters of pemphigus vulgaris
will form. Patients who develop autoantibodies directed
against only desmoglein 1 will histopathologically show
supercial intraepithelial clefting of the epidermis, but
oral mucosa will not be affected. Clinically, the ne
scaly red lesions of pemphigus foliaceous or pemphigus erythematosus will be evident.
Occasionally, a pemphigus-like oral and cutaneous
eruption may occur in patients taking certain medications (e.g., penicillamine, angiotensin-converting
enzyme [ACE] inhibitors, nonsteroidal antiinammatory drugs [NSAIDs]) or in patients with malignancy,
especially lymphoreticular malignancies (so-called
paraneoplastic pemphigus) (see page 769). Similarly, a variety of other conditions may produce chronic
CLINICAL FEATURES
The initial manifestations of pemphigus vulgaris often
involve the oral mucosa, typically in adults. The average
age at diagnosis is 50 years, although rare cases may
be seen in childhood. No sex predilection is observed,
and the condition seems to be more common in persons
of Mediterranean, South Asian, or Jewish heritage.
Patients usually complain of oral soreness, and
examination shows supercial, ragged erosions and
ulcerations distributed haphazardly on the oral mucosa
(Figs. 16-49 to 16-52). Such lesions may affect virtually
any oral mucosal location, although the palate, labial
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HISTOPATHOLOGIC FEATURES
Biopsy specimens of perilesional tissue show characteristic intraepithelial separation, which occurs just
above the basal cell layer of the epithelium (Fig.
16-54). Sometimes the entire supercial layers of the
epithelium are stripped away, leaving only the basal
cells, which have been described as resembling a row
of tombstones. The cells of the spinous layer of the
surface epithelium typically appear to fall apart, a
feature that has been termed acantholysis, and the
loose cells tend to assume a rounded shape (Fig.
16-55). This feature of pemphigus vulgaris can be used
in making a diagnosis based on the identication of
these rounded cells (Tzanck cells) in an exfoliative
cytologic preparation. A mild-to-moderate chronic
inammatory cell inltrate is usually seen in the underlying connective tissue.
The diagnosis of pemphigus vulgaris should be conrmed by direct immunouorescence examination of
fresh perilesional tissue or tissue submitted in Michels
solution. With this procedure, antibodies (usually IgG
or IgM) and complement components (usually C3) can
be demonstrated in the intercellular spaces between
the epithelial cells (Fig. 16-56) in almost all patients
with this disease. Indirect immunouorescence is also
typically positive in 80% to 90% of cases, demonstrating
the presence of circulating autoantibodies in the
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therefore, treatment consists primarily of systemic corticosteroids (usually prednisone), often in combination
with other immunosuppressive drugs (so-called steroidsparing agents), such as azathioprine. Although some
clinicians have advocated the use of topical corticosteroids in the management of oral lesions, the observed
improvement is undoubtedly because of the absorption
of the topical agents, resulting in a greater systemic
dose. The potential side effects associated with the
long-term use of systemic corticosteroids are signicant and include the following:
Diabetes mellitus
Adrenal suppression
Weight gain
Osteoporosis
Peptic ulcers
Severe mood swings
Increased
susceptibility to a wide range of
infections
Ideally, a physician with expertise in immunosuppressive therapy should manage the patient. The most
common approach is to use relatively high doses of
systemic corticosteroids initially to clear the lesions,
then attempt to maintain the patient on as low a dose
of corticosteroids as is necessary to control the condition. Often the clinician can monitor the success of
therapy by measuring the titers of circulating autoantibodies using indirect immunouorescence, because
disease activity frequently correlates with the abnormal antibody levels. Pemphigus may undergo complete
resolution, although remissions and exacerbations
are common. One study suggested that up to 75% of
patients will have disease resolution after 10 years of
treatment.
Before the development of corticosteroid therapy, as
many as 60% to 90% of these patients died, primarily
as a result of infections and electrolyte imbalances.
Even today, the mortality rate associated with pemphigus vulgaris is in the range of 5% to 10%, usually because
of the complications of long-term systemic corticosteroid use.
PARANEOPLASTIC PEMPHIGUS
(NEOPLASIA-INDUCED PEMPHIGUS;
PARANEOPLASTIC AUTOIMMUNE
MULTIORGAN SYNDROME)
Paraneoplastic pemphigus is a rare vesiculobullous
disorder that affects patients who have a neoplasm,
usually lymphoma or chronic lymphocytic leukemia. Approximately 150 cases have been documented.
Although the precise pathogenetic mechanisms are
unknown, some evidence suggests abnormal levels of
the cytokine, interleukin 6 (IL-6), could be produced
by host lymphocytes in response to the patients tumor.
IL-6 may then be responsible for stimulating the abnormal production of antibodies directed against antigens
associated with the desmosomal complex and the basement membrane zone of the epithelium. In addition
to a variety of different antibodies that attack these
epithelial adherence structures, recent reports have
described cutaneous and mucosal damage that appears
to be mediated by cytotoxic T lymphocytes in some
cases of paraneoplastic pemphigus. As a result of this
multifaceted immunologic attack, the disease manifests in an array of clinical features, histopathologic
ndings, and immunopathologic ndings that may be
perplexing if the clinician is unfamiliar with this
condition.
CLINICAL FEATURES
Patients typically have a history of a malignant lymphoreticular neoplasm, or less commonly, a benign lymphoproliferative disorder such as angiofollicular lymph
node hyperplasia (Castlemans disease) or thymoma.
In approximately one third of reported cases, paraneoplastic pemphigus developed before a malignancy was
identied, thus signaling the presence of a tumor. The
neoplastic disease may or may not be under control at
the time of onset of the paraneoplastic condition. Signs
and symptoms of paraneoplastic pemphigus usually
begin suddenly and may appear polymorphous. In
some instances, multiple vesiculobullous lesions affect
the skin (Fig. 16-57) and oral mucosa. Palmar or plantar
bullae may be evident, a feature that is uncommon in
pemphigus vulgaris. For other patients, skin lesions can
appear more papular and pruritic, similar to cutaneous
lichen planus. The lips often show hemorrhagic crusting similar to that of erythema multiforme (Fig. 16-58).
The oral mucosa shows multiple areas of erythema and
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Fig. 16-61 Paraneoplastic pemphigus. This mediumpower photomicrograph shows both intraepithelial and
subepithelial clefting.
diffuse, irregular ulceration (Fig. 16-59), affecting virtually any oral mucosal surface. If the lesions remain
untreated, then they persist and worsen. Some patients
may develop only oropharyngeal lesions, without cutaneous involvement.
Other mucosal surfaces are also commonly affected,
with 70% of patients having involvement of the conjunctival mucosa. In this area, a cicatrizing (scarring)
conjunctivitis develops, similar to that seen with cicatricial pemphigoid (Fig. 16-60). The vaginal mucosa
and mucosa of the respiratory tract may be involved.
HISTOPATHOLOGIC FEATURES
The features of paraneoplastic pemphigus on light
microscopic examination may be as diverse as the
clinical features. In most cases, a lichenoid mucositis is
seen, usually with subepithelial clefting (like pemphigoid) or intraepithelial clefting (like pemphigus) (Fig.
16-61).
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oid reaction with no demonstrable autoantibody production have infrequently been described.
CLINICAL FEATURES
Mucous membrane pemphigoid usually affects older
adults, with an average age of 50 to 60 years at the
onset of disease. Females are affected more frequently
than males by a 2:1 ratio. Oral lesions are seen in most
patients, but other sites, such as conjunctival, nasal,
esophageal, laryngeal, and vaginal mucosa, as well as
the skin (Fig. 16-62), may be involved.
The oral lesions of pemphigoid begin as either vesicles or bullae that may occasionally be identied clinically (Fig. 16-63). In contrast, patients with pemphigus
rarely display such blisters. The most likely explanation
for this difference is that the pemphigoid blister forms
in a subepithelial location, producing a thicker, stronger roof than the intraepithelial, acantholytic pemphigus blister. Eventually, the oral blisters rupture, leaving
large, supercial, ulcerated, and denuded areas of
mucosa (Fig. 16-64). The ulcerated lesions are usually
painful and persist for weeks to months if untreated.
Often this process is seen diffusely throughout the
mouth, but it may be limited to certain areas, especially
the gingiva (Fig. 16-65). Gingival involvement produces
a clinical reaction pattern termed desquamative gingivitis (see page 162). This pattern may also be seen in
other conditions, such as erosive lichen planus or,
much less frequently, pemphigus vulgaris.
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The most signicant complication of mucous membrane pemphigoid, however, is ocular involvement.
Although exact gures are not available, up to 25% of
patients with oral lesions may eventually develop
ocular disease. One eye may be affected before the
other. The earliest change is subconjunctival brosis,
which usually can be detected by an ophthalmologist
using slit-lamp examination. As the disease progresses,
the conjunctiva becomes inamed and eroded.
Attempts at healing lead to scarring between the bulbar
(lining the globe of the eye) and palpebral (lining the
inner surface of the eyelid) conjunctivae. Adhesions
called symblepharons result (Fig. 16-66). Without
treatment the inammatory changes become more
severe, although conjunctival vesicle formation is rarely
seen (Fig. 16-67). Scarring can ultimately cause the
eyelids to turn inward (entropion). This causes the
eyelashes to rub against the cornea and globe (trichiasis) (Fig. 16-68). The scarring closes off the openings
of the lacrimal glands as well, and with the loss of tears,
the eye becomes extremely dry. The cornea then produces keratin as a protective mechanism; however,
keratin is an opaque material, and blindness ensues.
End-stage ocular involvement may also be characterized by adhesions between the upper and lower eyelids
themselves (Fig. 16-69).
Other mucosal sites may also be involved and
cause considerable difculty for the patient. In females,
the vaginal mucosal lesions may cause considerable
pain during attempts at intercourse (dyspareunia).
Laryngeal lesions, which are fairly uncommon, may
be especially signicant because of the possibility of
airway obstruction by the bullae that are formed.
Patients who experience a sudden change in vocaliza-
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Fig. 16-70 Mucous membrane pemphigoid. Mediumpower photomicrograph of perilesional tissue shows
characteristic subepithelial clefting.
HISTOPATHOLOGIC FEATURES
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TOPICAL AGENTS
If only oral lesions are present, sometimes the disease
can be controlled with application of one of the more
potent topical corticosteroids to the lesions several
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times each day. Once control is achieved, the applications can be discontinued, although the lesions are
certain to are up again. Sometimes alternate-day
application prevents such exacerbations of disease
activity.
Patients with only gingival lesions often benet from
good oral hygiene measures, which can help to decrease
the severity of the lesions and reduce the amount of
topical corticosteroids required. As an additional aid in
treating gingival lesions, a exible mouth guard may be
fabricated to use as a carrier for the corticosteroid
medication.
SYSTEMIC AGENTS
If topical corticosteroids are unsuccessful, systemic
corticosteroids plus other immunosuppressive agents
(particularly cyclophosphamide) may be used if the
patient has no medical contraindications. This type of
aggressive treatment is absolutely indicated in the presence of advancing ocular disease. Recent studies have
suggested that treatment with intravenous (IV) human
immunoglobulin may be more effective in managing
ocular lesions of pemphigoid than systemic corticosteroid therapy. Attempts at surgical correction of any
symblepharons that might have formed must be done
when the disease is under control or quiescent; otherwise, the manipulation often induces an acute are of
the ocular lesions.
For patients with mild-to-moderate involvement by
mucous membrane pemphigoid, an alternative systemic therapy that may produce fewer serious side
effects is the use of dapsone, a sulfa drug derivative.
Some centers report good results with dapsone, but
others observe that a minority of patients respond adequately. Contraindications to its use include glucose-6phosphate dehydrogenase deciency or allergy to sulfa
drugs.
Another alternative systemic therapy that may be
used for patients with less severe disease is tetracycline
or minocycline and niacinamide (nicotinamide). Systemic daily divided doses of 0.5 to 2.0 g of each drug
have been reported (in open-label trials) to be effective
in controlling mucous membrane pemphigoid. Doubleblind, placebo-controlled studies on larger groups of
patients should be done to conrm this form of therapy,
however.
BULLOUS PEMPHIGOID
Bullous pemphigoid is the most common of the autoimmune blistering conditions, occurring at an estimated rate of 10 cases per million population per year.
The disease is characterized by the production of autoantibodies directed against components of the basement membrane. In many respects, bullous pemphigoid
CLINICAL FEATURES
Bullous pemphigoid typically develops in older people;
most patients are between 60 and 80 years of age. No
sex or racial predilection is generally reported, although
one group of investigators noted that men are overrepresented in this disease by a 2:1 margin when one
corrects for the skewing of the aging population toward
the female gender. Pruritus may be an early symptom.
This is followed by the development of multiple, tense
bullae on either normal or erythematous skin (Fig.
16-72). These lesions eventually rupture after several
days, causing a supercial crust to form. Eventually,
healing takes place without scarring.
Oral mucosal involvement is uncommon, although
the reported prevalence in several series of cases has
ranged from 8% to 39%. Referral bias may explain the
discrepancy in prevalence rates. The oral lesions, like
the skin lesions, begin as bullae, but they tend to rupture
sooner, probably as a result of the constant low-grade
trauma to which the oral mucosa is subjected. Large,
shallow ulcerations with smooth, distinct margins are
present after the bullae rupture (Fig. 16-73).
HISTOPATHOLOGIC FEATURES
Microscopic examination of tissue obtained from the
perilesional margin of a bulla shows separation of the
epithelium from the connective tissue at the basement
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membrane zone, resulting in a subepithelial separation. Modest numbers of both acute and chronic inammatory cells are typically seen in the lesional area, and
the presence of eosinophils within the bulla itself is
characteristic.
Direct immunouorescence studies show a continuous linear band of immunoreactants, usually IgG and
C3, localized to the basement membrane zone in 90%
to 100% of affected patients. These antibodies may bind
to proteins associated with hemidesmosomes, structures that bind the basal cell layer of the epithelium to
the basement membrane and the underlying connective tissue. These proteins have been designated as
bullous pemphigoid antigens (BP180 and BP230),
and immunoelectron microscopy has demonstrated
the localization of BP180 to the upper portion of the
lamina lucida of the basement membrane.
In addition to the tissue-bound autoantibodies, 50%
to 90% of the patients also have circulating autoantibodies in the serum, producing an indirect immunouorescent pattern that is identical to that of the direct
immunouorescence. Unlike pemphigus vulgaris, the
antibody titers seen in bullous pemphigoid do not
appear to correlate with disease activity. The antibodies alone do not appear to be capable of inducing bullae
in this disease. Instead, binding of the antibodies to the
basement membrane initiates the complement cascade,
which in turn results in degranulation of mast cells,
with recruitment of neutrophils and eosinophils to the
area. The damage to the basement membrane is thought
to be mediated by elastases and matrix metalloproteinases released by these inammatory cells.
CLINICAL FEATURES
ERYTHEMA MULTIFORME
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HISTOPATHOLOGIC FEATURES
Histopathologic examination of the perilesional mucosa
in erythema multiforme reveals a pattern that is characteristic but not pathognomonic. Subepithelial or
intraepithelial vesiculation may be seen in association
with necrotic basal keratinocytes (Fig. 16-81). A mixed
inammatory inltrate is present, consisting of lymphocytes, neutrophils, and often eosinophils. Sometimes these cells are arranged in a perivascular
orientation (Fig. 16-82). Because the immunopathologic features are also nonspecic, the diagnosis is
often based on the clinical presentation and the exclusion of other vesiculobullous disorders.
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Fig. 16-83 Erythema migrans. The erythematous, welldemarcated areas of papillary atrophy are characteristic of
erythema migrans affecting the tongue (benign migratory
glossitis). Note the asymmetrical distribution and the
tendency to involve the lateral aspects of the tongue.
CLINICAL FEATURES
The characteristic lesions of erythema migrans are
seen on the anterior two thirds of the dorsal tongue
mucosa. They appear as multiple, well-demarcated
zones of erythema (Figs. 16-83 and 16-84), concentrated at the tip and lateral borders of the tongue. This
erythema is due to atrophy of the liform papillae, and
these atrophic areas are typically surrounded at least
partially by a slightly elevated, yellow-white, serpentine or scalloped border (Fig. 16-85). The patient who
is aware of the process is often able to describe the
lesions as appearing quickly in one area, healing within
a few days or weeks, then developing in a very different
area. Frequently, the lesion begins as a small white
patch, which then develops a central erythematous
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HISTOPATHOLOGIC FEATURES
If a biopsy specimen of the peripheral region of erythema migrans is examined, a characteristic histopathologic pattern is observed. Hyperparakeratosis,
spongiosis, acanthosis, and elongation of the epithelial
rete ridges are seen (Fig. 16-88). In addition, collections of neutrophils (Munro abscesses) are observed
within the epithelium (Fig. 16-89); lymphocytes and
neutrophils involve the lamina propria. The intense
neutrophilic inltrate may be responsible for the
destruction of the supercial portion of the epithelium,
thus producing an atrophic, reddened mucosa as the
lesion progresses. Because these histopathologic features are reminiscent of psoriasis, this is called a psoriasiform mucositis. Despite the apparent lack of
association between dermatologic conditions and erythema migrans in one recent report, another casecontrol study of psoriatic patients showed that erythema
migrans occurred at a rate of about 10%; only 2.5% of
an age-matched and sex-matched population were
affected. A Brazilian study determined that both
patients with psoriasis and those with benign migratory
glossitis were more likely to have the same human
leukocyte antigen (HLA) group, namely HLA-Cw6.
Whether these ndings mean that erythema migrans
represents oral psoriasis or that patients with psoriasis
are just more susceptible to erythema migrans is open
to debate.
REACTIVE ARTHRITIS
(REITERS SYNDROME)
Reactive arthritis represents a group of uncommon
diseases that most likely have an immunologically
mediated cause. Current evidence suggests that these
disorders may be triggered by any one of several infectious agents in a genetically susceptible person. In
some instances, the arthritis will be accompanied by
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CLINICAL FEATURES
Reactive arthritis is particularly prevalent in young
adult men. According to most series, there is a male-tofemale ratio of 9:1. The majority (60% to 90%) of these
patients are positive for HLA-B27, a haplotype present
in only 4% to 8% of the population. The syndrome
usually develops 1 to 4 weeks after an episode of dysentery or venereal disease; in fact, two French physicians published a description of this entity affecting
four postdysenteric soldiers 1 week before Reiters
paper appeared.
Urethritis is often the rst sign and is seen in both
affected males and females. Females may also have
inammation of the uterine cervix. Conjunctivitis
usually appears concurrently with the urethritis, and
after several days, arthritis ensues. The arthritis usually
affects the joints of the lower extremities, although TMJ
involvement has been identied in one third of these
patients, typically as erosion of the condylar head. Skin
lesions often take the form of a characteristic lesion of
the glans penis (balanitis circinata). These lesions
develop in about 20% to 30% of patients with reactive
arthritis, and they appear as well-circumscribed erythematous erosions with a scalloped, whitish linear
boundary.
The oral lesions, which occur in slightly less than
20% of patients with this disorder, are described in
various ways. Some reports mention painless erythematous papules distributed on the buccal mucosa and
palate; other reports describe shallow, painless ulcers
that affect the tongue, buccal mucosa, palate, and
gingiva. Some authors have even implied that geographic tongue may be a component of reactive
arthritis, probably because geographic tongue bears a
supercial resemblance to the lesions of balanitis
circinata.
The American Rheumatism Association has dened
reactive arthritis based on the clinical ndings of a
HISTOPATHOLOGIC FEATURES
The histopathologic ndings of the cutaneous lesions
in patients with reactive arthritis are frequently similar
to those found in patients with psoriasis, particularly
with respect to the presence of microabscesses within
the supercial layers of the surface epithelium. Other
features in common with psoriasis include hyperparakeratosis with elongated, thin rete ridges.
LICHEN PLANUS
Lichen planus is a relatively common, chronic dermatologic disease that often affects the oral mucosa. The
strange name of the condition was provided by the
British physician Erasmus Wilson, who rst described
it in 1869. Lichens are primitive plants composed of
symbiotic algae and fungi. The term planus is Latin for
at. Wilson probably thought that the skin lesions
looked similar enough to the lichens growing on rocks
to merit this designation. Even though the term lichen
planus suggests a at, fungal condition, current evidence indicates that this is an immunologically mediated mucocutaneous disorder.
A variety of medications may induce lesions that
can appear clinically very similar to the idiopathic
form of the condition; however, the term lichenoid
mucositis (or lichenoid dermatitis, depending on
the site involved) is probably a better name for the
drug-related alterations (see page 347). Similarly,
foreign material that becomes inadvertently embedded in the gingiva may elicit a host response that
is termed lichenoid foreign body gingivitis (see page
160). Reports of hepatitis C infection associated with
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CLINICAL FEATURES
Most patients with lichen planus are middle-aged
adults. It is rare for children to be affected. Women
predominate in most series of cases, usually by a 3:2
ratio over men. Approximately 1% of the population
may have cutaneous lichen planus. The prevalence of
oral lichen planus is between 0.1% and 2.2%.
The skin lesions of lichen planus have been classically described as purple, pruritic, polygonal papules
(Fig. 16-90). These usually affect the exor surfaces of
the extremities. Excoriations may not be visible, despite
the fact that the lesions itch, because it hurts the patient
when he or she scratches them.
Careful examination of the surface of the skin
papules reveals a ne, lacelike network of white lines
(Wickhams striae). Other sites of extraoral involvement include the glans penis, the vulvar mucosa, and
the nails (Fig. 16-91). Essentially there are two forms
of oral lesions: reticular and erosive.
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Fig. 16-95 Lichen planus. A, A middle-aged woman with mild reticular lichen planus of the
left buccal mucosa. B, Same patient 2 weeks later, showing exacerbation of the lesions. Such
waxing and waning is characteristic of lichen planus.
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HISTOPATHOLOGIC FEATURES
The histopathologic features of lichen planus are characteristic but may not be specic, because other conditions, such as lichenoid drug reaction, lichenoid
amalgam reaction, oral graft-versus-host disease
(GVHD), lupus erythematosus (LE), chronic ulcerative stomatitis, and oral mucosal cinnamon reaction may also show a similar histopathologic pattern.
Fig. 16-98 Lichen planus. A, The dorsal surface of the tongue shows extensive ulceration
caused by erosive lichen planus. Note the ne white streaks at the periphery of the
ulcerations. B, Same patient after systemic corticosteroid therapy. Much of the mucosa has
reepithelialized, with only focal ulcerations remaining.
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Fig. 16-100 Lichen planus. A, This low-power photomicrograph of an oral lesion shows
hyperkeratosis, saw-toothed rete ridges, and a bandlike inltrate of lymphocytes immediately
subjacent to the epithelium. B, Higher-power view showing migration of lymphocytes into the
lower epithelium with interface degeneration of the basal cell layer.
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Fig. 16-102 Lichen planus. A, These relatively nondescript white lesions affected the buccal
mucosa of a patient who had complained of a burning sensation. Histopathologic evaluation of
the lesion showed a lichenoid mucositis with superimposed candidiasis. B, Same patient 2
weeks after antifungal therapy. Once the mucosal reaction to the candidal organism was
eliminated, the characteristic white striae of reticular lichen planus were identied.
DIAGNOSIS
The diagnosis of reticular lichen planus can often be
made based on the clinical ndings alone. The interlacing white striae appearing bilaterally on the posterior
buccal mucosa are virtually pathognomonic. Difculties in diagnosis may arise if candidiasis is superimposed on the lesions because the organism may disturb
the characteristic reticular pattern of the lichen planus
(Fig. 16-102).
Erosive lichen planus is sometimes more challenging to diagnose (based on clinical features alone) than
the reticular form. If the typical radiating white striae
and erythematous, atrophic mucosa are present at the
periphery of well-demarcated ulcerations on the posterior buccal mucosa bilaterally, then the diagnosis can
sometimes be rendered without the support of histopathologic ndings. However, a biopsy is often necessary to rule out other ulcerative or erosive diseases,
such as lupus erythematosus or chronic ulcerative
stomatitis.
Specimens of isolated erosive lichenoid lesions, particularly those of the soft palate, the lateral and ventral
tongue, or the oor of the mouth, should be obtained
for biopsy to rule out premalignant changes or malignancy. Another condition that may mimic an isolated
lesion of lichen planus, both clinically and histopatho-
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Chronic ulcerative stomatitis is another immunemediated disorder that affects the oral mucosa. This
condition was initially described in 1989, and slightly
more than 40 cases have been reported. Although the
precise pathogenetic mechanisms are unknown, these
patients develop autoantibodies against a 70-kD
nuclear protein that is very similar to p63 and may play
a role in epithelial growth and differentiation.
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Fig. 16-104 Chronic ulcerative stomatitis. A, White lesions with central erosion on the
buccal mucosa. B, Opposite buccal mucosa in the same patient. The lesions appear somewhat
lichenoid, although classic Wickhams striae are not evident.
CLINICAL FEATURES
Chronic ulcerative stomatitis usually affects adult
women, and the mean age at diagnosis is late in the
sixth decade of life. The condition may appear as desquamative gingivitis, although ulcerations or erosions
of the tongue or buccal mucosa are also quite common
(Fig. 16-104). The ulcers are generally surrounded by
patchy zones of erythema and streaky keratosis that
somewhat resemble lichen planus, although classic
striae formation is not evident. The ulcers heal without
scarring and often migrate around the oral mucosa. As
is typical with most immune-mediated conditions, the
severity of the oral lesions tends to wax and wane.
Fewer than 20% of affected patients will develop concurrent lichenoid skin lesions.
HISTOPATHOLOGIC FEATURES
Although the histopathologic features of chronic ulcerative stomatitis are similar to those of lichen planus, the
epithelium is generally more atrophic and the inam-
DIAGNOSIS
The diagnosis of chronic ulcerative stomatitis is essentially based on its characteristic immunopathologic
pattern. Although it may not be economically feasible
to do immunologic testing on every case of lichen
planus, this procedure should be considered for erosive
lichenoid lesions that do not have a characteristic
appearance or distribution, as well as for erosive lesions
that do not respond to topical corticosteroid therapy.
With direct immunouorescence studies, autoantibodies (usually IgG) that are directed against the nuclei
of stratied squamous epithelial cells in the basal and
parabasal regions of the epithelium are detected (Fig.
16-106). Indirect immunouorescence studies are also
positive for these stratied epithelium-specic antinuclear antibodies (ANAs), and some investigators believe
that conrmation of the diagnosis is necessary using
serum for indirect immunouorescence evaluation.
Other immune-mediated conditions (e.g., systemic
sclerosis and lupus erythematosus) may show ANA
deposition with direct immunouorescence; however,
nuclei throughout the entire thickness of the epithelium are positive with those diseases.
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GRAFT-VERSUS-HOST DISEASE
Graft-versus-host disease (GVHD) occurs mainly in
recipients of allogeneic bone marrow transplantation, a procedure performed on approximately 4000
patients in the United States each year. Such transplants are performed at major medical centers to treat
life-threatening diseases of the blood or bone marrow,
such as leukemia, lymphoma, multiple myeloma, aplastic anemia, thalassemia, sickle cell anemia, or disseminated metastatic disease. Cytotoxic drugs, radiation, or
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CLINICAL FEATURES
The systemic signs of GVHD are varied, depending on
the organ system involved and whether the problem is
acute or chronic. The severity of GVHD depends on
several factors, with milder disease seen in patients
who have a better histocompatibility match, are
younger, have received cord blood, and are female.
Acute GVHD is typically observed within the rst
few weeks after bone marrow transplantation. Although
acute GVHD has arbitrarily been dened as occurring
within 100 days after the procedure, most investigators
make this diagnosis based on the clinical features
rather than a specic time point. The disease affects
about 50% of bone marrow transplant patients. The
skin lesions that develop may range from a mild rash
to a diffuse severe sloughing that resembles toxic epidermal necrolysis (see page 777). These signs may be
accompanied by diarrhea, nausea, vomiting, abdominal pain, and liver dysfunction.
Chronic GVHD may represent a continuation of a
previously diagnosed case of acute GVHD, or it may
develop later than 100 days after bone marrow transplantation, sometimes not appearing for several years
after the procedure. Chronic GVHD can be expected
to develop in 30% to 70% of bone marrow transplant
recipients, and it often mimics any one of a variety of
autoimmune conditions, such as systemic lupus erythematosus (SLE), Sjgren syndrome, or primary biliary
cirrhosis. Skin involvement, which is the most common
manifestation, may resemble lichen planus or even systemic sclerosis.
The oral mucosal manifestations of GVHD can also
vary, depending on the duration and severity of the
attack and the targeted oral tissues. Of patients with
acute GVHD, 33% to 75% will have oral involvement;
of patients with chronic GVHD, 80% or more will have
oral lesions. Sometimes the oral lesions of GVHD are
the only sign of the disorder. In most patients with oral
GVHD, there is a ne, reticular network of white striae
that resembles oral lichen planus, although a more
diffuse pattern of pinpoint white papules has also been
described (Figs. 16-107 to 16-109). The tongue, the
labial mucosa, and the buccal mucosa are the oral
mucosal sites most frequently involved. Patients often
complain of a burning sensation of the oral mucosa,
and care must be taken not to overlook possible candidiasis. Atrophy of the oral mucosa may be present, and
this can contribute to the mucosal discomfort. Ulcerations that are related to the chemotherapeutic conditioning and neutropenic state of the patient often
develop during the rst 2 weeks after bone marrow
transplantation. Ulcers that persist longer than 2 weeks
may represent acute GVHD, and these should be differentiated from intraoral herpesvirus infection or bacterial infection. Bone marrow transplant patients have
a small but increased risk for the development of both
oral and cutaneous epithelial dysplasia and squamous
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Fig. 16-110 Squamous cell carcinoma arising in graftversus-host disease (GVHD). Erythematous, ulcerated mass
arising on the lateral border of the tongue. Note the
surrounding mucosal erosions, which represent GVHD.
HISTOPATHOLOGIC FEATURES
The histopathologic features of GVHD resemble those
of oral lichen planus to a certain degree. Both lesions
display hyperorthokeratosis, short and pointed rete
ridges, and degeneration of the basal cell layer. The
inammatory response in GVHD is usually not as
intense as in lichen planus. With advanced cases, an
abnormal deposition of collagen is present, similar to
the pattern in systemic sclerosis. Minor salivary gland
tissue usually shows periductal inammation in the
early stages, with gradual acinar destruction and extensive periductal brosis appearing later.
DIAGNOSIS
The diagnosis of GVHD may be difcult because of the
varied clinical manifestations. Such a diagnosis
is of great clinical signicance to the patient because
complications of the condition and its treatment
may be lethal. Although the diagnosis of GVHD is
based on the clinical and histopathologic ndings, each
patient may have a different constellation of signs and
symptoms. Oral lesions appear to have value as a highly
predictive index of the presence of GVHD.
PSORIASIS
Psoriasis is a common chronic skin disease affecting
approximately 2% of people in the United States.
According to some estimates, roughly 6 million people
in this country have psoriasis, and up to 250,000 new
cases are diagnosed each year.
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CLINICAL FEATURES
Psoriasis often has its onset during the second or third
decade of life and tends to persist for years, with
periods of exacerbation and quiescence. Patients
often report that the lesions improve during the
summer and worsen during the winter, an observation
that may be related to lesional exposure to ultraviolet
(UV) light. The lesions are often symmetrically distributed in certain favored locations, such as the scalp,
elbows, and knees. The classic description is a welldemarcated, erythematous plaque with a silvery scale
on its surface (Fig. 16-111). The lesions are often
asymptomatic, but it is not unusual for a patient to
complain of itchingin fact, the term psoriasis is
derived from the Greek word for itching. An unfortunate complication affecting approximately 11% of
these patients is psoriatic arthritis, which may involve
the TMJ.
Oral lesions may occur in patients with psoriasis, but
they are distinctly uncommon. Because descriptions of
these lesions have ranged from white plaques to red
plaques to ulcerations, it is difcult to determine the
true nature of intraoral psoriasis (Fig. 16-112). To
render a diagnosis of intraoral psoriasis, some investigators say that the activity of the oral lesions should
parallel that of the cutaneous lesions. Some authors
refer to erythema migrans (see page 779) as intraoral
psoriasis, and the prevalence of erythema migrans in
psoriatic patients appears to be slightly greater than
that seen in the rest of the population. It is difcult,
however, to prove a direct correlation of that common
mucosal alteration with psoriasis.
HISTOPATHOLOGIC FEATURES
Microscopically, psoriasis has a characteristic pattern.
The surface epithelium shows marked parakeratin production, and the epithelial rete ridges are elongated
(Fig. 16-113). The connective tissue papillae, which
contain dilated capillaries, approach close to the epithelial surface, and a perivascular chronic inammatory cell inltrate is present. In addition, collections of
neutrophils (Munro abscesses), are seen within the
parakeratin layer.
With respect to oral lesions, good correlation with
skin disease activity should be seen in addition to the
characteristic histopathologic features, because other
intraoral lesions, such as erythema migrans and oral
mucosal cinnamon reaction (see page 352), exhibit a
psoriasiform microscopic appearance.
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LUPUS ERYTHEMATOSUS
Lupus erythematosus (LE) is a classic example of an
immunologically mediated condition, and is the most
common of the so-called collagen vascular or connective tissue diseases in the United States, with more than
CLINICAL FEATURES
SYSTEMIC LUPUS ERYTHEMATOSUS
SLE can be a very difcult disease to diagnose in its
early stages because it often appears in a nonspecic,
vague fashion, frequently with periods of remission or
disease inactivity. Women are affected nearly 8 to 10
times more frequently than men. The average age at
diagnosis is 31 years. Common ndings include fever,
weight loss, arthritis, fatigue, and general malaise. In
40% to 50% of affected patients, a characteristic rash,
having the pattern of a buttery, develops over the
malar area and nose (Fig. 16-114), typically sparing
the nasolabial folds. Sunlight often makes the lesions
worse.
The kidneys are affected in approximately 40% to
50% of SLE patients. This complication may ultimately
lead to kidney failure; thus it is typically the most signicant aspect of the disease.
Cardiac involvement is also common, with pericarditis being the most frequent complication. At autopsy
nearly 50% of SLE patients display warty vegetations
affecting the heart valves (Libman-Sacks endocarditis). Its signicance is debatable, although some
patients may develop superimposed subacute bacterial
endocarditis on these otherwise sterile outgrowths of
brinoid material and connective tissue cells.
Oral lesions of SLE develop in 5% to 25% of these
patients, although some studies indicate prevalence as
high as 40%. The lesions usually affect the palate, buccal
mucosa, and gingivae. Sometimes they appear as
lichenoid areas, but they may also look nonspecic or
even somewhat granulomatous (Fig. 16-115). Involve-
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Table 16-4
Findings
95%
MUSCULOSKELETAL SYMPTOMS
Arthralgia/myalgia
Nonerosive polyarthritis
95%
95%
60%
CUTANEOUS SIGNS
Photosensitivity
Malar rash
Oral ulcers
Discoid rash
80%
70%
50%
40%
20%
HEMATOLOGIC SIGNS
Anemia (chronic disease)
Leukopenia (<4000/L)
Lymphopenia (<1500/L)
Thrombocytopenia (<100,000/L)
Hemolytic anemia
85%
70%
65%
50%
15%
10%
60%
50%
25%
20%
CARDIOPULMONARY SIGNS
Pleurisy, pericarditis, effusions
Myocarditis, endocarditis
60%
30%-50%
10%
RENAL SIGNS
Proteinuria >500 mg/24 hours,
cellular casts
Nephrotic syndrome
End-stage renal disease
30%-50%
30%-50%
25%
5%-10%
indicate that the lesions are exacerbated by sun exposure. With time, the lesions may heal spontaneously in
one area, only to appear in another area. The healing
process usually results in cutaneous atrophy with scarring and hypopigmentation or hyperpigmentation of
the resolving lesion. Conjunctival involvement by
CCLE has rarely been reported to cause cicatrizing
conjunctivitis, clinically similar to mucous membrane
pemphigoid.
In most cases the oral manifestations of CCLE
essentially appear clinically identical to the lesions
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HISTOPATHOLOGIC FEATURES
Fig. 16-117 Chronic cutaneous lupus erythematosus
(CCLE). Radiating keratotic striae surround erythematous
zones of the buccal mucosa. These features are similar to
those of erosive lichen planus.
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DIAGNOSIS
In addition to the clinical and microscopic features, a
number of additional immunologic studies may be
helpful in making the diagnosis of LE.
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Findings
Direct immunouorescence, lesional skin
Direct immunouorescence, normal skin
Antinuclear antibodies
Antidouble-stranded DNA antibodies
Anti-Sm antibodies
Frequency
Signicance
CCLE: 90%
SLE: 95%
CCLE: 0%
SLE: 25%-60%
CCLE: 0%-10%
SLE: 95%
CCLE: 0%
SLE: 70%-80%
CCLE: 0%
SLE: 10%-30%
CCLE, Chronic cutaneous lupus erythematosus; SLE, systemic lupus erythematosus; LE, lupus erythematosus.
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Microscopic examination of tissue involved by systemic sclerosis shows diffuse deposition of dense collagen within and around the normal structures (Fig.
16-128). This abnormal collagen replaces and destroys
the normal tissue, causing the loss of normal tissue
function.
DIAGNOSIS
During the early phases, it may be difcult to make a
diagnosis of systemic sclerosis. Generally, the clinical
signs of stiffened skin texture along with the development of Raynauds phenomenon are suggestive of the
diagnosis. A skin biopsy may be supportive of the diagnoses if abundant collagen deposition is observed
microscopically.
Laboratory studies may be helpful to the diagnostic process if anticentromere antibodies or anti-Scl 70
(topoisomerase I) is detected. Antitopoisomerase I antibodies are seen more often with systemic sclerosis;
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blood ow and lessen the symptoms of Raynauds phenomenon, but many patients can reduce episodes by
keeping warm (especially their hands and feet) or by
stopping cigarette smoking. Angiotensin-converting
enzyme (ACE) inhibitors often effectively control
hypertension if kidney involvement is prominent.
From a dental standpoint, problems may develop
for patients who wear prostheses because of the microstomia and inelasticity of the mouth. Collapsible dental
appliances with special hinges have been made to
facilitate the insertion and removal of dentures. Microstomia and inelastic soft tissue also hamper the maintenance of good oral hygiene, and affected patients
have a decreased ability to manipulate a toothbrush as
a result of sclerotic changes in the ngers and hands.
Surgical correction of open bite associated with condylar resorption has been described. Infrequently, the
resorption of the mandible may become so great as to
cause a pathologic fracture.
The prognosis is poor, although the outlook is better
for patients with limited cutaneous involvement than
for those with diffuse involvement. If the heart is
affected, then the prognosis is particularly poor, but
most patients die because of pulmonary involvement.
Overall survival gures are difcult to calculate because of a variety of factors, including the rarity of the
disease, the inherent variability of its natural course,
and the variation in treatments provided at medical
centers around the world. With current treatment
regimens, it is estimated that 10-year survival rates for
patients with limited cutaneous scleroderma approach
80% to 90%, whereas survival drops to 60% to 75% for
patients with diffuse systemic sclerosis.
CLINICAL FEATURES
As with systemic sclerosis, most patients with CREST
syndrome are women in the sixth or seventh decade of
life. The characteristic signs may not appear synchronously but instead may develop sequentially over a
period of months to years.
Calcinosis cutis occurs in the form of movable,
nontender, subcutaneous nodules, 0.5 to 2.0 cm in size,
which are usually multiple (Fig. 16-129). Larger, more
numerous or supercial calcications may occasionally become bothersome and require removal.
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DIAGNOSIS
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laboratory studies directed at identifying anticentromere antibodies may be useful, because this test is relatively specic for CREST syndrome.
ACANTHOSIS NIGRICANS
Acanthosis nigricans is an acquired dermatologic
problem characterized by the development of a velvety,
brownish alteration of the skin. In some instances, this
unusual condition develops in conjunction with gastrointestinal cancer and is termed malignant acanthosis
nigricans. The cutaneous lesion itself is benign, yet it
is signicant because it represents a cutaneous marker
for internal malignancy. The cause of malignant acanthosis nigricans is unknown, although a cytokine-like
peptide capable of affecting the epidermal cells may be
produced by the malignancy.
Most cases, estimated to affect as many as 5% of
adults, are not associated with a malignancy and are
termed benign acanthosis nigricans. A clinically
similar form, pseudoacanthosis nigricans, may occur
in some obese people. Some benign forms of acanthosis nigricans may be inherited or may occur in association with various endocrinopathies, such as diabetes
mellitus, Addisons disease, hypothyroidism, and acromegaly. Furthermore, benign acanthosis nigricans may
occur with certain syndromes (e.g., Crouzon syndrome)
or drug ingestion (e.g., oral contraceptives, corticosteroids). These forms of the condition are typically associated with resistance of the tissues to the effects of
insulin, similar to the insulin resistance seen in non
insulin-dependent diabetes mellitus (NIDDM). Even
though the affected individuals may not have overt diabetes mellitus, they often show increased levels of
insulin or an abnormal response to exogenously administered insulin.
CLINICAL FEATURES
HISTOPATHOLOGIC FEATURES
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Van der Meij EH, Slootweg PJ, van der Wal JE et al: Interobserver and intraobserver variability in the histologic assessment of oral lichen planus, J Oral Pathol Med 28:274-277,
1999.
Van der Meij EH, van der Waal I: Lack of clinicopathologic correlation in the diagnosis of oral lichen planus based on the
presently available diagnostic criteria and suggestions for
modications, J Oral Pathol Med 32:507-512, 2003.
Vote ABE, Schulten EAJM, Langendijk PNJ et al: Fluocinonide
in an adhesive base for treatment of oral lichen planus: a
double-blind, placebo-controlled clinical study, Oral Surg Oral
Med Oral Pathol 75:181-185, 1993.
Zakrzewska JM, Chan ES-Y, Thornhill MH: A systematic review
of placebo-controlled randomized clinical trials of treatments
used in oral lichen planus, Br J Dermatol 153:336-341,
2005.
Zhang LW, Michelsen C, Cheng X et al: Molecular analysis of
oral lichen planus. A premalignant lesion? Am J Pathol
151:323-327, 1997.
Chronic Ulcerative Stomatitis
Church LF, Schosser RH: Chronic ulcerative stomatitis associated with stratied epithelial specic antinuclear antibodies:
a case report of a newly described entity, Oral Surg Oral Med
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Woo S-B, Lee SJ, Schubert MM: Graft-vs-host disease, Crit Rev
Oral Biol Med 8:201-216, 1997.
Woo S-B, Sonis ST, Monopoli MM et al: A longitudinal study of
oral ulcerative mucositis in bone marrow transplant recipients, Cancer 72:1612-1617, 1993.
Psoriasis
Bruce AJ, Rogers RS: Oral psoriasis, Dermatol Clin 21:99-104,
2003.
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therapies, Cleve Clin J Med 67:105-106, 109-113, 117-119,
2000.
Doffy DL, Spelman LS, Martin NG: Psoriasis in Australian twins,
J Am Acad Dermatol 29:428-434, 1993.
Eastman JR, Goldblatt LI: Psoriasis: palatal manifestations and
physiologic considerations, J Periodontol 54:736-739, 1983.
Gelfand JM, Gladman DD, Mease PJ et al: Epidemiology of psoriatic arthritis in the population of the United States, J Am
Acad Dermatol 53:573, 2005.
Lowes MA, Bowcock AM, Krueger JG: Pathogenesis and therapy
of psoriasis, Nature 445:866-873, 2007.
Myers WA, Gottlieb AB, Mease P: Psoriasis and psoriatic arthritis: clinical features and disease mechanisms, Clin Dermatol
24:438-447, 2006.
Richardson LJ, Kratochvil FJ, Zieper MB: Unusual palatal presentation of oral psoriasis, J Can Dent Assoc 66:80-82, 2000.
Smith CH, Barker JNWN: Psoriasis and its management, Br Med
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Stern RS, Laird N: The carcinogenic risk of treatments for severe
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Younai FS, Phelan JA: Oral mucositis with features of psoriasis:
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Lupus Erythematosus
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Callen JP: Oral manifestations of collagen vascular disease, Semin
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Cervera R, Khamashta MA, Font J et al: Morbidity and mortality
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DCruz DP, Khamashta MA, Hughes GRV: Systemic lupus erythematosus, Lancet 369:587-596, 2007
De Rossi SS, Glick M: Lupus erythematosus: considerations for
dentistry, J Am Dent Assoc 129:330-339, 1998.
Doria A, Iaccarino L, Ghirardello A et al: Long-term prognosis
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Duong DJ, Spigel GT, Moxley RT et al: American experience with
low-dose thalidomide therapy for severe cutaneous lupus erythematosus, Arch Dermatol 135:1079-1087, 1999.
Fabbri P, Cardinali C, Giomi B et al: Cutaneous lupus erythematosus: diagnosis and management, Am J Clin Dermatol 4:449465, 2003.
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Chung L, Lin J, Furst DE et al: Systemic and localized scleroderma, Clin Dermatol 24:374-392, 2006.
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Pentenero M, Carrozzo M, Pagano M et al: Oral acanthosis
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Scully C, Barrett WA, Gilkes J et al: Oral acanthosis nigricans,
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Systemic Diseases
CHAPTER OUTLINE
Plummer-Vinson Syndrome
Pernicious Anemia
Pituitary Dwarsm
Gigantism
Acromegaly
Hypothyroidism
Hyperthyroidism
Hypoparathyroidism
Pseudohypoparathyroidism
Hyperparathyroidism
Hypercortisolism
Addisons Disease
Diabetes Mellitus
Hypophosphatasia
Vitamin DResistant Rickets
Crohns Disease
Pyostomatitis Vegetans
Uremic Stomatitis
Mucopolysaccharidosis
Lipid Reticuloendothelioses
Gaucher Disease
Niemann-Pick Disease
Tay-Sachs Disease
Lipoid Proteinosis
Jaundice
Amyloidosis
Vitamin Deciency
Vitamin A
Thiamin
Riboavin
Niacin
Pyridoxine
Vitamin C
Vitamin D
Vitamin E
Vitamin K
Iron-Deciency Anemia
MUCOPOLYSACCHARIDOSIS
The mucopolysaccharidoses are a heterogeneous
group of metabolic disorders that are usually inherited
in an autosomal recessive fashion. These disorders are
all characterized by the lack of any one of several
normal enzymes needed to process the important
intercellular substances known as glycosaminoglycans.
These substances used to be known as mucopolysaccharides, thus the term mucopolysaccharidosis. Examples of
glycosaminoglycans include the following:
Heparan sulfate
Dermatan sulfate
Keratan sulfate
Chondroitin sulfate
The type of mucopolysaccharidosis that is seen clinically depends on which of these substrates lacks its
particular enzyme. The mucopolysaccharidoses as a
group occur with a frequency of approximately 1 in
15,000 to 29,000 live births, although some types are
much less common.
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Eponym
Inheritance
Enzyme Deciency
Stored Substrate
Clinical Features
I-H
Hurler
AR
-L-Iduronidase
HS and DS
I-S
Scheie
AR
-L-Iduronidase
HS and DS
II
Hunter
X-Linked R
Iduronate-2-sulfatase
HS and DS
III-A
Sanlippo-A
AR
Sulfamidase
HS
III-B
Sanlippo-B
AR
-N-acetylglucosaminidase
HS
IV-A
Morquio-A
AR
Galactosamine-6-sulfatase
IV-B
Morquio-B
AR
-galactosidase
KS
VI
Maroteaux-Lamy
AR
N-acetylgalactosamine-4-sulfatase
Appears in infancy;
cloudy corneas,
growth retardation,
reduced intelligence,
coronary artery
disease; rarely live
10 years
Onset in late
childhood; cloudy
corneas, normal
intelligence, aortic
regurgitation; survive
to adulthood
Appears at 1 to 2 years
of age; clear corneas,
reduced intelligence,
growth retardation,
stiff joints
Appears at 4 to 6 years
of age; clear corneas,
reduced intelligence,
mild skeletal
changes; death in
adolescence
Generally same as
Sanlippo-A
Appears at 1 to 2 years
of age; cloudy
corneas, normal
intelligence, lax
joints; may survive
to middle age
Generally similar to
Morquio-A
Appears at 2 to 6 years
of age; cloudy
corneas, normal
intelligence, growth
retardation, stiff
joints; may survive
to adulthood
AR, Autosomal recessive; CS, chondroitin sulfate; dis, disulfate; DS, dermatan sulfate; GalNAc, N-acetylgalactosamine; HS, heparan sulfate; KS, keratan
sulfate; R, recessive; S, sulfate.
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No satisfactory systemic treatment of the mucopolysaccharidoses exists at this time. Several forms of mucopolysaccharidosis are associated with a markedly
reduced life span and with mental retardation. Attempts
to improve the survival and quality of life of these
patients using allogeneic bone marrow transplantation
have met with some success. Unfortunately, not all
aspects of the disease are corrected, and the complications associated with transplantation must be
addressed. Such complications are associated with a
15% to 20% mortality rate. Enzyme replacement therapy
currently is available for mucopolysaccharidosis I.
Initiation of the enzyme, laronidase, early in the
patients life appears to improve signicantly many of
the aspects of the disease, although complete resolution does not occur. Enzyme replacement strategies are
also being developed for several of the other forms of
this condition. Because of the rarity of these conditions
and the expense of developing the treatments, the
annual cost for such therapy typically exceeds
$340,000. Genetic counseling is indicated for the
parents and siblings of a patient affected by one of the
mucopolysaccharidosis syndromes. Prenatal diagnosis
is available for family planning as well.
Management of the dental problems of these patients
is essentially no different from that of other patients.
However, several factors may have to be taken into
account:
Degree of mental retardation (if any)
Presence or absence of a seizure disorder
Degree of joint stiffening
Extent of other related medical problems
Depending on which of these factors is present and
the extent of involvement, dental care may warrant
sedation, hospitalization, or general anesthesia of the
patient for optimal results. General anesthesia and
sedation may be challenging, however, because of
excess amounts of pharyngeal tissues that often produce
a smaller than normal airway. In severely affected
patients, general anesthesia probably should be considered only in life-threatening situations.
LIPID RETICULOENDOTHELIOSES
The lipid reticuloendothelioses are a relatively
rare group of inherited disorders. These include the
following conditions:
Gaucher disease
Niemann-Pick disease
Tay-Sachs disease
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NIEMANN-PICK DISEASE
Niemann-Pick disease occurs as three different types,
each associated with a different clinical expression and
prognosis. Types A and B are caused by a deciency of
acid sphingomyelinase, whereas type C is primarily the
result of mutation of NPC-1, a gene involved with cholesterol processing. Types A and C have neuronopathic
features, characterized by psychomotor retardation,
dementia, spasticity, and hepatosplenomegaly, with
death occurring during the rst or second decade of
life. Type B patients normally survive into adulthood
and exhibit visceral signs, primarily hepatosplenomegaly, and sometimes pulmonary involvement.
TAY-SACHS DISEASE
Tay-Sachs disease may have a wide clinical range
because the condition is genetically heterogeneous.
Some forms are mild, with patients surviving into adulthood. In the severe infantile form, however, rapidly
progressive neuronal degeneration develops shortly
after birth. Signs and symptoms include blindness,
developmental retardation, and intractable seizures.
Death usually occurs by 3 to 5 years of age.
HISTOPATHOLOGIC FEATURES
Histopathologic examination of an osseous lesion of
Gaucher disease shows sheets of lipid-engorged macrophages (Gaucher cells) exhibiting abundant bluish
cytoplasm, which has a ne texture resembling wrinkled silk. In Niemann-Pick disease, the characteristic
cell seen on examination of a bone marrow aspirate is
the sea blue histiocyte.
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LIPOID PROTEINOSIS
(HYALINOSIS CUTIS ET MUCOSAE;
URBACH-WIETHE SYNDROME)
A rare condition, lipoid proteinosis is inherited as an
autosomal recessive trait. It is characterized by the
deposition of a waxy material in the dermis and submucosal connective tissue of affected patients. The earliest thorough description of lipoid proteinosis was
by Urbach and Wiethe in 1929, and more than 300
patients, most of whom are of European background,
have been reported to date. Mutations of the ECM1
gene, which encodes a glycoprotein known as extracellular matrix protein 1, have recently been identied as
the cause for this condition.
CLINICAL FEATURES
The laryngeal mucosa and vocal cords are usually the
sites that are initially affected by lipoid proteinosis.
Therefore, the rst sign of the disease may be one of
the following:
An inability of the infant to make a crying sound
A hoarse cry in infancy
The development of a hoarse voice during early
childhood
The vocal cords become thickened as the accumulation of an amorphous material begins to affect the
laryngeal mucosa. This inltrative mucosal process
may also involve the pharynx, esophagus, tonsils, vulva,
HISTOPATHOLOGIC FEATURES
A biopsy specimen of an early lesion of lipoid proteinosis typically reveals the deposition of a lamellar material around the blood vessels, nerves, hair follicles, and
sweat glands. This material stains positively with the
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JAUNDICE (ICTERUS)
Jaundice is a condition characterized by excess bilirubin in the bloodstream. The bilirubin accumulates in
the tissues, which results in a yellowish discoloration
of the skin and mucosa. To understand jaundice, it is
important to know something about the metabolism of
bilirubin. Most bilirubin is derived from the breakdown of hemoglobin, the oxygen-carrying pigment of
erythrocytes. The average life span of an erythrocyte in
the circulation is 120 days. After this time, it undergoes
physiologic breakdown. The hemoglobin is degraded
and processed by the cells of the reticuloendothelial
system, and bilirubin is liberated into the bloodstream
in an unconjugated state. In the liver, bilirubin is taken
up by the hepatocytes and conjugated with glucuronic
acid, which produces conjugated bilirubin, a soluble
product that can be excreted in the bile.
There are numerous causes for increased serum
levels of bilirubin; some are physiologic, and many are
pathologic. Therefore, the presence of jaundice is not
a specic sign and generally necessitates physical
examination and laboratory studies to determine the
precise cause. The basic disturbances associated with
increased bilirubin levels include an increased production of bilirubin. This occurs when the red blood cells
(RBCs) are being broken down at such a rapid rate that
the liver cannot keep pace with processing. This breakdown is seen in such conditions as autoimmune
hemolytic anemia or sickle cell anemia.
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In addition, the liver may not be functioning correctly, resulting in decreased uptake of the bilirubin
from the circulation or decreased conjugation of bilirubin in the liver cells. Jaundice is frequently present
at birth as a result of the low level of activity of the
enzyme system that conjugates bilirubin. Defects in
this enzyme system may also be seen with certain
inherited problems, one of the more common of which
is Gilbert syndrome. This innocuous condition is
often detected on routine examination, and it is estimated to affect up to 5% of people in the United States.
Because most of these examples of jaundice occur with
impaired processing of bilirubin, laboratory studies
usually show unconjugated bilirubin in the serum.
The presence of conjugated bilirubinemia in jaundice can usually be explained by the reduced excretion
of bilirubin into the bile ducts. This can be the result of
swelling of the hepatocytes (resulting in an occlusion
of the bile canaliculi) or hepatocyte necrosis, with disruption of the bile canaliculi and liberation of conjugated bilirubin. Thus liver function may be disturbed
because of any one of a variety of infections (e.g.,
viruses) or toxins (e.g., alcohol). Occlusion of the bile
duct from gallstones, stricture, or cancer can also force
conjugated bilirubin into the bloodstream.
CLINICAL FEATURES
The patient affected by jaundice exhibits a diffuse,
uniform, yellowish discoloration of the skin and
mucosa. The color varies in intensity, depending on the
serum level of bilirubin and the anatomic site. Because
elastin bers have an afnity for bilirubin, tissues
that have a high content of elastin, including the
sclera, lingual frenum, and soft palate, are prominently
affected. The sclera of the eye is often the rst site at
which the yellow color is noted (Fig. 17-6). The yellow
discoloration caused by hypercarotenemia (resulting
from excess ingestion of carotene, a vitamin-A precursor found in yellow vegetables and fruits) may be confused with jaundice, but the sclera is not involved in
that condition.
Other signs and symptoms associated with jaundice
vary with the underlying cause of the hyperbilirubinemia. For example, patients with viral hepatitis usually
have a fever, abdominal pain, anorexia, and fatigue. The
patient with jaundice typically requires a complete
medical evaluation to determine the precise cause of
the condition so that proper therapy can be instituted.
AMYLOIDOSIS
Amyloidosis represents a heterogeneous group of
conditions characterized by the deposition of an extracellular proteinaceous substance called amyloid.
Virchow coined the term amyloid in the middle of the
nineteenth century because he believed it to be a
starchlike material (amyl = starch; oid = resembling).
We now understand that amyloid can be formed in a
variety of settings, each with its own specic type of
amyloid protein. Many of these amyloid proteins have
been identied precisely with respect to their biochemical composition, and ideally an attempt should
be made to categorize the type of amyloid specically
when this diagnosis is made. The various amyloid proteins are designated with an A, to indicate amyloid,
followed by an abbreviation for the specic amyloid
protein. For example, AL would identify amyloid composed of immunoglobulin light (L) chain molecules.
Although amyloid may have several sources, all types
of amyloid have the common feature of a -pleated
sheet molecular conguration, which can be seen with
x-ray diffraction crystallographic analysis. Because of
this similarity of molecular structure, the different
types of amyloid have similar staining patterns with
special stains.
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Amyloidosis can produce a variety of effects, depending on the organ of involvement and the extent to
which the amyloid is deposited. With limited cutaneous forms of amyloidosis, virtually no effect on survival
is seen. With some forms of systemic amyloidosis,
however, death may occur within a few years of the
diagnosis as a result of cardiac or renal failure. Furthermore, the presence of amyloid may be associated with
other problems, such as multiple myeloma or chronic
infections.
CLINICAL FEATURES
Several classications of amyloidosis have been proposed in the past decade, each evolving as the knowledge of this unusual condition increases. None of the
classications is completely satisfactory, although in
recent years, the biochemical makeup of these proteins
has gured more prominently in most classications.
This discussion attempts to be as concise and direct as
possible. Essentially, amyloidosis may be divided into
organ-limited and systemic forms from a clinical
standpoint.
ORGAN-LIMITED AMYLOIDOSIS
Although organ-limited amyloidosis may occur in a
variety of organs, it has rarely been reported in the oral
soft tissues. An example of a limited form of amyloidosis is the amyloid nodule, which appears as a solitary,
otherwise asymptomatic, submucosal deposit. Most of
the organ-limited forms of amyloidosis consist of aggregates of immunoglobulin light chains, which in some
cases are produced by a focal collection of monoclonal
plasma cells. By denition, such amyloid deposits are
not associated with any systemic alteration.
SYSTEMIC AMYLOIDOSIS
Systemic amyloidosis may occur in several forms:
Primary
Myeloma associated
Secondary
Hemodialysis associated
Heredofamilial
SECONDARY AMYLOIDOSIS
Secondary amyloidosis is so named because it characteristically develops as a result of a chronic inammatory process, such as long-standing osteomyelitis,
tuberculosis, or sarcoidosis. Cleavage fragments of a
circulating acute-phase reactant protein appear to
comprise this type of amyloidosis, which is thus designated AA. The heart is usually not affected as in other
forms of amyloidosis. Liver, kidney, spleen, and adrenal
involvement are typical, however. With the advent of
modern antibiotic therapy, this form of amyloidosis has
become much less common in the United States.
HEMODIALYSIS-ASSOCIATED AMYLOIDOSIS
Patients who have undergone long-term renal dialysis
also are susceptible to amyloidosis, although in this
case the amyloid protein has been identied as
2-microglobulin, and this type of amyloidosis is
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HEREDOFAMILIAL AMYLOIDOSIS
Heredofamilial amyloidosis is an uncommon but signicant form of the disease. Several kindred have been
identied in Swedish, Portuguese, and Japanese populations, and most types are inherited as autosomal
dominant traits. An autosomal recessive form, known
as familial Mediterranean fever, has also been described.
Several of these conditions appear as polyneuropathies,
although other manifestations, such as cardiomyopathy, cardiac arrhythmias, congestive heart failure, and
renal failure, eventually develop as the amyloid deposition continues.
HISTOPATHOLOGIC FEATURES
Biopsy of rectal mucosa has classically been used to
conrm a diagnosis of primary or myeloma-associated
amyloidosis, with up to 80% of such biopsy specimens
being positive. Aspiration biopsy of abdominal subcutaneous fat is a simpler procedure, however, and the
sensitivity of this technique has been reported to range
from 55% to 75%. Alternative tissue sources, however,
are the gingiva and labial salivary glands. Histopathologic examination of gingival tissue that has been
affected by amyloidosis shows extracellular deposition
in the submucosal connective tissue of an amorphous,
eosinophilic material, which may be arranged in a perivascular orientation or may be diffusely present
throughout the tissue (Fig. 17-9). Relatively low sensitivity has been reported for gingival biopsies, whereas
labial salivary gland tissue shows deposition of amyloid
in a periductal or perivascular location in more than
80% of the cases.
A standard means of identifying amyloid uses the
dye, Congo red, which has an afnity for the abnormal
protein. In tissue sections stained with Congo red, the
amyloid appears red. When the tissue is viewed with
polarized light, it exhibits an apple-green birefringence (Fig. 17-10). Microscopic sections stained with
crystal violet reveal a characteristic metachromasia;
this normally purple dye appears more reddish when
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ORAL MANIFESTATIONS
OF
SYSTEMIC DISEASES
DIAGNOSIS
Once the histopathologic diagnosis of amyloidosis has
been made, the patient must be evaluated medically to
determine the type of amyloidosis that is present. This
often entails a workup that includes serum immunoelectrophoresis to determine whether a monoclonal
gammopathy exists so that multiple myeloma can be
ruled out. Immunohistochemical studies are proving to
be very useful in distinguishing the specic type of
amyloid protein. Family history and physical examination ndings are also important.
825
CLINICAL FEATURES
VITAMIN A
VITAMIN DEFICIENCY
In the United States today, signicant vitamin deciencies are not common. Patients with malabsorption syndromes or eating disorders, persons who follow fad
diets, and alcoholics are the groups most commonly
affected.
Vitamin A (retinol) is essential for the maintenance
of vision, and it also plays a role in growth and tissue
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THIAMIN
A deciency of thiamin results in a condition called
beriberi, a problem that is relatively uncommon in the
Western world except in alcoholics or other individuals who do not receive a balanced diet. Thiamin deciency has also been documented in patients who have
had gastric bypass surgery for weight control, presumably because an adequate amount of the vitamin is not
obtained in the diet. The condition became prevalent
in southeast Asia when the practice of removing the
outer husks of the rice grain by machine was introduced. Because these outer husks contained nearly all
of the thiamin, people who subsisted on the polished
rice became decient in this vitamin. The disorder is
manifested by cardiovascular problems (e.g., peripheral vasodilation, heart failure, edema) and neurologic
problems (including peripheral neuropathy and Wernickes encephalopathy). Patients with Wernickes
encephalopathy experience vomiting, nystagmus, and
progressive mental deterioration, which may lead to
coma and death.
RIBOFLAVIN
A diet that is chronically decient in riboavin causes
a number of oral alterations, including glossitis, angular
cheilitis, sore throat, and swelling and erythema of the
oral mucosa. A normocytic, normochromic anemia
may be present, and seborrheic dermatitis may affect
the skin.
NIACIN
A deciency of niacin causes a condition known as
pellagra, a term derived from the Italian words pelle
agra, meaning rough skin. This condition may occur in
populations that use maize as a principal component
of their diets, because corn is a poor source of niacin.
Pellagra was once common in the southeastern United
States and may still be seen in some parts of the world.
The classic systemic signs and symptoms include the
triad of dermatitis, dementia, and diarrhea. The dermatitis is distributed symmetrically; sun-exposed areas,
such as the face, neck, and forearms, are affected most
severely (Fig. 17-11). The oral manifestations have
been described as stomatitis and glossitis, with the
tongue appearing red, smooth, and raw. Without correction of the niacin deciency, the disease may evolve
and persist over a period of years, eventually leading to
death.
PYRIDOXINE
A deciency of pyridoxine is unusual because of its
widespread occurrence in a variety of foods. A number
of drugs, such as the antituberculosis drug isoniazid,
act as pyridoxine antagonists; therefore, patients who
VITAMIN C
A deciency of vitamin C is known as scurvy, and its
occurrence in the United States is usually limited to
people whose diets lack fresh fruits and vegetables.
Commonly affected groups include inner-city infants
(whose diets often consist entirely of milk) and older
edentulous men, particularly those who live alone.
The clinical signs of scurvy are typically related to
inadequate collagen synthesis. For example, weakened
vascular walls may result in widespread petechial hemorrhage and ecchymosis. Similarly, wound healing is
delayed, and recently healed wounds may break down.
In childhood, painful subperiosteal hemorrhages may
occur.
The oral manifestations are well documented and
include generalized gingival swelling with spontaneous hemorrhage, ulceration, tooth mobility, and
increased severity of periodontal infection and periodontal bone loss. The gingival lesions have been
termed scorbutic gingivitis (Fig. 17-12). If untreated,
scurvy may ultimately lead to death, often as a result of
intracranial hemorrhage.
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VITAMIN K
VITAMIN D
A deciency of vitamin D during infancy results in a
condition called rickets; adults who are decient in
this vitamin develop osteomalacia. With the vitaminD supplementation of milk and cereal, rickets is a relatively uncommon disease today in the United States. In
past centuries, however, rickets was often seen, particularly in the temperate zones of the world, which often
do not receive adequate sunlight to ensure physiologic
levels of vitamin D. Even today in the United States,
children who are dark skinned and do not receive
adequate sun exposure, as well as solely breast-fed
infants, remain at risk for developing rickets. Nutritional rickets remains a problem in many developing
countries, although the condition is thought to be associated more with calcium deciency than vitamin-D
deciency.
Clinical manifestations of rickets include irritability,
growth retardation, and prominence of the costochondral junctions (rachitic rosary). As the child ages and
begins to put weight on the long bones of the legs, signicant bowing results because of the poor mineralization of the skeleton.
A similar pattern of poorly mineralized bone is seen
in osteomalacia in adults. Bone normally undergoes
continuous remodeling and turnover, and the osteoid
that is produced during this process does not have sufcient calcium to mineralize completely. Thus a weak,
fragile bone structure results. Patients affected by
osteomalacia frequently complain of diffuse skeletal
pain, and their bones are susceptible to fracture with
relatively minor injury.
VITAMIN E
A deciency of vitamin E is rare and occurs primarily
in children who suffer from chronic cholestatic liver
IRON-DEFICIENCY ANEMIA
Iron-deciency anemia is the most common cause of
anemia in the United States and throughout the world.
This form of anemia develops when the amount of iron
available to the body cannot keep pace with the need
for iron in the production of red blood cells (RBCs).
This type of anemia develops under four conditions:
1. Excessive blood loss
2. Increased demand for RBCs
3. Decreased intake of iron
4. Decreased absorption of iron
It is estimated that 20% of women of childbearing
age in the United States are iron decient as a result
of the chronic blood loss associated with excessive
menstrual ow (menorrhagia). Similarly, 2% of adult
men are iron decient because of chronic blood loss,
usually associated with gastrointestinal disease, such as
peptic ulcer disease, diverticulosis, hiatal hernia, or
malignancy.
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CLINICAL FEATURES
Patients with iron-deciency anemia that is severe
enough to cause symptoms may complain of fatigue,
easy tiring, palpitations, lightheadedness, and lack of
energy. Oral manifestations include angular cheilitis
and atrophic glossitis or generalized oral mucosal
atrophy. The glossitis has been described as a diffuse
or patchy atrophy of the dorsal tongue papillae, often
accompanied by tenderness or a burning sensation.
Such ndings are also evident in oral candidiasis, and
some investigators have suggested that iron deciency
predisposes the patient to candidal infection, which
results in the changes seen at the corners of the mouth
and on the tongue. Such lesions are rarely seen in the
United States, perhaps because the anemia is usually
detected relatively early before the oral mucosal
changes have had a chance to develop.
LABORATORY FINDINGS
PLUMMER-VINSON SYNDROME
(PATERSON-KELLY SYNDROME;
SIDEROPENIC DYSPHAGIA)
Plummer-Vinson syndrome is a rare condition characterized by iron-deciency anemia, seen in conjunction with glossitis and dysphagia. Its incidence in
developed countries has been declining, probably as a
result of the improved nutritional status of the populations. The condition is signicant in that it has been
associated with a high frequency of both oral and
esophageal squamous cell carcinoma; therefore, it is
considered a premalignant process.
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PERNICIOUS ANEMIA
LABORATORY FINDINGS
Hematologic studies show a hypochromic microcytic
anemia that is consistent with an iron-deciency
anemia.
HISTOPATHOLOGIC FEATURES
A biopsy specimen of involved mucosa from a patient
with Plummer-Vinson syndrome typically shows epithelial atrophy with varying degrees of submucosal
chronic inammation. In advanced cases, evidence of
epithelial atypia or dysplasia may be seen.
CLINICAL FEATURES
With respect to systemic complaints, patients with pernicious anemia often report fatigue, weakness, shortness of breath, headache, and feeling faint. Such
symptoms are associated with most anemias and probably reect the reduced oxygen-carrying capacity
of the blood. In addition, many patients report
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Fig. 17-15 Pernicious anemia. A, The dorsal tongue shows erythema and atrophy. B, After
therapy with vitamin B12, the mucosal alteration resolved.
HISTOPATHOLOGIC FEATURES
Histopathologic examination of an erythematous
portion of the oral mucosa shows marked epithelial
atrophy with loss of rete ridges, an increased nuclearto-cytoplasmic ratio, and prominent nucleoli (Fig.
17-16). This pattern can be misinterpreted as epithelial
dysplasia at times, although the nuclei in pernicious
anemia typically are pale staining and show peripheral
chromatin clumping. A patchy diffuse chronic inammatory cell inltrate is usually noted in the underlying
connective tissue.
LABORATORY FINDINGS
Hematologic evaluation of vitamin B12 deciency
shows a macrocytic anemia and reduced serum cobalamin levels. The Schilling test for pernicious anemia
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PITUITARY DWARFISM
Pituitary dwarsm is a relatively rare condition that
results from either the diminished production of
growth hormone by the anterior pituitary gland or a
reduced capacity of the tissues to respond to growth
hormone. Affected patients are typically much shorter
than normal, although their body proportions are generally appropriate.
Several conditions may cause short stature, and a
careful evaluation of the patient must be performed to
rule out other possible causes, such as the following:
1. Intrinsic defects in the patients tissues (e.g.,
certain skeletal dysplasias, chromosomal abnormalities, idiopathic short stature)
2. Alterations in the environment of the growing
tissues (e.g., malnutrition, hypothyroidism, diabetes mellitus)
If a lack of growth hormone is detected, the cause
should be determined. Sometimes the fault lies with
the pituitary gland itself (e.g., aplasia, hypoplasia). In
other instances, the problem may be related to destruction of the pituitary or hypothalamus by tumors, therapeutic radiation, or infection.
If the hypothalamus is affected, a deciency in
growth hormonereleasing hormone, which is produced by the hypothalamus, results in a deciency of
growth hormone. Often deciencies in other hormones, such as thyroid hormone and cortisol, are also
detected in patients with primary pituitary or hypothalamic disorders.
Some patients exhibit normal or even elevated levels
of growth hormone, yet still show little evidence of
growth. These individuals usually have inherited an
autosomal recessive trait, resulting in abnormal and
reduced growth hormone receptors on the patients
cells. Thus normal growth cannot proceed.
CLINICAL FEATURES
Perhaps the most striking feature of pituitary dwarsm
is the remarkably short stature of the affected patient.
Sometimes this is not noticed until the early years of
childhood, but a review of the patients growth history
should show a consistent pattern of failure to achieve
the minimal height on the standard growth chart. Often
the patients height may be as much as three standard
deviations below normal for a given age. Unlike the
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body proportions in many of the dysmorphic syndromes and skeletal dysplasias, the body proportions
of patients affected by a lack of growth hormone are
usually normal. One possible exception is the size of
the skull, which is usually within normal limits. Because
the facial skeleton does not keep pace with the skull,
however, the face of an affected patient may appear
smaller than it should be. Mental status is generally
within normal limits.
The maxilla and mandible of affected patients are
smaller than normal, and the teeth show a delayed
pattern of eruption. The delay ranges from 1 to 3 years
for teeth that normally erupt during the rst decade of
life and from 3 to 10 years for teeth that normally erupt
in the second decade of life. Often the shedding of
deciduous teeth is delayed by several years, and the
development of the roots of the permanent teeth also
appears to be delayed. A lack of development of the
third molars seems to be a common nding. The size
of the teeth is usually reduced in proportion to the
other anatomic structures.
LABORATORY FINDINGS
Radioimmunoassay for human growth hormone shows
levels that are markedly below normal.
GIGANTISM
Gigantism is a rare condition caused by an increased
production of growth hormone, usually related to a
functional pituitary adenoma. The increased production of growth hormone takes place before closure of
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ACROMEGALY
Acromegaly is an uncommon condition characterized
by the excess production of growth hormone after
closure of the epiphyseal plates in the affected patient.
Usually, this increase in growth hormone is due to a
functional pituitary adenoma. The incidence is estimated to be approximately three to ve new cases diagnosed per million population per year. The prevalence
is believed to be 66 affected patients per million.
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Fig. 17-20 Hypothyroidism. A, The facial appearance of this 9-year-old child is due to the
accumulation of tissue edema secondary to severe hypothyroidism. B, Same patient after 1
year of thyroid hormone replacement therapy. Note the eruption of the maxillary permanent
teeth.
HYPOTHYROIDISM (CRETINISM;
MYXEDEMA)
Hypothyroidism is a condition that is characterized
by decreased levels of thyroid hormone. When this
decrease occurs during infancy, the resulting clinical
problem is known as cretinism. If an adult has markedly decreased thyroid hormone levels for a prolonged
period, then deposition of a glycosaminoglycan ground
substance is seen in the subcutaneous tissues, producing a nonpitting edema. Some call this severe form of
hypothyroidism myxedema; others use the terms myxedema and hypothyroidism interchangeably.
Hypothyroidism may be classied as either primary
or secondary. In primary hypothyroidism, the thyroid
gland itself is in some way abnormal; in secondary
hypothyroidism, the pituitary gland does not produce
an adequate amount of thyroid-stimulating hormone
(TSH), which is necessary for the appropriate release
of thyroid hormone. Secondary hypothyroidism, for
example, often develops after radiation therapy for
brain tumors, resulting in unavoidable radiation
damage to the pituitary gland. Most cases, however,
represent the primary form of the disease.
Screening for this disorder is routinely carried out
at birth, and the prevalence of congenital hypothyroidism in North America is approximately 1 in 4000
births. Usually, this is due to hypoplasia or agenesis of
the thyroid gland. In other areas of the world, hypothyroidism in infancy is usually due to a lack of dietary
iodine. In adults, hypothyroidism is often caused by
autoimmune destruction of the thyroid gland (known
as Hashimotos thyroiditis) or iatrogenic factors, such
as radioactive iodine therapy or surgery for the treatment of hyperthyroidism. Because thyroid hormone is
necessary for normal cellular metabolism, many of the
clinical signs and symptoms of hypothyroidism can
be related to the decreased metabolic rate in these
patients.
CLINICAL FEATURES
The most common features of hypothyroidism include
such signs and symptoms as lethargy, dry and coarse
skin, swelling of the face (Fig. 17-20) and extremities,
huskiness of the voice, constipation, weakness, and
fatigue. The heart rate is usually slowed (bradycardia).
Reduced body temperature (hypothermia) may be
present, and the skin often feels cool and dry to the
touch. In the infant, these signs may not be readily
apparent, and the failure to grow normally may be the
rst indication of the disease.
With respect to the oral ndings, the lips may appear
thickened because of the accumulation of glycosaminoglycans. Diffuse enlargement of the tongue occurs
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HYPERTHYROIDISM
(THYROTOXICOSIS; GRAVES
DISEASE)
Fig. 17-22 Hypothyroidism. Photograph of the same
patient depicted in Fig. 17-20 before hormone replacement
therapy. Note the retained deciduous teeth, for which the
patient was initially referred.
for the same reason (Fig. 17-21). If the condition develops during childhood, the teeth may fail to erupt,
although tooth formation may not be impaired (Figs.
17-22 and 17-23).
LABORATORY FINDINGS
The diagnosis is made by assaying the free thyroxine
(T4) levels. If these levels are low, then TSH levels are
measured to determine whether primary or secondary
hypothyroidism is present. With primary thyroid
disease, TSH levels are elevated. With secondary
disease caused by pituitary dysfunction, TSH levels are
normal or borderline.
Hyperthyroidism is a condition caused by excess production of thyroid hormone. This excess production
results in a state of markedly increased metabolism in
the affected patient. Most cases (60% to 90%) are due
to Graves disease, a condition that was initially
described in the early nineteenth century. It is thought
to be triggered by autoantibodies that are directed
against receptors for thyroid-stimulating hormone
(TSH) on the surface of the thyroid cells. When the
autoantibodies bind to these receptors, they seem to
stimulate the thyroid cells to release inappropriate
thyroid hormone.
Other causes of hyperthyroidism include hyperplastic thyroid tissue and thyroid tumors, both benign
and malignant, which secrete inappropriate thyroid
hormone. Similarly, a pituitary adenoma may produce
TSH, which can then stimulate the thyroid to secrete
excess thyroid hormone.
CLINICAL FEATURES
Graves disease is ve to 10 times more common in
women than in men and is seen with some frequency.
It affects almost 2% of the adult female population.
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HISTOPATHOLOGIC FEATURES
Diffuse enlargement and hypercellularity of the thyroid gland are seen in patients with Graves disease,
typically with hyperplastic thyroid epithelium and
little apparent colloid production. Lymphocytic
inltration of the glandular parenchyma is also often
noted.
LABORATORY FINDINGS
The diagnosis of hyperthyroidism is made by assaying
free T4 (thyroxine) and TSH levels in the serum. In
affected patients, the T4 levels should be elevated and
the TSH concentration is typically depressed.
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HYPOPARATHYROIDISM
Calcium levels in extracellular tissues are normally
regulated by parathyroid hormone (PTH) (parathormone) in conjunction with vitamin D. If calcium levels
drop below a certain point, then the release of PTH is
stimulated. The hormone then acts directly on the
kidney and the osteoclasts of the bone to restore the
calcium to normal levels. In the kidney, calcium reabsorption is promoted, phosphate excretion is enhanced,
and the production of vitamin D is stimulated, which
increases the absorption of calcium from the gut.
Osteoclasts are activated to resorb bone and thus liberate calcium.
If a reduced amount of PTH is produced, the relatively rare condition known as hypoparathyroidism
results. Usually, hypoparathyroidism is due to inadvertent surgical removal of the parathyroid glands when
the thyroid gland is excised for other reasons, but
sometimes it is the result of autoimmune destruction
of the parathyroid tissue. Rare syndromes, such as
DiGeorge syndrome and the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
syndrome (endocrine-candidiasis syndrome), may
be associated with hypoparathyroidism.
CLINICAL FEATURES
With the loss of parathyroid function, the serum levels
of calcium drop, resulting in hypocalcemia. Often the
patient with chronic hypoparathyroidism adapts to the
presence of hypocalcemia and is asymptomatic unless
situations that further reduce the calcium levels are
encountered. Such situations include metabolic alkalosis, as seen during hyperventilation, when a state of
tetany may become evident.
Chvosteks sign is an oral nding of signicance,
characterized by a twitching of the upper lip when the
facial nerve is tapped just below the zygomatic process.
A positive response suggests a latent degree of tetany.
If the hypoparathyroidism develops early in life during
odontogenesis, then a pitting enamel hypoplasia and
failure of tooth eruption may occur (Fig. 17-25).
The presence of persistent oral candidiasis in a young
patient may signal the onset of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (see page 219). Hypoparathyroidism may be
only one of several endocrine deciencies associated
with this condition.
LABORATORY FINDINGS
PTH can be measured by means of a radioimmunoassay. If serum PTH levels are decreased in conjunction
with a decreased serum calcium concentration, ele-
vated serum phosphate level, and normal renal function, then a diagnosis of hypoparathyroidism can be
made.
PSEUDOHYPOPARATHYROIDISM
(ALBRIGHT HEREDITARY
OSTEODYSTROPHY;
ACRODYSOSTOSIS)
The rare condition known as pseudohypoparathyroidism represents at least two broad disorders in
which normal parathyroid hormone (PTH) is present
in adequate amounts but the biochemical pathways
responsible for activating the target cells are not functioning properly. The clinical result is a patient who
appears to have hypoparathyroidism.
In the case of pseudohypoparathyroidism type I,
three subcategories have been dened. For type Ia,
a molecular defect of a specic intracellular binding
protein known as Gsa seems to prevent the formation
of cyclic adenosine monophosphate (cAMP), a critical
component in the activation of cell metabolism.
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CLINICAL FEATURES
Pseudohypoparathyroidism most commonly appears
as type Ia disease. Patients affected by pseudohypoparathyroidism, either type Ia or Ic, have a characteristic array of features that includes mild mental
retardation, obesity, round face, short neck, and markedly short stature. Midfacial hypoplasia is also commonly observed. The metacarpals and metatarsals are
usually shortened, and the ngers appear short and
thick. Subcutaneous calcications (osteoma cutis)
may be identied in some patients. Other endocrine
abnormalities that are typically encountered include
hypogonadism and hypothyroidism.
Patients with type Ib and II disease clinically appear
normal, aside from their symptoms of hypocalcemia.
Dental manifestations of pseudohypoparathyroidism include generalized enamel hypoplasia, widened
pulp chambers with intrapulpal calcications, oligodontia, delayed eruption, and blunting of the apices of
the teeth. The pulpal calcications are often described
as dagger shaped.
The diagnosis of pseudohypoparathyroidism is made
based on elevated serum levels of PTH seen concurrently with hypocalcemia, hyperphosphatemia, and
otherwise normal renal function. More sophisticated
studies are necessary to delineate the various subtypes.
HYPERPARATHYROIDISM
Excess production of parathyroid hormone (PTH)
results in the condition known as hyperparathyroidism. PTH normally is produced by the parathyroid
glands in response to a decrease in serum calcium
levels.
Primary hyperparathyroidism is the uncontrolled
production of PTH, usually as a result of a parathyroid
adenoma (80% to 90% of cases) or parathyroid hyperplasia (10% to 15% of cases). Rarely (approximately 1%
of cases), a parathyroid carcinoma may be the cause
of primary hyperparathyroidism. Infrequently this
endocrine disturbance is caused by any one of several
inherited syndromes, including multiple endocrine
neoplasia type 1 or type 2a, or hyperparathyroidismjaw tumor syndrome. In the latter condition,
affected patients develop multiple jaw lesions that
histopathologically are consistent with central cementoossifying broma. There also appears to be an increased risk for these patients to develop parathyroid
carcinoma.
Secondary hyperparathyroidism develops when
PTH is continuously produced in response to chronic
low levels of serum calcium, a situation usually associated with chronic renal disease. The kidney processes
vitamin D, which is necessary for calcium absorption
from the gut. Therefore, in a patient with chronic renal
disease, active vitamin D is not produced and less
calcium is absorbed from the gut, resulting in lowered
serum calcium levels.
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HISTOPATHOLOGIC FEATURES
The brown tumor of hyperparathyroidism is histopathologically identical to the central giant cell granuloma of the jaws, a benign tumorlike lesion that
usually affects teenagers and young adults (see page
626). Both lesions are characterized by a proliferation
of exceedingly vascular granulation tissue, which serves
as a background for numerous multinucleated osteoclast-type giant cells (Fig. 17-29). Some lesions may
also show a proliferative response characterized by a
parallel arrangement of spicules of woven bone set
in a cellular broblastic background with variable
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HYPERCORTISOLISM (CUSHINGS
SYNDROME)
Hypercortisolism is a clinical condition that results
from a sustained increase in glucocorticoid levels. In
most cases this increase is due to corticosteroid therapy
that is prescribed for other medical purposes. If the
increase is caused by an endogenous source, such as
an adrenal or pituitary (adrenocorticotropic hormone
[ACTH]-secreting) tumor, then the condition is known
as Cushings disease. This latter condition is rather
rare and usually affects young adult women.
CLINICAL FEATURES
DIAGNOSIS
If the patient has been receiving large amounts of corticosteroids (greater than the equivalent of 20 mg of
prednisone) on a daily basis for several months, then
the diagnosis is rather obvious, given the classic signs
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ADDISONS DISEASE
(HYPOADRENOCORTICISM)
Insufcient production of adrenal corticosteroid hormones caused by the destruction of the adrenal cortex
results in the condition known as Addisons disease,
or primary hypoadrenocorticism. The incidence of
new cases diagnosed in the Western hemisphere is
110 to 140 per million population per year. The causes
are diverse and include the following:
Autoimmune destruction
Infections (e.g., tuberculosis and deep fungal
diseases, particularly in patients with acquired
immunodeciency syndrome [AIDS])
Rarely, metastatic tumors, sarcoidosis, hemochromatosis, or amyloidosis
If the pituitary gland is not functioning properly,
secondary hypoadrenocorticism may develop
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LABORATORY FINDINGS
The diagnosis of hypoadrenocorticism is conrmed by
a rapid ACTH stimulation test and measurement of
serum cortisol levels and plasma ACTH levels. If serum
cortisol levels are below 20 g/dL, then the patient
has adrenal insufciency. In primary hypoadrenocorticism, the plasma ACTH levels are high (>100 ng/L). In
secondary hypoadrenocorticism, the levels are normal
(9 to 52 ng/L) or low, as would be expected because
the condition results from decreased ACTH production by the pituitary gland.
because of decreased production of ACTH, the hormone responsible for maintaining normal levels of
serum cortisol.
CLINICAL FEATURES
The clinical features of hypoadrenocorticism do not
actually begin to appear until at least 90% of the glandular tissue has been destroyed. With gradual destruction of the adrenal cortex, an insidious onset of fatigue,
irritability, depression, weakness, and hypotension is
noted over a period of months. A generalized hyperpigmentation of the skin occurs, classically described as
bronzing. The hyperpigmentation is generally more
prominent on sun-exposed skin and over pressure
points, such as the elbows and knees; it is caused
by increased levels of beta-lipotropin or ACTH, each
of which can stimulate melanocytes. The patient
usually complains of gastrointestinal upset with
anorexia, nausea, vomiting, diarrhea, weight loss, and
a peculiar craving for salt. When hypoadrenocorticism
is accompanied by hypoparathyroidism and mucocutaneous candidiasis, the possibility of autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy
syndrome should be considered (see page 219).
The oral manifestations include diffuse or patchy,
brown, macular pigmentation of the oral mucosa
caused by excess melanin production (Fig. 17-32).
Often the oral mucosal changes are the rst manifestation of the disease, with the skin hyperpigmentation
occurring afterward. Sometimes the oral hypermelanosis may be difcult to distinguish from physiologic
racial pigmentation, but a history of a recent onset of
oral pigmentation should suggest the possibility of
Addisons disease.
DIABETES MELLITUS
Diabetes mellitus is a common disorder of carbohydrate metabolism that is thought to have several causes,
although the basic problem is one of either decreased
production of insulin or tissue resistance to the effects
of insulin. The net result of this abnormal state is an
increase in the blood glucose level (hyperglycemia).
Diabetes mellitus is usually divided into two presentations:
1. Type Iinsulin-dependent diabetes mellitus
(IDDM) or juvenile-onset diabetes
2. Type IInoninsulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes
Type I diabetes mellitus is characterized by a lack
of insulin production. Patients usually exhibit severe
hyperglycemia and ketoacidosis. The disease is typically diagnosed during childhood, and patients require
exogenous insulin injections to survive.
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Type II diabetes mellitus is sometimes more difcult to diagnose. It usually occurs in older, obese
adults. Although hyperglycemia is present, ketoacidosis rarely develops. Furthermore, patients can produce
some endogenous insulin. A few patients may take
insulin to help control their disease; the insulin injections, however, are usually not necessary for the
patients survival.
With respect to epidemiology, in the United States
diabetes mellitus affects approximately 7% of the population, or 21 million people, although nearly 6 million
of these cases remain undiagnosed. More than 1 million
new cases are identied each year in the United States.
Of these affected patients, most have type II diabetes;
only 5% to 10% have type I.
Diabetes is an important disease when we consider
the many complications associated with it and the economic effect it has on society. One of the main complications of diabetes is peripheral vascular disease, a
problem that results in kidney failure, as well as ischemia and gangrenous involvement of the limbs. By
some estimates, 25% of all new cases of kidney failure
occur in diabetic patients. Thus diabetes is the leading
cause of kidney failure in the United States. Each year
more than 50,000 amputations are performed for the
gangrenous complications of diabetes. This disease is
the leading cause of lower limb amputations in the
United States. Retinal involvement often results in
blindness; thus the leading cause of new cases of
blindness in working-age adults in the United States is
diabetes, with more than 12,000 people affected annually. Complications because of diabetes are estimated
to contribute to the deaths of more than 200,000
Americans each year.
The cause of diabetes mellitus is essentially unknown, although most cases of type I diabetes appear
to be caused by autoimmune destruction of the pancreatic islet cells, and this immunologic attack may be
precipitated by a viral infection in a genetically susceptible individual. Type II diabetes does not appear to
have an autoimmune cause, however, because no
destruction of the islet cells is seen microscopically.
Instead, genetic abnormalities have been detected in
patients with certain types of type II diabetes, which
may explain why the condition occurs so often in
families. If one parent is affected by type II diabetes,
then the chances of a child having the disorder is about
40%. Similarly, if one identical twin has type II diabetes, then the chances are 90% that the disease will also
develop in the other twin.
CLINICAL FEATURES
Although a complete review of the pathophysiology of
diabetes mellitus is beyond the scope of this text, the
clinical signs and symptoms of a patient with this
843
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COMPLICATIONS
Many complications of diabetes mellitus are directly
related to the microangiopathy caused by the disease.
The microangiopathy results in occlusion of the small
blood vessels, producing peripheral vascular disease.
The resultant decrease in tissue perfusion results in
ischemia. The ischemia predisposes the patient to infection, particularly severe infections such as gangrene.
Another contributing factor is the impairment of neutrophil function, particularly neutrophil chemotaxis.
Amputation of the lower extremity often is necessary because of the lack of tissue perfusion and the
patients inability to cope with infection. Similar vascular occlusion may affect the coronary arteries (which
places the patient at risk for myocardial infarction) or
the carotid arteries and their branches (predisposing
the patient to cerebrovascular accident, or stroke).
When microvascular occlusion affects the retinal
vessels, blindness typically results. Kidney failure is the
outcome of renal blood vessel involvement. If the ketoacidosis is not corrected in type I diabetes, the patient
may lapse into a diabetic coma.
The oral manifestations of diabetes mellitus are generally limited to patients with type I diabetes. Problems
include periodontal disease, which occurs more frequently and progresses more rapidly than in normal
patients. Healing after surgery may be delayed, and the
likelihood of infection is probably increased. Diffuse,
nontender, bilateral enlargement of the parotid glands,
called diabetic sialadenosis (see page 470), may be
seen in patients with either form of diabetes. In uncontrolled or poorly controlled diabetic patients, a striking
enlargement and erythema of the attached gingiva has
been described (Fig. 17-33). In addition, these patients
appear to be more susceptible to oral candidiasis in
its various clinical forms (see page 213). Erythematous
candidiasis, which appears as central papillary atrophy
of the dorsal tongue papillae, is reported in up to 30%
of these patients. Zygomycosis (see page 232) may
occur in patients with poorly controlled type I diabetes.
Some investigators have identied an increased prevalence of benign migratory glossitis (see page 779) in
patients with type I diabetes; however, others have not
been able to conrm this nding. Xerostomia, a subjective feeling of dryness of the oral mucosa, has been
reported as a complaint in one third of diabetic patients.
Unfortunately, studies that attempt to conrm an actual
decrease in salivary ow rate in diabetic patients have
produced conicting results. Some studies show a
decrease in salivary ow; some, no difference from
normal; and some, an increased salivary ow rate.
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HYPOPHOSPHATASIA
Hypophosphatasia is a rare metabolic bone disease
that is characterized by a deciency of tissue-nonspecic alkaline phosphatase. Approximately 150 distinct
mutations of the gene responsible for alkaline phosphatase production have been described. One of the
rst presenting signs of hypophosphatasia may be the
845
PERINATAL HYPOPHOSPHATASIA
The perinatal form has the most severe manifestations. It is usually diagnosed at birth, and the infant
rarely survives for more than a few hours. Death is due
to respiratory failure. Marked hypocalcication of the
skeletal structures is observed.
INFANTILE HYPOPHOSPHATASIA
Babies affected by infantile hypophosphatasia may
appear normal up to 6 months of age; after this time,
they begin to show a failure to grow. Vomiting and
hypotonia may develop as well. Skeletal malformations
that suggest rickets are typically observed; these malformations include shortened, bowed limbs. Deformities of the ribs predispose these patients to pneumonia,
and skull deformities cause increased intracranial
pressure. Nephrocalcinosis and nephrolithiasis also
produce problems for these infants. Radiographs show
a markedly reduced degree of ossication with a preponderance of hypomineralized osteoid. If these infants
survive, premature shedding of the deciduous teeth is
often seen.
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ADULT HYPOPHOSPHATASIA
DIAGNOSIS
The diagnosis of hypophosphatasia is based on the
clinical manifestations and the nding of decreased
levels of serum alkaline phosphatase and increased
amounts of phosphoethanolamine in both the urine
and the blood. Interestingly, as some patients grow
older, serum alkaline phosphatase levels may approach
normal.
HISTOPATHOLOGIC FEATURES
CHILDHOOD HYPOPHOSPHATASIA
The childhood form is usually detected at a later age
and has a wide range of clinical expression. One of the
more consistent features is the premature loss of the
primary teeth without evidence of a signicant inammatory response (Figs. 17-34 and 17-35). The deciduous incisor teeth are usually affected rst and may be
the only teeth involved. In some patients, this may be
the only expression of the disease. The teeth may show
enlarged pulp chambers in some instances, and a signicant degree of alveolar bone loss may be seen. More
severely affected patients may have open fontanelles
with premature fusion of cranial sutures. This early
fusion occasionally leads to increased intracranial
pressure and subsequent brain damage. Affected
patients typically have a short stature, bowed legs, and
a waddling gait. The development of motor skills is
often delayed.
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CLINICAL FEATURES
Patients with vitamin Dresistant rickets have a short
stature. The upper body segment appears more normal,
but the lower body segment is shortened. The lower
limbs are generally shortened and bowed.
Laboratory investigation reveals hypophosphatemia
with diminished renal reabsorption of phosphate and
decreased intestinal absorption of calcium. This typically results in rachitic changes that are unresponsive
to vitamin D (calciferol). With aging, ankylosis of the
spine frequently develops.
From a dental standpoint, the teeth have large pulp
chambers, with pulp horns extending almost to the
dentinoenamel junction (Figs. 17-37 and 17-38). In
some cases the cuspal enamel may be worn down by
attrition to the level of the pulp horn, causing pulpal
exposure and pulp death. The exposure may be so
small that the resulting periapical abscesses and gingival sinus tracts seem to affect what appear to be otherwise normal teeth (Fig. 17-39). Studies have also shown
that microclefts may develop in the enamel, giving the
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oral microora access to the dentinal tubules and subsequently to the pulp. One study examined a series of
affected children and found that 25% of these
patients had multiple abscesses involving the primary
dentition.
HISTOPATHOLOGIC FEATURES
Microscopic examination of an erupted tooth from a
patient with vitamin Dresistant rickets usually shows
markedly enlarged pulp horns. The dentin appears
abnormal and is characterized by the deposition of
globular dentin, which often exhibits clefting. The clefts
may extend from the pulp chamber to the dentinoenamel junction. Microclefts are also seen within the
enamel. The pulp frequently is nonvital, presumably
because of the bacterial contamination associated with
both the enamel and the dentinal clefts.
CLINICAL FEATURES
Most patients with Crohns disease are teenagers when
the disease rst becomes evident, although another
diagnostic peak of disease activity occurs in patients
more than 60 years of age. Gastrointestinal signs and
symptoms usually include abdominal cramping and
pain, nausea, and diarrhea, occasionally accompanied
by fever. Weight loss and malnutrition may develop,
which can lead to anemia, decreased growth, and short
stature.
A wide range of oral lesions has been clinically
reported in Crohns disease; however, many of the
abnormalities described are relatively nonspecic and
may be associated with other conditions that cause
orofacial granulomatosis (see page 341). The more
prominent ndings include diffuse or nodular swelling
of the oral and perioral tissues, a cobblestone appearance of the mucosa, and deep, granulomatous-appear-
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849
tively nonspecic, resembling orofacial granulomatosis. Special stains should be performed to rule out the
possibility of deep fungal infection, tertiary syphilis, or
mycobacterial infection.
HISTOPATHOLOGIC FEATURES
Microscopic examination of lesional tissue obtained
from the intestine or from the oral mucosa should
show nonnecrotizing granulomatous inammation
within the submucosal connective tissue (Fig. 17-41).
The severity of the granulomatous inammation may
vary tremendously from patient to patient and from
various sites in the same patient. Therefore, a negative
biopsy result at any one site and time may not necessarily rule out a diagnosis of Crohns disease. As with
the clinical lesions, the histopathologic pattern is rela-
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PYOSTOMATITIS VEGETANS
Pyostomatitis vegetans is a relatively rare condition
that has a controversial history. It has been associated
in the past with diseases such as pemphigus or pyodermatitis vegetans. Most investigators today, however,
believe that pyostomatitis vegetans is an unusual oral
expression of inammatory bowel disease, particularly
ulcerative colitis or Crohns disease. The pathogenesis of the condition, like that of inammatory bowel
disease, is poorly understood. A few patients with pyostomatitis vegetans have also been noted to have one
of several concurrent liver abnormalities.
CLINICAL FEATURES
Patients with pyostomatitis vegetans exhibit characteristic yellowish, slightly elevated, linear, serpentine pustules set on an erythematous oral mucosa. The lesions
primarily affect the buccal and labial mucosa, soft
palate, and ventral tongue (Figs. 17-42 and 17-43).
These lesions have been called snail track ulcerations,
although in most instances the lesions are probably not
truly ulcerated. Oral discomfort is variable but can be
surprisingly minimal in some patients. This variation
in symptoms may be related to the number of pustules
that have ruptured to form ulcerations. The oral lesions
may appear concurrently with the bowel symptoms, or
they may precede the intestinal involvement.
HISTOPATHOLOGIC FEATURES
A biopsy specimen of an oral lesion of pyostomatitis
vegetans usually shows marked edema, causing an
acantholytic appearance of the involved epithelium.
This may be the result of the accumulation of numerous eosinophils within the spinous layer, often forming
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B
Fig. 17-44 Pyostomatitis vegetans. Medium-power
photomicrograph showing intraepithelial abscesses
composed of eosinophils.
UREMIC STOMATITIS
Patients who have either acute or chronic renal failure
typically show markedly elevated levels of urea and
other nitrogenous wastes in the bloodstream. Uremic
stomatitis represents a relatively uncommon complication of renal failure. In two series that included 562
patients with renal failure, only eight examples of this
oral mucosal condition were documented. Nevertheless, for the patients in whom uremic stomatitis develops, this can be a painful disorder. The cause of the oral
lesions is unclear, but some investigators suggest that
urease, an enzyme produced by the oral microora,
may degrade urea secreted in the saliva. This degradation results in the liberation of free ammonia, which
presumably damages the oral mucosa.
CLINICAL FEATURES
Most cases of uremic stomatitis have been reported in
patients with acute renal failure. The onset may be
abrupt, with white plaques distributed predominantly
on the buccal mucosa, tongue, and oor of the mouth
(Fig. 17-45). Patients may complain of unpleasant taste,
oral pain, or a burning sensation with the lesions, and
the clinician may detect an odor of ammonia or urine
on the patients breath. The clinical appearance
stomatitis associated with undiagnosed renal failure, Gen Dent 42:410412, 1994.)
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cases, Oral Dis 5:299-302, 1999.
Hata T, Irei I, Tanaka K et al: Macrognathia secondary to dialysisrelated renal osteodystrophy treated successfully by parathyroidectomy, Int J Oral Maxillofac Surg 35:378-382, 2006.
Kalyvas D, Tosios KI, Leventis MD et al: Localized jaw enlargement in renal osteodystrophy: report of a case and review of
the literature, Oral Surg Oral Med Oral Pathol Oral Radiol Endod
97:68-74, 2004.
Khan A, Bilezikian J: Primary hyperparathyroidism: pathophysiology and impact on bone, CMAJ 163:173-175, 2000.
Ogata H, Koiwa F, Ito H et al: Therapeutic strategies for secondary hyperparathyroidism in dialysis patients, Ther Apher Dial
10:355-363, 2006.
Prado FO, Rosales AC, Rodrigues CI et al: Brown tumor of the
mandible associated with secondary hyperparathyroidism: a
case report and review of the literature, Gen Dent 54:341343, 2006.
Sakhaee K, Gonzalez GB: Update on renal osteodystrophy:
pathogenesis and clinical management, Am J Med Sci 317:251260, 1999.
Silverman S Jr, Gordon G, Grant T et al: The dental structures in
primary hyperparathyroidism. Studies in forty-two consecutive patients, Oral Surg Oral Med Oral Pathol 15:426-436,
1962.
Silverman S Jr, Ware WH, Gillooly C: Dental aspects of hyperparathyroidism, Oral Surg Oral Med Oral Pathol 26:184-189,
1968.
Slatopolsky E, Brown A, Dusso A: Pathogenesis of secondary
hyperparathyroidism, Kidney Int Suppl 73:S14-19, 1999.
Solt DB: The pathogenesis, oral manifestations, and implications
for dentistry of metabolic bone disease, Curr Opin Dent 1:783791, 1991.
Tejwani NC, Schachter AK, Immerman I et al: Renal osteodystrophy, J Am Acad Orthop Surg 14:303-311, 2006.
Triantallidou K, Zouloumis L, Karakinaris G et al: Brown tumors
of the jaws associated with primary or secondary hyperparathyroidism. A clinical study and review of the literature, Am
J Otolaryngol 27:281-286, 2006.
Cushings Disease
Findling JW, Raff H: Cushings syndrome: important issues in
diagnosis and management, J Clin Endocrinol Metab 91:37463753, 2006.
Gabrilove JL: Cushings syndrome, Compr Ther 18:13-16, 1992.
Katz J, Bouloux P-MG: Cushings: how to make the diagnosis,
Practitioner 243:118-124, 1999.
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Berndt M, Ehrich JHH, Lazovic D et al: Clinical course of hypophosphatemic rickets in 23 adults, Clin Nephrol 45:33-41,
1996.
Carpenter TO: New perspectives on the biology and treatment
of X-linked hypophosphatemic rickets, Pediatr Clin North Am
44:443-466, 1997.
Chaussin-Miller C, Sinding C, Wolikow M et al: Dental abnormalities in patients with familial hypophosphatemic vitamin
D-resistant rickets: prevention by early treatment with 1hydroxyvitamin D, J Pediatr 142:324-331, 2003.
Fadavi S, Rowold E: Familial hypophosphatemic vitamin D-resistant rickets: review of the literature and report of case, ASDC
J Dent Child 57:212-215, 1990.
Hanna JD, Niimi K, Chart JCM: X-linked hypophosphatemia:
genetic and clinical correlates, Am J Dis Child 145:865-870,
1991.
Hillman G, Geurtsen W: Pathohistology of undecalcied primary
teeth in vitamin D-resistant rickets. Review and report of two
cases, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 82:218224, 1996.
McWhorter AG, Seale NS: Prevalence of dental abscess in a
population of children with vitamin D-resistant rickets,
Pediatr Dent 13:91-96, 1991.
Miller WL, Portale AA: Genetic causes of rickets, Curr Opin
Pediatr 11:333-339, 1999.
Murayama T, Iwatsubo R, Akiyama S et al: Familial hypophosphatemic vitamin D-resistant rickets: dental ndings and
histologic study of teeth, Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 90:310-316, 2000.
Pereira CM, de Andrade CR, Vargas PA et al: Dental alterations
associated with X-linked hypophosphatemic rickets, J Endod
30:241-245, 2004.
Scriver CR, Tenenhouse HS, Glorieux HI: X-linked hypophosphatemia: an appreciation of a classic paper and a survey of
progress since 1958, Medicine (Baltimore) 70:218-228, 1991.
Seow WK, Needleman HL, Holm IA: Effect of familial hypophosphatemic rickets on dental development: a controlled, longitudinal study, Pediatr Dent 17:346-350, 1995.
Shroff DV, McWhorter AG, Seale NS: Evaluation of aggressive
pulp therapy in a population of vitamin D-resistant rickets
patients: a follow-up of 4 cases, Pediatr Dent 24:347-349,
2002.
Wang JT, Lin C-J, Burridge SM et al: Genetics of vitamin D 1hydroxylase deciency in 17 families, Am J Hum Genet
63:1694-1702, 1998.
Zambrano M, Nikitakis NG, Sanchez-Quevedo MC et al: Oral
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Crohns Disease
Brunner B, Hirschi C, Weimann R et al: Treatment-resistant
lingual Crohns disease disappears after iniximab, Scand J
Gastroenterol 40:1255-1259, 2005.
Challacombe SJ: Oro-facial granulomatosis and oral Crohns
disease: are they specic diseases and do they predict systemic Crohns disease? Oral Dis 3:127-129, 1997.
Dunlap CL, Friesen CA, Shultz R: Chronic stomatitis: an early
sign of Crohns disease, J Am Dent Assoc 128:347-348,
1997.
Dupuy A, Cosnes J, Revuz J et al: Oral Crohn disease: clinical
characteristics and long-term follow-up of 9 cases, Arch Dermatol 135:439-442, 1999.
Galbraith SS, Drolet BA, Kugathasan S et al: Asymptomatic
inammatory bowel disease presenting with mucocutaneous
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Girlich C, Bogenrieder T, Palitzsch K-D et al: Orofacial granulomatosis as initial manifestation of Crohns disease: a report of
two cases, Eur J Gastroenterol Hepatol 14:873-876, 2002.
Friedman S, Blumberg RS: Inammatory bowel disease. In
Kasper DL, Braunwald E, Fauci AS et al: Harrisons principles
of internal medicine, pp 1776-1789, ed 16, New York, 2005,
McGraw-Hill.
Harty S, Fleming P, Rowland M et al: A prospective study of the
oral manifestations of Crohns disease, Clin Gastroenterol
Hepatol 3:886-891, 2005.
Hegarty A, Hodgson T, Porter S: Thalidomide for the treatment
of recalcitrant oral Crohns disease and orofacial granulomatosis, Oral Surg Oral Med Oral Pathol Oral Radiol Endod 95:576585, 2003.
Hoffmann JC, Zeitz M: Treatment of Crohns disease, Hepatogastroenterology 47:90-100, 2000.
Kalmar JR: Crohns disease: orofacial considerations and disease
pathogenesis, Periodontol 2000 6:101-115, 1994.
Lisciandrano D, Ranzi T, Carrassi A et al: Prevalence of oral
lesions in inammatory bowel disease, Am J Gastroenterol
91:7-10, 1996.
Mills CC, Amin M, Manisali M: Salivary duct stula and recurrent buccal space infection: a complication of Crohns disease,
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Ottaviani F, Schindler A, Capaccio P et al: New therapy for orolaryngeal manifestations of Crohns disease, Ann Otol Rhinol
Laryngol 112:37-39, 2003.
Plauth M, Jenss H, Meyle J: Oral manifestations of Crohns
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1991.
Podolsky DK: Inammatory bowel disease, N Engl J Med 347:417429, 2002.
Rehberger A, Pspk A, Stallmeister T et al: Crohns disease
masquerading as aphthous ulcers, Eur J Dermatol 8:274-276,
1998.
Snchez AR, Rogers RS, Sheridan PJ: Oral ulcerations are associated with the loss of response to iniximab in Crohns disease,
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Scheper HJ, Brand HS: Oral aspects of Crohns disease, Int Dent
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Scully C, Cochran KM, Russell RI et al: Crohns disease of the
mouth: an indicator of intestinal involvement, Gut 23:198201, 1982.
Van de Scheur MR, van der Waal RIF, Vlker-Dieben HJ et al:
Orofacial granulomatosis in a patient with Crohns disease, J
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Weinstein TA, Sciubba JJ, Levine J: Thalidomide for the treatment of oral aphthous ulcers in Crohns disease, J Pediatr
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Ayangco L, Rogers RS, Sheridan PJ: Pyostomatitis vegetans as an
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Periodontol 73:1512-1516, 2002.
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18
Facial Pain and
Neuromuscular Diseases
Revised by THERESA S. GONZALES
CHAPTER OUTLINE
Bells Palsy
Trigeminal Neuralgia
Glossopharyngeal Neuralgia
Postherpetic Neuralgia
Atypical Facial Pain
Neuralgia-Inducing Cavitational Osteonecrosis
Cluster Headache
Paroxysmal Hemicrania
Migraine
Temporal Arteritis
Myasthenia Gravis
Motor Neuron Disease
Burning Mouth Syndrome
Dysgeusia and Hypogeusia
Frey Syndrome
Osteoarthritis
Rheumatoid Arthritis
Temporomandibular Joint Dysfunction
Temporomandibular Joint Ankylosis
CLINICAL FEATURES
People of all ages are susceptible to Bells palsy, but
middle-aged people are affected most frequently.
Women are affected more often (71%) than men.
Childhood involvement is usually associated with a
viral infection, Lyme disease, or earache.
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Box 18-1
Fig. 18-1 Bells palsy. Paralysis of the facial muscles on the patients left side. A, Patient is
trying to raise the eyebrows. B, Patient is attempting to close the eyes and smile. (Courtesy of Dr.
Bruce B. Brehm.)
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the duration, as will systemic corticosteroids and hyperbaric oxygen therapy. Surgical decompression of the
intratemporal facial nerve is used in select cases.
Topical ocular antibiotics and articial tears may be
required to prevent corneal ulceration, and the eyelid
may have to be taped shut.
Symptoms usually begin to regress slowly and spontaneously within 1 to 2 months of onset; more severe
cases take longer, as do those in older patients. Overall,
more than 82% of patients recover completely within
6 months. Residual symptoms that remain after 1 year
will probably remain indenitely. Recurrence is rare,
except in Melkersson-Rosenthal syndrome.
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(NICO) of the jaws (see page 866), Gradenigo syndrome (suppurative otitis media, trigeminal nerve pain,
abducens nerve palsy), and chronic paroxysmal hemicrania-tic syndrome may have pain so similar as to be
virtually indistinguishable from trigeminal neuralgia.
Because so many of its features are consistent with
a CNS disease, trigeminal neuralgia has been called a
pain syndrome with a peripheral cause but a central
pathogenesis. The seriousness of the disorder is underscored by the fact that it has one of the highest suicide
rates of any disease and is regarded as one of the most
painful afictions known.
CLINICAL FEATURES
TRIGEMINAL NEURALGIA
(TIC DOULOUREUX; TIC)
The head and neck region is a common site for neuralgias (pain extending along the course of a nerve) (Box
18-2). Because facial neuralgias produce pain that
often mimics pain of dental origin, the dental profession is frequently called on to rule out odontogenic or
inammatory causes. Trigeminal neuralgia, the most
serious and the most common of the facial neuralgias,
is characterized by an extremely severe electric shocklike or lancinating (i.e., sharp, jabbing) pain limited to
one or more branches of the trigeminal nerve. In the
majority of cases the pain is located in the maxillary
(V2) or the mandibular (V3) distribution of the nerve.
It is often idiopathic but is usually associated with
pathosis somewhere along the course of the nerve.
Occasionally, trigeminal neuralgia results from a brainstem tumor or infarction and is referred to as secondary
trigeminal neuralgia.
Trigeminal neuralgia is diagnosed in 6 of every
100,000 persons each year, but it develops in 4% of persons with multiple sclerosis (MS). Moreover, patients
with neuralgia-inducing cavitational osteonecrosis
Trigeminal neuralgia characteristically affects individuals older than 40 years of age (the average age at onset
is 50 years), although it may affect persons as early as
puberty. Women are affected slightly more often than
men, and the right side is involved more often than the
left. Any branch of the trigeminal nerve may be
involved, but the ophthalmic division is affected in only
5% of cases. More than one branch may be involved,
and the pain is occasionally bilateral.
Specic and strict criteria must be met for an accurate diagnosis (Box 18-3). If the pain pattern does not
meet these criteria, then a different diagnosis should
be considered. When these criteria are partially fullled, alternative terms such as atypical trigeminal neuralgia, atypical facial pain, and atypical facial neuralgia are
applied.
Box 18-3
Box 18-2
Atypical pain/neuralgia
Geniculate neuralgia
Glossopharyngeal neuralgia
Migrainous neuralgia
Occipital neuralgia
Raeders paratrigeminal neuralgia
Postherpetic facial neuralgia
Sphenopalatine ganglion neuralgia
Superior laryngeal neuralgia
Trigeminal neuralgia
Tympanic plexus neuralgia
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a variety of causes, the recognition of Raeders syndrome serves only to draw attention to the region of
the disturbance and does not imply causation.
When an obvious trigger point is present in trigeminal neuralgia, a pain attack may be brought on by a
stimulus to the area as mild as a breeze, a gentle movement, or a feather-light touch. Trigger points are found
most frequently on the nasolabial fold, the vermilion
border of the lip, or the midfacial and periorbital skin.
Intraoral trigger points are uncommon but do occur,
especially on the alveolus.
HISTOPATHOLOGIC FEATURES
No unique histopathologic characteristic to the nerves
in trigeminal neuralgia exists, although the trigger
points may show brosis and inltration by small
numbers of chronic inammatory cells. Focal areas of
myelin degeneration have been reported within the
gasserian ganglion and along the course of the cranial
nerve itself, but these also have been occasionally seen
in persons without trigeminal neuralgia. MS patients
with trigeminal neuralgia show unique amorphous
plaques in the ganglion.
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Box 18-4
GLOSSOPHARYNGEAL NEURALGIA
(VAGOGLOSSOPHARYNGEAL
NEURALGIA)
Neuralgia of the ninth cranial nerve, glossopharyngeal neuralgia, is similar in every way to trigeminal
neuralgia (see previous topic) except in the anatomic
location of the pain. In glossopharyngeal neuralgia, the
pain is centered on the tonsil and the ear. The pain
often radiates from the throat to the ear because of
the involvement of the tympanic branch of the glossopharyngeal nerve. Some unfortunate individuals have
a combination of glossopharyngeal neuralgia and
trigeminal neuralgia.
Glossopharyngeal neuralgia is rare, occurring only
once for every 100 cases of trigeminal neuralgia. The
pain also may affect sensory areas supplied by the pharyngeal and auricular branches of the vagus nerve. As
with trigeminal neuralgia, the cause is unknown.
CLINICAL FEATURES
The age of onset for glossopharyngeal neuralgia varies
from 15 to 85 years, but the average age is 50 years.
There is no sex predilection, and only rarely is there
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POSTHERPETIC NEURALGIA
An acute painful disorder (herpes zoster) (see page
250) and a chronic pain syndrome (postherpetic
neuralgia [PHN]) are associated with the varicellazoster virus (VZV). Herpes zoster, commonly referred
to as shingles, is characterized by a unilateral vesicular
eruption within a dermatome. More often than not, this
eruption is accompanied by severe pain. Herpes zoster
usually involves the thoracic dermatomes; in 23% of
cases, the rash and its associated pain follow a trigeminal distribution. The ophthalmic division of the trigeminal nerve (V1) is affected most frequently. Herpes
zoster is caused by the reactivation of the latent VZV
that is thought to lie dormant in the gasserian, geniculate, and dorsal root ganglia after chickenpox infection
in early life. The onset of acute herpes zoster is frequently preceded by exquisite pain in the affected
dermatome. Approximately 48 to 72 hours later, an
erythematous maculopapular rash evolves rapidly
into vesicular lesions (see discussion of herpes zoster,
page 250).
When the trigeminal nerve is involved, the lesions
may appear on the face, the eye, and the tongue.
Herpes zoster ophthalmicus is a debilitating condition that can result in blindness if aggressive antiviral
therapy is not promptly instituted. The combination of
a herpetic rash in the external auditory canal and a
facial palsy secondary to viral invasion of the geniculate
ganglion of the sensory branch of the facial nerve is
known as Ramsay Hunt syndrome (see page 252).
Often these patients lose their taste discrimination in
the anterior two thirds of the tongue before the development of the ipsilateral facial palsy.
CLINICAL FEATURES
The most signicant complication of herpes zoster is
the pain that is associated with acute neuritis and PHN.
PHN is dened as pain persisting for anywhere from 1
to 6 months or more after the onset of the rash. Postherpetic pain is described as a burning sensation with
episodic stabbing pains. Light touch over the previously involved area may elicit a painful response (tac-
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Once PHN has established itself, a variety of treatment options are available for pain management. In
addition to the judicious use of analgesics, including
both nonnarcotic and narcotic preparations, a wide
variety of drugs ranging from gabapentin, pregabalin,
and amitriptyline hydrochloride to topical agents, such
as lidocaine patches, EMLA (eutectic mixture of lidocaine and prilocaine), and capsaicin (0.025%), have
been reported to be benecial in pain relief. The topical
application of capsaicin, an extract of hot chili peppers,
has been reported to deplete the neurotransmitter substance P from nerve terminals, thereby desensitizing
them.
Tricyclic antidepressants such as amitriptyline, nortriptyline, and desiprimine have proven to be quite
useful in the management of the persistent pain that
characterizes PHN; however, the anticholinergic and
cardiovascular side effects may limit their utility, especially in older patients. Amitriptyline has consistently proven to be the single most effective drug, with
approximately 60% of patients reporting relief with this
agent. Patients are started at a low dose (10 mg) and
titrated to effect, with the majority of patients obtaining
signicant relief with a median dose of 75 mg daily.
These medications are usually given at bedtime to
prevent daytime somnolence and to improve tolerance.
Patients who report a stabbing pain in addition to the
burning sensation may derive additional benet from
the use of anticonvulsant medications such as carbamazepine or phenytoin. In recent studies, gabapentin and
pregabalin have been shown to reduce pain associated
with PHN by more than 30%, and these drugs are typically well tolerated in all patient cohorts.
Patients who fail medical therapy have a limited
range of surgical treatments available to them. However, the outcome of procedures (e.g., blockade of
peripheral nerves, roots, or sympathetic nervous
system; surgery at the level of the affected nerve [neurectomy] or dorsal root) is far from certain with regard
to pain management.
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Box 18-5
Allergy of sinuses
Cracked tooth syndrome
Headache with referred pain to face
Impingement of bone or blood vessel on nerve
Infection: dental, periodontal, sinuses, ear
Ischemic and inammatory marrow disease
Myofascial pain
Neuralgias, other
Temporomandibular joint disorder (TMD)
Trauma to nerve (including traumatic neuroma)
Tumors
CLINICAL FEATURES
Atypical facial pain affects women far more frequently
than men. It usually develops during the fourth
through sixth decades of life, but can occur as early as
the teenage years. The pain may be localized to a small
area of the face or alveolus (e.g., atypical odontalgia,
phantom toothache) but more frequently affects
most of a quadrant and may extend to the temple,
neck, or occipital area. Patients have great difculty
describing the pain, but most often portray it as a continuous, deep, diffuse, gnawing ache; an intense
burning sensation; a pressure; or a sharp pain. The
patient may nominally describe the pain using such
terms as drawing, aching, or pulling. It is important
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to differentiate the pain from that of trigeminal neuralgia (see page 861).
Bilateral involvement occasionally occurs, and
patients frequently attribute the onset of the pain to
trauma or a dental procedure. The mucosa of the
affected quadrant appears normal but typically contains a zone of increased temperature, tenderness, or
bone marrow activity (hot spot on technetium-99m
methylene diphosphonate [MDP] bone scan). Radiographic changes are not present. In some cases initially
diagnosed as atypical facial pain, signicant underlying
disease has ultimately been identied (e.g., nasopharyngeal carcinoma, occult lung tumors).
NEURALGIA-INDUCING
CAVITATIONAL OSTEONECROSIS
(NICO; ALVEOLAR CAVITATIONAL
OSTEOPATHOSIS; ISCHEMIC
OSTEONECROSIS; BONE
MARROW EDEMA)
One of the most controversial topics in the diagnosis
and management of orofacial pain is the entity referred
to as neuralgia-inducing cavitational osteonecrosis
(NICO). Since this concept rst appeared in the scientic literature in the late 1970s, there have been
numerous attempts by science-based investigators to
dene the clinical and radiographic features, as well
as the histopathology and neuropathology of these
lesions. However, to date, there is no consensus
among pain practitioners regarding this entity. The
following information is presented in the context of
completeness with regard to orofacial pain and to
facial neuralgias in particular.
Ischemic osteonecrosis is a bone disease characterized by degeneration and death of marrow and bone
from a slow or abrupt decrease in marrow blood ow.
Along with its lesser variants, bone marrow edema and
regional ischemic osteoporosis, it is one of the most
common bone diseases in humans, but only recently
has it been appreciated as a disorder of the head and
neck region. Numerous local and systemic factors are
associated with ischemic damage to marrow (Box
18-6), the most common being a hereditary (autosomal
dominant) tendency toward blood clot formation
within blood vessels. Bone is particularly susceptible to
this problem, which in the jaws may be accentuated by
dental infections and the vasoconstrictors in local
anesthetics.
The ischemia and infarctions of osteonecrosis are
typically associated with pain, often with an ill-dened
neuralgic or neuropathic character. Because of this,
presumed examples of this process in the jaws have
been referred to as NICO. NICO is included in this
chapter because of its strong association with pain, but
it should be remembered that osteonecrosis is not necessarily a painful condition and our understanding of
this disease is still incomplete.
Ischemic osteonecrosis most often affects the hips,
maxillofacial bones, and knees. NICO has been found
in 1 of every 11,000 adults, a prevalence rate similar
to that of hip cases. The NICO prevalence rate for
women (1 per 2000) is much higher than the rate for
men (1 per 20,000).
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867
Box 18-6
RARELY ASSOCIATED
Osteomyelitis
Starvation (anorexia nervosa)
HISTOPATHOLOGIC FEATURES
The microscopic appearance of ischemic osteonecrosis depends on the duration and intensity of the
diminished marrow blood ow. The features of bone
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CLINICAL FEATURES
Cluster headache may occur at any age, although it
usually affects persons in the third and fourth decades
of life and is rare before puberty. There is a strong male
predilection (a 6:1 male-to-female ratio). The pain is
almost always unilateral and follows the distribution of
the ophthalmic division of the trigeminal nerve.
It is usually felt deep within or behind the orbit,
radiating to the temporal and upper cheek regions.
However, it may simulate a toothache or neuralgic jaw
pain in the anterior maxillary region. Because of this,
patients may be treated inappropriately for dental pain
with endodontic therapy or tooth extraction, which is
thought to be successful when the pain subsequently
resolves. When each successive cluster returns, the
next tooth is treated, sometimes resulting in multiple,
repeated episodes of unnecessary dental therapy.
The pain is described as paroxysmal (i.e., abrupt
onset) and intense, with a burning or lancinating quality
and without a trigger zone. The attacks may last from
15 minutes to 3 hours and occur up to eight times daily
(or on alternate days). The cluster periods typically last
for weeks, with the intervening periods of remission
usually lasting for months (sometimes years). The pain
often begins at the same time in a given 24-hour period
(alarm clock headache), with most attacks occurring
in the middle of the night.
A chronic form occurs occasionally, with no remissions for years at a time, and episodic forms may
convert to the constant, chronic form. In addition,
cluster headache is rarely accompanied by the aura so
common to migraine headache. An important behavioral difference between migraine and cluster headache is that the patient is usually hyperactive during
the latter and retreats to a dark, quiet room during the
former.
In addition to the pain, the patient may experience
autonomic alterations such as nasal stufness, tearing,
facial ush, or congestion of conjunctival blood vessels. The latter sign, especially when associated with
increased intraocular pressure, may indicate chronic
paroxysmal hemicrania (Sjaastad syndrome), a rare
syndrome with short-duration, highly recurring, nonclustered pain (see following topic).
869
PAROXYSMAL HEMICRANIA
Paroxysmal hemicrania has a clinical presentation
similar to cluster headache. The headaches are strictly
unilateral, brief, and excruciating and have associated
autonomic features. Paroxysmal hemicrania can be differentiated from cluster headache primarily by the
high frequency but shorter duration of the attacks.
Although the differentiation can be subtle, it is worth
pursuing because paroxysmal hemicrania responds
dramatically and predictably to indomethacin. Therefore, an indomethacin challenge can be used to rule
out other trigeminal autonomic cephalgias. A predictable response to indomethacin is also observed in
hemicrania continua, a type of chronic daily headache that is unilateral, moderately severe, and associated with autonomic signs similar to those of cluster
headache.
CLINICAL FEATURES
In contradistinction to cluster headache, paroxysmal
hemicrania is more common in women by a ratio of
2:1. The headache is for the most part strictly unilateral, and the pain is centered on the ocular, maxillary,
temporal, and frontal regions. The symptoms typically
last from 2 to 30 minutes, and the pain is described as
a boring sensation that can be excruciating in terms
of severity. The headache has an abrupt onset and an
equally abrupt cessation. Ipsilateral cranial autonomic
features such as lacrimation, conjunctival injection,
and rhinorrhea also invariably occur. The patient may
experience anywhere from 2 to 40 attacks daily,
and the mean attack frequency is 14 per day. The
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Table 18-1
Type of Trigger
Hormonal
Dietary
Psychologic
Physical/environmental
Sleep related
Drugs
Miscellaneous
Subtypes
Menstruation
Ovulation
Oral contraceptives
Hormonal replacement therapy
Alcohol
Nitrite-laden meat
Monosodium glutamate
Aspartame
Chocolate
Aged cheese
Missing a meal
Stress/poststress
Anxiety/worry
Depression
Glare
Flashing lights
Fluorescent lights
Odors
Weather changes
High altitude
Lack of sleep
Excessive sleep
Nitroglycerine
Histamine
Reserpine
Hydralazine
Ranitidine
Estrogen
Head trauma
Physical exertion
Fatigue
sometimes with a clear autosomal dominant inheritance pattern. Migraine headaches are often associated
with endogenous or environmental triggers. Common
triggering events are listed in Table 18-1.
CLINICAL FEATURES
Migraine affects women three times more frequently
than men, and women tend to experience more severe
attacks than men. The disease is most prevalent in the
third through fth decades of life, but the rst symptoms often begin at puberty or shortly thereafter.
The unilateral headache lasts for 4 to 72 hours and
is usually felt in the temporal, frontal, and orbital
regions, as well as occasionally in the parietal, postauricular, or occipital areas. It begins as a poorly localized
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CLINICAL FEATURES
Women are affected by temporal arteritis somewhat
more often than men, and patients are usually older
than 50 years of age at the time of diagnosis (average
age, 70 years). The disease is most frequently a unilateral, throbbing headache that is gradually replaced by
an intense, aching, burning temporal and facial pain.
The throbbing frequently coincides with the patients
heartbeat (systole), and the pain may be lancinating.
The supercial temporal artery is exquisitely sensitive
to palpation and eventually appears erythematous,
swollen, tortuous, or rarely ulcerated.
Most patients complain of pain during mastication
(jaw claudication) or with the wearing of hats (pressure
over the artery). The pain occasionally mimics toothache or a neuralgic jaw or tongue pain. Signicantly,
ocular symptoms, such as loss of vision or retro-orbital
pain, may be the rst complaint. Prompt recognition of
signs and symptoms of temporal arteritis is important
because it is a preventable cause of blindness. The
blindness is caused by involvement of the posterior
ciliary artery supplying the optic disc, which results in
ischemic papillopathy. The visual loss may be transient
or permanent, unilateral or bilateral.
Fever, malaise, fatigue, nausea, anorexia, vomiting,
sore throat, and earache often occur, perhaps as prodromal symptoms, and the erythrocyte sedimentation
rate is usually elevated. A generalized muscle aching
and stiffness (polymyalgia rheumatica) frequently
follow an acute attack. Because muscle and joint aches
are quite common in older adults, the potential exists
for missed opportunities in the diagnosis and management of temporal arteritis.
HISTOPATHOLOGIC FEATURES
Biopsy conrms the diagnosis of temporal arteritis.
Microscopic changes tend to be segmental and can be
missed if the specimen is too small. At least 1 cm of the
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Box 18-7
MYASTHENIA GRAVIS
Myasthenia gravis is an autoimmune disease that
affects the acetylcholine receptors (AChR) of muscle
bers and results in an abnormal and progressive fatigability of skeletal muscle. Defective neuromuscular
transmission occurs, probably secondary to the coating
of the AChRs by circulating antibodies to those receptors. Such antibodies are not normally found in humans;
hence, the measurement of serum AChR antibody
levels is an important diagnostic tool for this disease.
The motor end plate itself is normal, and smooth and
cardiac muscles are not affected.
Many patients demonstrate either thymus hyperplasia or an actual neoplasm (thymoma) of the thymus
gland. Conversely, 75% of patients with thymoma have
myasthenia gravis, and 90% have circulating AChR
antibodies. The infant of an affected mother may be
affected for several weeks or months by maternal antibodies that traverse the placenta. Almost half of the
patients with myasthenia gravis have at least one additional autoimmune disorder, especially of the thyroid
gland. Each year 1 person in every 100,000 is diagnosed with myasthenia gravis.
CLINICAL FEATURES
Myasthenia gravis is more common in females (1:2
male-to-female ratio). It can begin at any age, and congenital cases have been reported. The disease appears
DIAGNOSIS
The diagnosis of myasthenia gravis is based on the
clinical symptoms, an elevated serum AChR antibody
level, and improved strength after intravenous (IV)
injection of edrophonium, a cholinesterase inhibitor.
Degenerated muscle bers are the only characteristic
histopathologic feature, with bers appearing much
smaller than normal (hypotrophy, atrophy), having
fewer nuclei, and showing a loss of the normal rounded
cross-sectional appearance.
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CLINICAL FEATURES
Progressive muscular atrophy occurs in childhood.
Most cases occur at birth or within the rst few months
of life, although adult onset is rarely seen. Males and
females are affected equally. There is progressive limb
weakness and sensory disturbances, which result in
difculty in walking, leg pain, paresthesia, and atrophy
of the feet and hands. Facial muscles are spared.
Progressive bulbar palsy typically affects children
and young adults and has no gender predilection. It
usually begins with a subtle but progressive difculty
in speaking or swallowing (dysphagia). Attempts to
swallow food produce bouts of choking and regurgitation, with liquids frequently thrown into the naso-
873
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Box 18-8
Systemic Factors
Xerostomia
Chronic mouth breathing
Chronic tongue thrust habit
Chronic mechanical trauma
Referred pain from teeth or
tonsils
Trigeminal neuralgia
Atypical facial pain or
neuralgia
Angioedema (angioneuroti
edema)
Oral candidiasis
Temporomandibular
dysfunction
Oral submucous brosis
Fusospirochetal infection
Contact stomatitis (allergy)
Trauma to lingual nerve
Vitamin B deciency
Vitamin B1 or B2
deciency
Pernicious anemia (B12)
Pellagra (niacin
deciency)
Folic acid deciency
Diabetes mellitus
Chronic gastritis or
regurgitation
Chronic gastric hypoacidity
Hypothyroidism
Mercurialism
Estrogen deciency
Anxiety, stress, depression
Parkinsons disease
Acquired immunodeciency
syndrome (AIDS)
CLINICAL FEATURES
Women are four to seven times more likely to have
burning tongue syndrome than men. The syndrome is
rare before the age of 30 years (40 years for men), and
the onset in women usually occurs within 3 to 12 years
after menopause.
This disorder also has a typically abrupt onset,
although it may be quite gradual. The dorsum of the
tongue develops a burning sensation, usually strongest
in the anterior third. Occasionally, patients will describe
an irritated or raw feeling. Mucosal changes are seldom
visible, although some patients will show diminished
numbers and size of liform papillae, and individuals
who rub the tongue against the teeth often have erythematous and edematous papillae on the tip of the
tongue. If the dorsum is signicantly erythematous and
smooth, an underlying systemic or local infectious
process, such as anemia or erythematous candidiasis,
should be suspected.
Close questioning often determines that additional
oral sites are affected similarly, especially the anterior
hard palate and the lips. There is seldom a signicant
decrease in stimulated salivary output in tests, despite
the frequent patient complaint of xerostomia. Salivary
levels of various proteins, immunoglobulins, and phosphates may be elevated, and there may be a decreased
salivary pH or buffering capacity.
One frequently described pattern is that of mild
discomfort on awakening, with increasing intensity
throughout the day. Other affected patients describe a
waxing and waning pattern that occurs over several
days or weeks. Usually the condition does not interfere
with sleep. A persistently altered (salty, bitter) or diminished taste may accompany the burning sensation.
Contact with hot food or liquid often intensies the
symptoms. A minority describe a constant degree of
discomfort.
As with other chronic discomforts, affected patients frequently demonstrate psychologic dysfunction,
usually depression, anxiety, or irritability. The dysfunction often disappears, however, with resolution of the
burning or painful tongue condition, and there is no
correlation between duration and intensity of the
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Box 18-9
Systemic Factors
Oral candidiasis
Oral trichomoniasis
Desquamative gingivitis
Oral galvanism
Periodontitis or
gingivitis
Chlorhexidine rinse
Oral lichen planus
Xerostomia
Vitamin A deciency
Vitamin B12 deciency
Zinc deciency
Iron deciency
Nutritional overdose (zinc,
vitamin A, pyridoxine)
Food sensitivity or allergy
Sjgren syndrome
Chorda tympani nerve damage
Anorexia, cachexia, bulimia
Severe vomiting during
pregnancy
Liver dysfunction
Crohns disease
Cystic brosis
Familial dysautonomia
Addisons disease
Turner syndrome
Alcoholism
Medications (200 types)
Psychosis or depression
Pesticide ingestion
Lead, copper, or mercury
poisoning
Temporal arteritis
Brainstem ischemia or infarction
Migraine headaches
Temporal lobe central nervous
system (CNS) tumor
Nerve trauma, gustatory nerves
Herpes zoster, geniculate
ganglion
Upper respiratory tract infection
Chronic gastritis or regurgitation
Bells palsy
Radiation therapy to head and
neck
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Pharmaceutical Action
Anticoagulant
Antihistamine
Antihypertensive or diuretic
Antimicrobial
Antineoplastic or immunosuppressant
Antiparkinsonian agent
Antipsychotic or anticonvulsant
Antirheumatic
Antiseptic
Antithyroid agent
Hypoglycemic
Opiate
Sympathomimetic
Vasodilator
Examples
Phenindione
Chlorpheniramine maleate
Captopril, diazoxide, ethacrynic acid
Amphotericin B, ampicillin, griseofulvin, idoxuridine, lincomycin, metronidazole,
streptomycin, tetracycline, tyrothricin
Doxorubicin, methotrexate, vincristine, azathioprine, carmustine
Baclofen, chlormezanone, levodopa
Carbamazepine, lithium, phenytoin
Allopurinol, colchicine, gold, levamisole, penicillamine, phenylbutazone
Hexetidine, chlorhexidine
Carbimazole, methimazole, thiouracil
Glipizide, phenformin
Codeine, morphine
Amphetamines, phenmetrazine
Oxyfedrine, bamifylline
produce a salty taste because of the high sodium chloride content of oozing crevicular uids.
CLINICAL FEATURES
In contrast to hypogeusia, dysgeusia is discerned
promptly and distressingly by affected individuals. The
clinician must be certain that the patients alteration is,
in fact, a taste disorder rather than an olfactory one,
because 75% of avor information (e.g., taste, aroma,
texture, temperature, irritating properties) is derived
from smell. Abnormal taste function should be veried
through formal taste testing by using standard tastants
that are representative of each of the four primary taste
qualities (i.e., sweet, sour, salty, bitter) in a nonodorous
solution. Additional electrical and chemical analysis of
taste bud function is frequently required. Because this
is outside the scope of most general practices, patients
are typically referred to a taste and smell center.
Affected patients may describe their altered taste as
one of the primary ones, but many describe the new
taste as metallic, foul, or rancid. The latter two are
more likely to be associated with aberrant odor perception (parosmia) than with dysgeusia. The altered taste
may require a stimulus, such as certain foods or liquids,
in which case the taste is said to be distorted. If no
stimulus is required, then the dysgeusia is classied as
a phantom taste.
FREY SYNDROME
(AURICULOTEMPORAL SYNDROME;
GUSTATORY SWEATING
AND FLUSHING)
First described by Baillarger in 1853, Frey syndrome
is characterized by facial ushing and sweating along
the distribution of the auriculotemporal nerve. These
signs occur in response to gustatory stimuli, and the
syndrome results from injury to the nerve.
This nerve, in addition to supplying sensory bers to
the preauricular and temporal regions, carries parasympathetic bers to the parotid gland and sympathetic vasomotor and sudomotor (sweat stimulating)
bers to the preauricular skin. After parotid abscess,
trauma, mandibular surgery, or parotidectomy, the
parasympathetic nerve bers may be severed. In their
attempt to reestablish innervation, these bers occasionally become misdirected and regenerate along the
sympathetic nerve pathways, establishing communication with the sympathetic nerve bers of sweat glands
and blood vessels of the facial skin. The most widely
accepted mechanism of Freys syndrome is aberrant
neuronal regeneration. Subsequent to these aberrant
neural connections, when salivation is stimulated, local
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CLINICAL FEATURES
The presenting signs and symptoms of Frey syndrome
include sweating, ushing, warmth, and occasionally
pain in the preauricular and temporal regions
during chewing. Within 2 months to 2 years (average,
9 months) after the nerve injury, the sweating and
ushing reactions commence and become steadily
more severe for several months, remaining constant
thereafter. When ushing occurs, the local skin temperature may be raised as much as 2 C. This may
occur without sweating, especially in females. Pain,
when present, is usually mild, and hypesthesia (hypoesthesia) or hyperesthesia are common features.
To detect sweating, Minors starch-iodine test may
be used. A 1% iodine solution is painted on the affected
area of the skin. This solution is allowed to dry, and the
area is then coated with a layer of starch. When the
patient is given something to eat, the moisture of the
sweat that is produced will mix with the iodine on the
skin. This allows the iodine to react with the starch and
produce a blue color (Fig. 18-6). Iodine-sublimated
paper, which changes color when wet, also can be
used, and thermography or surface thermometers will
document the temperature changes of the skin.
877
OSTEOARTHRITIS
(DEGENERATIVE ARTHRITIS;
DEGENERATIVE JOINT DISEASE)
Osteoarthritis is a common degenerative and destructive alteration of the joints that until recently was considered to be the inevitable result of simple wear and
tear on aging anatomic structures. It is now known to
have a strong inammatory component as well, especially in small joints, such as the temporomandibular
joint (TMJ), where there appears to be little association
with the aging process. The disease represents approximately 10% of patients evaluated for TMJ pain.
Osteoarthritis is thought by some to be unavoidable;
almost everyone older than 50 years of age is affected
to some extent. The TMJ is less affected than the heavy
weightbearing joints, but even that joint is involved at
the microscopic level in 40% of older adults and at the
radiographic level in 14%. Although osteoarthritis is
denitely an aging phenomenon, recent research also
has identied osteoarthritis in a majority of young
persons referred to a TMJ clinic for joint pain and
dysfunction.
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HISTOPATHOLOGIC FEATURES
The articulating surface of a joint affected by osteoarthritis has a diminished number of chondrocytes, is
roughened, and contains variable numbers of vertical
RHEUMATOID ARTHRITIS
Rheumatoid arthritis is a chronic, presumably autoimmune disorder characterized by nonsuppurative
inammatory destruction of the joints. It may result
from a cross-reaction of antibodies generated against
hemolytic streptococci or other microorganisms, or it
may represent an antibody attack against bacterial cell
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LABORATORY VALUES
Approximately 80% of patients with rheumatoid arthritis exhibit signicant elevations of rheumatoid factor
(RF), an autoantibody thought to be directed toward an
altered host IgG antibody that is no longer recognized
by the body as self. In addition, antinuclear antibodies (ANAs) can be detected in about 50% of the patients
with rheumatoid arthritis, although it is not diagnostically specic because it also may be associated with
other autoimmune diseases. During active phases of
the disease, almost all patients have an elevated erythrocyte sedimentation rate. In addition, some affected
patients have mild anemia.
HISTOPATHOLOGIC FEATURES
Needle biopsy is the most popular technique for obtaining diagnostic synovial material, but aspiration and
analysis of synovial uid from the affected joint frequently are undertaken to rule out other forms of
arthritis. These techniques are seldom used for TMJ
involvement.
Microscopically, early cases of rheumatoid arthritis
demonstrate hyperplasia of the synovial lining cells
with deeper portions of the membrane showing
hyperemia, edema, and inltration by lymphocytes,
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of these agents, and at present, no one drug has demonstrated a consistent advantage over the others. Methotrexate, a folic acid antagonist, is the most frequently
used rst-line agent in the disease-modifying group.
The literature suggests that patients who fail or who
have shown a suboptimal response to disease-modulating therapy might benet from tumor necrosis factor-
(TNF-) neutralizing agents (e.g., etanercept and iniximab), used alone or in combination with standard
disease-modulation algorithms.
Immunosuppressive drugs such as azathioprine,
cyclosporine, and cyclophosphamide appear to be
no more effective in the management of rheumatoid
arthritis than the previously mentioned disease-modulating antirheumatic drugs, and the side effect prole
of immunosuppressive therapy includes increased risk
for serious infections and potential predisposition to
the development of malignant neoplasms. Therefore,
immunosuppressive therapy should be reserved for
those patients who have failed all other efforts at disease
modulation.
Severely damaged joints may require surgical
replacement, with the goals of therapy being attenuation of pain and reduction of disability. Total joint
replacement of the hips, knees, and shoulders are
reported to have the highest satisfaction rates associated with surgical management of these patients.
TEMPOROMANDIBULAR
JOINT DYSFUNCTION
Pain and dysfunction of the TMJ are common and have
been proposed to result from a wide variety of etiologic
factors, both traumatic and nontraumatic (Box 18-10).
The syndrome of signs and symptoms (pain, altered
function, joint noises) is termed temporomandibular
joint dysfunction (TMD). TMD is a problem of the
entire masticatory system: teeth, jaws, joints, and
muscles. All facets must be evaluated to arrive at the
most specic diagnosis and management protocol.
Because of the extreme complexity of this disease, the
present discussion is limited to a brief overview of those
facets of the disorder that are appropriate to the production of pain.
Almost 15% of U.S. adults experience facial and
cervical pain, facial tenderness, and headache from
TMD, but fewer than 1% of those have symptoms
severe enough to warrant professional evaluation or
intervention.
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Box 18-10
881
Box 18-11
Classication of Temporomandibular
Disorders
MUSCULAR DISORDERS
Hyperactivity, spasm, and trismus
Inammation (myositis)
Trauma
Myofascial pain and bromyalgia
Atrophy or hypertrophy
ARTHROGENIC DISORDERS
Disc displacement (internal derangement)
Hypomobility of the disc (adhesions or scars)
Dislocation and subluxation
Arthritis
Infections
Metabolic disease (gout, chondrocalcinosis)
Capsulitis, synovitis
Ankylosis (brous, bony)
Fracture
Condylar hyperplasia, hypoplasia, aplasia
Neoplasia
Aspirin
Acetaminophen (with or without codeine)
Other nonsteroidal antiinammatory drugs (NSAIDs)
Centrally acting muscle relaxants (methocarbamol,
chlorzoxazone)
Benzodiazepine derivatives (diazepam,
chlordiazepoxide)
Glucocorticoids (cortisone, prednisone)
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TEMPOROMANDIBULAR JOINT
ANKYLOSIS
Ankylosis refers literally to a fusion of body parts, in
this case the opposing components of a joint. The fusion
can be brous or bony in natureusually brous when
the TMJ is involved. Joint infection, usually after trauma,
accounts for 50% of all TMJ ankylosis cases, but 30%
result from aseptic trauma. The remaining cases are
idiopathic or produced by rheumatoid arthritis.
The ankylosis may be intra-articular or extra-articular. Intra-articular ankylosis is characterized by the
destruction of the meniscus and the temporal fossa,
thickening and attening of the condylar head, and a
narrowing of the joint space. Opposing joint surfaces
then develop brous adhesions that inhibit normal
movements and may become ossied. Fibrotic intraarticular ankylosis is the most common type seen in
the TMJ, especially after trauma-induced hemorrhage
(hemarthrosis). Osseous ankylosis is more likely with
nonhemorrhagic infections of the joint.
Extra-articular involvement is less frequently seen
and produces an external brous or osseous encapsulation with minimal destruction of the joint itself.
CLINICAL FEATURES
TMJ ankylosis occurs predominantly in the rst decade
of life, and males and females are equally affected.
Almost all cases are unilateral. The condition results in
a gradually worsening inability to open the jaws, with
the mandible shifting toward the affected side on
opening. Pain, tenderness, and malocclusion may be
present, but this is not usually the case.
In severe examples, there is almost complete immobilization of the mandible, and the mandible may protrude forward as the excess tissues occupy the joint
space. In very young children, unilateral micrognathia
(hemifacial microsomia) may result from diminished
growth on the affected side. Malocclusion may be
severe in such cases.
HISTOPATHOLOGIC FEATURES
TMJ ankylosis is characterized by an excessive amount
of dense, rather avascular brous connective tissue or
new bone formation. Intra-articular ankylosis demonstrates irregular destruction of cartilage and bone with
a sparse lymphocytic inltration.
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with giant cell arteritis in the American College of Rheumatology giant cell arteritis classication criteria cohort, Am J
Med 100:193-196, 1996.
Neff AG, Greifenstein EM: Giant cell arteritis update, Semin
Ophthalmol 14:109-112, 1999.
Nesher G, Sonnenblick M, Friedlander Y: Analysis of steroid
related complications and mortality in temporal arteritis: a
15-year survey of 43 patients, J Rheumatol 21:1283-1286,
1994.
Turbin RE, Kupersmith MJ: Giant cell arteritis, Curr Treat Options
Neurol 1:49-56, 1999.
van der Wal JE, van der Waal I: Oral manifestations of giant cell
arteritis, Mund Kiefer Gesichtschir 1:65-67, 1997.
Myasthenia Gravis
Anlar B: Juvenile myasthenia: diagnosis and treatment, Paediatr
Drugs 2:161-169, 2000.
Daskalakis GJ, Papageorgiou IS, Petrogiannis ND et al: Myasthenia gravis and pregnancy, Eur J Obstet Gynecol Reprod Biol
89:201-204, 2000.
Iani C, Caramia M, Morosetti M et al: The treatment of severe
forms of myasthenia gravis, Funct Neurol 13:231-237, 1998.
Lisak RP: Myasthenia gravis, Curr Treat Options Neurol 1:239-250,
1999.
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21:425-440, 2001.
Robertson NP, Deans J, Compston DA: Myasthenia gravis: a
population based epidemiological study in Cambridgeshire,
UK, J Neurol Neurosurg Psychiatry 65:492-496, 1998.
Sasakura Y, Kumasaka S, Takahashi T et al: Myasthenia gravis
associated with reduced masticatory function, Int J Oral Maxillofac Surg 29:381-383, 2000.
Scherer K, Bedlack RS, Simel DL: Does this patient have myasthenia gravis? JAMA 293:1906-1914, 2005.
Weijnen FG, Kuks JB, van der Bilt A et al: Tongue force in
patients with myasthenia gravis, Acta Neurol Scand 102:303308, 2000.
Motor Neuron Disease
Adams RD, Victor M, Ropper AH, editors: Principles of neurology,
ed 6, pp 1089-1094, New York, 1997, McGraw-Hill.
Bromberg MB: Pathogenesis of amyotrophic lateral sclerosis: a
critical review, Curr Opin Neurol 12:581-588, 1999.
Francis K, Bach JR, DeLisa JA: Evaluation and rehabilitation of
patients with adult motor neuron disease, Arch Phys Med
Rehabil 80:951-963, 1999.
Leighton SE, Burton MJ, Lund WS et al: Swallowing in motor
neurone disease, J R Soc Med 87:801-805, 1994.
Rames CM, Newcombe RG, Harper PS et al: Risk estimates for
developing motor neuron disease in rst-degree relatives,
Clin Genet 47:13-16, 1995.
Ross MA: Acquired motor neuron disorders, Neurol Clin 15:481500, 1997.
Strober JB, Tennekoon GI: Progressive spinal muscular atrophies, J Child Neurol 14:691-695, 1999.
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Williams DB, Windebank AJ: Motor neuron disease (amyotrophic lateral sclerosis), Mayo Clin Proc 66:54-82, 1991.
Wokke JH: Diseases that masquerade as motor neuron disease,
Lancet 347:1347-1348, 1996.
Wong PC, Rothstein JD, Price DL: The genetic and molecular
mechanisms of motor neuron disease, Curr Opin Neurobiol
8:791-799, 1998.
Yapijakis C, Kapaki E, Boussious M et al: Prenatal diagnosis of
X-linked spinal and bulbar muscular atrophy in a Greek
family, Prenat Diagn 16:262-265, 1996.
Burning Tongue Syndrome and Glossodynia
Bergdahl M, Bergdahl J: Burning mouth syndrome: prevalence and associated factors, J Oral Pathol Med 28:350-354,
1999.
Bessho K, Okubo Y, Hori S et al: Effectiveness of kampo medicine (sai-boku-to) in treatment of patients with glossodynia,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 86:682-686,
1998.
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patients with burning mouth syndrome, Psychosom Med
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Brown RS, Krakow AM, Douglas T et al: Scalded mouth syndrome caused by angiotensin converting enzyme inhibitors:
two case reports, Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 83:665-667, 1997.
Formaker BK, Frank ME: Taste function in patients with oral
burning, Chem Senses 25:575-581, 2000.
Grinspan D, Fernandez Blanco G, Allevato MA et al: Burning
mouth syndrome, Int J Dermatol 34:483-487, 1995.
Grushka M, Bartoshuk LM: Burning mouth syndrome and oral
dysesthesias, Can J Diagnos 99-109, June 2000.
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Am 35:171-184, 1991.
Haberland CM, Allen CM, Beck FM: Referral patterns, lesion
prevalence, and patient care parameters in a clinical oral
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Lamey PJ: Burning mouth syndrome, Dermatol Clin 14:339-354,
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Cutis 64:29-35, 1999.
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63:329-335, 1998.
Wesselmann U, Reich SG: The dynias, Semin Neurol 16:63-74,
1996.
Dysgeusia and Hypogeusia
Ackerman BH, Kasbekar N: Disturbances of taste and smell
induced by drugs, Pharmacotherapy 17:482-496, 1997.
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Am Fam Physician 61:427-436, 438, 2000.
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Nelson GM: Biology of taste buds and the clinical problem of
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Osaki T, Ohshima M, Tomita Y et al: Clinical and physiological
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Frey Syndrome
Bonanno PC, Palaia D, Rosenberg M et al: Prophylaxis against
Freys syndrome in parotid surgery, Ann Plast Surg 44:498501, 2000.
Dulguerov P, Quinodoz D, Cosendai G et al: Frey syndrome
treatment with botulinum toxin, Otolaryngol Head Neck Surg
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syndrome in late childhood: an unusual variant presenting as
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57:642-649, 1999.
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107:1496-1501, 1997.
Mellor TK: Freys syndrome following fracture of the mandibular
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1996.
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12:287-292, 1998.
Shaw JE, Parker R, Hollis S et al: Gustatory sweating in diabetes
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Osteoarthritis
Dahlstrom L: Diagnoses among referrals to a Swedish clinic specialized in temporomandibular disorders, Acta Odontol Scand
56:143-147, 1998.
de Bont LG, Boering G, Liem RS et al: Osteoarthritis and internal
derangement of the temporomandibular joint: a light microscopic study, J Oral Maxillofac Surg 44:634-643, 1986.
de Leeuw R, Boering G, van der Kuijl B et al: Hard and soft tissue
imaging of the temporomandibular joint 30 years after diagnosis of osteoarthrosis and internal derangement, J Oral Maxillofac Surg 54:1270-1280, 1996.
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Gynther GW, Holmlund AB, Reinholt FP et al: Temporomandibular joint involvement in generalized osteoarthritis and
rheumatoid arthritis: a clinical, arthroscopic, histologic, and
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Ong TK, Franklin CD: A clinical and histopathological study of
osteoarthrosis of the temporomandibular joint, Br J Maxillofac
Surg 34:186-192, 1996.
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Moskowitz RW, Howell DS, Goldberg VM, editors: Osteoarthritis, diagnosis and medical/surgical management, ed 2, pp
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Forensic Dentistry
EDWARD E. HERSCHAFT
CHAPTER OUTLINE
Record Management
Identication
Personal Recognition
Fingerprinting
Physical Anthropologic Examination of Bones and
Teeth
Serologic and Genetic (DNA) Comparison
Dental Evaluation
Bite Pattern Evidence
Basic Principles
Forensic dentistry, which is also referred to as forensic
odontology, is the area of dentistry concerned with the
correct management, examination, evaluation, and
presentation of dental evidence in criminal or civil
legal proceedings in the interest of justice. Thus the
forensic dentist must be knowledgeable in both dentistry and law.
Classically, forensic dentistry can be considered a
subspecialty of oral and maxillofacial pathology. This is
analogous to the relationship in medicine between
forensic pathology and pathology. The requirements of
forensic dental eld work, however, often demand an
interdisciplinary knowledge of dental science. This has
resulted in other dental specialists and general dentists
joining oral and maxillofacial pathologists in providing
legal authorities with dental expertise.
Regardless of background, forensic dentists assist
legal authorities by preparing dental evidence in the
following situations:
Management and maintenance of dental records
that comply with legal requirements to document all
unique dental informationthese data are the foundation on which dental identication of the patient
is accomplished and potential malpractice litigation
is reduced.
Identication of human remains, through the comparison of antemortem and postmortem dental information, in cases that involve the death of an individual
or multiple deaths in mass fatality incident (MFI)
situations.
Collection and analysis of patterned marks (bite
marks) in inanimate material or injured tissuethis
evidence can be compared with, and potentially
related to, a specic human or animal dentition.
Recognition of the signs and symptoms of human
abuse (including intimate-partner violence [IPV],
elder abuse, and child abuse) and the dental health
care practitioners rights and responsibilities when
reporting such abuse.
Presentation of dental evidence as an expert witness
in identication, bite mark, human abuse, malpractice, fraud, and personal injury cases.
RECORD MANAGEMENT
The dental record is a legal document, owned by the
dentist or an incorporated dental practice, which contains all subjective and objective information about the
patient. Initially, this information is secured when the
patients medical and dental history is obtained. Results
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Fig. 19-1 The x-ray uorescence (XRF) spectrum from a particle recovered from a cremation
retort. The spectrum makes this a match for the restorative resin Four Seasons or Tetric
Ceram (Ivoclar, Amherst, NY). (Courtesy of Dr. Mary A. Bush and Peter J. Bush.)
of the physical examination of the dentition and supporting oral and paraoral structures are recorded.
In addition, the results of clinical laboratory tests,
study casts, photographs, and radiographs become
components of the record. With this database, the
dentist can develop a thorough assessment of all of the
patients medical and dental problems. Subsequent
documentation of this problem list facilitates the
development of a plan of treatment and prognosis for
the patient.
The treatment plan addresses the management of
both systemic and oral problems. It can then be periodically revised and updated as problems resolve or as
new ones develop. Supplemental material, such as
dental laboratory authorizations, referral letters from
other practitioners, statements of informed consent,
written prescriptions, and insurance and nancial
statements, also is included and stored in the record.
The progress notes (i.e., daily log of actual treatment
rendered) should contain information about restorative and therapeutic procedures provided. This information should include documentation of the specic
brand of dental material used in restorative procedures. This concept has forensic import because each
dental restorative product contains inorganic materials, trace elements, and llers that are unique to that
product and can be detected by x-ray uorescence
(XRF) technology even after incineration. The XRF
trace element and major element analysis of dental
remains may be useful as an adjunct to traditional
evaluation of dental information in some forensic settings, including cremation and dismemberment cases
(Fig. 19-1).
Unusual physiologic and psychologic reactions and
the patients comments concerning therapy are entered
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IDENTIFICATION
Legal situations often revolve around the establishment
of a persons proper identity. Any death not certied by
an individuals own physician must be referred to the
medical examiner (ME) or coroner for review. However,
cases requiring an autopsy to determine the time,
cause, and manner of death represent a small percentage of cases. When required, these tasks are the responsibility of a coroner or ME. These ofcials are charged
with the role of establishing identication; determining
the cause, mechanism, and mode or manner of death;
and issuing a death certicate. Besides identication
of the decedent, these key issues of death investigation
for the coroner or ME are dened according to the
following:
Cause of death. The disease, injury, or chemical or
physical agent responsible for initiating the lethal
sequence of events (e.g., myocardial infarction,
cancer, bullet, knife, poison, ligature, lightning, infectious agent)
Mechanism of death. The pathologic process that
results in death (e.g., congestive heart failure, cardiac
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PERSONAL RECOGNITION
Personal recognition is the least reliable method used
to identify an individual. It is often based on the visual
identication of a decedent by a family member, friend,
or acquaintance. This process assesses artifactual material, such as clothing, jewelry, keys, wallet contents,
luggage, other personal effects, scars, and tattoos to
determine identication. Evidence in this type of identication can be accidentally or purposely exchanged
between bodies. This can occur in MFI situations or
when there is criminal intent to create a misidentication in cases of identity theft or alias associated with
criminal activity.
Even when a body is viewed shortly after death,
distraught relatives can inadvertently misidentify the
decedent. After the occurrence of postmortem changes
associated with soft tissue decomposition, insect and
burn artifact, or dismemberment, this method of identication may be precluded (Figs. 19-2 and 19-3).
FINGERPRINTING
Anthropometry was the rst scientic system police
used to identify criminals. The French law enforcement ofcer Alphonse Bertillon developed this system
in the latter part of the nineteenth century. The method
was unreliable and awed because it relied on biometric physical measurements of the head and body, individual markings including scars and tattoos, and other
personal characteristics. Bertillons anthropometry
identication process was eventually replaced by
analysis of the epidermal friction ridges of the
ngers, palms, and feet commonly referred to as
ngerprinting.
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identication, in which numerous charting and toothnumbering systems are used. Because soft tissues
decompose shortly after death, the friction ridge patterns within the epidermis may not be retrievable for
ngerprint comparison. This is the principal disadvantage of ngerprint identication.
PHYSICAL ANTHROPOLOGIC
EXAMINATION OF BONES AND TEETH
Forensic anthropologists and forensic dentists often
work together to resolve problems associated with
identication. Both disciplines are concerned with
analysis of calcied structures of the bodybones and
teeth. Historically, this anatomic material has assisted
forensic anthropologists and dentists in determining
the race, age, and sex of a person (Table 19-1). These
characteristics have become less distinct in some populations as individuals from different cultures and races
have intermarried and blended these genetically determined features in their offspring.
Determination of the age of an individual is helpful
in cases involving limited population fatality incidents
in which the ages of the victims vary. Immigration ofcials often deal with situations in which designation of
juvenile or adult is important when considering the
status of refugees or illegal aliens. In these settings the
assessment of dental evidence may provide resolution.
In addition to the study of osseous material, the
teeth can be evaluated clinically, radiographically, and
biochemically to determine the age of the decedent.
The basis for this analysis is related to progressive
Width
Height
Prole
Orbit
Nasal opening
Palate
White
Black
Asian/Native American
Narrow
High
Straight
Triangular/teardrop
Tapered
Narrow
Narrow
Low
Prognathic
Square
Wide
Wide
Broad
Intermediate
Intermediate
Circular
Rounded
Intermediate
SEXUAL CHARACTERISTICS
Size
Glabellar (supraorbital) ridges
Mastoid process
Occipital area
Mandible
Forehead
Male
Female
Large
Pronounced
Large
Pronounced muscle lines
Larger, broader ramus
Steeper, slopes posteriorly
Small
Not developed
Small
Minimal muscle lines
Smaller
Rounded, more vertical
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changes in forming and developing teeth, eruption patterns, and levels of metabolically stable tissue factors,
including aspartic acid enantiomers. This information,
combined with analysis of the calcication centers of
the hand and wrist, can be used to estimate the precise
age of a person who is younger than 20 years of age.
Depending on the type of case being studied, several
techniques are available to estimate chronologic dental
age. In individuals younger than 20 years old, this is
most often accomplished through morphologic and
histologic analysis of dental and skeletal material.
Included in the methodology for this type of age evaluation is the radiographic assessment of the calcication
stage of the third molars and analysis of ground sections of teeth for variations in the following patterns:
Attrition
Periodontal attachment
Secondary dentin
Cementum apposition
Root resorption
Transparency
There are variations in the calcication and eruption patterns among various ethnic and cultural groups,
and studies have been undertaken to delineate these
differences further. After the third molars, long bones,
and bones of the wrist and hand are completely developed, evaluation of biochemical components of the
calcied structures and collagen is the most accurate
method for determining chronologic age.
Methods that rely on an analysis of the rate of racemization of the stereoisomers of aspartic acid in enamel
and dentin can be used to determine an accurate
chronologic age. This is related to the fact that the
change from the L-form of this amino acid to its mirror
image D-form occurs over time. Thus the ratio of the
L- to D-forms of aspartic acid in the dentition is directly
related to the age of the individual. Often, anthropologic and dental age analysis is helpful in arriving at a
presumptive identication based on the criteria noted
previously.
Positive identication may be achievable when the
skull and facial bones are used as a foundation to
reconstruct the facial soft tissues (Figs. 19-4 to 19-6).
Three-dimensional (3D) computer images, computed
tomography (CT) images, and radiographs have even
been used in the replication of the face of Europes
oldest mummied human, a male dubbed tzi, whose
5300-year-old remains were removed from glacial ice
in the tztal Alps on the Austrian-Italian border.
With knowledge of the anatomic relationships
between the skull and face, antemortem facial photographs or radiographs can be superimposed for comparison with the skull of an unknown. Video
superimposition with two television cameras and an
electronic mixing device has been used successfully to
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Every individual is unique by virtue of his or her chromosomal DNAa polymer structured as a double helix
and composed of four different nucleotides. The polymorphic sequencing of these nucleotides along the two
strands of the DNA molecule accounts for the genetic
diversity of all living things. This ultimate identication material was rst used forensically to obtain a
conviction in a criminal case in 1986, and DNA comparison has since become an accepted forensic method
to resolve problems of identication.
Before 1986, comparison of antigenic markers
found on red blood cells (RBCs) and in body uids of
secretors of these markers among the human population was traditionally used as a means of exculpatory
(exclusionary) evidence. Because the ABH antigenic
surface markers of RBCs are not discriminatory, this
type of evidence was primarily used to exclude a
suspect or victim when negative comparative results
were achieved. Positive comparisons were justied
only to place the suspect or victim in a population of
individuals having similar serologic antigens.
Although DNA has become the principal biologic
substance used to effect a positive identication, antigenic surface markers A, B, and H of the ABO blood
group system, as well as various components of the
rhesus (Rh) and Lewis systems, continue to be accepted
for medicolegal comparison. The ability to secrete the
ABH antigens in saliva and other body uids is genetically determined, and more than 80% of individuals
are secretors. With appropriate laboratory tests, even
dried samples of uid and blood can be analyzed for
these markers.
DNA found in human cells is composed of chromosomal and mitochondrial DNA (mtDNA). Two copies
of chromosomal DNA are incorporated into the nuclei
of a persons cells by DNA provided from both parents.
However, hundreds of copies of mtDNA are contained
in the cytoplasm of these cells. This DNA is only
maternally transferred and can be isolated from cells
without nuclei such as RBCs. Unlike nuclear DNA,
mtDNA is single stranded and circular. Because there
is no mixing of sequence types from generation to generation in maternally transferred mtDNA, it can be
compared with that of distant maternal relatives to
effect identication when other reference sources are
unavailable.
Restriction fragment length polymorphism (RFLP)
and polymerase chain reaction (PCR) analyses are the
principal laboratory techniques used to compare and
evaluate fragments of DNA material from a suspect or
victims biologic forensic specimens (e.g., semen,
vaginal uid, teeth, soft tissues, saliva). Both are
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DENTAL EVALUATION
BASIC PRINCIPLES
In an identication case, the principal advantage of
dental evidence is that, like other hard tissue, it is often
preserved indenitely after death. Although the status
of a persons teeth changes throughout life, the combination of decayed, missing, and lled teeth is measurable, reproducible, and comparable at any xed point
in time. Therefore, like the comparison of unique patterns in a ngerprint, a scientic, objective analysis
of antemortem and postmortem dental variables is
achievable.
The presence and position of individual teeth and
the respective anatomic, restorative, and pathologic
components provide the database for the antemortem
and postmortem comparison (Fig. 19-7). The pattern
of the palatal ridge, ridges on the lip surface, and radiographic outline of the maxillary and frontal sinuses are
also considered unique. In addition, the legal community accepts the fact that dentists can recognize procedures that they have performed.
Problems associated with dental identication information are often related to acquiring and interpreting
antemortem records. Most antemortem dental records
are retrieved from private-sector dental providers.
However, dental records may be recovered from insurance carriers, dental schools, hospitals, clinics, state
and federal prisons, military les, and the FBI National
Crime Information Center (NCIC).
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To initiate a request for antemortem records, a putative (suspected) identication is required. Reports of
missing and unidentied persons, obtained from law
enforcement agencies, are the principal source for this
material. Thousands of victims who cannot be identied by ngerprint methods remain unidentied because a putative identication has not been
established.
The FBI-NCIC computer registry of missing and
unidentied persons was established to help rectify
this problem. This computer system maintains demographic, dental, and medical information on missing
persons. It attempts to match these data with similar
facts obtained from unidentied bodies. The latter
information is submitted by various investigative and
legal agencies. Potentially, the otherwise unidentiable
victims of random violence, serial homicides, terrorist
acts, and child abduction can now be identied without
the need to determine a putative identication. A disadvantage of the NCIC computer identication system
is that it does not have the capability to identify possible decedents based solely on dental information.
The National Dental Image Repository (NDIR) has
been established to address this issue. Law enforcement agencies can voluntarily post supplemental dental
images related to NCIC Missing, Unidentied, and
Wanted Person records on the NDIR secure website.
Thus access, retrieval, and review of dental information
by qualied forensic odontologists who are members
of the NDIR Review Panel can facilitate dental
comparisons. The NDIR website is located at Law
Enforcement Online (LEO) at http://cgate.leo.gov. This
repository permits law enforcement, criminal justice,
and public safety authorities to maintain a national and
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Table 19-2
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PERMANENT TEETH
Maxillary Right
Mandibular Right
Maxillary Left
Mandibular Left
7
7
6
6
ZSIGMONDY/PALMER SYSTEM
5 4 3 2 1 1 2 3 4 5
5 4 3 2 1 1 2 3 4 5
6
6
7
7
8
8
DECIDUOUS TEETH
UNIVERSAL NUMBERING SYSTEM
A B C D E F G H I J
T S R Q P O N M L K
ALTERNATE UNIVERSAL NUMBERING SYSTEM
4D 5D 6D 7D 8D 9D 10D 11D 12D 13D
29D 28D 27D 26D 25D 24D 23D 22D 21D 20D
E
E
ZSIGMONDY/PALMER SYSTEM
D C B A A B C D E
D C B A A B C D E
The Zsigmondy/Palmer System stresses the anatomic likeness of the eight tooth types in each symbolically identied dental quadrant. Homologous
permanent teeth are assigned the same number from
1 to 8. Deciduous teeth are assigned letters A
through E.
The FDI Two-Digit System is endorsed by the World
Health Organization (WHO) and is used in most developed countries, except the United States. The rst digit
represents the quadrant. Quadrants 1 to 4 are assigned
for permanent teeth; 5 to 8 represent quadrants for
the primary dentition. As in the Universal Numbering
System, the quadrants are identied in a clockwise direction, beginning with the maxillary right. The
second digit designates the permanent tooth type from
1 to 8, or deciduous tooth type from 1 to 5.
Thus in the Universal Numbering System, tooth 12
is the maxillary left rst bicuspid. In the FDI Two-Digit
System, tooth 12 (one-two) is the maxillary right lateral
incisor. In the Zsigmondy/Palmer System, all lateral
incisors are designated with a No. 2 code. The position
of a specic No. 2 tooth is diagrammatically indicated
by a symbolic quadrant.
Unless the forensic dentist knows which system has
been used to encode the teeth in the antemortem
record, all teeth should be referred to by their actual
names. This method will prevent errors because all
dentists use the same anatomic nomenclature when
referring to individual teeth.
Dental identication problems may be further compounded because dental radiographs can be mounted
and viewed from right to left or vice versa. Intraoral
radiographic duplicating lm does not contain a raised
dot to assist the dentist in orienting the lm for mounting. The lack of this orienting device can lead to
transposition of dental evidence and potential misidentication based on an incorrect comparison. Panoramic
radiographic duplicating lm, however, does contain a
series of notches on one side to indicate that the lm
is not an original.
With the advent of aesthetic materials for posterior
restorations and the reduction in the incidence of
caries, it may be difcult for the forensic dentist to
determine whether restorations are present by simple
visual assessment of the teeth. In addition, the postmortem dental evaluation is often performed in an autopsy
room, temporary morgue, or funeral home. In these
locations, proper lighting and access to dental instruments, which can facilitate analysis of the oral
structures, are not readily available for detailed
examination.
Often, there are additional demands for immediacy
in providing a coroner, ME, or other legal agent with
the results of a dental identication. These demands
further compound the forensic dentists technical and
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Box 19-1
POSTMORTEM EXAMINATION
The postmortem dental evidence is gathered by photographic, radiographic, and charting techniques. All
records should include the case number, date, demographic and anthropologic information, the name of
the authority that is requesting the dental examination,
the location of the examination, and the name of the
examining dentist.
Photographs should be taken of full head and face
views. Images of the occlusal planes of both dental
arches and individual views of unusual pathologic or
restorative ndings are also obtained. A single-lens
reex (SLR), 35-mm, lm-based or digital camera and
appropriate electronic ash and lens systems for closeup photography should be used. Routinely, both color
and black-and-white exposures are recommended for
use in each case.
Dental impressions and jaw resection may also be
required after the initial full head photographs have
been obtained. If requested by the coroner or ME, then
the dental specimens from the autopsy may have to be
retained and preserved in a 10% formalin solution.
The guidelines for body identication recognize that
the dentist and dental auxiliary personnel involved in
performing forensic dental procedures do so at the
request and direction of a legal authority, such as a
coroner or ME. Therefore, it is only with the permission
of these individuals that techniques involving postmortem facial dissection or jaw resection are performed
by the forensic dentist to achieve complete access to
dental tissues.
These measures are used most often in decomposed,
dismembered, or incinerated bodies to make postmortem dental charting and radiographic examination
easier. Resection or soft tissue dissection may be necessary in visually recognizable bodies when the oral
cavity is inaccessible because of rigor mortis.
When the jaws are removed with a reciprocating
(Stryker) saw or osteotome and mallet, a Le Fort I fracture of the maxilla is created. The dissection instruments are placed above the inferior nasal spine and
malar processes to ensure that the apices of the maxillary teeth are not transected. Similarly, if the mandible
is not removed by disarticulation, then cuts into the
mandibular rami should be high enough to prevent
damage to impacted third molars.
While obtaining postmortem radiographic evidence,
the forensic dentist may encounter technical obstacles
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NATURAL DISASTERS
Natural mass disasters include earthquakes, tornadoes,
hurricanes, volcanic eruptions, re storms, tsunamis,
and oods. These may occur over relatively short
periods or may be protracted over days or weeks.
Victims may be scattered throughout broad areas, extending for miles. In addition, many victims in natural
MFI situations may be unknowns who cannot be presumptively identied. Several countries or states can be
affected, as in the 2004 Indian Ocean tsunami event.
Transients, homeless individuals, and tourists who
are visiting an area involved in a natural MFI are often
difcult to identify.
In a natural disaster, the principal problem for the
dental identication team is that the environmental
infrastructure is often compromised. For example,
after Hurricane Katrina, medical and dental ofces
and hospital facilities containing antemortem records
had been destroyed by tornado activity and ooding.
In addition, communication lines and roads were
damaged, preventing the retrieval of most available
antemortem records. All of these factors delayed or
precluded the prompt identication of many victims.
ACCIDENTS
Accidental MFI events are most often associated with
transportation accidents, res, industrial and mining
accidents, and military accidents. These situations
usually occur over short time periods and are associated with closed populations (e.g., airplane, bus, or
train passengers; mine or factory workers).
Airlines maintain passenger logs of individuals who
are registered on specic ights. However, it has been
estimated that at any given time as many as 10% of air
travelers may purchase their tickets using an alias for
identication. The mining company, mill, or industrial
plant can document those who have reported for work.
In these examples, the victims of accidents should logically come from the closed population of employees
on that shift. Therefore, antemortem records are rst
solicited from the families and health care providers
of these individuals. Another source of medical and
CRIMINAL DISASTERS
Unlike natural and accidental MFIs, criminal mass
disasters involving death may occur over extremely
long time periods and wide ranges of territory (e.g.,
different cities or states). This was the pattern of the
rapes and murders committed by Ted Bundy, whose
victims included young women residing in states from
Washington to Florida from 1974 to 1978. The remains
of the victims of serial killers can be hidden, as in the
Green River homicides in the Pacic Northwest and
the murders of young men committed by John Wayne
Gacey in Chicago. Dismemberment and mutilation of
victims is exemplied by the Jeffrey Dahmer case.
Dental structures in these situations may not always be
available for postmortem review.
Law enforcement agencies are often unaware of the
victims of serial killers from other jurisdictions. Each
agency may be investigating an individual homicide
without recognizing a pattern of broader criminal
involvement. Until the development of the FBI-NCIC
computer registry, coordinated efforts at identication
were hampered.
The rise in national and international terrorism in
the twenty-rst century has changed the paradigm
associated with the traditional participation of the
dental profession in an MFI setting. Until recently,
forensic odontologists and other dental professionals
were simply tasked as experts in the identication of
the decedents. Currently, there are ongoing efforts
within organized dentistry to develop effective
responses to acts of bioterrorism. These efforts are
exemplied by the professions encouragement of legislation authorizing dental professionals, in federally
declared emergencies, to perform various procedures
that are routinely not within the practice of the profession. Under these provisions, dentists registered and
trained in emerging medical diseases, bioterrorism,
and emergency medical care would be indemnied for
actions taken in the performance of these services.
Acts of terrorism may include exposure to biologic
agents, chemical toxins, and the discharge of nuclear
devices. Thus the dentist involved in MFI recovery and
identication after an act of terrorism may additionally
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RESPONSIBILITIES
In the United States, the National Response Plan (NRP)
provides a comprehensive, risk-based, emergency
management plan to respond to any hazardous event.
The NRP establishes guidelines to manage domestic
response to radiological, technical, natural, or terrorist
incidents by developing 12 emergency services functions and delineating the agencies charged with performing specic tasks in a response.
As part of the presidential directive that created the
U.S. Department of Homeland Security after the September 11, 2001 terrorist attacks, the National Incident Management System (NIMS) was also developed.
The overall objective of this system is coordination of
governmental agencies, nongovernmental organizations, and the private sector in the resolution of nationally signicant incidents.
Regardless of the type of MFI, the local coroner or
ME is ultimately responsible for performing the autopsies and identifying the victims. In accidents that
involve modes of public transportation, the National
Transportation Safety Board (NTSB) is empowered to
investigate and determine the cause of the crash. Other
agencies with jurisdiction at a disaster scene may represent local police, public safety, and funeral home
personnel. In addition, there may be representatives of
the Federal Emergency Management Agency (FEMA),
members of the FBI ngerprint team, members of the
clergy, or personnel with the Disaster Mortuary Operational Response Team (DMORT) or Disaster Medical
Assistance Team (DMAT).
Although DMORT and DMAT units include dental
personnel, these teams may not be mobilized in all
MFIs. In these situations, forensic dentists and support
staff responsible for identication or care of the injured
should also be organized into teams. Several state
dental associations (including California, Washington,
Michigan, New York, South Carolina, Nevada, and
Iowa) have developed, supplied, and trained such
groups in preparation for emergencies requiring their
expertise. Training sessions include mock MFI exercises. These drills can prepare the dental team members
for dealing with the technical problems of cases involving multiple fatalities.
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with additional resources to enable recovery, documentation, storage, and comparison of forensic dental
evidence in MFIs, as well as in other situations requiring forensic dental expertise (e.g., bite mark analysis,
documentation of human abuse). Among these
advances are developments in the following:
Digital photography. The basic digital camera used
for forensic evidence documentation should include
a through-the-lens (TTL), light-metering, SLR, 35mm digital camera body with interchangeable lenses
or an adjustable lens capable of normal range (30
to 50 mm) to macro range (90 to 100 mm) focal
length. A removable ash memory card with adequate storage capacity is also required. The Scientic
Working Group on Imaging Technology (SWGIT)
imaging guidelines provide the forensic odontologist with information regarding the limitations and
parameters imposed by the judicial system regarding
the manipulation and presentation of digital photographic evidence.
Digital radiography (DR) equipment. Electronically generated and stored radiographic imaging can
be accomplished by the following:
Scanning normally processed radiographic lm
into a computer
Using a phosphor substrate shaped and used like
radiographic lm to expose and scan radiographic
information into the computer by a special proprietary device
Using a sensor sized and shaped like a radiographic lm that is made of a scintillation
screen and a charge-coupled device (CCD) or
complementary metal oxide semiconductor
(CMOS)
Direct digital radiography (DDR). When energized by radiation, this device creates a direct image
on the pixels of its CCD or CMOS. This radiographic
image is then sent to a computer through wire or
wireless technology. Thus because of its ability to
save time, DDR technology is recommended for
clinical and forensic casework. Additionally, DDR
procedures reduce exposure times by requiring 90%
less radiation than that required to expose a standard
type D lm radiograph and 50% less radiation than
that required in exposure of type E lm radiographs.
The parameters by which the quality of a radiograph
is evaluated include resolution and contrast sensitivity. Image resolution describes the detail an image
holds. In lm-based radiographs, this is expressed as
a function of how close lines can be to each other and
still be visibly distinguished. Digital imaging measures resolution as pixel counts. The contrast sensitivity is a measure of the smallest percentage change
in an objects base thickness (density) that can be
detected in a radiograph. The high resolution of the
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Fig. 19-11 Insect bites on the skin that mimic the pattern
injury associated with bite mark trauma. In a decedent, this
pattern may additionally be mistakenly interpreted as
antemortem trauma. (Courtesy of Dr. David K. Ord.)
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Table 19-3
Histopathologic and Clinical Changes Used to Monitor the Time Elapsed (Aging) in Skin
Injuries Associated with Bite Marks
Time
HOURS
4-8
12
16-24
24-36
DAYS
1-3
3+
4
4-5
6
10-14
AND
MAXILLOFACIAL PATHOLOGY
Predominant Cellular
Inltrate and Deposits
Healing
Blue-black
Peripheral broblasts
Central necrosis
Hemosiderin
Green-blue
Collagen bers
Capillary growth
Lymphocytes peak at periphery
Granulation tissue
Brown-yellow-green
Tan-yellow
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907
EVIDENCE COLLECTION
EXAMINATION OF THE VICTIM AND THE SUSPECT
Both the victim and the suspect are examined, and
evidence from each is gathered for comparative study
and evaluation. Collection of evidence must be performed in a manner that protects the rights of the
person who is providing the evidence and that permits
the eventual acceptance of the evidence in court.
A standard health history and informed consent are
obtained before any evidence recovery procedure
regarding the suspect is performed. An intraoral and
extraoral examination of the suspect is completed,
which includes dental charting, soft tissue and tongue
evaluation, and probing of the periodontium. Therefore, knowledge of the medical history of the suspect
relative to systemic problems associated with cardiovascular disease, allergy, seizure disorder, diabetes, or
requirements for antibiotic prophylaxis has medicolegal importance in forensic casework, as well as in traditional patient evaluation.
A search warrant, court order, or legal consent may
be required before evidence is collected from a suspect.
A specic list of the dental-related evidence desired
should be recorded in the legal document. This list
usually includes facial and oral photographs, impres-
sions of the teeth, occlusal registrations and bite exemplars, and saliva samples. These documents protect the
rights of the suspect against unreasonable search and
seizure and provide for due process, as guaranteed by
the Fourth and Fourteenth Amendments, respectively,
to the U.S. Constitution.
Bite marks are considered similar to such physical
evidence as ngerprints, hair, blood, and semen
samples, as well as to sobriety tests. Therefore, this
material is not protected under provisions of the Fifth
Amendment, which deals with self-incrimination.
PHOTOGRAPHY
Because evidence associated with bite marks, human
abuse, and sexual and physical assault is transitory,
there is an immediacy associated with the collection of
physical evidence in these cases. Initial photographs of
the pattern mark should be taken before any investigative procedures that may alter the pristine bite mark
evidence (e.g., touching, removing, impressing, swabbing, cleansing).
Ideally, standard visible-light photographic techniques include the use of a 35-mm, SLR, lm or digital
camera with a at-eld macro lens and dedicated electronic ash. Numerous images using different camera
and lighting positions, exposure settings, and color and
black-and-white exposures should be obtained. If lm
is used, the submission of this evidence for development should strictly follow protocols for evidence preservation and maintenance of the chain of custody.
Additional legal considerations and protocols related
to the documentation of image enhancement, restoration, compression, and analysis have been established
for digital bite mark images.
Orientation positions and close-up views with a reference scale are required. A reference scale permits
the bite mark images to be measured and prepared
as life-size (i.e., 1:1) representations of the pattern
injury. Ultimately, these images can then be compared
with casts and other exemplars obtained from the
suspect. The scale should be stabilized and positioned
next to, and in the same plane as, the bite mark to
eliminate potential distortion artifacts in the resultant
images. It should never be hand-held. Omitting the
scale from at least one view documents that no
marks or other injuries have been intentionally hidden
by it.
The ABFO No. 2 reference scale (Lightning Powder
Company, Inc; Salem, Ore.) was developed for use in
bite mark photography (Fig. 19-13). This standardized,
accurate scale has become the gold standard in bite
mark photographic analysis. Variations of it have eventually come to be used in all varieties of forensic casework requiring accurate measurement of evidence at
crime scenes or in the laboratory.
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Table 19-4
Light wavelength
Filter
Visible Light
UV Light
400-700 nm
None
200-400 nm
700-1000 nm
Kodak
Kodak
Wratten Filter No. 18A gel
gel 87
(visibly opaque glass lter)
450 nm
Kodak
gel 15
+
+
+
+
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IR Light
+
+
+
+
ALI Fluorescence
+
+
+
+
+
+
+
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SALIVA EVIDENCE
Although the forensic dentist is concerned principally
with the analysis of the physical evidence associated
with a bite mark, biologic evidence in the form of serologic and DNA material is also of probative importance. Collection of saliva trace evidence from the
surface of the bite injury of the victim is performed
before other evidence-gathering manipulation of the
injury. There is an increase in the yield of recovered
DNA for analysis when this procedure is carried out
according to the two-swab protocol developed by Dr.
David Sweet and others at the Bureau of Legal
Dentistry, University of British Columbia.
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TISSUE SAMPLES
Tissue samples of a bite mark can be retained from
decedents. With the permission of the ME or coroner,
the epidermis, dermis, and underlying muscle and
adipose tissue can be removed for transillumination
analysis. Before excision, an acrylic ring or stent
must be secured within 1 inch of the borders of the
injured tissue sample. The ring or stent prevents shrinkage and distortion of the specimen when it is placed
into a 4% formalin solution for xation. The acrylic
material is bound to the skin surface with cyanoacrylate and sutures (Fig. 19-14). These tissues samples
can be transilluminated by backlighting. This process
permits observation of the pattern injury in the bruised
skin by a manner that is not possible when the tissue
is in situ.
EVIDENCE ANALYSIS
The responsibility of comparing the photographs of the
bite pattern injury with the dentition of the suspect
rests with the forensic dentist. As an expert in the analysis of these patterns, this person objectively evaluates
the evidence. The forensic dentist rst determines
whether the pattern is truly a result of biting or whether it is an artifact. Patterns of blood splatter around
a wound, other tool marks, or insect artifacts unrelated
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HUMAN ABUSE
EPIDEMIOLOGY AND CLASSIFICATION
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Box 19-2
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Other characteristics of child and elder abuse injuries are related to their multiplicity and repetitive
nature. They often appear in various stages of resolution. Some injuries are acute; others are healing or
even scarred. Therefore, the dentist should examine
the skin of the pediatric, geriatric, or disabled dental
patient. Suspicion of abuse is increased when the child
or older patient appears overdressed for seasonal conditions; overdressing may be an attempt to mask or
hide the physical signs of abuse.
By adulthood, 10% of men and 25% of women are
the victims of sexual abuse. Oral infections associated
with sexually transmitted diseases (STDs) are obviously
signs of sexual abuse when they are observed in a
minor. Erythematous or petechial lesions of the palate
or ulceration of the sublingual area should be noted
because these ndings can result from the physical
trauma associated with performing fellatio or cunnilingus (see page 307).
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SUMMARY
Each practitioner has a responsibility to understand
the forensic implications associated with the practice
of his or her profession. This understanding should
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BIBLIOGRAPHY
Arany S, Ohtani S, Yoshioka N et al: Age estimation from aspartic
racemization of root dentin by internal standard method,
Forensic Sci Int 141:127-130, 2004.
Austin-Smith D, Maples WR: The reliability of skull/photograph
superimposition individual identication, J Forensic Sci
39:446-455, 1994.
Barsley RE: Forensic and legal issues in oral diagnosis, Dent Clin
North Am 37:143-144, 1993.
Berger MA: Evidentiary framework. In Cecil JS et al: Shepards
reference manual on scientic evidence, pp 39-117, New York,
1994, McGraw-Hill.
Blankenship JA, Mincer HH, Anderson KM et al: Third molar
development in the estimation of chronologic age in American blacks as compared with whites, J Forensic Sci 52:428433, 2007.
Bowers CM, Johansen RJ: Photographic evidence protocol: the
use of digital imaging methods to rectify angular distortion
and create life size reproductions of bite mark evidence, J
Forensic Sci 47:179-186, 2002.
Bush MA, Bush PJ, Miller RG: Detection and classication of
composite resins in incinerated teeth for forensic purposes, J
Forensic Sci 51:636-642, 2006.
Bush MA, Miller RG, Prutsman-Pfeiffer J et al: Identication
through XRF analysis of dental restorative resin materials: a
comprehensive study of non-cremated, and processed cremated individuals, J Forensic Sci 52:157-165, 2007.
Child Abuse Prevention and Treatment Act of 1974 (PL93-247),
DHEW Pub No 78-30137, 42 USCS Section 5106 g (4),
Washington, DC, 1988.
Chiodo GT, Tolle SW, Tilden VP: The dentist and family violence, Gen Dent 46:20-25, 1998.
CODIS, Combined DNA Index System. Available at http://www.
fbi.gov/hq/lab/codis/clickmap.htm. Accessed January 15,
2008.
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APPENDIX
DEFINITIONS
To better describe the appearances of lesions and
communicate these features to colleagues, the
clinician should be familiar with the following
terms:
Macule. Focal area of color change that is not elevated or depressed in relation to its surroundings.
Papule. Solid, raised lesion that is less than 5 mm
in diameter.
Nodule. Solid, raised lesion that is greater than
5 mm in diameter.
Sessile. Describing a tumor or growth whose base
is the widest part of the lesion.
Pedunculated. Describing a tumor or growth
whose base is narrower than the widest part of the
lesion.
Papillary. Describing a tumor or growth exhibiting
numerous surface projections.
Verrucous. Describing a tumor or growth exhibiting a rough, warty surface.
Vesicle. Supercial blister, 5 mm or less in diameter, usually lled with clear uid.
Bulla. Large blister, greater than 5 mm in
diameter.
Pustule. Blister lled with purulent exudate.
Ulcer. Lesion characterized by loss of the surface
epithelium and frequently some of the underlying
connective tissue. It often appears depressed or
excavated.
Erosion. Supercial lesion, often arising secondary to rupture of a vesicle or bulla, that is characterized by partial or total loss of the surface
epithelium.
Fissure. Narrow, slitlike ulceration or groove.
Plaque. Lesion that is slightly elevated and is at
on its surface.
Petechia. Round, pinpoint area of hemorrhage.
Ecchymosis. Nonelevated area of hemorrhage,
larger than a petechia.
Telangiectasia. Vascular lesion caused by dilatation of a small, supercial blood vessel.
Cyst. Pathologic epithelium-lined cavity, often lled
with liquid or semi-solid contents.
Unilocular. Describing a radiolucent lesion having
a single compartment.
Multilocular. Describing a radiolucent lesion
having several or many compartments.
By using these terms, the clinician can describe the
characteristics of lesions efciently and uniformly.
Applying these clinical descriptors to the lesions also
can help categorize them with respect to the differential diagnosis. By adding additional characteristics such
as prevalence, patient race or nationality, patient
age at diagnosis, patient sex, and sites of predilection,
the clinician can hone the differential diagnosis list
considerably.
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A. Unilocular Radiolucencies:
Pericoronal Location
B. Unilocular Radiolucencies:
Periapical Location
C. Unilocular Radiolucencies:
Other Locations
D. Multilocular Radiolucencies
E. Radiolucencies: Poorly Dened or
Ragged Borders
F. Radiolucencies: Multifocal or Generalized
G. Radiopacities: Well-Demarcated Borders
H. Radiopacities: Poorly Demarcated Borders
I. Radiopacities: Multifocal or Generalized
J. Mixed Radiolucent/Radiopaque Lesions:
Well-Demarcated Borders
K. Mixed Radiolucent/Radiopaque Lesions:
Poorly Demarcated Borders
L. Mixed Radiolucent/Radiopaque Lesions:
Multifocal or Generalized
M. Unique Radiographic Appearances:
Ground Glass (Frosted Glass)
Radiopacities
N. Unique Radiographic Appearances:
Cotton Wool Radiopacities
O. Unique Radiographic Appearances:
Sunburst Radiopacities
P. Unique Radiographic Appearances:
Onion-Skin Radiopacities
Q. Soft Tissue Radiopacities
926
920
920
921
921
921
922
922
923
924
924
925
926
926
927
927
927
928
928
928
928
A.
B.
C.
D.
E.
F.
G.
H.
I.
J.
K.
L.
M.
N.
929
929
929
930
930
931
931
931
932
932
932
933
933
933
933
933
933
934
934
934
934
934
935
935
935
935
936
936
936
936
936
919
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Frequency
of Occurrence
Lesion or Condition
Secondary syphilis
Diphtheria
Page
13
213
350
920
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289
293
291
188
186
285
8
388
398
405
782
286
13
403
268
217
794
401
743
744
745
746
190
851
Appendix
DIFFERENTIAL DIAGNOSIS
Frequency
of Occurrence
OF
ORAL
Lesion or Condition
AND
MAXILLOFACIAL DISEASES
921
Page
779
***
***
Candidiasis
Lichen planus
**
Burns
**
Actinic cheilosis
**
**
**
Nicotine stomatitis
Erythroleukoplakia
Cinnamon reaction
Lupus erythematosus
Scarlet fever
Verruciform xanthoma
D. RED LESIONS
***
***
***
Pharyngitis
Traumatic erythema
Denture stomatitis
183
216
***
***
Erythematous candidiasis
Erythema migrans
215
779
***
**
**
*
Angular cheilitis
Thermal burns
Erythroplakia
Anemia
Hemangioma
*
*
Lupus erythematosus
Scarlet fever
*
*
213
782
289
405
403
392
352
794
184
372
216
289
397
827
538
794
184
159
294
305
306
253
585
307
573
587
Continued
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APPENDIX
Frequency
of Occurrence
Lesion or Condition
Submucosal hemorrhage
***
Amalgam tattoo
***
Mucocele
**
**
**
Eruption cyst
Salivary duct cyst
Hemangioma
**
**
Ranula
Kaposis sarcoma
*
*
*
*
*
Amalgam tattoo
***
**
**
**
*
*
*
*
Oral melanoacanthoma
Drug ingestion
Peutz-Jeghers syndrome
*
*
*
Addisons disease
Neurobromatosis type I
McCune-Albright
syndrome
Heavy metal poisoning
Melanotic
neuroectodermal tumor
of infancy
*
*
Page
754
801
15
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305
308
454
682
457
538
456
270
28
Chapter 11
692
386
433
308
13
379
316
308
382
433
380
317
753
841
529
636
313
533
Appendix
DIFFERENTIAL DIAGNOSIS
Frequency
of Occurrence
OF
Lesion or Condition
H. YELLOW LESIONS
***
Fordyce granules
**
**
**
Supercial abscess
Accessory lymphoid
aggregate
Lymphoepithelial cyst
**
*
Lipoma
Jaundice
Verruciform xanthoma
Pyostomatitis vegetans
ORAL
AND
MAXILLOFACIAL DISEASES
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572
37
523
821
372
850
Frequency of
Occurrence
Lesion or Condition
A. VESICULOEROSIVE AND ULCERATIVE LESIONS: ACUTE (SHORT DURATION AND SUDDEN ONSET)
***
Traumatic ulcer
Mild-to-moderate pain; history of local trauma
***
Aphthous stomatitis
Extremely painful; may be single or multiple; nonkeratinized
movable mucosa; often recurs
***
Recurrent herpes labialis
Vermilion and labial skin; begins as multiple vesicles; often
recurs
**
Primary herpetic
Fever and malaise; children and young adults; multiple vesicles;
gingivostomatitis
gingiva consistently affected
**
Necrotizing ulcerative
Painful destruction of gingival papillae; fetid odor; mostly in
gingivitis (NUG)
teenagers and young adults
**
Mucosal burns
Chemical or thermal
**
Recurrent intraoral herpes Gingiva or hard palate (except in immunocompromised); focal
simplex
cluster of vesicles and shallow ulcers
**
Allergic reactions
Example: Caused by topical medications or dental materials;
erythema and vesicles
**
Erythema multiforme
Predominantly in children and young adults; multiple blisters
and ulcers; often crusting, hemorrhagic lip lesions; may have
associated target skin lesions or involvement of ocular and
genital mucosa (Stevens-Johnson syndrome)
**
Herpangina
Especially in children; multiple small ulcers on soft palate and
tonsillar pillars
*
Varicella (chickenpox)
Associated with skin eruption; few oral vesicles and ulcers;
usually in children
*
Herpes zoster
Unilateral involvement along nerve distribution; usually middleaged and older adults; painful vesicles and ulcers
*
Hand-foot-and-mouth
Especially in children; multiple vesicles and ulcers; associated
disease
vesicles on hands and feet
*
Necrotizing
Usually posterior lateral hard palate; prior swelling may be
sialometaplasia
present; deep crater-like ulcer; may be only minimal pain
*
Anesthetic necrosis
Usually at site of palatal injection
*
Primary syphilis
Chancre at site of inoculation; usually painless with clean ulcer
bed
*
Behets syndrome
Aphthous-like ulcers; genital ulcers and ocular inammation
B. VESICULOEROSIVE AND ULCERATIVE LESIONS: CHRONIC (LONG DURATION)
***
Erosive lichen planus
Associated with white striae; usually in middle-aged and older
adults; most common on buccal mucosa and gingiva
(desquamative gingivitis)
**
Squamous cell carcinoma
Usually in middle-aged and older adults; usually indurated and
may have rolled border; may be painless
**
Mucous membrane
Most common in middle-aged and older women; most
pemphigoid
commonly presents as a desquamative gingivitis; may
involve ocular and genital mucosa
**
Traumatic granuloma
Solitary, non-healing ulcer
*
Lupus erythematosus
May have associated red and white change; usually with skin
involvement
*
Pemphigus vulgaris
Usually in middle-aged and older patients; multiple oral blisters
and ulcers usually precede skin lesions
*
Deep fungal infections
Examples: histoplasmosis, blastomycosis; may be painless
*
Tuberculosis
Associated mass may be present; may be painless
*
Sarcoidosis
May be associated with erythematous macules or plaques; may
be painless
924
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287
331
243
241
157
289
244
350
776
257
248
250
257
471
303
188
336
785
409
771
287
794
765
Chapter 6
195
338
Appendix
DIFFERENTIAL DIAGNOSIS
Frequency of
Occurrence
OF
Lesion or Condition
ORAL
AND
MAXILLOFACIAL DISEASES
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925
Page
761
850
345
602
201
190
13
362
512
364
391
409
268
509
372
422
366
367
751
803
Frequency of
Occurrence
Lesion or Condition
BUCCAL MUCOSA
Usually normal in color; along occlusal plane
May be yellow; soft to palpation
Typically pale blue; often exhibits cyclic swelling and rupturing
Usually buccinator node; movable submucosal mass
Examples: hemangioma, neurobroma
Tumor with rough, granular, irregular surface
Pleomorphic adenoma and mucoepidermoid carcinoma most
common
454
507
409
Chapter 12
457
Chapter 11
406
507
Chapter 11
457
459
Chapter 12
27
507
523
454
571
Chapter 12
409
Chapter 11
136
510
517
***
**
521
520
**
*
*
*
*
*
*
*
GINGIVA/ALVEOLAR MUCOSA
Fistula from nonvital tooth
Ill-tting denture
Usually red, ulcerated, easily bleeding; increased frequency in
pregnant women
Peripheral ossifying broma May be red or normal in color; may be ulcerated
Peripheral giant cell
Reddish purple; frequently ulcerated
granuloma
Fibroma
Usually normal in color
Squamous cell carcinoma
Tumor with rough, granular, irregular surface
Metastatic tumors
May be painful and destroy bone
Gingival cyst of the adult
Most common in mandibular bicuspid-cuspid region; may be
blue
Traumatic neuroma
Edentulous mandible in mental foramen area; often painful to
palpation
Kaposis sarcoma
Especially in AIDS patients; usually purple
Peripheral odontogenic
Example: peripheral ameloblastoma
tumors
Congenital epulis
Usually in females; especially anterior maxilla
Page
926
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507
409
563
692
524
270
710
537
Appendix
DIFFERENTIAL DIAGNOSIS
Frequency of
Occurrence
OF
ORAL
Lesion or Condition
AND
MAXILLOFACIAL DISEASES
Lingual thyroid
**
**
*
*
*
*
*
*
*
Kaposis sarcoma
Nasopalatine duct cyst
Other mesenchymal
tumors
Squamous cell carcinoma
Mucocele/salivary duct
cyst
Lymphoma
Melanocytic nevus/
melanoma
Necrotizing
sialometaplasia
Adenomatoid hyperplasia
of minor salivary glands
TONGUE
Usually normal in color; most common on margins of tongue
Tumor with rough, granular, irregular surface
Usually anterior ventral surface; usually bluish or clear color
Dome-shaped; usually on dorsum of tongue
Examples: lymphangioma, hemangioma, neurobroma, osseous
choristoma
Usually red, ulcerated, easily bleeding
Especially mucoepidermoid carcinoma and adenoid cystic
carcinoma
Usually posterior midline of dorsal surface; usually in women
HARD OR SOFT PALATE
Associated with nonvital tooth
Pedunculated hyperplastic growth beneath ill-tting denture
Especially pleomorphic adenoma, mucoepidermoid carcinoma,
adenoid cystic carcinoma, polymorphous low-grade
adenocarcinoma; may have bluish hue
Usually purple; may be multiple; usually associated with AIDS
Fluctuant swelling of anterior midline palate
Examples: broma, hemangioma, neurobroma
927
Page
533
Chapter 12
456
459
409
37
33
Chapter 11
Chapter 12
507
409
454
536
Chapter 12
517
Chapter 11
12
136
511
Chapter 11
270
28
Chapter 12
409
595
471
471
454
382, 433
Continued
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928
APPENDIX
Frequency of
Occurrence
Lesion or Condition
Scurvy
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Page
270
529
367
822
338
532
757
760
35
33
457
571
32
523
253
417
592
Chapter 11
461
36
197, 338
205
547
457
Chapter 12
156
163
166
587
345
826
Frequency of
Occurrence
Lesion or Condition
*
Orthokeratinized
odontogenic cyst
*
Ameloblastoma
Especially unicystic type
*
Ameloblastic broma
Usually in younger patients
*
Adenomatoid
Usually in anterior region of jaws; most often with maxillary
odontogenic tumor
canine; usually in teenagers
*
Calcifying odontogenic
Gorlin cyst
cyst
*
Carcinoma arising in
Mostly in older adults
dentigerous cyst
*
Intraosseous mucoMostly in posterior mandible
epidermoid carcinoma
*
Other odontogenic
Examples: calcifying epithelial odontogenic tumor, odontogenic
lesions
myxoma, central odontogenic broma
B. UNILOCULAR RADIOLUCENCIES: PERIAPICAL LOCATION
***
Periapical granuloma
Nonvital tooth
***
Periapical cyst
Nonvital tooth
**
Periapical cementoEspecially in black females; usually apical to mandibular
osseous dysplasia (early)
anteriors; teeth are vital
*
Periapical scar
Usually endodontically treated tooth with destruction of
cortical plate
*
Dentin dysplasia type I
Multiple periapical granulomas or cysts; shortened, malformed
roots
C. UNILOCULAR RADIOLUCENCIES: OTHER LOCATIONS
***
Developing tooth bud
Within alveolar bone
**
Lateral radicular cyst
Nonvital tooth; lateral canal
**
Nasopalatine duct cyst
Between and apical to maxillary central incisors; palatal
swelling may occur
**
Lateral periodontal cyst
Especially in mandibular bicuspid-cuspid region
**
Residual (periapical) cyst
Edentulous area
**
Odontogenic keratocyst
**
Central giant cell
Especially in anterior mandible
granuloma
**
Stafne bone defect
Angle of mandible below mandibular canal
*
Cemento-osseous
Early stage; usually in young adult and middle-aged black
dysplasia
women; usually in mandible
*
Central ossifying broma
Early-stage lesion
*
Ameloblastoma
Especially unicystic type
*
Other odontogenic cysts
Examples: ameloblastic broma, central odontogenic broma,
and tumors
calcifying odontogenic cyst
*
Langerhans cell
Histiocytosis X; usually in children or young adults
histiocytosis
Page
680
679
682
683
687
702
719
713
695
700
490
Chapter 15
127
130
641
130
108
132
28
692
132
683
626
24
640
646
702
Chapter 15
590
Continued
929
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930
APPENDIX
Frequency of
Occurrence
Lesion or Condition
*
*
*
*
*
Page
533
31
528
683
702
719
729
726
716
687
692
695
634
629
838
490
635
*
Ewings sarcoma
Almost always in children
*
Other primary bone
Examples: brosarcoma, lymphoma
malignancies
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626
540
127
619
141
299
631
669
296
604
711
660
664
667
Appendix
DIFFERENTIAL DIAGNOSIS
Frequency of
Occurrence
OF
Lesion or Condition
ORAL
AND
MAXILLOFACIAL DISEASES
*
Osteoma
Associated with bony surface mass
*
Enamel pearl
Furcation area of molar tooth
*
Osteoblastoma/osteoid
Late-stage lesions
osteoma/cementoblastoma
H. RADIOPACITIES: POORLY DEMARCATED BORDERS
**
Cemento-osseous
Late stage lesions; especially in middle-aged and older black
dysplasia
women; usually in mandible
**
Condensing osteitis
Usually at apex of nonvital tooth
**
BisphosphonateSclerosis of alveolar crestal bone; exposed necrotic bone
associated
osteonecrosis
**
Sclerosing osteomyelitis
May be painful
**
Fibrous dysplasia
Ground glass appearance; onset usually in younger patients
*
Pagets disease of bone
Cotton wool appearance; late-stage lesions; in older patients
*
Proliferative periostitis
Onion-skin cortical change; in younger patients; often
associated with nonvital tooth
931
Page
658
622
866
640
688
604
629
838
590
19
147
620
320
724
724
640
650
93
653
640
147
299
144
635
623
148
Continued
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932
APPENDIX
Frequency of
Occurrence
Lesion or Condition
**
BisphosphonateMultifocal sites of involvement; sclerosis of alveolar crestal
associated
bone; exposed necrotic bone
osteonecrosis
*
Pagets disease of bone
Cotton wool appearance; late-stage lesions; in older patients;
more common in maxilla
*
Gardner syndrome
Multiple osteomas; epidermoid cysts; gastrointestinal polyps
with high tendency toward malignant transformation;
hereditary
*
Polyostotic brous
Ground glass appearance; onset usually in younger patients;
dysplasia
may be associated with caf au lait skin pigmentation and
endocrine abnormalities (McCune-Albright syndrome)
*
Osteopetrosis
Hereditary; recessive form may be associated with secondary
osteomyelitis, visual and hearing impairment
J. MIXED RADIOLUCENT/RADIOPAQUE LESIONS: WELL-DEMARCATED BORDERS
***
Developing tooth
**
Cemento-osseous
Intermediate-stage lesions; especially in middle-aged black
dysplasia
women; usually in mandible
**
Odontoma
Compound or complex type; in younger patients; may prevent
eruption of teeth
*
Central ossifying broma
*
Ameloblastic
Usually in children
bro-odontoma
*
Adenomatoid
Usually in anterior region of jaws; most often with maxillary
odontogenic tumor
canine; usually in teenagers
*
Calcifying epithelial
Pindborg tumor; often associated with impacted tooth; may
odontogenic tumor
show driven snow opacities
*
Calcifying odontogenic
Gorlin cyst; may be associated with odontoma
cyst
*
Osteoblastoma/osteoid
Intermediate-stage lesion; usually in younger patients; often
osteoma
painful
*
Cementoblastoma
Intermediate-stage lesion; attached to tooth root
K. MIXED RADIOLUCENT/RADIOPAQUE LESIONS: POORLY DEMARCATED BORDERS
**
Osteomyelitis
With sequestrum formation or with sclerosing type; often
painful
**
Bisphosphonate-associated Exposed necrotic bone
osteonecrosis
*
Metastatic carcinoma
Especially prostate and breast carcinomas; may be painful
*
Osteosarcoma/
May be painful
chondrosarcoma
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Page
660
664
641
620
299
623
651
635
615
640
724
646
721
713
716
695
653
655
141
299
669
660
Appendix
DIFFERENTIAL DIAGNOSIS
Frequency of
Occurrence
OF
ORAL
Lesion or Condition
AND
MAXILLOFACIAL DISEASES
Myositis ossicans
933
Page
641
299
623
635
838
640
623
651
645
660
540
148
667
590
308
459
197
16
185
552
801
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Frequency of
Occurrence
Lesion or Condition
Page
77
1
651
618
77
1
741
Cone-shaped teeth
Stunted tooth development
750
58
*
Facial hemihyperplasia
Affected side only; nondental tissues also enlarged
*
Gigantism
Abnormally tall stature
84
84
83
38
831
D. MICRODONTIA
***
***
**
77
83
90
**
*
*
*
*
*
E. MALFORMED CROWN
***
Mesiodens and other
supernumeraries
**
Environmental enamel
hypoplasia
**
Peg-shaped lateral incisors
**
Dens invaginatus
**
**
*
*
*
*
Turners tooth
Fusion or gemination
Talon cusp
Dens evaginatus
Amelogenesis imperfecta
Dentinogenesis imperfecta
1
83
741
58
190
831
77
55
Cone-shaped teeth
Cone-shaped teeth; tendency toward pulpal death and
periapical pathosis
Infection or trauma to associated primary tooth
Double tooth
Extra cusp on lingual of anterior tooth
Extra cusp on occlusal of premolar tooth
Hereditary defect in enamel formation
Fracturing away of enamel due to hereditary defect in dentin
formation; gray-yellow opalescent teeth; calcied pulp
chambers
83
90
934
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56
84
87
88
99
106
Appendix
DIFFERENTIAL DIAGNOSIS
Frequency of
Occurrence
OF
ORAL
Lesion or Condition
MAXILLOFACIAL DISEASES
E. MALFORMED CROWNcontd
*
Regional odontodysplasia
*
Congenital syphilis
*
Vitamin Dresistant rickets
*
Renal osteodystrophy
*
Hypoparathyroidism
*
Pseudohypoparathyroidism
*
Epidermolysis bullosa
*
Radiotherapy during
childhood
F. ENAMEL LOSS AFTER TOOTH FORMATION
***
Caries
***
Trauma
***
Attrition
***
Abrasion
**
Erosion
*
Dentinogenesis imperfecta
*
AND
Amelogenesis imperfecta
Page
112
190
847
839
837
837
761
58
Fractured tooth
Physiologic loss of tooth structure
Pathologic loss of tooth structure
Chemical loss of tooth structure
Hereditary defect in dentin formation; poor junction between
enamel and dentin
Hereditary defect in enamel formation; especially hypocalcied
types
60
60
60
106
Black or brown
Brown or black
Brown, black, green, or orange
Yellow-brown
70
70
70
70
935
99
72
58
73
65
123
106
99
71
71
65
97
96
98
84
94
93
655
58
106
108
Continued
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936
APPENDIX
Frequency of
Occurrence
Lesion or Condition
Current orthodontic
therapy
Increased occlusal function
Systemic sclerosis
(scleroderma)
Sarcoma or carcinoma
inltration
Osteomalacia
Pagets disease of bone
Fibrous dysplasia
Page
65
94
106
112
847
845
108
126
123
123
106
108
135
Generalized widening
798
661, 669
838
Avulsed tooth
Premature alveolar bone loss
AIDS, leukemia, chemotherapy
173
272
842
141
583
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108
827
623
635
590
108
112
176
845
826
Index
Page numbers followed by f indicate gures; t, tables; b, boxes.
A
Abfraction, tooth wear by, 61-62, 64, 64f
Abrasion, tooth wear by, 61-62, 62f, 63f
Abscess(es)
gingival, 171
Munro
in erythema migrans, 781, 781f
in psoriasis, 794
periapical, 128, 135-138. See also
Periapical abscess.
periodontal
clinical and radiographic features
of, 170-171, 170f, 171f
treatment and prognosis of, 173
Abuse
human
classication of, 911-912
epidemiology of, 911-912, 912b
recognizing and reporting, dentistry
in, 913-914
signs and symptoms of, 912-913,
912f, 913f
methamphetamine, orofacial
complications of, 303, 303f
ABVD regimen, for Hodgkins
lymphoma, 595
Acantholysis
in Dariers disease, 751
in pemphigus vulgaris, 768, 768f
Acantholytic dyskeratosis, focal, 752-753
Acanthomatous ameloblastoma, 705706, 706f
Acanthosis
in leukoplakia, 394
in nicotine stomatitis, 403, 403f
Acanthosis nigricans, 803-804, 803f,
804f
Acanthotic form, of seborrheic keratosis,
375
Accessory cusps, 87-90
clinical features of, 87-89
cusp of Carabelli as, 87, 87f
dens evaginatus as, 88-89, 89f
prognosis for, 90
radiographic features of, 87-89
talon cusp as, 87-88, 88f
treatment of, 89-90
Accidents, mass fatality identication in,
dentistrys role in, 900
Acinic cell adenocarcinoma, 491-492,
491f, 492f
Ackermans tumor, 422-423
937
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938
Index
http://dentalebooks.com
Amyloidosis, 822-825
clinical features of, 823-824, 823f,
824f
diagnosis of, 825
hemodialysis-associated, 823-824
heredofamilial, 824
histopathologic features of, 824-825,
824f
macroglossia in, 11
myeloma-associated, 823
organ-limited, 823
primary, 823
secondary, 823
systemic, 823-824
treatment and prognosis of, 825
Amyotrophic lateral sclerosis (ALS), 873
Analgesics
opioid, for atypical facial pain, 866
for osteoarthritis, 878
Anaphylactic stomatitis, from systemic
drug administration, 347-348
Ancient neurilemomas, 527
Anemia, 576-578, 577b
aplastic, 580-581, 581f
Cooleys, 579
Fanconis, aplastic anemia in, 580
hemolytic, autoimmune, bilirubin
excess in, 821
iron-deciency, oral manifestations of,
827-828
Mediterranean, 579
myelophthisic, 588
sickle cell, 576-578, 578f
bilirubin excess in, 821
Anesthesia dolorosa, after surgery for
trigeminal neuralgia, 863
Anesthetic necrosis, 303-304, 304f
Aneurysmal bone cyst, 634-635, 634f,
635f
Angina, Ludwigs, 138-141. See also
Ludwigs angina.
Angina bullosa hemorrhagica, 774
Angiocentric immunoproliferative lesion,
602-604
Angiocentric T-cell lymphoma, 602-604
Angioedema, 356-358, 357f, 358f
Angiobromas
facial, in tuberous sclerosis, 758, 758f
nasopharyngeal, 544-546, 545f, 546f
Angiogenesis, in squamous cell
carcinoma, 419
Angiolipoma, 524
Angiomatosis
bacillary, in cat-scratch disease, 206
of bone, massive osteolysis related to,
622
encephalotrigeminal, 543-5444, 543f,
544f
Sturge-Weber, 543-544, 543f, 544f
Angiomyolipoma, in tuberous sclerosis,
758
Angiomyomas, 549-550, 550f
Angioneurotic edema, 356-358, 357f,
358f
Angiosarcoma, 556-557, 556f, 557f
Index
Angular cheilitis, 214t, 216, 217f
infectious causes of, 304
in iron-deciency anemia, 828
Anidulafungin, for candidiasis, 224
Ankyloglossia, 11-12, 11f
Ankylosis, 75-77, 76f
temporomandibular joint, 882
Anodontia, 77
in ectodermal dysplasia, 742
Anthropometry, 890
Antibiotics
for actinomycosis, 204-205
for Ludwigs angina, 140
for neuralgia-inducing cavitational
osteonecrosis, 868
for periapical abscess, 138
for periodontal abscess, 173
for periodontitis, 172
for sinusitis, 208
for suppurative osteomyelitis, 143
Antibody(ies)
cytoplasmic, basal cell, in allergic
mucosal reactions to systemic
drug administration, 349
monoclonal, in chronic lymphocytic
leukemia, 589
Anticonvulsants, for trigeminal neuralgia,
862
Antidepressants, tricyclic
for atypical facial pain, 866
for postherpetic neuralgia, 865
Antigens, bullous pemphigoid, 776
Antiinammatory agents, for migraine,
871
Antimalarials
discolorations of oral mucosa related
to, 317, 318
for rheumatoid arthritis, 880
Antineoplastic therapy
dental hypoplasia caused by, 58, 58f
noninfectious oral complications of,
294-299
clinical features of, 294-297, 295f,
296f, 297f
dermatitis as, 295
hemorrhage as, 294
loss of taste as
clinical features of, 296
treatment and prognosis of,
298-299
mucositis as
clinical features of, 294-295,
295f, 296f
treatment and prognosis of, 298
osteoradionecrosis as
clinical features of, 296-297, 297f
treatment and prognosis of, 299
treatment and prognosis of,
298-299
trismus as, 297
xerostomia as
clinical features of, 295-296, 296f
treatment and prognosis of, 298
Antirheumatid drugs, disease-modifying,
880
939
Antitoxin, for diphtheria, 187
Antivirals, early, for postherpetic
neuralgia, 864
Antoni A, in neurilemoma, 527, 527f
Antoni A tissue, in palisaded
encapsulated neuroma, 526
Antoni B, in neurilemoma, 527, 527f
Antral pseudocysts, 320, 321-323, 321f,
322f
Antrolith
in aspergillosis, 234
in chronic sinusitis, 208
Anxiety, lichen planus and, 783
APECED (autoimmune
polyendocrinopathycandidiasis-ectodermal
dystrophy) syndrome, 219,
220f
Apert syndrome, 43-45, 44f, 45f
Aphasia, before migraine, 871
Aphthosis
complex, 334
simple, 334
Aphthous stomatitis, recurrent, 331-336.
See also Recurrent aphthous
stomatitis.
Aphthous ulcerations
herpetiform, 333
clinical features of, 334, 334f
HIV-associated, 278, 278f
major, 333
clinical features of, 334, 334f
minor, 333
clinical features of, 333-334, 334f
Aphthouslike lesions, nonspecic, drugs
associated with, 348b
Apical periodontal cyst, 130-135. See also
Periapical cyst.
Apical periodontitis
acute, 135
chronic, 127-130. See also Periapical
granuloma.
Aplasia, salivary gland, 453-454, 454f
Aplastic anemia, 580-581, 581f
Appliances, for orofacial clefts, 4
ARC (AIDS-related complex), 266
Argyria, 315, 315f
Arsenic, systemic intoxication from,
314
clinical features of, 315
Arteriovenous malformations, 540
intrabony, 541f
treatment of, 543
Arteritis
cranial, 871-872
giant cell, 871-872
temporal, 871-872
Artery, caliber-persistent, 16, 16f
Arthralgia, in temporomandibular joint
dysfunction, 881
Arthritis
in Behets syndrome, 338
degenerative, 877-878
psoriatic, in psoriasis, 793
reactive, 781-782
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940
Index
http://dentalebooks.com
Index
Calcicationscontd
tramlilne, in skull in Sturge-Weber
angiomatosis, 543, 544f
Calcifying cystic odontogenic tumor,
695-697, 695f, 696f, 697f
Calcifying epithelial odontogenic tumors,
716-718, 716f, 717f
Calcifying broblastic granuloma,
521-523
Calcifying ghost cell odontogenic cyst,
695-697, 695f, 696f, 697f
Calcifying odontogenic cyst, 695-697,
695f, 696f, 697f
Calcinosis cutis, in CREST syndrome,
801, 802f
Calcitonin, for giant cell granuloma, 628
Calcium, for pseudohypoparathyroidism,
838
Caliber-persistent artery, 16, 16f
Canalicular adenoma, 484, 484f
Canals of Scarpa, 29
Cancrum oris, 158, 201-203
Candidal leukoplakia, 214t, 217-218,
219f, 389-390, 389f
Candidiasis, 213-224
atrophic, acute, 215
chronic multifocal, 214t, 216, 217f
clinical features of, 213-219
diagnosis of, 221
erythematous, 214t, 215-217, 215f,
216f, 217f, 218f
histopathologic features of, 219-220,
220f, 221f
HIV-associated, 267-268, 267f, 268f
hyperplastic
chronic, 214t, 217-218, 219f
squamous cell carcinoma and, 412
mucocutaneous, 214t, 218-219,
220f
oral, complicating diabetes, 844
prognosis of, 221-224
pseudomembranous, 213-215, 214f,
214t, 215f
treatment of, 221-224, 222-223t
amphotericin B in, 221, 222-223t
clotrimazole in, 221-222, 222-223t
echinocandins in, 224
uconazole in, 222-223t, 223-224
imidazole agents in, 221-223,
222-223t
iodoquinol in, 224
itraconazole in, 222-223t, 224
ketoconazole in, 222-223, 222-223t
nystatin in, 221, 222-223t
polyene agents in, 221, 222-223t
posaconazole in, 224
triazoles in, 222-223t, 223-224
Candidosis, 213. See also Candidiasis.
Canker sores, 331-336
Cannons disease, 743-744
Capdeponts teeth, 106-108
Capillary lymphangioma, 547
Capillary malformation, histopathologic
features of, 542, 542f
Capsaicin, for herpes zoster, 253
941
Capsaicin cream, topical, for trigeminal
neuralgia, 862
Carbamazepine, for trigeminal neuralgia,
862
Carcinoma(s)
adenoid cystic, 495-497, 495f, 496f
adenosquamous, 425
ameloblastic, 711-712, 711f, 712f
basosquamous, 431
lobular, 497-498
lung, metastatic, 564f
lymphoepithelial, 466
maxillary sinus, 426-427, 426f
Merkel cell, 432-433, 432f
mucoepidermoid, 487-491. See also
Mucoepidermoid carcinoma.
adenosquamous carcinoma as,
425
nasopharyngeal, 428-428, 428f, 429f
nonkeratinizing, nasopharyngeal, 429
odontogenic, 700-701, 700f, 701f
clear cell, 712-713, 712f, 713f
ghost cell, 697
self-healing, 406-408
snuff dippers, 401
spindle cell, 423-425, 424f
squamous, basaloid, 425-426, 426f
squamous cell, 409-421. See also
Squamous cell carcinoma.
oral, HIV-associated, 279, 279f
proliferative verrucous leukoplakia
transforming into, 392
smokeless tobacco-related, 400-401
terminal duct, 497-498
verrucous, 392, 422-423, 422f, 443f
Carcinoma ex papillary cystadenoma
lymphomatosum, 483
Carcinoma ex pleomorphic adenoma
clinical features of, 493, 493f
histopathologic features of, 494
treatment and prognosis of, 494
Carcinoma in situ, 394-395, 395f
ex mixed tumor, 494
Carcinosarcoma
ameloblastic, 723
clinical features of, 493
histopathologic features of, 494
treatment and prognosis of, 494-495
Cardiac rhabdomyoma, in tuberous
sclerosis, 758
Carotid artery syndrome, 24
Carotid body tumor, 535-536, 536f
Cartilage-hair syndrome, neutropenia in,
582
Cartilaginous choristomas, 552, 552f
Cartilaginous rests, in soft tissues, 318
Caspofungin, for candidiasis, 224
Cat-scratch disease, 205-207, 205f,
206f
Cauterization, chemical, for odontogenic
keratocysts, 686
Cavernous lymphangioma, 547, 548f
Cavernous sinus thrombosis, 138, 139
clinical features of, 139-140, 140f
treatment and prognosis of, 141
http://dentalebooks.com
Cavitations, in neuralgia-inducing
cavitational osteonecrosis, 868,
868f
Celiac sprue, iron-deciency anemia in,
828
Cellular blue nevus, 387
Cellulitis, 138-141
cavernous sinus thrombosis
complicating, 138-141. See also
Cavernous sinus thrombosis.
complicating periapical abscess,
135-136
Ludwigs angina complicating, 138141. See also Ludwigs angina.
Cemental dysplasia, 641, 641f, 642f
Cementifying broma, 646-648. See also
Ossifying broma.
Cemento-osseous dysplasias of jaws,
640-645
clinical and radiographic features of,
640-643, 641f, 642f, 643f
diagnosis of, 644
orid, 641-643, 642f, 643f
focal, 640, 641f
histopathologic features of, 643-644,
644f
periapical, 641, 641f, 642f
treatment and prognosis of, 644-645
Cemento-ossifying broma, 646-648. See
also Ossifying broma.
Cementoblastoma, 655-656, 655f, 656f,
731-732
Cementoma(s), 641, 641f, 642f
gigantiform, familial, 645-646, 646f
true, 655-656, 655f, 656f, 731-732
Cementum-like particles, in cementoosseous dysplasias of jaws, 644,
644f
Central giant cell granuloma, 626-629.
See also Giant cell granuloma.
Central mucoepidermoid carcinoma,
490-491
Central nervous system, in Behets
syndrome, 338
Central odontogenic broma, 727
Central osteoma, 650
Central papillary atrophy of tongue,
214t, 216
Cephalgia, histaminic, 868-869
Cerebral palsy, Riga-Fede disease in,
289
Cervical enamel extensions, 93, 94, 94f
Cervical lymphangiomas, 547-548
Cervical lymphoepithelial cyst, 36-37,
37f
Cervical ranula, 457, 457f
Cervical resorption, invasive, 68-69
Cervicofacial emphysema, 323-324,
323f
Chancre, in primary syphilis, 188,
189f
Charm needles/pins, implantation of,
311, 312, 313f
Cheek chewing, chronic, 285-287, 286f,
287f
942
Index
Cheilitis
actinic, 405-406
angular, 214t, 216, 217f
infectious causes of, 304
in iron-deciency anemia, 828
exfoliative, 304-305, 305f, 306f
lupus, in systemic lupus
erythematosus, 795
Cheilitis glandularis, 462-463, 463f
Cheilitis granulomatosa of Miescher,
342, 342f
Cheilocandidiasis, 216, 217f, 304
Cheilosis, actinic, 404, 405-406, 405f,
406f
lip vermilion carcinoma associated
with, 414
Chelating agents, for heavy metal
intoxication, 316
Chemical cauterization, for odontogenic
keratocysts, 686
Chemical injuries
anesthetic necrosis as, 303-304, 304f
from antineoplastic therapy, 294-299.
See also Antineoplastic therapy,
noninfections oral
complications of.
bisphosphonate-associated
osteonecrosis as, 299-303. See
also Bisphosphonate-associated
osteonecrosis (BON).
from methamphetamine abuse, 303,
303f
myospherulosis as, 324-325, 324f
of oral mucosa, 291-294
from aspirin, 292, 292f
clinical features of, 293, 293f
from endodontic materials, 292293, 293f
histopathologic features of, 293,
294f
from hydrogen peroxide, 292, 292f
from phenol, 292, 292f
from silver nitrate, 292
treatment and prognosis of,
293-294
smokers melanosis as, 316-317, 316f
systemic metallic intoxication as, 313316. See also Metallic
intoxication, systemic.
Chemical irritation, pulpitis from, 121
Chemodectoma, 535-536
Chemotherapy
for actinic keratoses in xeroderma
pigmentosum, 748
for Burkitts lymphoma, 602
dental hypoplasia caused by, 58
for Ewing sarcoma, 668
for Hodgkins lymphoma, 594-595
for leukemia, 589
for multiple myeloma, 605
for non-Hodgkins lymphoma, 598
noninfectious oral complications of,
294-295, 295f
for osteosarcoma of jaw, 663
for squamous cell carcinoma, 420-421
http://dentalebooks.com
Index
Complement pathway, activation of, in
angioedema, 357
Complex hemihyperplasia, 39
Complex odontomas, 724, 725f, 726f
Compound nevus
clinical features of, 383
histopathologic features of, 384, 384f
Compound odontomas, 724, 725f, 726f
Computed tomography, cone-beam, in
mass fatality incident
identication, 902
Computer software technology, in mass
fatality incident identication,
902-903
Concrescence
clinical features of, 85-86, 86f, 87f
denition of, 84
prognosis for, 87
treatment of, 87
Condensing osteitis, 147-148, 148f, 620
Condylar aplasia, 19
Condylar hyperplasia, 17-18, 18f
Condylar hypoplasia, 18-19
Condylar osteomas, 650
Condyle, bid, 19, 19f
Condyloma acuminatum, 366-367, 366f,
367f
Condylomata lata, in secondary syphilis,
189, 190f, 192f
Cone-beam computed tomography, in
mass
fatality
incident
identication,
902
Congenital agranulocytosis, 583
Congenital condylar hypoplasia, 18-19
Congenital epulis, 537-538, 537f, 538f,
539f
Congenital erythropoietic porphyria,
tooth discoloration in, 71, 71f
Congenital stulas, of lower lip, 5-6, 6f
Congenital granular cell lesion, 537-538,
537f, 538f, 539f
Congenital melanocytic nevus, 385-386,
385f
Congenital rubella syndrome (CRS), 261
Congenital syphilis, clinical features of,
190-191, 191f
Congenital toxoplasmosis, 236
Conical supernumerary teeth, 81
Conjunctival musoca, in paraneoplastic
pemphigus, 770, 770f
Consumption, 196
Contact stomatitis
allergic, 350-351
from articial cinnamon avoring,
352-354, 353f, 354f
lichenoid, from dental restorative
materials, 354-356, 355f, 356f
Cooleys anemia, 579
Cornea, in hereditary benign
intraepithelial dyskeratosis,
744
Coronal dens invaginatus, 90-91, 90f,
91f
Coronal dentin dysplasia, 110, 111f
Coronoid hyperplasia, 17
943
Corps ronds, in Dariers disease, 751
Corticosteroids
for Behets syndrome, 338
for chronic ulcerative colitis, 789
for giant cell granuloma, 628
for infectious mononucleosis, 254-255
for paraneoplastic pemphigus, 771
for pemphigus, 769
for recurrent aphthous stomatitis, 335,
335f
replacement, for Addisons disease,
842
systemic
for Bells palsy, 861
for mucous membrane pemphigoid,
775
for pyostomatitis vegetans, 850
for temporal arteritis, 872
topical
for erosive lichen planus, 787,
788f
for graft-versus-host disease lesions,
792
for mucous membrane pemphigoid,
774-775
for psoriasis, 794
Cotton roll burn, 293, 293f
Cowden syndrome, 760-761
Coxsackieviruses, 256-259
CP. See Cleft palate.
Cranial arteritis, 871-872
Craniectomy, in Apert syndrome, 44
Craniofacial dysostosis, 42-43, 43f
Craniofacial brous dysplasia, 636
CREST syndrome, 801-803
Cretinism, oral manifestations of,
834-835
Cribriform pattern in adenoid cystic
carcinoma, 496, 496f
Criminal disasters, mass fatality
identication in, dentistrys role
in, 900-901
Crocodile tears, 877
Crohns disease, oral manifestations of,
848-849, 848f, 849f
Crouzon syndrome, 42-43, 43f
Crowes sign, in neurobromatosis type
I, 530
CRS (congenital rubella syndrome), 261
Cryosurgery, for hereditary hemorrhagic
telangiectasia lesions, 755
Cryotherapy, liquid nitrogen, for verruca
vulgaris, 366
Cryptococcosis, 231-232, 232f
Cunnilingus, oral lesions from, 308,
308f
Cushings syndrome, oral manifestations
of, 840-841
Cusp(s)
accessory, 87-90. See also Accessory
cusps.
of Carabelli
clinical and radiographic features
of, 87, 87f
treatment and prognosis of, 89-90
http://dentalebooks.com
Cusp(s)contd
talon
clinical and radiographic features
of, 87-88, 88f
treatment and prognosis of, 90
Cutaneous horns
in actinic keratosis, 404
in verruca vulgaris, 364
Cutaneous sinus, from dental abscesses,
136, 137f
Cutaneous T-cell lymphoma, 598-600,
599f, 600f
Cutright lesion, 318-319
Cyclic neutropenia, 583-584, 584f
Cylindrical cell papilloma, 370-371
Cyst(s)
apical periodontal, 130-135. See also
Periapical cyst.
bone
aneurysmal, 634-635, 634f, 635f
simple, 631-634. See also Simple
bone cyst.
Stafne, 24-25, 26f
buccal bifurcation, 698-700, 699f
denition of, 25
developmental, 25-38
Bohns nodules as, 26-27
branchial cleft cyst as, 36 to 37, 37f
dermoid cyst as, 33-35, 34f, 35f
Epsteins pearls as, 26-27, 27f
follicular cysts of skin as, 32-33, 32f,
33f, 34f
globulomaxillary cyst as, 28
Klestadt cyst as, 27-28
median mandibular cyst as, 32
median palatal cyst as, 31-32, 31f
nasoalveolar cyst as, 27-28
nasolabial cyst as, 27-28, 27f, 28f
nasopalatine duct cyst as, 28-31,
29f, 30f, 31f
nasopalatine duct cysts as. See also
nasopalatine duct cysts.
oral lymphoepithelial cyst as, 37-38,
38f, 39f
palatal cysts of newborn as, 26-27,
27f
thyroglossal duct cyst as, 35-36, 36f
epidermoid, of skin in Gardner
syndrome, 652, 653f
eruption, 682, 682f, 683f
gingival
of adult, 692, 692f, 693f
of newborn, 691-692, 692f
of incisive papilla, 30, 30f
maxillary, postoperative, 320, 321
mucus duct, 457-459, 458f
mucus retention, 457-459, 458f
odontogenic, 678-701. See also
Odontogenic cysts.
periapical, 128, 130-135. See also
Periapical cyst.
primordial, 683, 683f
radicular, 130-135. See also Periapical
cyst.
retention, 321
944
Index
Cyst(s)contd
salivary duct, 457-459, 458f
subchondral, in osteoarthritis, 878
surgical ciliated, 320, 322f
traumatic ciliated, 320
Cystadenoma lymphomatosum,
papillary, 482-483, 482f, 483f
Cystic hygroma, 547, 548
Cystic lymphangioma, 547
Cytoid, in lichen planus, 786
Cytomegalovirus (CMV, HHV-5), 240,
255-256, 256f
Cytoplasmic vacuoles, in hereditary
mucoepithelial dysplasia, 749,
749f
D
D-penicillamine, for rheumatoid
arthritis, 880
Dapsone
for leprosy, 201
for recurrent aphthous stomatitis, 336
Dariers disease, 751-752, 751f, 752f
isolated, 752-753
Darrier-White disease, 751-752
Daubert v. Merrell Dow Pharmaceuticals
ruling, 904
Death
cause of, determining, 889
mechanism of, determining, 889
mode or manner of, determining, 889
undetermined, 889
Dedifferentiated chondrosarcoma, 666
Dedifferentiated liposarcomas, 554
Dedifferentiation, in spindle cell
carcinoma, 424
Deferoxamine, in thalassemia major
management, 580
Degenerative arthritis, 877-878
Degenerative joint disease, 877-878
Demastication, 61
Denigerous cyst, carcinoma arising in,
700, 700f
Denileukin diftitox, for mycosis
fungoides, 600
Dens evaginatus
clinical and radiographic features of,
88-89, 89f
treatment and prognosis of, 90
Dens in dente, 90-93
Dens invaginatus, 90-93
clinical and radiographic features of,
90-92, 90f, 91f, 92f
treatment and prognosis of, 92-93
Dense bone island, 620
Dental evaluation, in identication,
894-903
Dental uorosis, 58-60, 59f
Dental plaque, periodontitis and, 168
Dental restorative materials. See also
Amalgam, dental.
lichenoid contact stomatitis from,
354-356, 355f, 356f
tooth discoloration from, 72-73, 73f
Dental transposition, 81
http://dentalebooks.com
Dermatobroma, 514
Dermatosis, bullous, linear IgA, 774
Dermatosis papulosa nigra, in seborrheic
keratosis, 374, 374f
Dermoid cyst, 33-35, 34f, 35f
Desferrioxamine, in thalassemia major
management, 580
Desmoids, extraabdominal, 515
Desmoplasia, in squamous cell
carcinoma, 419
Desmoplastic ameloblastoma, 704,
705f
histopathologic features of, 706, 706f
Desmoplastic bromas, 515
of jaws, 658-660, 659f
Desmopressin, for factor VIII deciency,
574
Desmosomes, immunologic attack on,
in pemphigus vulgaris,
765-766
Desquamative gingivitis, 162-163
in chronic ulcerative colitis, 789
in erosive lichen planus, 785, 785f
in mucous membrane pemphigoid,
771, 772f
Developmental abnormalities, from
radiation therapy, 298
Diabetes mellitus
clinical features of, 843-844
complications of, 844
oral manifestations of, 842-845
treatment and prognosis of, 844-845
Differentiated nonkeratinizing
carcinoma, nasopharyngeal,
429
Diffuse hyperplastic oncocytosis, 481
Diffuse inltrative lymphocytosis
syndrome (DILS), HIVassociated, 275
Diffuse linear pulp calcications, 126,
127, 127f
Diffuse sclerosing osteomyelitis,
144-147
DiGeorge syndrome,
hypoparathyroidism in, 837
Digital photography, in mass fatality
incident identication, 902
Digital radiography, for dental record,
888
Dilaceration, 97-98, 97f, 98f
Dilated odontome, 91
DILS (diffuse inltrative lymphocytosis
syndrome), HIV-associated,
275
2,3-Dimercaptopropane-1 sulfonate
(DMPS), for heavy metal
intoxication, 316
2,3-Dimercaptopropanol (BAL), for
heavy metal intoxication, 316
2,3-Dimercaptosuccinic acid (DMSA),
for heavy metal intoxication,
316
Dimorphism, in Candida albicans, 213
Diphtheria, 186-188
Discoid lupus erythematosus, 795
Index
Discoloration of teeth, environmental,
70-74, 70b
extrinsic
from bacterial stains, 70
from chlorophyll-containing foods,
70-71
clinical features of, 70-71, 70b, 71f
from medications, 71
from tea/coffee use, 70
from tobacco use, 70, 71f
intrinsic, 71-73, 72f, 73f
prognosis for, 74
treatment of, 73-74
Disseminated aspergillosis, 234
Disseminated coccidioidomycosis, 230
Disseminated histoplasmosis, 225
Distodens, 81
Distomolar, 81
Distraction osteogenesis, for orofacial
clefts, 5
DLX3 gene mutation, in amelogenesis
imperfecta, 100
DMPS (2,3-dimercaptopropane-1
sulfonate), for heavy metal
intoxication, 316
DMSA (2,3-dimercaptosuccinic acid), for
heavy metal intoxication, 316
DNA, in identication, 893-894
Dopamine antagonists, for migraine, 871
Down syndrome, macroglossia in, 10f,
11
Drainage
of periapical abscess, 138
for suppurative osteomyelitis, 143
Drug(s)
administration of, systemic, allergic
mucosal reactions to, 347-350.
See also Allergic mucosal
reactions to systemic drug
administration.
associated with altered taste, 876t
causing agranulocytosis, 582-583
causing neutropenia, 582
discolorations of oral mucosa related
to, 317-318, 317f, 318f
erythema multiforme major from, 777
lichenoid reactions to, 782
lichen planus resembling, 785
pemphigus-like eruptions from, 766
producing xerostomia, 465t
for temporomandibular joint
dysfunction, 881b
tooth discoloration from
extrinsic, 71
intrinsic, 73, 73f
toxic epidermal necrolysis triggered
by, 777-778
Drug-related gingival hyperplasia, 163166, 163b, 163f, 164f, 165f
clinical features of, 164-165, 164f,
165f
histopathologic features of, 165
medications associated with, 163b
treatment and prognosis of, 165-166
Dry socket, 150-151
945
DSPP gene mutation, in dentinogenesis
imperfecta, 106
Ductal papillomas, 485-487, 486f, 487f
Duct(s)
nasopalatine, 28
development of, 28
thyroglossal, cysts of, 35-36, 36f
Dwarsm, pituitary, oral manifestations
of, 831
Dysgeusia and hypogeusia, 875-876,
875b, 876t
Dyskeratoma
follicular, 752-753
warty, 752-753, 752f
Dyskeratosis
acantholytic, focal, 752-753
intraepithelial, hereditary benign,
744-745, 744f, 745f
Dyskeratosis congenita, 746-747, 747f
aplastic anemia in, 580
neutropenia in, 582
Dyskeratosis follicularis, 751-752
isolated, 752-753
Dyspareunia, in mucous membrane
pemphigoid, 772
Dysphagia
in basaloid squamous carcinoma, 425
in Plummer-Vinson syndrome,
828-829
in progressive bulbar palsy, 873
sideropenic, oral manifestations of,
828-829
Dystrophic types, of epidermolysis
bullosa, 761-763, 762f, 762t,
763f
E
Eagle syndrome, 23-24, 24f
Early-onset periodontitis, 173
EBV. See Epstein-Barr virus.
Ecchymosis
in submucosal hemorrhage, 305
in thrombocytopenia, 585, 585f
Ecchymotic type, of Ehler-Danlos
syndrome, 757
Echinocandins, for candidiasis, 224
Echoviruses, 256-259
Ectodermal dysplasia, 741-743
Ectomesenchyme, odontogenic, tumors
of, 726-732
cementoblastoma as, 731-732
odontogenic broma as, 726-729. See
also Odontogenic bromas.
odontogenic myxoma as, 729-731,
730f, 731f
Ectopic enamel, 93-94
Eczema herpeticum, 244
Eczematous stage, of mycosis fungoides,
599
Edema
angioneurotic, 356-358, 357f, 358f
bone marrow, 866-868
EDTA (ethylenediaminetetraacetic acid),
for heavy metal intoxication,
316
http://dentalebooks.com
946
Index
http://dentalebooks.com
Esophageal webs
in Plummer-Vinson syndrome, 829
squamous cell carcinoma and, 411
Esthesioneuroblastoma, 555-556
Ethambutol, for tuberculosis, 198
Ethnicity, AIDS cases and, 265t, 266
Ethylenediaminetetraacetic acid (EDTA),
for heavy metal intoxication,
316
Ewing sarcoma, 667-669, 668f
Exanthema subitum, 240
Exfoliative cheilitis, 304-305, 305f, 306f
Exophthalmos, in Graves disease, 836,
836f
Exophytic osteoma, 650
Exophytic papilloma, 369
Exostoses, 19-23, 20f
buccal, 19-20, 20f
in osteoarthritis, 878
Expert witnesses, dentists as, 914
Extraabdominal desmoids, 515
Extraction, surgical, for
cementoblastoma, 655-656
Extramedullary plasmacytoma, 606
Extranodal NK/T-cell lymphoma,
nasal-type, 602-604, 603f
Extraosseous ameloblastoma, 710-711
Extraosseous form of calcifying
odontogenic cysts, 697
Eye(s)
in Behets syndrome, 338
in Graves disease, 836, 836f
in hereditary benign intraepithelial
dyskeratosis, 744, 745f
in hereditary mucoepithelial dysplasia,
749
in mucous membrane pemphigoid,
772, 772f
yellow color of, in jaundice, 822, 822f
F
Facial angiobromas, in tuberous
sclerosis, 758, 758f
Facial cleft
lateral, 2-3
oblique, 3
Facial dysesthesia, after surgery for
trigeminal neuralgia, 863
Facial hemiatrophy, progressive, 40-41,
41f
Facial pain
atypical, 861, 865-866, 865b
in Bells palsy, 859-861
in burning mouth syndrome, 873-875,
874b
in cluster headache, 868-869
in glossopharyngeal neuralgia,
863-864
in migraine, 870-871
in motor neuron disease, 873
in myasthenia gravis, 872-873, 872b
in neuralgia-inducing cavitational
osteonecrosis, 866-868, 867b,
867f, 868f
in osteoarthritis, 877-878
Index
Facial paincontd
in paroxysmal hemicrania, 869-870
in postherpetic neuralgia, 864-865
in temporal arteritis, 871-872
in trigeminal neuralgia, 861-863
Facies, masklike, in systemic sclerosis,
799, 799f
Facies leprosa, 200
Factor IX deciency, 573, 573t, 574f,
575
Factor VIII deciency, 573-575, 573t,
574f
Famciclovir
prophylactic, for
immunocompromised patients,
247
for recurrent herpes labialis, 247
Familial dysautonomia, Riga-Fede
disease in, 289
Familial gigantiform cementoma,
645-646, 646f
Familial white folded dysplasia, 743-744
Fanconis anemia, aplastic anemia in,
580
Fasciculation, in amyotrophic lateral
sclerosis, 873
Federation Dentaire International TwoDigit System for dental
numbering, 896, 896t
Fellatio, submucosal palatal hemorrhage
from, 307, 308f
Ferguson Smith type of
keratoacanthoma, 407
Fetal rhabdomyomas, 551-552
Fever blister, clinical features of,
243-244, 243f
Fever(s)
glandular, 253-255, 254f
San Joaquin Valley, 230-231
uveoparotid, associated with
sarcoidosis, 339
Fibrinolytic alveolitis, 150-151
Fibro-odontoma, ameloblastic, 721-722,
721f, 722f, 724
Fibro-odontosarcomas, ameloblastic,
723
Fibro-osseous lesions of jaws, 635-670
cemento-osseous dysplasias as, 640645. See also Cemento-osseous
dysplasias of jaws.
cementoblastoma as, 655-656
familial gigantiform cementoma as,
645-646
brous dysplasia as, 635-640. See also
Fibrous dysplasia, of jaws.
osseous dysplasia as, 640-645. See also
Cemento-osseous dysplasias of
jaws.
ossifying broma as, 646-648, 647f,
648f. See also Ossifying broma.
true cementoma as, 655-656
Fibroameloblastic dentinoma,
peripheral, 727
Fibroblastic granuloma, calcifying,
521-523
947
Fibroblasts, cellular proliferation of, in
desmoplastic broma, 659,
659f
Fibrodentin, 124
Fibrodentinoma, ameloblastic, 722
Fibroepithelial polyp, 511, 512f
Fibrolipoma, 523-524
Fibroma(s), 507-510, 508f, 509f
ameloblastic, 719-720, 720f, 722
cementifying, 646-648. See also
Ossifying broma.
cemento-ossifying, 646-648. See also
Ossifying broma.
chondromyxoid, of jaws, 657, 657f
denture, leaike, 511
desmoplastic, 515
of jaws, 658-660, 659f
giant cell, 509-510, 509f, 510f
odontogenic, 726-729. See also
Odontogenic broma(s).
ossifying, 646-648, 647f, 648f. See also
Ossifying broma.
peripheral, 521-523, 521f, 522f
peripheral, with calcication, 521-523
Fibromatosis, 515, 515f
gingival, 166-168, 166f, 167f, 168f
Fibromatosis gingivae, 166-168, 166f,
167f, 168f
Fibromyxomas, 731
Fibrosarcoma(s), 553, 553f
ameloblastic, 722-723, 723f
postirradiation, 664
Fibrosis
nodular subepidermal, 514
submucous, oral, 401-403, 402f
Fibrous dysplasia
of dentin, 110
of jaws, 635-640
clinical and radiographic features
of, 636-639, 636f, 637f, 638f
histopathologic features of, 639,
639f
monostotic, 636, 636f, 637f, 638f
polyostotic, 636-637, 638f, 639
treatment and prognosis of,
639-640
Fibrous histiocytoma, 514-515, 514f
malignant, 553-554, 554f
Fibrous hyperplasia, from cunnilingus,
308, 308f
Fibrous nodule, 507-509
Fibrous periapical scars, 130, 130f
Fibroxanthoma, 514
Fingerprinting, identication by,
890-891
Fissured tongue, 13, 13f, 780, 780f
Fistula(s)
congenital, of lower lip, 5-6, 6f
soft palate, lateral, 16-17, 17f
Fixed drug eruptions, medications
implicated in, 348b
Flat torus, 21
Fluconazole
for candidiasis, 222-223t, 223-224
for cryptococcosis, 232
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948
Index
Fusion
clinical features of, 84-85, 85f, 86f
denition of, 84
prognosis for, 86-87
treatment of, 86-87
G
Galvanic lesions, 354-355
Ganciclovir, for cytomegalovirus
infections, 256
Gangrene, orofacial, 201-203
Gangrenous stomatitis, 201-203
Gardner syndrome, 32, 651-653, 652f,
653f
Garment nevus, 385
Gaucher disease, 819-820
Riga-Fede disease in, 289
Gemination
bilateral, 84f
clinical features of, 84-85, 84f, 85f
denition of, 84
prognosis for, 86-87
treatment of, 86-87
Generalized pattern, of hypoplastic
amelogenesis imperfecta, 101,
101f
Generalized thin hypoplastic
amelogenesis imperfecta, 102
Generalized Wegeners granulomatosis,
345
Genetic comparison, in identication,
893-894
Genetic factors, in orofacial cleft
development, 2, 2b
Genital lesions, in Behets syndrome,
337
Geographic tongue, 779-781
German measles, 261-263
Germinal centers, in lymphoid
hyperplasia, 572
Ghost cell tumors
dentinogenic, 695-697, 695f, 696f,
697f
epithelial odontogenic, 695
Ghost cells, eosinophilic, in calcifying
odontogenic cyst, 696-6976f,
697f
Ghost teeth, 112, 113f
Giant cell arteritis, 871-872
Giant cell broma, 509-510, 509f, 510f
Giant cell granuloma
central odontogenic broma
associated with, 727, 728f
clinical and radiographic features of,
626-628, 627f
histopathologic features of, 628,
628f
of jaws in hyperparathyroidism, 839840, 840f
peripheral, 520-521, 520f, 521f
treatment and prognosis of, 628-629
Giant-cell hyaline angiopathy, in
periapical cyst, 133
Giant cell lesion, 626-629
Giant cell tumors, 626-629
Giant cells
in cementoblastoma, 655, 656f
in cherubism, 630, 632f
in giant cell granuloma, 628, 628f
multinucleated, in aneurysmal bone
cyst, 635, 635f
Warthin-Finkedey, in rubeola, 261,
261f
Giant hairy nevus, 385
Gigantiform cementoma, familial,
645-646, 646f
Gigantism, oral manifestations of,
831-832
Gilbert syndrome, jaundice in, 822
Gingival cyst
of adult, 692, 692f, 693f
of newborn, 691-692, 692f
Gingival erythema, linear, HIVassociated, 272-273, 273f
Gingival bromatosis, 166-168, 166f,
167f, 168f
Gingival granular cell tumor of newborn,
537
Gingival hemorrhage, green tooth
staining secondary to, 71
Gingivectomy, for gingival bromatosis,
168
Gingivitis, 154-163
chronic hyperplastic, 156, 156f
clinical features of, 154-156, 155f,
156f
desquamative, 162-163
in chronic ulcerative colitis, 789
in erosive lichen planus, 785, 785f
in mucous membrane pemphigoid,
771, 772f
foreign body, 160-161, 161f, 162f
lichenoid, 782
granulomatous, 160-162, 161f, 162f
histopathologic features of, 157, 157f
local factors associated with, 155,
155b
marginal, 156, 156f
necrotizing ulcerative. See Necrotizing
ulcerative gingivitis (NUG).
papillary, 156
plasma cell, 159-160, 159f, 160g
puberty, 154, 155f
scorbutic, 826, 827f
strawberry, 345, 345f
systemic factors associated with, 155,
155b
treatment and prognosis of, 157
types of, 155b
Gingivostomatitis
atypical, 159-160
herpetic, acute, clinical features of,
242, 242f, 243f
herpetic acute, treatment and
prognosis of, 246-247
necrotizing, 158
Glands, salivary. See Salivary glands.
Glandular epithelium, in pleomorphic
adenomas, 479
Glandular fever, 253-255, 254f
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Index
Granuloma(s)contd
broblastic, calcifyiing, 521-523
giant cell, 626-629. See also Giant cell
granuloma.
central odontogenic broma
associated with, 727, 728f
peripheral, 520-521, 520f, 521f
histiocytic, atypical, 287, 289f
Langerhans cell, 590-592, 591f, 592f
lethal, midline, 602-604
periapical, 127-130. See also Periapical
granuloma.
pulse, in periapical cyst, 133
pyogenic, 517-519, 518f, 519f
gingivitis with, 156, 156f
traumatic, 287, 288f
Granulomatosis
Langerhans cell, 590-592, 591f, 592f
lymphomatoid, 602-603
orofacial, 341-345. See also Orofacial
granulomatosis.
in Crohns disease, 848-849
Wegeners, 345-347, 345f, 346f
Granulomatous gingivitis, 160-162,
161f, 162f
Graves disease, 835-836
Growth hormone
production of
diminished, in pituitary dwarsm,
831
increased
in acromegaly, 832
in gigantism, 831-832
replacement therapy with, for pituitary
dwarsm, 831
Guillain-Barre syndrome, facial
weakness in, 860
Gum boil, complicating periapical
abscess, 136
Gumma, in tertiary syphilis, 190
Gustatory lacrimation syndrome, 877
Gustatory sweating and ushing,
876-877
H
HAART (highly active antiretroviral
therapy)
for cytomegalovirus infections in AIDS
patients, 256
for HIV infection, 280, 281b
for Kaposis sarcoma in HIV infection,
271
Hailey-Hailey disease, 766
Haim-Munk syndrome, 176
Hairy leukoplakia, oral, 14
Epstein-Barr virus causing, 253
in HIV infection, 268-270, 269f
Hairy tongue, 13-15, 14f, 15f
Halo nevus, 386, 386f
Hamartoma(s)
epithelial, odontogenic, 727
multiple, gingival bromatosis in, 166
odontomas as, 724
Hamazaki-Wesenberg bodies, in
sarcoidosis, 340
949
Hammans crunch, in
pneumomediastinum, 324
Hand-foot-and-mouth disease, clinical
features of, 257-258, 258f
Hand-Schller-Christian disease,
histiocytosis in, 590
Hansen disease, 198-201. See also
Leprosy.
Hashimotos thyroiditis, 834
Headache
alarm clock, 869
cluster, 868-869
migraine, 870-871, 870t
Hecks disease, 367-368, 367f, 368f
Heerfordts syndrome, associated with
sarcoidosis, 339
Hemangioendothelioma, 556
kaposiform, 540
Hemangioma(s)
histopathologic features of, 541-542,
541f, 542f
of infancy, clinical and radiographic
features of, 539-540, 540f
lobular capillary, 518
in multiple hamartoma syndrome,
760
sclerosing, 514
strawberry, 539-540, 540f
treatment and prognosis of, 542-543
tufted, 540
Hemangiopericytoma-like tumor,
546-547
Hemangiopericytomasolitary brous
tumor (HPC-SFT), 546-547,
546f
Hematoma(s)
eruption, 682, 682f
in submucosal hemorrhage, 305, 307f
in thrombocytopenia, 585, 585f
Hematopoiesis, cyclic, 583-584, 584f
Hemiageusia, 875
Hemicrania, paroxysmal, 869-870
Hemicrania continua, 869
Hemidesmosomal type, of epidermolysis
bullosa, 761
Hemidesmosomes, antibodies binding to,
in bullous pemphigoid, 776
Hemifacial atrophy, progressive, 40-41,
41f
Hemifacial hyperplasia, 18, 39
macroglossia in, 11
Hemifacial microsomia, 19
in temporomandibular joint ankylosis,
882
Hemihypertrophy, 38-40, 39b, 40f
Hemiphyperplasia, 38-40, 39b, 40f
Hemochromatosis, from blood
transfusions for thalassemia
major, 580
Hemodialysis, amyloidosis associated
with, 823-824
Hemoglobin H (HbH) disease, 580
Hemoglobinopathies, 576
Hemolytic anemia, autoimmune,
bilirubin excess in, 821
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950
Index
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Hutchinsons incisors, 60
in congenital syphilis, 191, 191f
Hutchinsons triad, in congenital syphilis,
190
Hyaline, in lichen planus, 786
Hyaline bodies, in periapical cyst, 133,
134f
Hyalinosis cutis et mucosae, oral
manifestations of, 820-821
Hydrocortisone cream, for exfoliative
cheilitis, 305, 306f
Hydrogen peroxide, mucosal burns from,
292, 292f
Hydrop fetalis, 580
Hydropic degeneration, of epithelium, in
lichen planus, 786, 786f
Hydroxychloroquine therapy, for chronic
ulcerative colitis, 789-790
Hyperbaric oxygen therapy, for Bells
palsy, 861
Hyperbilirubinemia, tooth discoloration
associated with, 71-72, 72f
Hypercarotenemia, jaundice confused
with, 822
Hypercementosis, 96-97, 96b, 96f, 97f
Hyperchromatic nuclei, in squamous cell
carcinoma, 419
Hypercortisolism, oral manifestations of,
840-841
Hyperdontia, 77
clinical features of, 80-81, 80f, 81f
syndromes associated with, 78b
Hyperelasticity of skin, in Ehlers-Danlos
syndromes, 756, 756f
Hyperglycemia, in diabetes mellitus,
842
Hyperkeratosis
in leukoplakia, 394
in nicotine stomatitis, 403, 403f
Hyperkeratotic form, of seborrheic
keratosis, 375
Hypermobility type, of Ehlers-Danlos
syndrome, 756t, 757
Hyperorthokeratosis, in leukoplakia,
394, 394f
Hyperparakeratosis, in leukoplakia, 394
Hyperparathyroidism, 838-840
Hyperpigmentation
in Addisons disease, 842, 842f
HIV-associated, 274
Hyperplastic candidiasis, chronic, 214t,
217-218, 219f
Hyperplastic gingivitis, chronic, 156,
156f
Hypersensitivity, to dental resins, 355
Hypertaurodontism, 95, 95f
Hyperthyroidism, oral manifestations of,
835-836
Hypertrichosis, in congenital
melanocytic nevus, 385, 385f
Hypoadrenocorticism, 841-842
Hypocalcied amelogenesis imperfecta,
103-104, 104f
Hypodactylia, in oromandibular-limb
hypergenesis syndromes, 9
Index
Hypodontia, 77
clinical features of, 79-80, 79f
in ectodermal dysplasia, 742
in incontinentia pigmenti, 750, 750f
prognosis for, 82
syndromes associated with, 78b
treatment of, 82
Hypoglossia, 9
Hypohidrotic ectodermal dysplasia,
741-742
Hypomaturation amelogenesis
imperfecta, 102-103, 104f
Hypomaturation/hypoplastic
amelogenesis imperfecta, 104105, 105f
Hypomelia, in oromandibular-limb
hypergenesis syndromes, 9
Hypoparathyroidism, oral manifestations
of, 837, 837f
Hypophosphatasia, oral manifestations
of, 845-847, 846f
Hypoplastic amelogenesis imperfecta,
101-102, 101f, 102f, 103f
Hypotaurodontism, 95, 95f
Hypothermia, in hypothyroidism, 834
Hypothyroidism
macroglossia in, 11
oral manifestations of, 834-835, 834f,
835f
I
Icterus, oral manifestations of, 821-822
Identication, forensic
dental, 894-903, 895f, 896t
antemortem record examination in,
898-899
comparison of antemortem and
postmortem records and
written conclusions in, 899,
899f
guidelines for, 897-899
postmortem examination in, 897898, 898f
exclusion of evidence for, 890
by ngerprinting, 890-891
in forensic dentistry, 889-903
instrument kit for, 897b
insufcient evidence for, 890
in mass fatality incident
dentistrys role in, 899-903
technologic aides in, 90-1-903
by personal recognition, 890, 890f
by physical anthropologic examination
of bones and teeth, 891-893,
891t, 892f
positive, criteria for, 889
presumptive, criteria for, 889-890
by serologic and genetic comparison,
893-894
Idiopathic bone cavity, 631-634. See also
Simple bone cyst.
Idiopathic facial pain, 865-866
Idiopathic midline destructive disease,
602-604
Idiopathic osteosclerosis, 620-622, 621f
951
Idiopathic thrombocytopenic purpura
(ITP), 585-586
Imidazole agents, for candidiasis, 221223, 222-223t
Immune-mediated dermatologic
diseases, 764-804. See also
Dermatologic diseases ,
immune-mediated.
Immune thrombocytopenic purpura
(ITP), 585-586
Immunobullous diseases, 764
Immunocompromised hosts
cytomegalovirus infections in, 255
HSV infections in
recurrent, clinical features of, 244245, 245f
treatment of, 247
Immunodeciency-associated Burkitts
lymphoma, 601
Immunouorescence
direct, 764, 764f
indirect, 764f, 765
Immunologic disease
Behets syndrome as, 336-338, 337f
orofacial granulomatosis as, 341-345.
See also Orofacial
granulomatosis.
recurrent aphthous stomatitis as. See
also Recurrent aphthous
stomatitis.
recurrent aphthous stomatitis as,
331-336
sarcoidosis as, 338-341. See also
Sarcoidosis.
Wegeners granulomatosis as,
345-347
Immunoprecipitation studies, in
paraneoplastic pemphigus
diagnosis, 770
Immunoproliferative lesion,
angiocentric, 602-604
Immunosuppression
Kaposis sarcoma associated with,
558
squamous cell carcinoma and, 412
Immunosuppressive therapy
for mucous membrane pemphigoid,
775
for paraneoplastic pemphigus, 771
Impaction, 74-75, 74f, 75f
Impetiginized dermatitis, 181
Impetigo, 181-182, 182f
staphylococcal, 181-182
Impetigo contagiosa, 181
Incisive canal cyst, 28-31. See also
Nasopalatine duct cyst.
Incisive canals, 28
Incisive papilla, cysts of, 30, 30f
Incisor(s)
Hutchinsons, 60
in congenital syphilis, 191, 191f
shovel-shaped
clinical and radiographic features
of, 89, 89f
treatment and prognosis of, 90
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952
Index
K
Kabuki syndrome, 6
Kallikrein-4, disorders of, in
amelogenesis imperfecta, 100
Kaposiform hemangioendothelioma, 540
Kaposis sarcoma herpesvirus (KSHV),
240-241
Kaposis sarcoma (KS), 240-241, 557559, 557f, 558f
in HIV infection, 270-271, 270f, 271f
Kaposis varicelliform eruption, 244
Kasabach-Merritt phenomenon,
hemangiomas associated with,
540
Keratin horn
in actinic keratosis, 404
in verruca vulgaris, 364
Keratin pearls, in squamous cell
carcinoma, 419
Keratinizing squamous cell carcinoma,
nasopharyngeal, 429
Keratinocytes, eosinophilic, necrotic, in
erythema multiforme, 778,
779f
Keratoacanthoma, 406-408, 407f, 408f
Keratocarcinoma, 406-408
Keratoconjunctivitis sicca, in Sjgren
syndrome, 467, 468
Keratocyst, odontogenic, 683-687. See
also Odontogenic keratocyst.
Keratocystic odontogenic tumor, 683
Keratoderma palmoplantar of UnnaThost syndrome, 176
Keratohyaline granules, in
orthokeratinized odontogenic
cyst, 687, 688f
Keratosis follicularis, 751-752
Keratosis(es)
acral, in multiple hamartoma
syndrome, 760
actinic, 404-405, 404f, 405f
arsenical, 315
frictional, 390, 390f
sanguinaria-associated, 389, 389f
seborrheic, 374-375, 374f, 375f
smokeless tobacco, 398-401. See also
Smokeless tobacco keratosis.
spit tobacco, 398-401. See also
Smokeless tobacco keratosis.
tobacco pouch, 398-401. See also
Smokeless tobacco keratosis.
with verrucous carcinoma, 422
Kerotosis follicularis, similarity of warty
dyskeratoma to, 752
Ketoconazole, for candidiasis, 222-223,
222-223t
Kidney
carcinoma of, metastatic to tongue,
563f
failure of, uremic stomatitis in, 851,
851f
stones in, in hyperparathyroidism, 838
Kissing disease, 253-255, 254f
Kleeblattschdel deformity, in Crouzon
syndrome, 43
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Index
Leonine facies, in multibacillary leprosy,
199
Leontiasis ossea, in Pagets disease of
bone, 624
Lepromatous leprosy, 199, 199f, 200f,
201f
tooth discoloration in, 72
Leprosy, 198-201
clinical features of, 199-200, 199f
diagnosis of, 201
histopathologic features of, 200-201,
200f, 201f
lepromatous, 199, 199f, 200f, 201f
tooth discoloration in, 72
multibacillary, 199, 199f, 200f,
201f
paucibacillary, 199, 200f
treatment and prognosis of, 201
tuberculoid, 199
Lesch-Nyhan syndrome
Riga-Fede disease in, 289
self-inicted bites in, 903
Leser-Trlat sign, in seborrheic keratosis,
375
Letterer-Siwe disease, histiocytosis in,
590
Leukemia, 587-590
acute lymphoblastic
in children, prognosis of, 589
clinical features of, 588
acute myeloid, 587
clinical features of, 587-588
treatment and prognosis of, 590
chronic lymphocytic
clinical features of, 588
paraneoplastic pemphigus
associated with, 769
prognosis of, 590
treatment of, 589
chronic myeloid, 587
clinical features of, 587-588
treatment and prognosis of, 590
diagnosis of, 589
genetic disorders associated with,
587
histopathologic features of, 588
treatment and prognosis of, 589-590
Leukoedema, 8-9, 8f, 9f
Leukokeratosis, 388-397. See also
Leukoplakia.
Leukoplakia, 388-397
alcohol and, 389
candidal, 214t, 217-218, 219f, 389390, 389f
causes of, 388-390
clinical features of, 390-393, 390f,
391f, 392f, 393f
granular, 391, 391f, 392f, 393f
histopathologic features of, 394-396,
394f, 395f
homogeneous, 391, 391f
incidence of, 388
malignant transformation in, 394-396
risk of, 396-397
microorganisms and, 389-390, 389f
953
Leukoplakiacontd
oral hairy, 14
Epstein-Barr virus causing, 253
in HIV infection, 268-270, 269f
in oral submucous brosis, 402
prevalence of, 388
proliferative verrucous, 391-392, 392f
sanguinaria and, 389, 389f
speckled, 392, 393f
squamous cell carcinoma and, 410
thick, 391, 391f, 393f
thin, 391, 391f, 393f
tobacco and, 388-389
trauma and, 390, 390f
treatment and prognosis of, 396-397
ultraviolet radiation and, 389
verrucous, 391, 392f, 393f
in verrucous carcinoma, 422
Lhermitte-Duclos disease, multiple
hamartoma syndrome and,
760
Libman-Sachs endocarditis, in systemic
lupus erythematosus, 795
Lichen planus, 766t, 782-788
bullous, 785
clinical features of, 783-785, 783f,
784f, 785f
diagnosis of, 787
erosive
clinical features of, 785, 785f
desquamative gingivitis in, 771
diagnosis of, 787
treatment and prognosis of,
787-788
histopathologic features of, 785-787,
786f
malignant transformation of, 788
reticular
clinical features of, 783, 784f, 785
diagnosis of, 787, 787f
treatment and prognosis of, 787
treatment and prognosis of, 787-788
Lichenoid amalgam reaction, lichen
planus resembling, 785
Lichenoid contact stomatitis, from dental
restorative materials, 354-356,
355f, 356f
Lichenoid dermatitis, 782
Lichenoid drug reaction, lichen planus
resembling, 785
Lichenoid eruptions, medications
implicated in, 348b
Lichenoid foreign body gingivitis, 782
Lichenoid lesions, betel quid, 402
Lichenoid mucositis, 782
Lie bumps, 330-331
Liesegang ring calcications, in
calcifying epithelial
odontogenic tumors, 717,
717f
Limited Wegeners granulomatosis, 345
Linea alba, 285
Linear gingival erythema, HIVassociated, 272-273, 273f
Linear IgA bullous dermatosis, 774
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954
Index
Lymphoproliferative disorder,
posttransplant, 596
Lyon hypothesis, 742
M
Macrodontia, 83-84
Macroglossia, 9, 9f
causes of, 10b
in hemihyperplasia, 39, 40f
Macule, oral melanotic, 379-380, 380f
Maffucci syndrome, 656
Magrognathia, 83
Major aphthous ulcerations, 333
clinical features of, 334, 334f
Malformation syndromes, associated
with hemihyperplasia, 39b
Malignant acanthosis nigricans, 803
Malignant ameloblastomas, 711-712
Malignant brous histiocytoma, 553554, 554f
Malignant lymphoepithelial lesion, 466
Malignant melanoma, 433-439. See also
Melanoma.
Malignant mixed tumors, 491-495
carcinoma ex pleomorphic adenoma
as
clinical features of, 493, 493f
histopathologic features of, 494,
494f
treatment and prognosis of, 494
carcinosarcoma as
clinical features of, 493
histopathologic features of, 494
treatment and prognosis of,
494-495
metastasizing
clinical features of, 493-494
histopathologic features of, 494
treatment and prognosis of, 495
Malignant osteopetrosis, 616
Malignant peripheral nerve sheath
tumor, 555
complicating neurobromatosis type I,
531, 531f
Malignant schwannoma, 555
complicating neurobromatosis type I,
531, 531f
Malignant transformation
of keratoacanthoma, 408
of leukoplakia, 394-396
risk of, 396-397
of lichen planus, 788
of oral submucous brosis, 402-403
Malignant transformation potential,
denition of, 388b
Malignant Triton tumor, 555
Malignant Warthin tumor, 483
MALT lymphomas, epimyoepithelial
islands in, 466
Mandible
in cherubism, 629, 630f, 631f
enlarged, in acromegaly, 832, 833f
Mandibular cyst, median, 32
Mandibular dysostosis, 45-46, 45f
Mandibulofacial dysostosis, 19
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Index
Melanomacontd
histopathologic features of, 436-437,
436f, 437f
incidence of, 433
juvenile, benign, 386
lentigo maligna, clinical features of,
435, 435f
metastatic to gingiva, 563f
nodular
clinical features of, 435
histopathologic features of, 436437, 437f
oral, 435, 435f, 436f
radial growth phase of, 434
risk factors for, 433
sites of, 433-434
staging of, 437, 438t
supercial spreading
clinical features of, 434-435, 434f
histopathologic features of, 436,
436f
treatment and prognosis of, 437-439
vertical growth phase of, 434
Melanosis
focal, 379-380, 380f
smokers, 316-317, 316f
Melanotic neuroectodermal tumor of
infancy, 533-535, 534f
Melanotic progonoma, 533
Melasma, 378-379, 379f
Meleda disease, 176
Melkersson-Rosenthal syndrome, 342,
342f, 343f
tongue in, 13
Membranous basal cell adenoma, 485
MEN (multiple endocrine neoplasia)
type 2A, 532
MEN (multiple endocrine neoplasia)
type 2B, 532-533, 532f, 533f
Meningoencephalitis, in mumps, 264
Meniscectomy, for synovial
chondromatosis, 658
Menorrhagia, iron deciency from, 827
Mental retardation, in Apert syndrome,
44
Mercury
in dental amalagam, lichenoid contact
stomatitis from, 354-355
systemic intoxication from, 313-314
clinical features of, 314-315
Merkel cell carcinoma, 432-433, 432f
Mesenchymal chondrosarcomas, 666
of jaw, 666-667, 667f
Mesiodens, 80f, 81
Mesotaurodontism, 95, 95f
Metallic intoxication, systemic, 313-316
arsenic, 314
clinical features of, 315
bismuth, 314
clinical features of, 315
clinical features of, 314-316
gold, 314
clinical features of, 315-316
lead, 313
clinical features of, 314
955
Metallic intoxication, systemiccontd
mercury, 313-314
clinical features of, 314-315
silver, 314
clinical features of, 315, 315f
treatment and prognosis of, 316
Metamorphosis, calcic, 123, 125f
Metastases
to jaws, 669-670, 669f, 670f
to oral soft tissues, 563-564, 563f,
564f
Metastasizing mixed tumor
clinical features of, 493-494
histopathologic features of, 494
treatment and prognosis of, 495
Methamphetamine abuse, orofacial
complications of, 303, 303f
Methotrexate, for rheumatoid arthritis,
880
8-Methoxypsoralen, for mycosis
fungoides, 600
Metronidazole, for noma, 202-203
MHA-TP (microhemabblutination assay
for antibody to T. pallidum) for
syphilis, 192
Micafungin, for candidiasis, 224
Microangiopathy, complicating diabetes
mellitus, 844
Microdontia, 83, 83f
Microglossia, 9, 9f
Microhemagglutination assay for
antibody to T. pallidum (MHATP) for syphilis, 192
Microinfarction, in neuralgia-inducing
cavitational osteonecrosis,
868
Microorganisms, leukoplakia and,
389-390, 389f
Microsomia, hemifacial, in
temporomandibular joint
ankylosis, 882
Microstomia, in systemic sclerosis, 799,
799f
Midline lethal granuloma, 602-604
Midline malignant reticulosis, 602-604
Migraine, 870-871, 870t
Migrainous neuralgia, 868-869
Migratory glossitis, benign, 779-781
in diabetes, 844
Mikulicz disease, 465
Mikulicz syndrome, 465
Mikuliczs aphthae, 333
Miliary tuberculosis, 196
Mineralization, in enamel development,
55
Minocycline
discolorations of oral mucosa related
to, 317-318, 317f, 318f
for mucous membrane pemphigoid,
775
tooth discoloration from, 73
Minor aphthous ulcerations, 333
clinical features of, 333-334, 333f
MMP-20 gene mutation, in amelogenesis
imperfecta, 100
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956
Index
Mucopolysaccharidosis, oral
manifestations of, 816-818,
817t, 818f
Mucosa-associated lymphoid tissue,
lymphomas of, epimyoepithelial
islands in, 466
Mucosal lentiginous melanoma, clinical
features of, 435
Mucositis
from antineoplastic therapy
clinical features of, 294-295, 295f,
296f
treatment and prognosis of, 298
lichenoid, 782
necrotizing ulcerative, 158, 158f
in noma, 202, 202f
psoriasiform, in erythema migrans,
781
Mucous cells, in mucoepidermoid
carcinoma, 488, 488f, 489f
Mucous membrane pemphigoid, 766t,
771-775
bullous pemphigoid resembling, 775
clinical features of, 771-773, 771f,
772f, 773f
conditions mimicking, 774
histopathologic features of, 773-774,
773f
systemic agents for, 775
topical agents for, 774-775
treatment and prognosis of, 774-775
Mucous patches, in secondary syphilis,
189, 189f
Mucus duct cyst, 457-459, 458f
Mucus escape reaction, 454-456, 454f,
455f, 455t, 456f
Mucus extravasation phenomenon,
454-456, 454f, 455f, 455t,
456f
Mucus retention cyst, 457-459, 458f
Muir-Torre syndrome, keratoacanthomas
in, 407
Mulberry molars, 60
in congenital syphilis, 191, 191f
Multibacillary leprosy, 199, 199f, 200f,
201f
Multicystic intraosseous ameloblastoma,
702-707. See also
Ameloblastoma(s), conventional
solid or multicystic
intraosseous.
Multifocal epithelial hyperplasia, 367368, 367f, 368f
Multifocal papilloma virus epithelial
hyperplasia, 367-368, 367f,
368f
Multinodular oncocytic hyperplasia, 481
Multiple endocrine neoplasia (MEN)
type 2A, 532
type 2B, 532-533, 532f, 533f
macrogloassia in, 11
Multiple hamartoma, gingival
bromatosis in, 166
Multiple hamartoma syndrome, 760761, 760f, 761f
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Index
Neuralgiacontd
trigeminal, 861-863, 861b, 863b
tympanic plexus, 863
vagoglossopharyngeal, 863-864
Neuralgia-inducing cavitational
osteonecrosis (NICO), 866-868,
867b, 867f, 868f
Neurilemoma, 526-528, 527f
Neuroblastoma, olfactory, 555-556, 556f
Neuroendocrine carcinoma of skin,
432-433
Neurobroma, 528-529, 528f, 529f
Neurobromatosis, 528-529
macroglossia in, 11
Neurobromatosis type I (NF1),
529-531, 529b, 529f, 530f,
531f
Neurobromatosis type II (NF2), 526,
527
Neurobrosarcoma, 555
complicating neurobromatosis type I,
531, 531f
Neurogenic sarcoma, 555
Neuroma(s)
in multiple hamartoma syndrome,
760
palisaded encapsulated, 525-526,
526f
solitary circumscribed, 525-526,
526f
traumatic, 524-526, 524f, 525f
Neuronopathic features, of NiemannPick disease, 819
Neurosurgical procedures, for trigeminal
neuralgia, 862-863
Neutropenia, 581-582
cyclic, 583-584, 584f
Nevoid basal cell carcinoma syndrome,
431
clinical features of, 688-690, 688b,
689f
histopathologic features of, 690, 691f
multiple odontogenic keratocysts in,
684, 688, 690
radiographic features of, 689, 689f,
690, 690f
treatment and prognosis of, 691
Nevus ammeus, in Sturge-Weber
angiomatosis, 543, 544f
Nevus(i)
bathing trunk, 385
Beckers, 41
blue, 386-388, 387f
compound
clinical features of, 383
histopathologic features of, 384,
384f
developmental, types of, 382b
garment, 385
giant hairy, 385
halo, 386, 386f
intradermal
clinical features of, 383, 383f
histopathologic features of, 384,
384f
957
Nevus(i)contd
intramucosal
clinical features of, 383, 383f
histopathologic features of, 384,
384f
Jadassohn-Tiche, 386-388
junctional
clinical features of, 383
histopathologic features of, 384,
384f
melanocytic
acquired, 382-385, 383f, 384f. See
also Melanocytic nevus,
acquired.
congenital, 385-386, 385f
variants of, 385-388
spindle and epithelioid cell, 386
Spitz, 386
white sponge, 743-744, 743f, 744f
NF1 (neurobromatosis type I), 529531, 529b, 529f, 530f, 531f
NF2 (neurobromatosis type II, 526,
527
NHL (non-Hodgkins lymphoma), in HIV
infection, 272, 272f
Niacin
deciency of, clinical features of, 826,
826f
functions and sources of, 825
Niacinamide, for mucous membrane
pemphigoid, 775
NICO (neuralgia-inducing cavitational
osteonecrosis), 866-868, 867b,
867f, 868f
Nicotine palatinus, 403-404
Nicotine stomatitis, 403-404, 403f
Niemann-Pick disease, 819, 820
Nikolsky sign, positive, in pemphigus
vulgaris, 768
Nitrosamines, in candidiasis, squamous
cell carcinoma and, 412
Nodular basal cell carcinoma, 430
Nodular leukoplakia, 391
Nodular lymphocyte-predominant
Hodgkins lymphoma, 594
Nodular melanoma
clinical features of, 435
histopathologic features of, 436-437,
437f
Nodular oncocytic hyperplasia, 481-482,
482f
Nodular sclerosis subtype of Hodgkins
lymphoma, 594
Nodular stage, of Kaposis sarcoma,
558
Nodular subepidermal brosis, 514
Nodular torus, 21
Nodule(s)
Bohns, 691
brous, 507-509
Lisch, in neurobromatosis type I, 530
rheumatoid, 879
Noduloulcerative basal cell carcinoma,
430, 430f
Noma, 158, 201-203, 202f
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958
Index
Odontogenic cystscontd
orthokeratinized, 687-688
primordial cyst as, 683
sialo-odontogenic cysts as, 697-698,
698f
Odontogenic epithelial hamartoma, 727
Odontogenic broma(s), 726-729
central, 726-727, 726f, 727f
granular cell, 729, 729f
peripheral, 727-729, 728f
peripheral ameloblastoma
differentiated from, 710
Odontogenic ghost cell carcinoma, 697
Odontogenic keratocyst, 28
carcinoma arising in, 700, 701f
clinical and radiographic features of,
684-685, 684f, 685f
histopathologic features of, 685-686,
685f, 686f
treatment and prognosis of, 686-687,
686f
Odontogenic myxoma, 720f, 729-731,
731f
Odontogenic tumors, 701-732
classication of, 702b
ectomesenchymal, 726-732
cementoblastoma as, 731-732
odontogenic bromas as, 726-729.
See also Odontogenic bromas.
odontogenic myxoma as, 729-731,
730f, 731f
epithelial, 702-719
adenomatoid, 713-715, 713f, 714f,
715f
ameloblastoma as, 702-712. See also
Ameloblastoma(s).
calcifying, 716-718, 716f, 717f
clear cell, 712-713, 712f, 713f
clear cell odontogenic carcinoma as,
712-713, 712f, 713f
granular cell, 729, 729f
mixed, 719-726
ameloblastic bro-odontoma as,
721-722, 721f, 722f
ameloblastic broma as, 719-720,
720f, 722
ameloblastic brosarcoma as, 722723, 723f
ameloblastic sarcoma as, 722-723,
723f
odontoameloblastoma as, 723-724
squamous, 718-719, 718f
Odontology, forensic, 887. See also
Forensic dentistry.
Odontoma(s), calcifying odontogenic cyst
associated with, 695
Odontomaxillary dysplasia, segmental,
41-42, 42f
Odontome, dilated, 91
OHL. See Oral hairy leukoplakia.
Olfactory neuroblastoma, 555-556, 556f
Oligodontia, 77
in ectodermal dysplasia, 742, 742f
in incontinentia pigmenti, 750
Ollier disease, 656
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Index
Osteomyelitiscontd
secondary, 141
suppurative, 141
acute
clinical and radiographic features
of, 141-142, 142f
histopathologic features of, 143,
143f
treatment and prognosis of, 143
chronic
clinical and radiographic features
of, 142-143, 142f7
histopathologic features of, 143,
143f
treatment and prognosis of,
143-144
treatment and prognosis of, 143-144
Osteonecrosis
bisphosphonate-associated, 299-303.
See also Bisphosphonateassociated osteonecrosis
(BON).
cavitational, neuralgia-inducing,
866-868, 867b, 867f, 868f
Osteopetrosis, 615-617, 616f, 617f
focal periapical, 620
Osteophytes
in osteoarthritis, 878
in temporomandibular joint
dysfunction, 881
Osteoporosis circumscripta, in Pagets
disease of bone, 624
Osteoporotic marrow defect, focal,
619-620, 620f
Osteoradionecrosis, from antineoplastic
therapy
clinical features of, 296-297, 297f
treatment and prognosis of, 299
Osteosarcoma(s)
complicating Pagets disease of bone,
626
of jaws, 660-664
clinical and radiographic features
of, 660-661, 660f, 661f,
662f
histopathologic features of, 662,
662f
peripheral, 663-664, 663f
treatment and prognosis of,
662-663
postirradiation, 664
Osteosclerosis, idiopathic, 148, 620-622,
621f
Ostia, 207
Otalgia, in temporomandibular joint
dysfunction, 881
Oxyphilic adenoma, 480-481, 481f
P
Pachyonychia congenita, 745-746, 745f,
746f
Pagets disease of bone, 623-626
hypercementosis with, 96
monostotic, 624
polyostotic, 624
959
Pain
congenital indifference to, Riga-Fede
disease in, 289
facial, 859-886. See also Facial pain.
in temporomandibular joint
dysfunction, 880-881
in trigeminal neuralgia, 862
Palatal cysts of newborn, 26-27, 27f
Palatal exostoses, 20, 20f
Palatal tubercles, 20
Palatine cyst, 31-32
Palatinus, nicotine, 403-404
Palisaded encapsulated neuroma, 525526, 526f
Palmar surfaces, in pachyonychia
congenita, 746
Palmoplantar keratosis, in multiple
hamartoma syndrome, 760
Palsy, Bells, 859-861, 860f
Pannus, in rheumatoid arthritis, 879
Papilla
incisive, cysts of, 30, 30f
retrocuspid, 510, 510f
Papillary cystadenoma lymphomatosum,
482-483, 482f, 483f
Papillary gingivitis, 156
Papillary hyperplasia, inammatory,
512-514, 513f
Papillitis, lingual, transient, 330-331,
331f
Papilloma(s)
cylindrical cell, 370-371
ductal, 485-487, 486f, 487f
exophytic, 369
fungiform, 369, 369f
intraductal, 485-487
inverted, 369-370, 370f
inverted ductal, 486-487, 487f
septal, 369
sinonasal, 368-369
squamous, 362-364, 363f, 364f, 368,
369
Papillomatosis
denture, 512-514, 513f
laryngeal, 363-364
oral orid, 423
squamous papilloma differentiated
from, 363
Papillomavirus, human. See Human
papillomavirus (HPV).
Papillon-Lefvre syndrome, 176-178,
176f, 177f
Papyraceous scarring of skin, in EhlersDanlos syndrome, 757, 757f
Paracoccidioidomycosis, 229-230, 229f
Paradental cyst, 679, 699
Paragangliomas, 535-536, 536f
Parakeratin plugs, in verrucous
carcinoma, 423
Parakeratosis, in lichen planus, 786
Paralysis
bulbar, 873
facial
in Bells palsy, 859-861, 860f
in herpes zoster, 252
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960
Index
Periodontitiscontd
aggressivecontd
histopathologic features of, 175
localized, clinical and radiographic
features of, 174-175, 174f
treatment and prognosis of,
175-176
apical
acute, 135
chronic, 127-130. See also Periapical
granuloma.
associated with systemic disease, 169
chronic, clinical and radiographic
features of, 169-170, 170f
classication of, 168-169, 169b
early-onset, 173
generalized juvenile, 173
histopathologic features of, 172
localized juvenile, 173
necrotizing ulcerative, 169. See also
Necrotizing ulcerative
periodontitis (NUP).
prepubertal, 173
rapidly progressing, 173
systemic disorders with, 169b
treatment and prognosis of, 172-173
Perioral dermatitis, 352, 352f
Periosteal form of osteosarcoma of jaw,
663f, 664
Periosteal osteoma, 650
Periostitis, proliferative, osteomyelitis
with, 148-150. See also
Osteomyelitis, with proliferative
periostitis.
Periostitis ossicans, 148-150
Peripheral ameloblastoma, 710f,
719-711
Peripheral broma with calcication,
521-523
Peripheral giant cell granuloma, 520521, 520f, 521f
Peripheral odontogenic broma, 727729, 728f
peripheral ameloblastoma
differentiated from, 710
Peripheral ossifying broma, 521-523,
521f, 522f
Peripheral osteoma, 650
Peripheral vascular disease, in diabetes
mellitus, 843
Peritonitis, necrotizing ulcerative. See
Necrotizing ulcerative
periodontitis (NUP).
Perlche, 216
Pernicious anemia, oral manifestations
of, 829-831, 830f
Perocoronitis, treatment and prognosis
of, 173
Persistent generalized lymphadenopathy
(PGL), in HIV infection, 271272, 272f
Petechiae
in submucosal hemorrhage, 305, 306f
in thrombocytopenia, 585
Peutz-Jeghers syndrome, 753-754, 753f
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Index
Plasmacytoma, 606-607, 606f
Plasminogen deciency, 575-576, 575f,
576f
Plasmostasis, in bone marrow edema,
868
Platelets
decrease in, in thrombocytopenia,
584-585
destruction of, increased,
thrombocytopenia from, 584
production of, reduced,
thrombocytopenia from, 584
transfusion of, for thrombocytopenia,
585-586
Pleomorphic adenoma, 477-480, 477f,
478f, 479f, 480f
clinical and radiographic features of,
477-478, 477f, 478f, 479f
histopathologic features of, 478-479,
479f, 480f
treatment and prognosis of, 480
Pleomorphic lipomas, 524
Pleomorphic liposarcomas, 554
Plexiform ameloblastoma, 705, 706f
Plexiform unicystic ameloblastomas,
708f, 709, 709f
Plummer-Vinson syndrome
oral manifestations of, 828-829
squamous cell carcinoma in, 411
Plunging ranula, 457, 457f
PMNR (periadenitis mucosa necrotica
recurrens), 333
Pneumomediastinum, 324
Pneumoparotid, 323
Polyarthralgia, in rheumatoid arthritis,
879
Polycythemia rubra vera, 586-587
Polycythemia vera, 586-587
Polydipsia, in diabetes mellitus, 843
Polyene agents, for candidiasis, 221,
222-223t
Polymerase chain reaction (PCR)
analysis, in forensic
identication, 893, 894
Polymorphic reticulosis, 602-604
Polymorphous low-grade
adenocarcinoma, 497-498,
497f, 498f
Polymyalgia rheumatica, in temporal
arteritis, 871
Polyostotic brous dysplasia of jaws,
636-637, 638f, 639
Polyp(s)
broepithelial, 511, 512f
intestinal, in Peutz-Jeghers syndrome,
753
pulp, 121-122
Polyphagia, in diabetes mellitus, 843
Polypoid squamous cell carcinoma, 423425, 424f
Polyuria, in diabetes mellitus, 843
Popliteal pterygium syndrome, 6
Porphyria, erythropoietic, congenital,
tooth discoloration in, 71, 71f
Port wine stain, 543-544
961
Posaconazole, for candidiasis, 224
Postherpetic neuralgia (PHN), 252,
864-865
Postoperative maxillary cyst, 320, 321
Posttransplant lymphoproliferative
disorder, 596
PPD (puried protein derivative) skin
test for tuberculosis, 198
Precancer terminology, 388b
Precancerous condition, denition of,
388b
Precancerous lesion
denition of, 388b
of oral, pharyngeal, and laryngeal
mucosa, 410t
Pregnancy
mask of, 378-379, 379f
pyogenic granuloma in, 518, 518f
Premalignancy, denition of, 388b
Prepubertal periodontitis, 173
Primordial cysts, 583f, 683
Progeria, secondary dentin formation
and, 123
Progonoma, melanotic, 533
Progressive facial hemiatrophy, 40-41,
41f
Progressive hemifacial atrophy, 40-41,
41f
Progressive muscular atrophy, 873
Progressive systemic sclerosis, 798-801
Proliferative verrucous leukoplakia
(PVL), 391-392, 392f
Proptosis, in Graves disease, 836, 836f
Protein, Bence Jones, in multiple
myeloma, 604
Proteinosis, lipoid, oral manifestations of,
820-821, 820f, 821f
Proteus-like syndrome, multiple
hamartoma syndrome and, 760
Proteus syndrome, 531
Protooncogenes, squamous cell
carcinoma and, 412
Protozoal diseases, toxoplasmosis as,
235-237, 236f, 237f
Prune belly syndrome, gingival
bromatosis in, 166
Psammomatoid juvenile ossifying
broma, 648-649
Pseudo-horn cysts, in seborrheic
keratosis, 374, 375f
Pseudoacanthosis nigricans, 803
Pseudocarcinoma, 406-408
Pseudocarcinomatous hyperplasia, in
blastomycosis, 228
Pseudocysts, antral, 320-323, 321f, 322f
Pseudoepitheliomatous hyperplasia, in
blastomycosis, 228
Pseudohypoparathyroidism, 837-838
Psoralen, for graft-versus-host disease
lesions, 792
Psoriasiform mucositis, in erythema
migrans, 781
Psoriasis, 793-794, 793f, 794f
in reactive arthritis, 782
Psoriatic arthritis, in psoriasis, 793
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962
Index
Radiation therapycontd
for Langerhans cell histiocytosis, 592
for leukemia, 589
for massive osteolysis, 623
for melanoma, 439
for nasopharyngeal carcinoma, 429
for non-Hodgkins lymphoma, 598
noninfectious oral complications of,
294, 295-298, 296f, 297f
for plasmacytoma, 606
postoperative, for mucoepidermoid
carcinoma, 490
for squamous cell carcinoma, 420,
421
for verrucous carcinoma, 423
Radicular cyst, 130-135. See also
Periapical cyst.
Radicular dens invaginatus, 91-92, 92f
Radicular dentin dysplasia, 109-110,
109f, 110b, 110f
Radioactive iodine, for Graves disease,
836
Radiography, digital, for dental record,
888
Ramsay-Hunt syndrome, 252, 864
Ranula, 456-457, 456f, 457f
Rapidly progressing periodontitis, 173
Raynauds phenomenon
in CREST syndrome, 802
in systemic sclerosis, 798
Reactionary dentin, 124
Reactive arthritis, 781-782
Reactive osseous and chondromatous
metaplasia, 318-319, 319f
Reactive subpontine exostosis, 20, 20f
Recrudescent HSV-1 infection, 241
clinical features of, 243-244, 243f,
244f
Recurrent aphthous stomatitis, 331-336
clinical features of, 333-334, 333f,
334f
diagnosis of, 335
histopathologic features of, 334-335
systemic disorders associated with,
332b
treatment and prognosis of, 335-336,
335f
Recurrent HSV-1 infection, 241
clinical features of, 243-244, 243f,
244f
Red blood cells
destruction of, localized, tooth
discoloration from, 72
in sickle cell anemia, 577
Red strawberry tongue, in scarlet fever,
185
Reed-Sternberg cells, in Hodgkins
lymphoma, 592, 593, 594f
Reective ultraviolet photography, of
bite marks for evidence, 908
Regional enteritis, 848-849
Regional ileitis, 848-849
Regional odontodysplasia, 112-113,
112b, 113f
Reimpaction, 75
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Retinol
deciency of, clinical features of, 825
functions and sources of, 825
Retrocuspid papilla, 510, 510f
Reverse polarization of peripheral
columnar cells in follicular
ameloblastoma, 705, 705f
Rhabdomyomas, 550-552, 551f
cardiac, in tuberous sclerosis, 758
Rhabdomyosarcoma, 559-561, 560f,
560t, 561f
Rheumatoid arthritis, 878-880
Riboavin
deciency of, clinical features of, 826
functions and sources of, 825
Ribs, bid, in nevoid basal cell
carcinoma syndrome, 689,
689f
Rice bodies, in rheumatoid arthritis, 880
Rickets, 827
vitamin D-resistant, oral
manifestations of, 847-848,
847f, 848f
Rifampin
for leprosy, 201
for tuberculosis, 198
Riga-Fede disease, 82, 288-289, 288f
Riley-Day syndrome, Riga-Fede disease
in, 289
Rodent ulcer, 430
Romberg syndrome, 40-41, 41f
Root(s), tooth
dilaceration of, 97-98, 97f, 98f
resorption of
impaction-related, 75, 75f
multiple idiopathic, 69, 69f
supernumerary, 98-99, 99f
Rootless teeth, 109-110, 109f, 110f,
111f
Roseola, 240
Rough pattern, of hypoplastic
amelogenesis imperfecta, 102,
103f
Round cell liposarcoma, 554
Rubella, 261-263
Rubeola, 259-261, 260f, 261f
Rudimentary supernumerary teeth, 81
Russell bodies, in periapical granuloma,
129
Rutherfurd syndrome, gingival
bromatosis in, 166
S
Saint Anthonys re, 182
Salicylic acid, topical, for verruca
vulgaris, 366
Salivary adenocarcinoma, 498-499,
499f
Salivary duct cyst, 457-459, 458f
Salivation, excessive, 463-464
San Joaquin Valley fever, 230-231
Sanlippo-A syndrome, features of,
817t
Sanlippo-B syndrome, features of, 817t
Sanguinaria, leukoplakia and, 389, 389f
Index
Sarcoidosis, 338-341
clinical features of, 339-340, 339f,
340f
diagnosis of, 340-341
histopathologic features of, 340, 340f
treatment and prognosis of, 341
Sarcoma(s)
alveolar soft-part, 562-563, 562f
ameloblastic, 722-723, 723f
bone, postirradiation, 664
Ewing, 667-669, 668f
granulocytic, in leukemia, 588
Kaposis, 240-241, 557-559, 557f,
558f
in HIV infection, 270-271, 270f,
271f
neurogenic, 555
soft tissue, 552-564. See also Soft tissue
sarcomas.
synovial, 560-561, 561f
Sarcomatoid squamous cell carcinoma,
423-425, 424f
Scaphocephaly, in Crouzon syndrome,
42
Scarlatina, 184-185, 185f
Scarlet fever, 184-185, 185f
Scheie syndrome, features of, 817t
Schirmer test, in Sjgren syndrome
diagnosis, 469
Schneiderian papilloma
inverted, 369-370, 370f
oncocytic, 370-371
Schwachman-Diamond syndrome,
neutropenia in, 582
Schwannoma, 526-528, 527f
malignant, 555
complicating neurobromatosis type
I, 531, 531f
Scintillation, before migraine, 871
Scirrhous change, in squamous cell
carcinoma, 419
Sclera, yellow color of, in jaundice, 822,
822f
Sclerodactyly, in CREST syndrome, 802,
802f
Scleroderma, 40, 798-801
limited, 801-803
localized, 799-800, 800f
Sclerosing basal cell carcinoma, 431
Sclerosing hemangioma, 514
Sclerosing osteomyelitis, focal chronic,
620
Sclerosing panencephalitis, subacute,
complicating rubeola, 260
Sclerotherapy
for lymphangiomas, 549
for vascular malformations, 543
Sclerotic lesions, in cemento-osseous
dysplasias of jaws, 644, 644f
Scorbutic gingivitis, 826, 827f
Scotoma, before migraine, 871
Scrofula, 196, 196f
Scrotal tongue, 13, 13f
Scrumpox, 244
Scurvy, 826, 827f
963
Sebaceous cyst, 32
Sebaceous hyperplasia, 375-376, 376f
Seborrheic keratosis, 374-375, 374f,
375f
Segmental odontomaxillary dysplasia,
41-42, 42f
Seizures, in tuberous sclerosis,
management of, 759
Senile lentigo, 377-378
Sensory decit, in postherpetic
neuralgia, 864
Septal papilloma, 369
Sequestration, bone, oral ulceration with,
319-320, 320f
Serologic comparison, in identication,
893-894
Serum alkaline phosphatase levels,
elevated, in diagnosis of Pagets
disease of bone, 625
Seventh nerve paralysis, 859-861
Severe congenital neutropenia, 582
Sex, AIDS cases and, 265, 265t
Sexual activity, HSV-2 exposure and,
241
Sexual practices, oral trauma from, 307308, 308f
Sexually transmitted disease (STD),
condyloma acuminatum as,
366
Szary cells, in mycosis fungoides, 600
Szary syndrome, 599, 600
Shagreen patches, in tuberous sclerosis,
758
Shell teeth, 107, 108f
Shingles, 250-253. See also Herpes
zoster.
facial pain in, 864
Shock, insulin, 845
Shock wave lithotripsy, for sialolithiasis,
461
Shovel-shaped incisors
clinical and radiographic features of,
89, 89f
treatment and prognosis of, 90
Sialadenitis, 461-462, 461f, 462f
myoepithelial, 465-466, 466f
Sialadenoma papilliferum, 486-487,
487f
Sialadenoscopy, for sialadenitis, 462
Sialadenosis, 470-471, 471f
diabetic, 844
Sialo-odontogenic cyst, 697-698, 698f
Sialocyst, 457-459, 458f
Sialolithiasis, 459-461, 459f, 460f
Sialometaplasia, necrotizing, 471-473,
472f
Sialorrhea, 463-464
Sialosis, 470-471, 470b, 471f
Sickle cell anemia, 576-578, 578f
bilirubin excess in, 821
Sickle cell crisis, 577-578
Sickle cell disease, 577
Sickle cell trait, 577
Sideropenic dysphagia, oral
manifestations of, 828-829
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964
Index
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Index
Submandibular tumor(s), 475, 475t
Submucosal hemorrhage, 305-307,
306f, 307f
Submucous brosis, oral, 401-403,
402f
Submucous palatal cleft, 3-4, 4f
Subpontic osseous hyperplasia, 20
Subpontic osseous proliferation, 20
Sulfasalazine
for Crohns disease, 849
for pyostomatitis vegetans, 850
for rheumatoid arthritis, 880
Sulfonamides, for
paracoccidioidomycosis, 230
Sulfur granules, in actinomycosis, 203
Sumatriptan, for cluster headache, 869
Sunlight, avoidance of
in Dariers disease, 752
for xeroderma pigmentosum, 748
Supercial basal cell carcinoma, 431
Supercial mucocele, 455, 455f
Supercial spreading melanoma
clinical features of, 434-435, 434f
histopathologic features of, 436, 436f
Supercial Wegeners granulomatosis,
345
Supernumerary roots, 98-99, 99f
Supernumerary teeth, 77, 80-81, 80f,
81f
treatment of, 82
Supplemental supernumerary teeth, 81
Surgical ciliated cyst, 320, 322f
Susuk implantation, 311, 312, 313f
Suttons disease, 333
Sweating, gustatory, 876-877
Swift disease, from mercury exposure in
infants and children, 315
Symblepharons, in mucous membrane
pemphigoid, 772, 772f, 773f
Syndactyly, in Apert syndrome, 44, 44f
Syngnathia, in Kabuki syndrome, 6
Synovectomy, total, for synovial
chondromatosis, 658
Synovial chondromatosis, 657-658, 658f
Synovial sarcoma, 560-561, 561f
Synovitis, in rheumatoid arthritis, 879
Synovitis-acne-pustulosis hyperostosisosteomyelitis (SAPHO)
syndrome, 144
clinical and radiographic features of,
146
Syphilis
clinical features of, 188-191
congenital, 188
clinical features of, 190-191, 191f
stigmata of, 192t
diagnosis of, 193
histopathologic features of, 191-193,
192f
latent, 190
primary, clinical features of, 188, 189f
secondary, clinical features of,
188-190
squamous cell carcinoma and,
411-412
965
Syphiliscontd
tertiary, clinical features of, 190, 190f,
191f
treatment and prognosis of, 193
Syphilitic hypoplasia of enamel, 60
Systemic diseases, oral manifestations of,
816-858
Systemic lupus erythematosus (SLE),
graft-versus-host disease
mimicking, 791
Systemic sclerosis, 798-801
clinical and radiographic features of,
798-800, 798f, 799, 800f
diagnosis of, 800-801
histopathologic features of, 800,
801f
treatment and prognosis of, 801
T
T. pallidum hemagglutination assay
(TPHA) for syphilis, 192
T. pallidum particle agglutination assay
(TPPA) for syphilis, 192
T-cell lymphoma
angiocentric, 602-604
cutaneous, 598-600, 599f, 600f
Talisman, 311
Talon cusp
clinical and radiographic features of,
87-88, 88f
treatment and prognosis of, 90
Target lesions, in erythema multiforme,
777, 777f
Taste
altered or diminished, 875-876, 875b,
876t
distorted, 875-876
loss of, from antineoplastic therapy
clinical features of, 296
treatment and prognosis of,
298-299
phantom, 875-876
Tattoo
amalgam, 308-311, 309f, 310f, 311f
intraoral, intentional, 309-310, 310f
Taurodontism, 94-96, 94f, 95b, 95f
amelogenesis imperfecta with, 104105, 105f
Tay-Sachs disease, 819, 820
TB. See Tuberculosis.
Tea, tooth discoloration from, 70
Telangiectasia
in CREST syndrome, 802, 802f
hereditary hemorrhagic, 754-755,
754f, 755f
in Merkel cell carcinoma, 432
Temporal arteritis, 871-872
Temporomandibular joint (TMJ)
ankylosis of, 882
dysfunction of, 880-882, 881b
glossopharyngeal neuralgia
differentiated from, 863
osteoarthritis of, 877-878
in rheumatoid arthritis, 879
synovial chondromatosis of, 658
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966
Index
-Tocopherol
deciency of, clinical features of, 827
functions and sources of, 825
Tongue
ageusia of half of, 875
bid, 311, 312f
black hairy, 13-15, 14f, 15f
carcinoma of, 415, 415f
central papillary atrophy of, 214t, 216
coated, 14-15, 14f
in dyskeratosis congenita, 747, 747f
enlargement of, in hypothyroidism,
834-835, 835f
eosinophilic granuloma of, 287, 290f
ssured, 13, 13f
in erythema migrans, 780, 780f
forked, 311, 312f
geographic, 779-781
hairy, 13-15, 14f, 15f
in hereditary hemorrhagic
telangiectasia, 754, 754f
large, 9, 9f
metastases to, 563, 563f
missing, 9
neurilemomas of, 527
neurobroma of, 528, 528f
in pernicious anemia, 830, 830f
piercings of, 311-312, 312f
small, 9, 9f
split, 311, 312f
strawberry, in scarlet fever, 185, 185f
wandering rash of, 779-781
woody, in Ludwigs angina, 139
Tongue-tie, 11-12, 11f
Tongue torches, 330-331
Tonsilitis, streptococcal, 183-184, 184f
Tonsillar concretions, 185-186
Tonsillolithiasis, 185-186, 186f
Tooth (teeth), abnormalities of, 54-119
Tooth-whitening products, mucosal
burns from, 291, 291f
Toothpaste
allergic contact stomatitis to, 351,
351f
sanguinaria, leukoplakia and, 389,
389f
Torus mandibularis, 19, 22-23, 22f, 23f
Torus palatinus, 19, 21-22, 21f
Tourette syndrome, Riga-Fede disease in,
289
Toxic epidermal necrolysis, 777-778
Toxoplasmosis, 235-237, 236f, 237f
TPHA (T. pallidum hemagglutination
assay) for syphilis, 192
TPPA (T. pallicum particle agglutination
assay) for syphilis, 192
Trabecular carcinoma of skin, 432-433
Trabecular juvenile ossifying broma,
648, 649, 650f
Tranquilizers, discolorations of oral
mucosa related to, 317, 318,
318f
Transfusions
blood, for thalassemia major, 580
platelet, for thrombocytopenia,
585-586
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Tuberculosis (TB)contd
diagnosis of, 198
histopathologic features of, 197-198,
197f, 198f
HIV-associated, 274
miliary, 196
primary, 195
secondary, 196
treatment and prognosis of, 198
Tuberous sclerosis, 757-759, 758f, 759f
Tubular pattern in adenoid cystic
carcinoma, 496
Tufted hemangioma, 540
TUGSE (traumatic ulcerative granuloma
with stromal eosinophilia),
287
Tumor-node-metastasis (TNM) staging
system for oral carcinoma,
418-419t
Tumor stage, of mycosis fungoides, 599,
599f, 600
Tumor suppressor genes, squamous cell
carcinoma and, 412
Tumor(s)
Ackermans, 422-423
brown, of hyperparathyroidism, 839,
893f
ghost cell
dentinogenic, 695-697, 695f, 696f,
697f
epithelial odontogenic, 695
giant cell, 629-635. See also Giant cell
tumors.
glomus jugulare, 535-536
glomus tympanicum, 535-536
Merkel cell, 432-433
odontogenic, 701-732. See also
Odontogenic tumors.
calcifying cystic, 695-697, 695f,
696f, 697f
keratocystic, 683
Pindborg, 716-718, 716f, 717f
salivary gland, 473-499
acinic cell adenocarcinoma as, 491492, 491f, 492f
adenoid cystic carcinoma as, 495497, 495f, 496f
basal cell adenoma as, 484-485,
485f
benign mixed tumor as, 477-480.
See also Pleomorphic adenoma.
canalicular adenoma as, 484, 484f
classication of, 473b
ductal papillomas as, 485-487,
486f, 487f
intraductal papilloma as, 485-487
inverted ductal papilloma as, 486487, 487f
labial, 475, 477t
lobular carcinoma as, 497-498
malignancy of, frequency of, 474t
malignant mixed, 492-495. See also
Malignant mixed tumors.
of minor glands, 475, 476t, 477t
monomorphic adenoma as,
483-484
Index
Tumor(s)contd
salivary glandcontd
mucoepidermoid carcinoma as,
487-491. See also
Mucoepidermoid carcinoma.
oncocytoma as, 480-481, 481f
oncocytosis as, 481-482, 482f
palatal, 475, 476t
papillary cystadenoma
lymphomatosum as, 482-483,
482f, 483f
parotid, 473, 474t
pleomorphic adenoma as, 477-480.
See also Pleomorphic adenoma.
polymorphous low-grade
adenocarcinoma as, 497-498,
497f, 498f
primary epithelial, sites of
occurrence of, 474t
salivary adenocarcinoma as, 498499, 499f
sialadenoma papilliferum as, 486487, 487f
sublingual, 475
submandibular, 45t, 475
terminal duct carcinoma as,
497-498
Warthin tumor as, 482-483, 482f,
483f
soft tissue, 507-570. See also Soft tissue
tumors.
Turners hypoplasia, 56-58, 57f
Turners tooth, 56-58
Tympanic plexus neuralgia, 863
Tyndall effect, in blue nevus, 387
Tzanck cells
in herpes simplex infection, 245
in pemphigus vulgaris, 768
U
Ulcer, rodent, 430
Ulceration(s)
aphthous
clinical features of, 334, 334f
in Crohns disease, 849, 849f
herpetiform, 333
HIV-associated, 278, 278f
major, 333
clinical features of, 334, 334f
minor, 333
clinical features of, 333-334, 334f
recurrent, 331-336
with bone sequestration, 319-320,
320f
in graft-versus-host disease, 792
oral, in cyclic neutropenia, 583, 584f
snail track, in pyostomatitis vegetans,
850, 850f
traumatic, 287-289, 288f, 289f
in Wegeners granulomatosis, 346,
346f
Ulcerative stomatitis, chronic, 788-790,
789f, 790f
lichen planus resembling, 785
Ultraviolet B (UVB) therapy, for
psoriasis, 794
967
Ultraviolet (UV) light exposure
chronic, actinic lentigo from, 377
nevoid basal cell carcinoma syndrome
trigged by, 691
Ultraviolet (UV) radiation
leukoplakia from, 389
melanoma and, 433
squamous cell carcinoma and, 411
Undifferentiated nonkeratinizing
carcinoma, nasopharyngeal,
429
Unicystic ameloblatoma, 708-710, 708f,
709f
Universal Tooth Numbering System,
896, 896t
Urbach-Wiethe syndrome, oral
manifestations of, 820-821
Uremic stomatitis
morsicatio buccarum differentiated
from, 286
oral manifestations of, 851, 851f
Uveoparotid fever, associated with
sarcoidosis, 339
Uvula, cleft or bid, 3, 4f
V
Vaccine
bacillus Calmette-Gurin, for
tuberculosis, 198
MMR, 261
varicella, 250
VZV, live attenuated, for herpes zoster,
253
Vacuoles, cytoplasmic, in hereditary
mucoepithelial dysplasia, 749,
749f
Vagoglossopharyngeal neuralgia,
863-864
Valacyclovir
prophylactic, for
immunocompromised patients,
247
for recurrent herpes labialis, 247
Valley fever, 230
van der Woude syndrome, 5-6, 6f
Varicella, 248-250, 248f, 249f
Varicella-zoster virus (VZV, HHV-3),
240, 248-250
HIV-associated, 276
Varices, 15-16, 15f
Varicosities, oral, 15-16, 15f
Vascular hyperplasia, intraoral, in
Sturge-Weber angiomatosis,
543-544, 544f
Vascular leiomyomas, 549-550
Vascular malformations
classication of, 539b
clinical and radiographic features of,
540, 540f
histopathologic features of, 542, 542f
intrabony, clinical and radiographic
features of, 540-541, 541f
treatment and prognosis of, 543
Vascular type, of Ehlers-Danlos
syndrome, 756t, 757
Vasodilators, for Bells palsy, 860
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968
Index
Vitamin B1
deciency of, clinical features of, 826
functions and sources of, 825
Vitamin B2
deciency of, clinical features of, 826
functions and sources of, 825
Vitamin B3
deciency of, clinical features of, 826,
826f
functions and sources of, 825
Vitamin B6
deciency of, clinical features of, 826
functions and sources of, 825
Vitamin B12 deciency, pernicious
anemia from, 829
Vitamin C
deciency of, clinical features of, 826,
827f
functions and sources of, 825
Vitamin D
deciency of, clinical features of, 827
functions and sources of, 825
for pseudohypoparathyroidism, 838
Vitamin Dresistant rickets, oral
manifestations of, 847-848,
847f, 848f
Vitamin deciency, oral manifestations
of, 825-827
Vitamin E
deciency of, clinical features of, 827
functions and sources of, 825
Vitamin K
deciency of, clinical features of, 827
functions and sources of, 825
Vocal cords, thickened, in lipoid
proteinosis, 820
Von Recklinghausens disease of skin,
529-531
von Willebrands disease, 573, 573t,
574
Vulvodynia, 874
VZV (varicella-zoster virus), 240,
248-250
W
Waldeyers ring, 37
nasopharyngeal carcinoma of, 428
Waldeyers tonsillar tissue,
nasopharyngeal carcinoma of,
428
Wandering rash of tongue, 779-781
Wart
common, 364-366, 365f
venereal, 366-367, 366f, 367f
Warthin-Finkedey giant cells, in rubeola,
261, 261f
Warthin tumor, 482-483, 482f, 483f
Warty dyskeratoma, 752-753, 752f
Wegeners granulomatosis, 345-347,
345f, 346f
Well-differentiated liposarcoma, 554
White line, 285
White sponge nevus, 743-744, 743f,
744f
White strawberry tongue, in scarlet
fever, 185, 185f
Wickhams striae, in lichen planus, 783,
783f
Witkop von Sallmann syndrome,
744-745, 744f, 745f
Witkops classication of amelogenesis
imperfecta, 99, 99t
Woody tongue, in Ludwigs angina, 139
X
X-irradiation, squamous cell carcinoma
and, 411
X-linked pattern, of hypomaturation
amelogenesis imperfecta, 103,
104f
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