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intensivemedicalcare,somepatientsdieasaresultofinfectiouscomplications.
The mitten deformity of the hands, seen in recessive dystrophic epidermolysis bullosa, can be corrected with
plasticsurgery,buttheproblemusuallyrecursafteraperiodoftime,andsurgicalinterventionisrequiredevery2
yearsonaverage.Withesophagealinvolvement,dysphagiamaybeasignificantproblem,resultinginmalnutrition
andweightloss.Placementofagastrostomytubemaybenecessaryattimes.Patientswiththerecessivedystrophic
formsarealsopredisposedtodevelopmentofcutaneoussquamouscellcarcinoma.Thismalignancyoftendevelops
inareasofchroniculcerationduringthesecondthroughthirddecadesoflifeandrepresentsasignificantcauseof
death for these patients. Infrequently, the lingual mucosa of affected patients has been reported to undergo
malignanttransformationaswell.
Managementoftheoralmanifestationsalsodependsonthetypeofthedisease.Forpatientswhoaresusceptibleto
mucosal bulla formation, dental manipulation should be kept to a minimum. To achieve this, topical 1% neutral
sodiumfluoridesolutionshouldbeadministereddailytopreventdentalcaries.Asoftdietthatisasnoncariogenicas
possible,aswellasatraumaticoralhygieneprocedures,shouldbeencouraged.Maintainingadequatenutritionfor
affectedpatientsiscriticaltoensureoptimalwoundhealing.Endosseousdentalimplants,followedbyfixeddental
prostheses,havebeensuccessfullyplacedinsomepatientswithrecessivedystrophicepidermolysisbullosa.
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
extensivedentalcare,endotrachealanesthesiamaybeperformedwithoutsignificantproblemsinmostcases.
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.
ImmuneMediatedDiseasesandTheirEvaluation
Severalconditionsdiscussedinthischapteraretheresultofinappropriateproductionofantibodiesbythepatient
(autoantibodies).Theseautoantibodiesaredirectedagainstvariousconstituentsofthemolecularapparatusthathold
epithelialcellstogetherorthatbindthesurfaceepitheliumtotheunderlyingconnectivetissue.Theensuingdamage
producedbytheinteractionoftheseautoantibodieswiththehosttissueisseenclinicallyasadiseaseprocess,often
termed an immunobullous disease. Because each disease is characterized by production of specific types of
autoantibodies, identification 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
immunofluorescenceand2)indirectimmunofluorescencestudies.Followingisabriefoverviewofhowtheywork.
Directimmunofluorescenceisusedtodetectautoantibodiesthatareboundtothepatientstissue.Beforetesting
cantakeplace,severalproceduresmustoccur.Inoculatinghumanimmunoglobulinsintoagoatcreatesantibodies
directedagainstthesehumanimmunoglobulins.Theantibodiesraisedinresponsetothehumanimmunoglobulins
are harvested from the animal and tagged with fluorescein, a dye that glows when viewed with UV light. As
illustrated on the left side of Fig. 1647, a frozen section of the patients tissue is placed on a slide, and this is
incubated with fluoresceinconjugated 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
viewedwithamicroscopehavingaUVlightsource.
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ImmunofluorescenceTechniques.Comparisonofthetechniquesfordirectandindirectimmunofluorescence.Theleft
sidedepictsthedirectimmunofluorescentfindingsincicatricialpemphigoid,adiseasethathasautoantibodiesdirectedtowardthe
basementzone.Therightsideshowstheindirectimmunofluorescentfindingsforpemphigusvulgaris,adiseasethathas
autoantibodiesdirectedtowardtheintercellularareasbetweenthespinouscellsoftheepithelium.Ig,ImmunoglobulinUV,
ultraviolet.
FIG.1647
With indirect immunofluorescence studies, the patient is being evaluated for presence of antibodies that are
circulatingintheblood.AsshownontherightsideofFig.1647,afrozensectionoftissuethatissimilartohuman
oralmucosa(e.g.,OldWorldmonkeyesophagus)isplacedonaslideandincubatedwiththepatientsserum.Ifthere
are autoantibodies directed against epithelial attachment structures in the patients serum, then they will attach to
thehomologousstructuresonthemonkeyesophagus.Theexcessserumiswashedoff,andfluoresceinconjugated
goatantihumanantibodyisincubatedwiththesection.Theexcessiswashedoff,andthesectionisexaminedwith
UVlighttodetectthepresenceofautoantibodiesthatmighthavebeenintheserum.
ExamplesofthemolecularsitesofattackoftheautoantibodiesareseendiagrammaticallyinFig.1648.Eachsiteis
distinctiveforaparticulardisease;however,thecomplexitiesoftheepithelialattachmentmechanismsarestillbeing
elucidated, and more precise mapping may be possible in the future. A summary of the clinical, microscopic, and
immunopathologicfeaturesofthemoreimportantimmunemediatedmucocutaneousdiseasesisfoundinTable16
3.
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EpithelialAttachmentApparatus.Schematicdiagramdemonstratingtargetedstructuresinseveralimmunemediated
diseases.BMZ,Basementmembranezone.
FIG.1648
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TABLE163
ChronicVesiculoulcerativeDiseases
Condition
MeanAge
Pemphigus
vulgaris
Fourthto
sixth
decade
Paraneoplastic
pemphigus
Sex
Clinical
Predilection
Features
Equal
Histopathologic
Features
Direct
Indirect
Immunofluorescence
Immunofluorescence
Vesicles,
Intraepithelial
erosions,
clefting
and
ulcerations
onany
oral
mucosalor
skin
surface
Positiveintercellular
Positive
Sixthto
Equal
seventh
decade
Vesicles,
Subepithelialand
erosions,
intraepithelial
and
clefting
ulcerations
onany
mucosalor
skin
surface
Positive,intercellular
andbasement
membranezone
Positive(ratbladder)
Mucous
membrane
pemphigoid
Sixthto
Female
seventh
decade
Primarily
mucosal
lesions
Subepithelial
clefting
Positive,basement
membranezone
Negative
Bullous
pemphigoid
Seventhto
eighth
decade
Equal
Primarilyskin Subepithelial
lesions
clefting
Positive,basement
membranezone
Positive
Erythema
multiforme
Thirdto
fourth
decade
Male
Skinand
mucosa
involved;
target
lesionson
skin
Subepithelial
edemaand
perivascular
inflammations
Nondiagnostic
Negative
Lichenplanus
Fifthto
sixth
decade
Female
Oraland/or
skin
lesions;
mayor
maynot
beerosive
Hyperkeratosis,
sawtoothed
reteridges,
bandlike
infiltrateof
lymphocytes
Fibrinogen,basement
membranezone
Negative
Pemphigus
Theconditionknownaspemphigusrepresentsfourrelateddiseasesofanautoimmuneorigin:
1.Pemphigusvulgaris
2.Pemphigusvegetans
3.Pemphiguserythematosus
4.Pemphigusfoliaceus
Onlythefirsttwooftheseaffecttheoralmucosa,andthediscussionislimitedtopemphigusvulgaris.Pemphigus
vegetansisrare;mostauthoritiesnowfeelitrepresentssimplyavariantofpemphigusvulgaris.
Pemphigusvulgarisisthemostcommonofthesedisorders(vulgarisisLatinforcommon). Even so, it is not seen
very often. The estimated incidence is one to five cases per million people diagnosed each year in the general
population.Nevertheless,pemphigusvulgarisisanimportantconditionbecause,ifuntreated,itoftenresultsinthe
patientsdeath.Furthermore,theorallesionsareoftenthefirstsignofthedisease,andtheyarethemostdifficultto
resolvewiththerapy.Thishaspromptedthedescriptionoftheorallesionsasthefirsttoshow,andthelasttogo.
Theblisteringthattypifiesthisdiseaseisduetoanabnormalproduction,forunknownreasons,ofautoantibodies
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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
responsibleforadherence.Asa 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
epidermisandoralepithelium,whereasdesmoglein1isfoundprimarilyinthesuperficialportionoftheepidermis,
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
autoantibodiesdirectedagainstonlydesmoglein1willhistopathologicallyshowsuperficialintraepithelialcleftingof
theepidermis,butoralmucosawillnotbeaffected.Clinically,thefinescalyredlesionsofpemphigusfoliaceusor
pemphiguserythematosuswillbeevident.
Occasionally,apemphiguslikeoralandcutaneouseruptionmayoccurinpatientstakingcertainmedications(e.g.,
penicillamine,angiotensinconvertingenzyme[ACE]inhibitors,nonsteroidalantiinflammatorydrugs[NSAIDs])or
in patients with malignancy, especially lymphoreticular malignancies (socalled paraneoplastic pemphigus) (see
page716).Similarly,avarietyofotherconditionsmayproducechronicvesiculoulcerativeorerosivelesionsofthe
oralmucosa,andtheseoftenneedtobeconsideredinthedifferentialdiagnosis(seeTable163).Inaddition,arare
geneticconditiontermedchronicbenignfamilialpemphigusorHaileyHaileydiseasemayhaveerosivecutaneous
lesions,butoralinvolvementinthatprocessappearstobeuncommon.
ClinicalFeatures
Theinitialmanifestationsofpemphigusvulgarisofteninvolvetheoralmucosa,typicallyinadults.Theaverageage
at diagnosis is 50 years, although rare cases may be seen in childhood. No sex predilection is observed, and the
conditionseemstobemorecommoninpersonsofMediterranean,SouthAsian,orJewishheritage.
Patients usually complain of oral soreness, and examination shows superficial, ragged erosions and ulcerations
distributedhaphazardlyontheoralmucosa(Figs.1649to1652).Suchlesionsmayaffectvirtuallyanyoralmucosal
location,althoughthepalate,labialmucosa,buccalmucosa,ventraltongue,andgingivaeareofteninvolved.Patients
rarely report vesicle or bulla formation intraorally, and such lesions can seldom be identified by the examining
clinician,probablybecauseofearlyruptureofthethin,friableroofoftheblisters.Morethan50%ofthepatientshave
oral mucosal lesions before the onset of cutaneous lesions, sometimes by as much as 1 year or more. Eventually,
however,nearlyallpatientshaveintraoralinvolvement.Theskinlesionsappearasflaccidvesiclesandbullae(Fig.
1653) that rupture quickly, usually within hours to a few days, leaving an erythematous, denuded surface.
Infrequently ocular involvement may be seen, usually appearing as bilateral conjunctivitis. Unlike cicatricial
pemphigoid,theocularlesionsofpemphigustypicallydonotcausescarringandsymblepharonformation(seepage
719).
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FIG.1649
PemphigusVulgaris.Multipleerosionsoftheleftbuccalmucosaandsoftpalate.
FIG.1650
PemphigusVulgaris.Large,irregularlyshapedulcerationsinvolvingthefloorofthemouthandventraltongue.
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FIG.1651
PemphigusVulgaris.Multipleerosionsaffectingthemarginalgingiva.
PemphigusVulgaris.Thepatient,withaknowndiagnosisofpemphigusvulgaris,hadbeentreatedwith
immunosuppressivetherapy.Theoralerosionsshownhereweretheonlypersistentmanifestationofherdisease.
FIG.1652
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FIG.1653
PemphigusVulgaris.Thisflaccidcutaneousbullaischaracteristicofskininvolvement.
Withoutpropertreatment,theoralandcutaneouslesionstendtopersistandprogressivelyinvolvemoresurface
area.Acharacteristicfeatureofpemphigusvulgarisisthatabullacanbeinducedonnormalappearingskiniffirm
lateralpressureisexerted.ThisiscalledapositiveNikolskysign.
HistopathologicFeatures
Biopsy specimens of perilesional tissue show characteristic intraepithelial separation, which occurs just above the
basalcelllayeroftheepithelium(Fig.1654).Sometimestheentiresuperficiallayersoftheepitheliumarestripped
away,leavingonlythebasalcells,whichhavebeendescribedasresemblingarowoftombstones.Thecellsofthe
spinous layer of the surface epithelium typically appear to fall apart, a feature that has been termed acantholysis,
andtheloosecellstendtoassumearoundedshape(Fig.1655).Thisfeatureofpemphigusvulgariscanbeusedin
making a diagnosis based on the identification of these rounded cells (Tzanck cells) in an exfoliative cytologic
preparation. A mildtomoderate chronic inflammatory cell infiltrate is usually seen in the underlying connective
tissue.
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PemphigusVulgaris.Lowpowerphotomicrographofperilesionalmucosaaffectedbypemphigusvulgaris.An
intraepithelialcleftislocatedjustabovethebasalcelllayer.
FIG.1654
PemphigusVulgaris.Highpowerphotomicrographshowingrounded,acantholyticepithelialcellssittingwithinthe
intraepithelialcleft.
FIG.1655
The diagnosis of pemphigus vulgaris should be confirmed by direct immunofluorescence examination of fresh
perilesionaltissueortissuesubmittedinMichelssolution.Withthisprocedure,antibodies(usuallyIgGorIgM)and
complement components (usually C3) can be demonstrated in the intercellular spaces between the epithelial cells
(Fig.1656)inalmostallpatientswiththisdisease.Indirectimmunofluorescenceisalsotypicallypositivein80%to
90% of cases, demonstrating the presence of circulating autoantibodies in the patients serum. Enzymelinked
immunosorbentassays(ELISAs)havebeendevelopedtodetectcirculatingautoantibodiesaswell.
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PemphigusVulgaris.Photomicrographdepictingthedirectimmunofluorescencepatternofpemphigusvulgaris.
Immunoreactantsaredepositedintheintercellularareasbetweenthesurfaceepithelialcells,resultinginachickenwirepattern.
FIG.1656
It is critical that perilesional tissue be obtained for both light microscopy and direct immunofluorescence to
maximize the probability of a diagnostic sample. If ulcerated mucosa is submitted for testing, then the results are
ofteninconclusivebecauseofeitheralackofanintactinterfacebetweentheepitheliumandconnectivetissueora
greatdealofnonspecificinflammation.
TreatmentandPrognosis
A diagnosis of pemphigus vulgaris should be made as early in its course as possible because control is generally
easiertoachieve.Pemphigusisasystemicdisease;therefore,treatmentconsistsprimarilyofsystemiccorticosteroids
(usuallyprednisone),oftenincombinationwithotherimmunosuppressivedrugs(socalledsteroidsparingagents),
such as mycophenolate mofetil or 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
absorptionofthetopicalagents,resultinginagreatersystemicdose.Thepotentialsideeffectsassociatedwiththe
longtermuseofsystemiccorticosteroidsaresignificantandincludethefollowing:
Diabetesmellitus
Adrenalsuppression
Weightgain
Osteoporosis
Pepticulcers
Severemoodswings
Increasedsusceptibilitytoawiderangeofinfections
Ideally,aphysicianwithexpertiseinimmunosuppressivetherapyshouldmanagethepatient.Themostcommon
approachistouserelativelyhighdosesofsystemiccorticosteroidsinitiallytoclearthelesions,andthenattemptto
maintainthepatientonaslowadoseofcorticosteroidsasisnecessarytocontrolthecondition.Oftentheclinician
can monitor the success of therapy by measuring the titers of circulating autoantibodies using indirect
immunofluorescence, because disease activity frequently correlates with the abnormal antibody levels. The use of
rituximab,amonoclonalantibodythattargetsBlymphocytes,representsanotherpromisingapproachtomanaging
thisdisease,asittargetsthecellsresponsibleforproducingtheautoantibodiesthatcausepemphigus.
Pemphigus may undergo complete resolution, although remissions and exacerbations are common. One study
suggestedthatupto75%ofpatientswillhavediseaseresolutionafter10yearsoftreatment,althoughmostcenters
reportaremissionrateofapproximately30%.
Before the development of corticosteroid therapy, as many as 60% to 90% of these patients died, primarily as a
resultofinfectionsandelectrolyteimbalances.Eventoday,themortalityrateassociatedwithpemphigusvulgarisis
intherangeof5%to10%,usuallybecauseofthecomplicationsoflongtermsystemiccorticosteroiduse.
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ParaneoplasticPemphigus(NeoplasiaInducedPemphigus
ParaneoplasticAutoimmuneMultiorganSyndrome)
Paraneoplastic pemphigus is a rare vesiculobullous disorder that affects patients who have a neoplasm, usually
lymphoma or chronic lymphocytic leukemia. Approximately 250 cases have been documented. Although the
precise pathogenetic mechanisms are unknown, some evidence suggests abnormal levels of the cytokine,
interleukin6 (IL6), could be produced by host lymphocytes in response to the patients tumor. IL6 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, some investigators have described cutaneous and
mucosal damage that appears to be mediated by cytotoxic T lymphocytes in some cases of paraneoplastic
pemphigus.Asaresultofthismultifacetedimmunologicattack,thediseasemanifestsinanarrayofclinicalfeatures,
histopathologicfindings,andimmunopathologicfindingsthatmaybeperplexingiftheclinicianisunfamiliarwith
thiscondition.
ClinicalFeatures
Patients typically have a history of a malignant lymph
oreticular neoplasm, or less commonly, a benign lymph
oproliferativedisordersuchasangiofollicularlymphnodehyperplasia(Castlemandisease).Inapproximatelyone
third of reported cases, paraneoplastic pemphigus developed before a neoplasm was identified, 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. 1657) and oral
mucosa. Palmar or plantar bullae may be evident, a feature that is uncommon in pemphigus vulgaris. For other
patients,skinlesionscanappearmorepapularandpruritic,similartocutaneouslichenplanus.Thelipsoftenshow
hemorrhagic crusting similar to that of erythema multiforme (Fig. 1658). Oral mucosal involvement is an early,
consistent feature of paraneoplastic pemphigus, and patients develop multiple areas of erythema and diffuse,
irregular ulceration (Fig.1659), affecting virtually any oral mucosal surface. If the lesions remain untreated, then
theypersistandworsen.Somepatientsmaydeveloponlyoropharyngeallesions,withoutcutaneousinvolvement.
ParaneoplasticPemphigus.Thebullaandcrustedulcerationsonthispatient'sarmarerepresentativeofthe
polymorphouscutaneouslesions.
FIG.1657
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ParaneoplasticPemphigus.Crusted,hemorrhagicliplesionsmaybemistakenforerythemamultiformeorherpes
simplexinfection.
FIG.1658
FIG.1659
ParaneoplasticPemphigus.Thesediffuseoralulcerationsarequitepainful.
Othermucosalsurfacesarealsocommonlyaffected,with70%ofpatientshavinginvolvementoftheconjunctival
mucosa.Inthisarea,acicatrizing(scarring)conjunctivitisdevelops,similartothatseenwithcicatricialpemphigoid
(Fig. 1660). The anogenital, nasopharyngeal, esophageal, and respiratory tract mucosa may also be involved.
Involvementofthebronchiolarmucosaisparticularlysignificantbecausetheliningepitheliumsloughsandoccludes
thebronchiolarluminaandthealveoliofthelung,resultinginaconditionknownasbronchiolitisobliterans.
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FIG.1660
ParaneoplasticPemphigus.Ocularinvolvement.
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
intraepithelialclefting(likepemphigus)(Fig.1661).
FIG.1661
ParaneoplasticPemphigus.Thismediumpowerphotomicrographshowsbothintraepithelialandsubepithelialclefting.
Direct immunofluorescence studies may show a weakly positive deposition of immunoreactants (IgG and
complement) in the intercellular zones of the epithelium and/or a linear deposition of immunoreactants at the
basement membrane zone. Although antibodies directed against desmoglein 1 and 3, as well as the bullous
pemphigoidantigensareoftenproduced,antibodiesdirectedagainsttheplakinfamilyofdesmosomalcomponents
are more commonly identified and are more specific for paraneoplastic pemphigus. ELISA or immunoblotting
techniquesareusedtoconfirmthepresenceofantibodiesdirectedagainstperiplakinorenvoplakinspecifically.If
these tests are not available, then indirect immunofluorescence can be conducted using a transitional type of
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epithelium (e.g., rat urinary bladder mucosa) as the substrate due to its rich expression of plakins. This technique
shows a fairly specific pattern of antibody localization to the intercellular areas of the epithelium. Examples of
paraneoplasticpemphigusthatshowonlyalichenoidreactionwithnodemonstrableautoantibodyproductionhave
infrequentlybeendescribed.
Paraneoplastic pemphigus is often a very serious condition with a high morbidity and mortality rate, with some
series having a mortality rate of 90%. For the infrequent cases associated with a benign lymphoproliferative
condition,surgicalremovalofthetumormayresultinregressionoftheparaneoplasticpemphigus.Forthosecases
associated with malignancy, treatment usually consists of systemic prednisone combined with cyclosporine.
Cyclophosphamide, another immunosuppressive agent, may be added to this regimen, although other
immunosuppressiveandimmunemodulatingdrugsarealsobeingevaluated.Aswithpemphigusvulgaris,theskin
lesions usually respond more quickly to treatment than the oral lesions. Unfortunately, although the
immunosuppressive therapy often manages to control the autoimmune disease, this immunosuppression often
seems to trigger a reactivation of the malignant neoplasm. Thus a high mortality rate is seen, with patients
succumbing to complications of the vesiculobullous lesions, complications of immune suppressive therapy,
respiratory failure due to bronchiolitis obliterans, or progression of malignant disease. Occasionally, longterm
survivors are reported, but these seem to be in the minority. As more of these patients are identified, therapeutic
strategiescanbebetterevaluatedandmodifiedforoptimalcareinthefuture.
MucousMembranePemphigoid(CicatricialPemphigoidBenign
MucousMembranePemphigoid)
Evidencehasaccumulatedtosuggestthatmucousmembranepemphigoidrepresentsagroupofchronic,blistering,
mucocutaneous autoimmune diseases in which tissuebound autoantibodies are directed against one or more
components of the basement membrane. As such, this condition has a heterogeneous origin, with autoantibodies
being produced against any one of a variety of basement membrane components, all of which produce similar
clinical manifestations. The precise prevalence is unknown, but most authors believe that it is at least twice as
commonaspemphigusvulgaris.
The term pemphigoid is used because clinically it often appears similar (the meaning of the oid suffix) to
pemphigus.Theprognosisandmicroscopicfeaturesofpemphigoid,however,areverydifferent.
Althoughavarietyoftermshavebeenusedoverthedecadestodesignatethiscondition,agroupofexpertsfrom
bothmedicineanddentistrymetin1999andcametoanagreementthatmucousmembranepemphigoidwouldbe
themostappropriatenameforthedisease.Cicatricialpemphigoid,anothercommonlyusednameforthisprocess,is
derivedfromthewordcicatrix,meaningscar.Whentheconjunctivalmucosaisaffected,thescarringthatresultsis
the most significant aspect of this disorder because it invariably results in blindness unless the condition is
recognizedandtreated.Interestingly,theorallesionsseldomexhibitthistendencyforscarformation.
ClinicalFeatures
Mucous membrane pemphigoid usually affects older adults, with an average age of 50 to 60 years at the onset of
disease.Femalesareaffectedmorefrequentlythanmalesbya2:1ratio.Orallesionsareseeninmostpatients,but
othersites,suchasconjunctival,nasal,esophageal,laryngeal,andvaginalmucosa,aswellastheskin(Fig. 1662),
maybeinvolved.
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MucousMembranePemphigoid.Althoughcutaneouslesionsarenotcommon,tensebullaesuchasthesemaydevelop
ontheskinof20%ofaffectedpatients.(CourtesyofDr.CharlesCamisa.)
FIG.1662
Theorallesionsofpemphigoidbeginaseithervesiclesorbullaethatmayoccasionallybeidentifiedclinically(Fig.
1663). In contrast, patients with pemphigus rarely display such blisters. The most likely explanation for this
differenceisthatthepemphigoidblisterformsinasubepitheliallocation,producingathicker,strongerroofthanthe
intraepithelial, acantholytic pemphigus blister. Eventually, the oral blisters rupture, leaving large, superficial,
ulcerated,anddenudedareasofmucosa(Fig.1664).Theulceratedlesionsareusuallypainfulandpersistforweeks
tomonthsifuntreated.
MucousMembranePemphigoid.Oneormoreintraoralvesicles,asseenonthesoftpalate,maybedetectedinpatients
withcicatricialpemphigoid.Usually,ulcerationsoftheoralmucosaarealsopresent.
FIG.1663
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FIG.1664
MucousMembranePemphigoid.Large,irregularoralulcerationscharacterizethelesionsaftertheinitialbullaerupture.
Often this process is seen diffusely throughout the mouth, but it may be limited to certain areas, especially the
gingiva(Fig.1665).Gingivalinvolvementproducesaclinicalreactionpatterntermeddesquamativegingivitis(see
page148).Thispatternmayalsobeseeninotherconditions,suchaserosivelichenplanusor,muchlessfrequently,
pemphigusvulgaris.
MucousMembranePemphigoid.Oftenthegingivaltissuesaretheonlyaffectedsite,resultinginaclinicalpattern
knownasdesquamativegingivitis.Suchapatternmayalsobeseenwithlichenplanusandpemphigusvulgaris.
FIG.1665
Themostsignificantcomplicationofmucousmembranepemphigoid,however,isocularinvolvement.Although
exactfiguresarenotavailable,upto25%ofpatientswithorallesionsmayeventuallydevelopoculardisease.One
eyemaybeaffectedbeforetheother.Theearliestchangeissubconjunctivalfibrosis,whichusuallycanbedetected
byanophthalmologistusingslitlampmicroscopicexamination.Asthediseaseprogresses,theconjunctivabecomes
inflamed and eroded. Attempts at healing lead to scarring between the bulbar (lining the globe of the eye) and
palpebral(liningtheinnersurfaceoftheeyelid)conjunctivae.Adhesionscalledsymblepharonsresult(Fig.1666).
Withouttreatmenttheinflammatorychangesbecomemoresevere,althoughconjunctivalvesicleformationisrarely
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seen(Fig.1667).Scarringcanultimatelycausetheeyelidstoturninward(entropion).Thiscausestheeyelashesto
rubagainstthecorneaandglobe(trichiasis)(Fig.1668).Thescarringclosesofftheopeningsofthelacrimalglands
aswell,andwiththelossoftears,theeyebecomesextremelydry.Thecorneathenproduceskeratinasaprotective
mechanism;however,keratinisanopaquematerial,andblindnessensues.Endstageocularinvolvementmayalso
becharacterizedbyadhesionsbetweentheupperandlowereyelidsthemselves(Fig.1669).
MucousMembranePemphigoid.Althoughtheearliestocularchangesaredifficulttoidentify,patientswithocular
involvementmayshowadhesions(symblepharons)betweenthebulbarandpalpebralconjunctivaebeforesevereoculardamage
occurs.
FIG.1666
MucousMembranePemphigoid.Thediseasehascausedtheuppereyelidofthispatienttoturninward(entropion),
resultingintheeyelashesrubbingagainsttheeyeitself(trichiasis).Alsonotetheobliterationofthelowerfornixoftheeye.
FIG.1667
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MucousMembranePemphigoid.Apatientwithocularinvolvementshowssevereconjunctivalinflammation.An
ophthalmologistremovedthelowereyelashesbecauseoftrichiasisassociatedwithentropion.
FIG.1668
MucousMembranePemphigoid.Inthispatient,theocularinvolvementhasresultedinnearlycompletescarringbetween
theconjunctivalmucosaandtheeyelidsthemselves,producingblindness.
FIG.1669
Othermucosalsitesmayalsobeinvolvedandcauseconsiderabledifficultyforthepatient.Infemales,thevaginal
mucosallesionsmaycauseconsiderablepainduringattemptsatintercourse(dyspareunia).
Laryngeallesions,whicharefairlyuncommon,maybeespeciallysignificantbecauseofthepossibilityofairway
obstruction by the bullae that are formed. Patients who experience a sudden change in vocalization or who have
difficultybreathingshouldundergoexaminationwithlaryngoscopy.
Biopsyofperilesionalmucosashowsasplitbetweenthesurfaceepitheliumandtheunderlyingconnectivetissuein
the region of the basement membrane (Fig. 1670). A mild chronic inflammatory cell infiltrate is present in the
superficialsubmucosa.
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MucousMembranePemphigoid.Mediumpowerphotomicrographofperilesionaltissueshowscharacteristic
subepithelialclefting.
FIG.1670
Directimmunofluorescencestudiesofperilesionalmucosashowacontinuouslinearbandofimmunoreactantsat
thebasementmembranezoneinnearly90%ofaffectedpatients(Fig.1671).Theimmunedepositsconsistprimarily
of IgG and C3, although IgA and IgM may also be identified. One study has suggested that, when IgG and IgA
depositsarefoundinthesamepatient,thediseasemaybemoresevere.Alloftheseimmunoreactantsmayplaya
role in the pathogenesis of the subepithelial vesicle formation by weakening the attachment of the basement
membrane through a variety of mechanisms, including complement activation with recruitment of inflammatory
cells,particularlyneutrophils.
MucousMembranePemphigoid.Directimmunofluorescencestudiesshowadepositionofimmunoreactantsatthe
basementmembranezoneoftheepithelium.(CourtesyofDr.RonaldGrimwood.)
FIG.1671
Indirectimmunofluorescenceispositiveinonly5%to25%ofthesepatients,indicatingarelativelyconsistentlack
ofreadilydetectablecirculatingautoantibodies.Onetypeofmucousmembranepemphigoidproduceslowlevelsof
circulating autoantibodies to epiligrin (laminin5), a component of the basement membrane. Antiepiligrin mucous
membrane pemphigoid seems to have more widespread involvement, affecting oral, nasal, ocular, and laryngeal
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mucosa,comparedwithotherformsofmucousmembranepemphigoid.Incontrast,anothergroupofinvestigators
has shown that pemphigoid patients with only oral mucosal involvement have circulating autoantibodies to 6
integrin,acomponentofthehemidesmosome.
For an accurate diagnosis, perilesional tissuerather than the ulcerated lesion itselfshould be obtained. Often
theepitheliumintheareaofthelesionissolooselyattachedthatitstripsoffastheclinicianattemptstoperformthe
biopsy.Suchtissueisnotusuallyadequatefordiagnosticpurposesbecausetheinterfacebetweentheepitheliumand
connective tissue is no longer intact (although some investigators have shown positive immunofluorescence with
thistissue).
Other relatively rare conditions can mimic pemphigoid histopathologically. These include linear IgA bullous
dermatosis,anginabullosahemorrhagica,andepidermolysisbullosaacquisita.
LinearIgABullousDermatosis
LinearIgAbullousdermatosis,asthenameindicates,ischaracterizedbythelineardepositionofonlyIgAalongthe
basement membrane zone. Even though some cases of mucous membrane pemphigoid may have IgA antibodies,
linear IgA bullous dermatosis predominantly affects the skin and, therefore, can usually be distinguished from
mucousmembranepemphigoidonaclinicalbasis.
AnginaBullosaHemorrhagica
Angina bullosa hemorrhagica is a rare, poorly characterized oral mucosal disorder that exhibits variably painful,
bloodfilled vesicles or bullae, usually affecting the soft palate of middleaged or older adults (Fig. 1672). The
blisterstypicallyrupturespontaneouslyandhealwithoutscarring.Asubepithelialcleftisnotedmicroscopically.No
hematologic or immunopathologic abnormalities have been detected, and although the cause is unknown, many
patientshaveahistoryoftraumaorcorticosteroidinhaleruse.
AnginaBullosaHemorrhagica.Hemorrhagicblistersonthesoftpalateinapatientwhoregularlyusedacorticosteroid
inhaler.(CourtesyofDr.PeterLyu.)
FIG.1672
EpidermolysisBullosaAcquisita
Epidermolysisbullosaacquisitaisanimmunologicallymediatedconditioncharacterizedbyautoantibodiesdirected
againsttypeVIIcollagen,theprincipalcomponentoftheanchoringfibrils.Theanchoringfibrilsplayanimportant
roleinbondingtheepitheliumtotheunderlyingconnectivetissue.Asaresult,theirimmunologicdestructionleads
to the formation of bullous lesions of the skin and mucosa with minimal trauma. The disease was named
epidermolysis bullosa acquisita (acquisita means acquired) because of its clinical resemblance to the inherited
condition,dystrophicepidermolysisbullosa.Unliketheinheriteddisorder,epidermolysisbullosaacquisitatypically
affectsmiddleagedorolderadults.
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Oral lesions are present in nearly 50% of the cases, although such lesions are uncommon in the absence of
cutaneous lesions. To distinguish epidermolysis bullosa acquisita from other immunobullous diseases with
subepithelialclefting,aspecialtechniqueisperformed.Asampleofthepatientsperilesionalskinisincubatedina
concentratedsaltsolution;thiscausestheepitheliumtoseparatefromtheconnectivetissue,forminganartificially
induced bulla. Immunohistochemical evaluation shows deposition of IgG autoantibodies on the floor (connective
tissueside)ofthebullawheretypeVIIcollagenresides.Thisfindingisincontrasttothatofmostformsofmucous
membranepemphigoid,inwhichtheautoantibodiesareusuallylocalizedtotheroofoftheinducedblister.
Once the diagnosis of mucous membrane pemphigoid has been established by light microscopy and direct
immunofluorescence,thepatientshouldbereferredtoanophthalmologistwhoisfamiliarwiththeocularlesionsof
this condition for a baseline examination of the conjunctivae. This should be done whether or not the patient is
experiencingocularcomplaints.Inaddition,ifthepatientisexperiencingsymptomsatotheranatomicsites,thenthe
appropriatespecialistshouldbeconsulted.
Because this condition is characterized by heterogeneous pathogenetic mechanisms, it is not surprising that
treatments advocated over the years have been varied. In fact, there is no single good therapy for every patient;
treatment must be individualized, depending on lesional distribution, disease activity, and therapeutic response.
Perhaps as the various forms of pemphigoid are better defined immunopathologically, more specific, directed
therapycanbedevised.
TopicalAgents
Ifonlyorallesionsarepresent,sometimesthediseasecanbecontrolledwithapplicationofoneofthemorepotent
topical corticosteroids to the lesions several times each day. Once control is achieved, the applications can be
discontinued,althoughthelesionsarecertaintoflareupagain.Sometimesalternatedayapplicationpreventssuch
exacerbationsofdiseaseactivity.
Patientswithonlygingivallesionsoftenbenefitfromgoodoralhygienemeasures,whichcanhelptodecreasethe
severity of the lesions and reduce the amount of topical corticosteroids required. As an additional aid in treating
gingivallesions,aflexiblemouthguardmaybefabricatedtouseasacarrierforthecorticosteroidmedication.
SystemicAgents
If topical corticosteroids are unsuccessful, systemic treatments are available. Dapsone, which is a sulfa drug
derivative, can be used to treat patients with mildtomoderate involvement by mucous membrane pemphigoid.
Systemictreatmentwithdapsonetypicallyhasfewerserioussideeffectswhencomparedtosystemiccorticosteroid
therapy,forexample.
Somecentersreportgoodresultswithdapsone,butothersobservethataminorityofpatientsrespondadequately.
Contraindicationstoitsuseincludeglucose6phosphatedehydrogenasedeficiencyorallergytosulfadrugs.
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(inopenlabeltrials)tobeeffectiveincontrollingmucousmembranepemphigoid.Doubleblind,placebo
controlledstudiesonlargergroupsofpatientsshouldbedonetoconfirmthisformoftherapy,however.
For more severely affected patients with mucous membrane pemphigoid, corticosteroids plus other
immunosuppressive/immunemodulatingagents,(suchas,rituximab,mycophenolatemofetil,orcyclophosphamide)
maybeused.Thistypeofaggressivetreatmentisoftenindicatedinthepresenceofadvancingoculardisease,butit
must be realized that many of these patients are older and may have preexisting medical conditions that may
precludeaggressiveimmunesuppression.Somestudieshavesuggestedthattreatmentwithintravenous(IV)human
immunoglobulin (which is very expensive) may be more effective in managing ocular lesions of pemphigoid than
systemiccorticosteroidtherapy.Attemptsatsurgicalcorrectionofanysymblepharonsthatmighthaveformedmust
bedonewhenthediseaseisundercontrolorquiescent;otherwise,themanipulationofteninducesanacuteflareof
theocularlesions.
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BullousPemphigoid
Bullouspemphigoidisthemostcommonoftheautoimmuneblisteringconditions,occurringatanestimatedrate
of ten cases per million population per year. The disease is characterized by the production of autoantibodies
directedagainstcomponentsofthebasementmembrane.Inmanyrespects,bullouspemphigoidresemblesmucous
membranepemphigoid,butmostinvestigatorsnotethatthereareenoughdifferencestoconsiderthesediseasesas
distinctbutrelatedentities.Onesignificantdifferenceisthattheclinicalcourseinpatientswithbullouspemphigoid
isusuallycharacterizedbyperiodsofremissionfollowedbyrelapse,whereasthecourseinpatientswithmucous
membranepemphigoidisusuallyprotractedandprogressive.
ClinicalFeatures
Bullouspemphigoidtypicallydevelopsinolderpeople;mostpatientsarebetween75and80yearsofage.Nosexor
racialpredilectionisgenerallyreported,althoughonegroupofinvestigatorsnotedthatmenareoverrepresentedin
thisdiseasebya2:1marginwhenonecorrectsfortheskewingoftheagingpopulationtowardthefemalegender.
Pruritusisoftenanearlysymptom.Thisisfollowedbythedevelopmentofmultiple,tensebullaeoneithernormal
orerythematousskin(Fig.1673).Theselesionseventuallyruptureafterseveraldays,causingasuperficialcrustto
form.Eventually,healingtakesplacewithoutscarring.
BullousPemphigoid.Cutaneousvesiculobullouslesionsoftheheel.Thebullaeeventuallyrupture,leavinghemorrhagic
crustedareas.
FIG.1673
Oral mucosal involvement is uncommon, with approximately 10% to 20% of patients being affected. The oral
lesions,liketheskinlesions,beginasbullae,buttheytendtorupturesooner,probablyasaresultoftheconstant
lowgradetraumatowhichtheoralmucosaissubjected.Large,shallowulcerationswithsmooth,distinctmargins
arepresentafterthebullaerupture(Fig.1674).
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FIG.1674
BullousPemphigoid.Theseorallesionsappearaslarge,shallowulcerationsinvolvingthesoftpalate.
Microscopic examination of tissue obtained from the perilesional margin of a bulla shows separation of the
epithelium from the connective tissue at the basement membrane zone, resulting in a subepithelial separation.
Modest numbers of both acute and chronic inflammatory cells are typically seen in the lesional area, and the
presenceofeosinophilswithinthebullaitselfischaracteristic.
Direct immunofluorescence 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 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
upperportionofthelaminalucidaofthebasementmembrane.
Inadditiontothetissueboundautoantibodies,50%to90%ofthepatientsalsohavecirculatingautoantibodiesin
the serum, producing an indirect immunofluorescent pattern that is identical to that of the direct
immunofluorescence.Unlikepemphigusvulgaris,theantibodytitersseeninbullouspemphigoiddonotappearto
correlatewithdiseaseactivity.Theantibodiesalonedonotappeartobecapableofinducingbullaeinthisdisease.
Instead, binding of the antibodies to the basement membrane initiates the complement cascade, which in turn
resultsindegranulationofmastcells,withrecruitmentofneutrophilsandeosinophilstothearea.Thedamageto
the basement membrane is thought to be mediated by elastases and matrix metalloproteinases released by these
inflammatorycells.
Treatment of patients with mild or localized bullous pemphigoid consists of application of one of the stronger
topical corticosteroid preparations. Management of the patient with moderatetosevere, widespread bullous
pemphigoid consists of systemic immunosuppressive therapy. Moderate daily doses of systemic prednisone
usually control the condition, after which alternateday therapy may be given to reduce the risk of corticosteroid
complications.Ifthelesionsdonotrespondtoprednisonealone,thenanotherimmunosuppressiveagent(suchas,
azathioprine,methotrexate,ormycophenolatemofetil)maybeaddedtotheregimen.Dapsone,asulfaderivative,
may be used as an alternative therapeutic agent, and tetracycline and niacinamide therapy is reported to be
effectiveforsomepatients.Themoresevere,resistantcasesrequireprednisonecombinedwithcyclophosphamide;
however,thisregimenhasthepotentialforsignificantsideeffects.
The prognosis is generally good with respect to control of the skin lesions, with many patients experiencing
remission. Recent reports based on a relatively large series of bullous pemphigoid patients have suggested that
problemsfrequentlydevelopduetotheimmunosuppressivetherapyusedinthisolderadultpopulation.Mortality
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ratesthatarethreetimesthatofanageandsexmatchedcontrolpopulationmaybeseen,withapproximately20%
ofpatientsexpiring1yearafterdiagnosis.
ErythemaMultiforme
Erythema multiforme is a blistering, ulcerative mucocutaneous condition of uncertain etiopathogenesis. This is
probablyanimmunologicallymediatedprocess,althoughthecauseispoorlyunderstood.Inabout50%ofthecases,
thecliniciancanidentifyanapparentprecipitatingcause,usuallyaprecedinginfection,suchasherpessimplexor
Mycoplasma pneumoniae, or less commonly, exposure to any one of a variety of drugs and medications,
particularly antibiotics or analgesics. These agents may trigger the immunologic derangement that produces the
disease.SophisticatedtechniquesinmolecularbiologyhavedemonstratedthepresenceofherpessimplexDNAin
patientswithrecurrenterythemamultiforme,thussupportingtheconceptofanimmunologicprecipitatingevent.
Interestingly, direct and indirect immunofluorescence studies are nonspecific and are not really very useful
diagnosticallyexcepttoruleoutothervesiculobullousdiseases.
For many years it was thought that erythema multiforme exhibited a spectrum of severity, ranging from
erythemamultiformeminorthrougherythema multiforme major (traditionally thought to be synonymous with
StevensJohnsonsyndrome) and toxic epidermal necrolysis (Lyell disease). Most authorities currently feel that
erythemamultiformeminorandmajormayrepresentadistinctlydifferentprocessfromthelattertwoconditions.
Therefore, StevensJohnson syndrome and toxic epidermal necrolysis will be discussed separately in the next
section.
ClinicalFeatures
Erythemamultiformetypicallyhasanacuteonsetandusuallyaffectsyoungadultsintheir20sor30s,withaslight
female predilection in current series of cases. Prodromal symptoms are often present and include fever, malaise,
headache,cough,andsorethroat,occurringapproximately1weekbeforeonset.Theconditionmayshowvarying
degreesofseverityinaffectedpatients.Mildercases,knownaserythemamultiformeminor,usuallybeginwiththe
developmentofslightlyelevated,round,duskyredpatchesontheskinoftheextremities.Theselesionsmayhavea
varietyofappearances,however(multiformemeansmanyforms).Someoftheseskinlesionsdevelopfeaturesthatare
highly characteristic for the disease. These lesions appear as concentric circular erythematous rings resembling a
target or bullseye (targetlesions)(Fig.1675). In more severe cases, these may evolve into bullae with necrotic
centers.
ErythemaMultiforme.Theconcentricerythematouspatternofthecutaneouslesionsonthefingersresemblesatarget
orbull'seye.
FIG.1675
The oral cavity is the most frequently involved mucosal site, although the conjunctival, genitourinary, and
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respiratory mucosa also may be affected. Involvement of extraoral mucosal areas is usually associated with the
moresevereformofthiscondition,erythemamultiformemajor.
The frequency of oral involvement is difficult to determine and is reported to range from 25% to 70%.
Discrepanciesintheprevalencemaybeduetoreferralpatternsordegreeofscrutinyoftheoralmucosa.Theoral
lesionsbeginaserythematouspatchesthatundergoepithelialnecrosisandevolveintolarge,shallowerosionsand
ulcerationswithirregularborders(Fig.1676).Hemorrhagiccrustingofthevermilionzoneofthelipsiscommon
(Fig.1677).Theseorallesions,liketheskinlesions,emergequicklyandareuncomfortable.Sometimespatientsare
dehydratedbecausetheyareunabletoingestliquidsasaresultofmouthpain.Theulcerationsoftenhaveadiffuse
distribution. The lips, labial mucosa, buccal mucosa, tongue, floor of the mouth, and soft palate are the most
commonsitesofinvolvement.Usually,thegingivaeandhardpalatearerelativelyspared.
ErythemaMultiforme.Focalhemorrhagiccrustingofthelipsisseeninconjunctionwithdiffuseshallowulcerationsand
erosionsinvolvingthispatient'smandibularlabialmucosa.
FIG.1676
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ErythemaMultiforme.SamepatientasFigure1676.Diffuseshallowulcerationsofvaryingsizesarenotedontheright
buccalmucosa.Thepatienthadfinishedacourseofsulfamethoxazoleandtrimethoprimforaurinarytractinfectionafewdays
beforetheonsetofthelesions.
FIG.1677
ErythemaMultiformeMajor
Adiagnosisoferythemamultiformemajorcanbemadeiftwoormoremucosalsitesareaffectedinconjunctionwith
widespreadskinlesions.Inmostcasestheoralmucosaisinvolvedinadditiontoeithertheocular(Fig.1678)or
genitalmucosae.Withsevereocularinvolvement,scarring(symblepharonformation)mayoccur,similartothatin
cicatricialpemphigoid(seepage719).
ErythemaMultiformeMajor.WhileinvolvementofothermucosalsurfacesismorefrequentlyseenwithStevens
Johnsonsyndrome,thispatient'sconditionwasprecededbyoralherpeticinfection.Thisfinding,combinedwithhiscutaneous
manifestations,resultedinadiagnosisoferythemamultiformemajor,inthiscasecausingthesevereconjunctivitisdepictedinthis
photograph.
FIG.1678
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Histopathologic examination of the perilesional mucosa in erythema multiforme reveals a pattern that is
characteristicbutnotpathognomonic.Subepithelialorintraepithelialvesiculationmaybeseeninassociationwith
necrotic basal keratinocytes (Fig. 1679). A mixed inflammatory infiltrate is present, consisting of lymphocytes,
neutrophils, and often eosinophils. Sometimes these cells are arranged in a perivascular orientation (Fig. 1680).
Because the immunopathologic features are also nonspecific, the diagnosis is often based on the clinical
presentationandtheexclusionofothervesiculobullousdisorders.
ErythemaMultiforme.Thismediumpowerphotomicrographshowsinflammationandintraepithelialvesicleformationin
thebasilarportionoftheepithelium.Numerousnecroticandapoptoticeosinophilickeratinocytesarepresentintheblisterarea.
FIG.1679
ErythemaMultiforme.Thismediumpowerphotomicrographshowstheperivascularinflammatoryinfiltrate,typically
seeninerythemamultiforme.
FIG.1680
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Managementoferythemamultiforme,inmanyrespects,remainscontroversial.Inthepast,theuseofsystemicor
topical corticosteroids was often advocated, especially in the early stages of the disease. Although there is little
good clinical evidence from controlled trials that such treatment is beneficial, this treatment is typically used at
mostcenters.Ifacausativedrugisidentifiedorsuspected,thenitshouldbediscontinuedimmediately.
If the patient is dehydrated as a result of an inability to eat because of oral pain, then IV rehydration may be
necessaryalongwithtopicalanestheticagentstodecreasediscomfort.
Eventhoughthediseaseisselflimiting,usuallylasting2to6weeks,about20%ofpatientsexperiencerecurrent
episodes,usuallyinthespringandautumn.Ifrecurrentepisodesoferythemamultiformeareaproblem,thenan
initiatingfactor,suchasrecurrentherpesvirusinfectionordrugexposure,shouldbesought.Ifdiseaseistriggered
by herpes simplex, then continuous oral acyclovir or valacyclovir therapy can prevent recurrences. Very
infrequentlypatientsmayhavecontinuouslesionsoferythemamultiforme.Inmostcaseserythemamultiformeis
notlifethreateningexceptinitsmostsevereform.
StevensJohnsonSyndromeandToxicEpidermalNecrolysis
Inthepast,manydermatologistsconsideredStevensJohnsonsyndromeandtoxicepidermalnecrolysistorepresent
themostsevereendoftheerythemamultiformespectrum.Ascarefuldocumentationoftheclinicalfeaturesofthese
uncommondiseaseswascompiled,itbecameevidentthatthereweresubtle,butdistinct,differencesbetweenthese
two conditions. Although the inciting event in erythema multiforme is usually a herpesvirus infection, Stevens
Johnsonsyndromeandtoxicepidermalnecrolysisarealmostalwaystriggeredbydrugexposure,withmorethan
200differentmedicationshavingbeenimplicated.Recentstudieshaveshownthatthedamagetotheepitheliumis
duetoincreasedapoptosisoftheepithelialcells,andseveralmechanismshavebeenpostulatedtoaccountforthis
phenomenon.
ClinicalFeatures
The difference between StevensJohnson syndrome and toxic epidermal necrolysis is the degree of skin
involvement, with StevensJohnson syndrome having less than 10% of the body surface affected by lesions, and
toxicepidermalnecrolysishavingmorethan30%involvement.Thesesevereblisteringdiseasesarerare.Stevens
Johnsonsyndromeoccursatanaveragerateofonetosevencasespermillionpopulationperyear,whereastoxic
epidermalnecrolysisoccursatarateofaboutonecasepermillionperyear.In
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contrasttoStevensJohnsonsyndrome,whichisusuallyseeninyoungerpatients,toxic
epidermalnecrolysistendstooccurinpeopleover60yearsofage.Afemalepredilectionis
observed.
These patients usually have flulike prodromal signs and symptoms, including fever, malaise, sore throat,
headache,andlossofappetite.Withinafewdays,skinlesionsbegintodevelop,butunlikeerythemamultiforme,the
cutaneous lesions of StevensJohnson syndrome and toxic epidermal necrolysis initially appear on the trunk,
presenting as erythematous macules (completely flat). Within 1 to 14 days, however, sloughing of the skin and
flaccidbullaedevelop.Virtuallyallofthesepatientswillhavemucosalsitesofinvolvement(Fig.1681),particularly
theoralmucosa.Diffusesloughingofasignificantproportionoftheskinandmucosalsurfacesmakesitappearasif
the patient had been badly scalded (Figs. 1682 and 1683). If the patient survives, then the cutaneous process
resolves in 3 to 5 weeks; however, oral lesions may take longer to heal, and significant residual ocular damage is
evidentinhalfofthepatients.
StevensJohnsonSyndrome.Genitalulcerations,demonstratedinthispatientbytheinvolvementoftheglanspenis,
maybeacomponentofStevensJohnsonsyndrome,whichtendstobemoreseverethanerythemamultiformemajor.
FIG.1681
https://bookshelf.vitalsource.com/#/books/9781455770526/cfi/6/64!/4/2/2@0:0
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ToxicEpidermalNecrolysis.Thisseriousmucocutaneousdisorderischaracterizedbydiffusebullousskin
lesions.(CourtesyofDr.PeterLarsen.)
FIG.1682
ToxicEpidermalNecrolysis.Thedesquamationoftheskinofthefootischaracteristicofthediffusesloughing
cutaneouslesions.(CourtesyofDr.PeterLarsen.)
FIG.1683
Biopsy of a developing bulla of StevensJohnson syndrome or toxic epidermal necrolysis typically shows a
subepithelial blister that is characterized by degenerating, necrotic basal keratinocytes. The underlying connective
tissueusuallysupportsarathersparsepopulationofchronicinflammatorycells.
One of the most important aspects in managing patients with StevensJohnson syndrome and toxic epidermal
necrolysisisidentifyingandimmediatelydiscontinuinganydrugthatmightbeinitiatingthecondition.Becausethe
lesionsoftoxicepidermalnecrolysisareanalogoustothosesufferedbyburnpatients,managementofthesepatients
in the burn unit of the hospital is recommended. Corticosteroids should be avoided in the management of toxic
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epidermalnecrolysisbecausesomeinvestigatorshavefoundthatsuchdrugsmaybedetrimental.IVadministration
ofpooledhumanimmunoglobulinshasbeenshowninseveralopenlabeltrialstoproduceremarkableresolutionof
toxic epidermal necrolysis, presumably because of blockade of Fas ligand, which is believed to play a role in
inducingepithelialcellapoptosis.Themortalityrateinpatientswithtoxicepidermalnecrolysishistoricallyhasbeen
approximately25%to30%;therateinthosewithStevensJohnsonsyndromeis1%to5%.
ErythemaMigrans(GeographicTongueBenignMigratory
GlossitisWanderingRashoftheTongueErythemaAreata
MigransStomatitisAreataMigrans)
Erythemamigrans is a common benign condition that primarily affects the tongue. It is often detected on routine
examinationoftheoralmucosa.Thelesionoccursin1%to3%ofthepopulation.Someepidemiologicstudieshave
shownthatfemalesareaffectedmorefrequentlythanmalesbya2:1ratio,whereasotherseriesdonotidentifya
genderpredilection.Patientsoccasionallymayconsultahealthcareprofessionaliftheyhappentonoticetheunusual
appearanceoftheirtongueorifthelingualmucosabecomessensitivetohotorspicyfoodsasaresultoftheprocess.
Eventhougherythemamigranshasbeendocumentedformanyyears,theetiopathogenesisisstillunknown.Some
investigatorshavesuggestedthaterythemamigransoccurswithincreasedfrequencyinatopicindividuals;however,
one large epidemiologic study in the United States found no statistically significant association between erythema
migrans and a variety of conditions that had previously been postulated either to cause or influence this process.
Erythema migrans was not seen as frequently in cigarette smokers, while there seemed to be no significant
differences in frequency related to age, sex, oral contraceptive use, presence of allergies, diabetes mellitus, or
psychologicalordermatologicconditions.AsimilarstudyinTurkeyessentiallyagreedwiththesefindings,withthe
exceptionofanassociationwithahistoryofallergyoratopy.
ClinicalFeatures
Thecharacteristiclesionsoferythemamigransareseenontheanteriortwothirdsofthedorsaltonguemucosa.They
appear as multiple, welldemarcated zones of erythema (Figs.1684 and 1685), concentrated at the tip and lateral
bordersofthetongue.Thiserythemaisduetoatrophyofthefiliformpapillae,andtheseatrophicareasaretypically
surrounded at least partially by a slightly elevated, yellowwhite, serpentine or scalloped border (Fig. 1686). The
patient who is aware of the process is often able to describe the lesions as appearing quickly in one area, healing
withinafewdaysorweeks,andthendevelopinginaverydifferentarea.Frequently,thelesionbeginsasasmall
whitepatch,whichthendevelopsacentralerythematousatrophiczoneandenlargescentrifugally.Approximately
onethirdofpatientswithfissuredtongue(seepage11)areaffectedwitherythemamigransaswell.Somepatients
may have only a solitary lesion, but this is uncommon. The lesions are usually asymptomatic, although a burning
sensationorsensitivitytohotorspicyfoodsmaybenotedwhenthelesionsareactive.Onlyrarelyistheburning
sensationmoreconstantandsevere.
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ErythemaMigrans.Theerythematous,welldemarcatedareasofpapillaryatrophyarecharacteristicoferythema
migransaffectingthetongue(benignmigratoryglossitis).Notetheasymmetricaldistributionandthetendencytoinvolvethe
lateralaspectsofthetongue.
FIG.1684
ErythemaMigrans.LingualmucosaofadifferentpatientthantheoneinFig.1684.Thelateraldistributionofthe
lesionsisshown.
FIG.1685
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FIG.1686
ErythemaMigrans.Strikinginvolvementofthedorsalandlateralsurfacesofthetongue.
Veryinfrequently,erythemamigransmayoccuronoralmucosalsitesotherthanthetongue.Intheseinstances,the
tongueisalmostalwaysaffected;however,otherlesionsdeveloponthebuccalmucosa,onthelabialmucosa,and
(lessfrequently)onthesoftpalateorfloorofthemouth(Figs.1687and1688).Theselesionstypicallyproduceno
symptomsandcanbeidentifiedbyayellowwhiteserpentineorscallopedborderthatsurroundsanerythematous
zone.Thesefeaturesshouldpreventconfusionwithsuchconditionsascandidiasisorerythroplakia.
FIG.1687
ErythemaMigrans.Lesionsofthelowerlabialmucosa.
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ErythemaMigrans.Thesepalatallesionsshowwelldemarcatederythematousareassurroundedbyawhiteborder,
similartotheprocessinvolvingthetongue.
FIG.1688
If a biopsy specimen of the peripheral region of erythema migrans is examined, a characteristic histopathologic
patternisobserved.Hyperparakeratosis,spongiosis,acanthosis,andelongationoftheepithelialreteridgesareseen
(Fig.1689).Inaddition,collectionsofneutrophils(Munroabscesses) are observed within the epithelium (Fig.16
90);lymphocytesandneutrophilsinvolvethelaminapropria.Theintenseneutrophilicinfiltratemayberesponsible
forthedestructionofthesuperficialportionoftheepithelium,thusproducinganatrophic,reddenedmucosaasthe
lesion progresses. Because these histopathologic features are reminiscent of psoriasis,thisiscalledapsoriasiform
mucositis.Despitetheapparentlackofassociationbetweendermatologicconditionsanderythemamigransinsome
reports, at least one casecontrol study of psoriatic patients showed that erythema migrans occurred at a rate of
about10%;only2.5%ofanagematchedandsexmatchedpopulationwereaffected.ABrazilianstudydetermined
thatbothpatientswithpsoriasisandthosewithbenignmigratoryglossitisweremorelikelytohavethesamehuman
leukocyteantigen(HLA)group,namelyHLACw6.Whetherthesefindingsmeanthaterythemamigransrepresents
oralpsoriasisorthatpatientswithpsoriasisarejustmoresusceptibletoerythemamigransisopentodebate.
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ErythemaMigrans.Thislowpowerphotomicrographshowstheelongationofthereteridgeswithparakeratosisand
neutrophilicinfiltration.Suchfeaturesarealsocommoninpsoriasis,whichexplainswhythisisknownasapsoriasiform
mucositis.
FIG.1689
ErythemaMigrans.Thismediumpowerphotomicrographshowscollectionsofneutrophilsinthesuperficialspinous
layeroftheepithelium.
FIG.1690
Generallynotreatmentisindicatedforpatientswitherythemamigrans.Reassuringthepatientthattheconditionis
completely benign is often all that is necessary. Infrequently, patients may complain of tenderness or a burning
sensationthatissoseverethatitdisruptstheirlifestyle.Insuchcases,topicalcorticosteroids,suchasfluocinonideor
betamethasonegel,mayprovidereliefwhenappliedasathinfilmseveraltimesadaytothelesionalareas.
ReactiveArthritis(ReiterSyndrome)
Reactivearthritis represents a group of uncommon diseases that most likely have an immunologically mediated
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cause.Currentevidencesuggeststhatthesedisordersmaybetriggeredbyanyoneofseveralinfectiousagentsina
genetically susceptible person. In some instances, the arthritis will be accompanied by mucocutaneous findings,
includingorallesions.Aclassictriadofsignshasbeendescribed:
1.Nongonococcalurethritis
2.Arthritis
3.Conjunctivitis
However,mostpatientsdonotexhibitallthreeofthesesigns.Althoughreactivearthritiswithamucocu
taneous
componentisalsoknownasReitersyndrome,someauthorshaveadvocatedremovingtheReitereponymbecauseof
HansReitersNazicriminalactivitiesduringWorldWarII,andhewasnotthefirsttodescribethissyndrome.
Itisinterestingthatreactivearthritishasbeenreportedwithsomefrequencyinpatientsinfectedwiththehuman
immunodeficiencyvirus(HIV).
ClinicalFeatures
Reactivearthritisisparticularlyprevalentinyoungadultmen.Insomeseries,amaletofemaleratioofupto9:1has
beenreported.Themajority(60%to80%)ofthesepatientsarepositiveforHLAB27,ahaplotypepresentinonly10%
ofthepopulation.Thesyndromeusuallydevelops1to4weeksafteranepisodeofdysenteryorvenerealdisease;in
fact,twoFrenchphysicianspublishedadescriptionofthisentityaffectingfourpostdysentericsoldiers1weekbefore
Reiterspaperappeared.
Urethritis is often the first sign and is seen in both affected males and females. Females may also have
inflammationoftheuterinecervix.Conjunctivitisusuallyappearsconcurrentlywiththeurethritis,andafterseveral
days,arthritisensues.Thearthritisusuallyaffectsthejointsofthelowerextremities,althoughTMJinvolvementhas
beenidentifiedinonethirdofthesepatients,typicallyaserosionofthecondylarhead.Skinlesionsoftentakethe
formofacharacteristiclesionoftheglanspenis(balanitiscircinata).Theselesionsdevelopinabout20%to30%of
patients with reactive arthritis, and they appear as wellcircumscribed erythematous erosions with a scalloped,
whitishlinearboundary.
Theorallesions,whichoccurinslightlylessthan20%ofpatientswiththisdisorder,aredescribedinvariousways.
Some reports mention painless erythematous papules distributed on the buccal mucosa and palate; other reports
describeshallow,painlessulcersthataffectthetongue,buccalmucosa,palate,andgingiva.Someauthorshaveeven
impliedthatgeographictonguemaybeacomponentofreactivearthritis,probablybecausegeographictonguebears
asuperficialresemblancetothelesionsofbalanitiscircinata.
TheAmericanRheumatismAssociationhasdefinedreactivearthritisbasedontheclinicalfindingsofaperipheral
arthritisthatlastslongerthan1monthinconjunctionwithurethritis,cervicitis,orboth.
Thehistopathologicfindingsofthecutaneouslesionsinpatientswithreactivearthritisarefrequentlysimilartothose
foundinpatientswithpsoriasis, particularly with respect to the presence of microabscesses within the superficial
layers of the surface epithelium. Other features in common with psoriasis include hyperparakeratosis with
elongated,thinreteridges.
Some patients with reactive arthritis experience spontaneous resolution of their disease after 3 to 12 months, but
manyothershavechronicsymptomsthatmaywaxandwane.Treatmentmaynotbenecessaryforthemildercases.
NSAIDs are initially used for managing arthritis, and sulfasalazine may be helpful in resolving cases that do not
respond. Immunosuppressive or immune modulating agents, including corticosteroids, azathioprine, etanercept,
andmethotrexate,arereservedforthemostresistantcasesiftheyarenotassociatedwithHIVinfection.
Physical therapy probably helps to reduce joint fibrosis associated with arthritis. About 15% to 20% of patients
withthisdisorderhaveseveredisability,usuallyfromarthritis.
LichenPlanus
Lichenplanusisarelativelycommon,chronicdermatologicdiseasethatoftenaffectstheoralmucosa.Thestrange
nameoftheconditionwasprovidedbytheBritishphysicianErasmusWilson,whofirstdescribeditin1869.Lichens
are primitive plants composed of symbiotic algae and fungi. The term planus is Latin for flat. Wilson probably
thoughtthattheskinlesionslookedsimilarenoughtothelichensgrowingonrockstomeritthisdesignation.Even
though the term lichen planus suggests a flat, fungal condition, current evidence indicates that this is an
immunologicallymediatedmucocutaneousdisorder.
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Avarietyofmedicationsmayinducelesionsthatcanappearclinicallyverysimilartotheidiopathicformofthe
condition; however, the term lichenoid mucositis (or lichenoid dermatitis, depending on the site involved) is
probably a better name for the drugrelated alterations (see page 317). Similarly, foreign material that becomes
inadvertentlyembeddedinthegingivamayelicitahostresponsethatistermedlichenoidforeignbodygingivitis
(seepage146).ReportsofhepatitisCinfectionassociatedwithorallichenplanusoccasionallyhaveappearedinthe
literature,usuallyfromtheMediterraneancountries,butthisdoesnotappeartobeasignificantassociationinthe
UnitedStatesorGreatBritain.Morerecent,carefullycontrolledepidemiologicstudiesdonotappeartosupportan
associationoforallichenplanuswithhepatitisC.However,geneticinfluencespresumablymayhaveaneffectonthe
expressionoflichenplanusinselectpopulations.
The relationship of stress or anxiety to the development of lichen planus is controversial, and most cited cases
appear to be anecdotal or lack appropriate controls. Those studies that have applied psychologic questionnaires
oftenfindincreasedlevelsofanxietyinthesepatients;however,manypatientswhohavebeentoldthattheyhave
lichen planus are aware that anxiety has been linked to the disorder. Whether this awareness may influence the
mannerinwhichtheyanswerthepsychologicquestionnairescouldbedebated.Inonestudythatusedpsychologic
questionnairestoattempttoresolvethisquestion,patientswithorallichenplanushadnogreaterdegreeofstressin
their lives than did agematched and sexmatched control patients. It might be that stress has no bearing on the
pathogenesis of lichen planus; however, an alternative explanation might be that those patients who have lichen
planussimplyrespondinthisfashiontolevelsofstressthatdonotinducelesionsinotherpeople.
ClinicalFeatures
Mostpatientswithlichenplanusaremiddleagedadults.Itisrareforchildrentobeaffected.Womenpredominate
inmostseriesofcases,usuallybya3:2ratioovermen.Approximately1%ofthepopulationmayhavecutaneous
lichenplanus.Theprevalenceoforallichenplanusisbetween0.1%and2.2%.
Theskinlesionsoflichenplanushavebeenclassicallydescribedaspurple,pruritic,polygonalpapules(Fig.1691).
Theseusuallyaffecttheflexorsurfacesoftheextremities.Excoriationsmaynotbevisible,despitethefactthatthe
lesionsitch,becauseithurtsthepatientwhenheorshescratchesthem.
FIG.1691
LichenPlanus.Thecutaneouslesionsonthewristappearaspurple,polygonalpapules.
Careful examination of the surface of the skin papules reveals a fine, lacelike network of white lines (Wickham
striae)(Fig.1692). Other sites of extraoral involvement include the glans penis, the vulvar mucosa, and the nails.
Essentiallytherearetwoformsoforallesions:reticularanderosive.
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LichenPlanus.Closerviewofaskinlesionoflichenplanus.Carefulexaminationshowsanetworkoffinewhitelines
(Wickhamstriae)onthesurfaceofthepapules.
FIG.1692
ReticularLichenPlanus
Reticularlichenplanusismuchmorecommonthantheerosiveform,buttheerosiveformpredominatesinseveral
studies.Thisisprobablybecauseofreferralbias(becausetheerosiveformissymptomaticand,therefore,thepatient
ismorelikelytobereferredtoanacademiccenterforevaluation).Thereticularformusuallycausesnosymptoms
and involves the posterior buccal mucosa bilaterally (Fig. 1693). Postinflammatory melanosis occasionally
accompaniesthereticularstriae,particularlyinpersonsofcolor(Fig.1694).Otheroralmucosalsurfacesmayalsobe
involvedconcurrently,suchasthelateralanddorsaltongue,thegingivae,thepalate,andvermilionborder(Fig.16
95).
LichenPlanus.Theinterlacingwhitelinesandpapulesaretypicalofreticularlichenplanusinvolvingthebuccal
mucosa,themostcommonsiteoforalinvolvement.
FIG.1693
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LichenPlanus.Inpersonsofcolorwhodeveloplichenplanus,itisnotunusualtoseepatchyareasofreactive(benign)
melanosisdevelopinthelesions,presumablyduetostimulationofthemelanocytesinthisareabytheinflammatorycellsthat
causethiscondition.
FIG.1694
FIG.1695
LichenPlanus.Reticularlesionsofthelowerlipvermilion.
Reticularlichenplanusisthusnamedbecauseofitscharacteristicpatternofinterlacingwhitelines(alsoreferred
toasWickhamstriae);however,thewhitelesionsmayappearaspapulesinsomeinstances.Theselesionsaretypically
notstaticbutwaxandwaneoverweeksormonths(Fig.1696).Thereticularpatternmaynotbeasevidentinsome
sites,suchasthedorsaltongue,wherethelesionsappearmoreaskeratoticplaqueswithatrophyofthepapillae(Fig.
1697). In addition, superficial mucoceles may develop within, or adjacent to, mucosal areas that are involved by
lichenplanus.
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LichenPlanus.A,Amiddleagedwomanwithmildreticularlichenplanusoftheleftbuccalmucosa.B,Samepatient2
weekslater,showingexacerbationofthelesions.Suchwaxingandwaningischaracteristicoflichenplanus.
FIG.1696
LichenPlanus.Withinvolvementofthedorsaltonguebyreticularlichenplanus,thecharacteristicinterlacingstriae
seeninthebuccalmucosallesionsareusuallynotpresent.Instead,smoothwhiteplaquesaretypicallyobservedreplacingthe
normalpapillarysurfaceofthetongue.
FIG.1697
ErosiveLichenPlanus
Erosivelichenplanus,althoughnotascommonasthereticularform,ismoresignificantforthepatientbecausethe
lesionsareusuallysymptomatic.Clinically,thereareatrophic,erythematousareaswithcentralulcerationofvarying
degrees.Theperipheryoftheatrophicregionsisusuallyborderedbyfine,whiteradiatingstriae(Figs.1698and16
99).Sometimestheatrophyandulcerationareconfinedtothegingivalmucosa,producingthereactionpatterncalled
desquamativegingivitis(seepage148)(Fig.16100). In such cases, biopsy specimens should be obtained for light
microscopicandimmunofluorescentstudiesofperilesionaltissue,becausemucousmembranepemphigoid(seepage
718)andpemphigusvulgaris(seepage712)mayappearinasimilarfashion.
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LichenPlanus.Ulcerationofthebuccalmucosashowsperipheralradiatingkeratoticstriae,characteristicoforal
erosivelichenplanus.
FIG.1698
LichenPlanus.A,Thedorsalsurfaceofthetongueshowsextensiveulcerationcausedbyerosivelichenplanus.Note
thefinewhitestreaksattheperipheryoftheulcerations.B,Samepatientaftersystemiccorticosteroidtherapy.Muchofthe
mucosahasreepithelialized,withonlyfocalulcerationsremaining.
FIG.1699
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FIG.16100
LichenPlanus.Erosivelichenplanusoftenappearsasadesquamativegingivitis,producinggingivalerythemaand
tenderness.
If the erosive component is severe, epithelial separation from the underlying connective tissue may occur. This
resultsintherelativelyrarepresentationofbullouslichenplanus.
The histopathologic features of lichen planus are characteristic but may not be specific, because other conditions,
such as lichenoid drug reaction, lichenoid amalgam reaction, oral graftversushost disease (GVHD), lupus
erythematosus (LE), chronic ulcerative stomatitis, and oral mucosal cinnamon reaction may also show a similar
histopathologic pattern. Varying degrees of orthokeratosis and parakeratosis may be present on the surface of the
epithelium,dependingonwhetherthebiopsyspecimenistakenfromanerosiveorreticularlesion.
Thethicknessofthespinouslayercanalsovary.Thereteridgesmaybeabsentorhyperplastic,buttheyclassically
haveapointedorsawtoothedshape(Fig.16101).
LichenPlanus.A,Thislowpowerphotomicrographofanorallesionshowshyperkeratosis,sawtoothedreteridges,
andabandlikeinfiltrateoflymphocytesimmediatelysubjacenttotheepithelium.B,Higherpowerviewshowingmigrationof
lymphocytesintothelowerepitheliumwithinterfacedegenerationofthebasalcelllayer.
FIG.16101
Destructionofthebasalcelllayeroftheepithelium(hydropicdegeneration)isalsoevident.Thisisaccompanied
byanintense,bandlikeinfiltrateofpredominantlyTlymphocytesimmediatelysubjacenttotheepithelium(Fig.16
102).Degeneratingkeratinocytesmaybeseenintheareaoftheepitheliumandconnectivetissueinterfaceandhave
beentermedcolloid,cytoid,hyaline,orCivattebodies.Nosignificantdegreeofepithelialatypiaisexpectedinoral
lichenplanus,althoughlesionshavingasuperimposedcandidalinfectionmayappearworrisome.Theseshouldbe
reevaluated histopathologically after the candidal infection is treated. On occasion, the chronic inflammatory host
responsetotheatypicalcellsofepithelialdysplasiacanappearvirtuallyindistinguishablehistopathologicallyfrom
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lichenplanus,particularlyinmildercasesofepithelialdysplasia.Suchambiguitymaycontributetothecontroversy
relatedtothemalignanttransformationpotentialoflichenplanus.
LichenPlanus.A,Highpowerphotomicrographofnormalepitheliumshowinganintactbasalcelllayerandno
inflammation.B,Highpowerphotomicrographoflichenplanusshowingdegenerationofthebasalepitheliallayerandanintense
lymphocyticinfiltrateinthesuperficiallaminapropria.
FIG.16102
The immunopathologic features of lichen planus are nonspecific. Most lesions show the deposition of a shaggy
bandoffibrinogenatthebasementmembranezone.
Diagnosis
The diagnosis of reticular lichen planus can often be made based on the clinical findings alone. The interlacing
white striae appearing bilaterally on the posterior buccal mucosa are virtually pathognomonic. Difficulties in
diagnosismayariseifcandidiasisissuperimposedonthelesionsbecausetheorganismmayalterthecharacteristic
reticularpatternofthelichenplanus(Fig.16103).
LichenPlanus.A,Theserelativelynondescriptwhitelesionsaffectedthebuccalmucosaofapatientwhohad
complainedofaburningsensation.Histopathologicevaluationofthelesionshowedalichenoidmucositiswithsuperimposed
candidiasis.B,Samepatient2weeksafterantifungaltherapy.Oncethemucosalreactiontothecandidalorganismwaseliminated,
thecharacteristicwhitestriaeofreticularlichenplanuswereidentified.
FIG.16103
Erosive lichen planus is sometimes more challenging to diagnose (based on clinical features alone) than the
reticularform.Ifthetypicalradiatingwhitestriaeanderythematous,atrophicmucosaarepresentattheperipheryof
welldemarcated ulcerations on the posterior buccal mucosa bilaterally, then the diagnosis can sometimes be
renderedwithoutthesupportofhistopathologicfindings.However,abiopsy,oftenwithdirectimmunofluorescence
studies, may be necessary to rule out other ulcerative or erosive diseases, such as lupus erythematosus or chronic
ulcerativestomatitis.
Specimensofisolatederosivelichenoidlesions,particularlythoseofthesoftpalate,thelateralandventraltongue,
orthefloorofthemouth,shouldbeobtainedforbiopsytoruleoutpremalignantchangesormalignancy.Another
conditionthatmaymimicanisolatedlesionoflichenplanus,bothclinicallyandhistopathologically,isalichenoid
reactiontodentalamalgam(seepage324).
Reticular lichen planus typically produces no symptoms, and no treatment is needed. Occasionally, affected
patientsmay have superimposed candidiasis, in which case they may complain of a burning sensation of the oral
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mucosa.Antifungaltherapyisnecessaryinsuchacase.Someinvestigatorsrecommendannualreevaluationofthe
reticularlesionsoforallichenplanus.
Erosive lichen planus is often bothersome because of the open sores in the mouth. Because it is an
immunologically mediated condition, corticosteroids are recommended. The lesions respond to systemic
corticosteroids, but such drastic therapy is usually not necessary. One of the stronger topical corticosteroids (e.g.,
fluocinonide,betamethasone,orclobetasolgel)appliedasathinfilmseveraltimesperdaytothemostsymptomatic
areasisusuallysufficienttoinducehealingwithin1or2weeks.Thepatientshouldbewarnedthattheconditionwill
undoubtedly flare up again, in which case the corticosteroids should be reapplied. In addition, the possibility of
iatrogeniccandidiasisassociatedwithcorticosteroiduseshouldbemonitored(Fig.16104).Someinvestigatorshave
recommendedcompoundingcorticosteroidointmentswithanadhesivemethylcellulosebase,butpatientcompliance
may be reduced because this material is difficult to apply. Although the use of agents (such as, topical retinoids,
tacrolimus,mycophenolatemofetil,orcyclosporine)hasoccasionallybeenadvocatedforrecalcitrantcasesoferosive
lichenplanus,reportsoftheirefficacyhaveusuallybeenlimitedtosmallseriesofcasesorhavebeencontradictory.
Furthermore,theirsideeffectscanbesignificant,andinthecaseoftacrolimusorcyclosporine,thecostofthedrug
maybeprohibitive.Someinvestigatorssuggestthatpatientswithoralerosivelichenplanusbeevaluatedevery3to6
months,particularlyifthelesionsarenottypical.
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LichenPlanus.A,Thispatientwasdiagnosedwitherosivelichenplanusaffectingthebuccalmucosaandwastreated
withtopicalcorticosteroids.B,Samepatient2weekslater.Thecreamywhiteplaquesofpseudomembranouscandidiasishave
developedasaresultofthecorticosteroidtherapy.C,Samepatientafterantifungaltherapy.Atthispoint,hewasasymptomatic.
FIG.16104
Thequestionofthemalignantpotentialoflichenplanus,particularlytheerosiveform,isyettoberesolved.Most
cases of reported malignant transformation are rather poorly documented. Some of these reported cases may not
have been true lichen planus, but rather they may have actually been dysplastic leukoplakias with a secondary
lichenoidinflammatoryinfiltratethatmimickedlichenplanus(lichenoiddysplasia).Inaddition,theargumentcan
be made that because both lichen planus and squamous cell carcinoma are not rare, some people may have both
problemssimultaneously,andthetwoprocessesmaybeunrelatedtooneanother.Conversely,someinvestigators
saythattheatrophicepitheliumoflichenplanusmaybemoresusceptibletotheactionofcarcinogens,resultingin
an increased risk of malignant transformation. Two studies have examined the molecular characteristics of classic
reticular lichen planus, comparing the loss of heterozygosity at purported tumor suppressor gene loci in these
lesionswiththatofvaryinggradesoforalepithelialdysplasia,squamouscellcarcinoma,normaloralmucosa,and
oralreactivelesions.Themolecularprofileoforallichenplanusmorecloselyresembledthatofnormalorreactive
oralmucosa,afindingthatprovideslesssupportfortheconceptoflichenplanusbeingprecancerous.Anotherstudy
evaluated the malignant transformation rate of typical oral lichen planus compared with oral lichenoid lesions.
Thelichenoidlesionshadsomefeaturesoflichenplanus,butwerenotcompletelyrepresentative,eitherclinicallyor
histopathologically, of that disease. These investigators found that there was no transformation of characteristic
lichen planus, although several of the lichenoid lesions developed into squamous cell carcinoma. Additional
prospectiveclinicalstudieswithstrictclinicalandhistopathologiccriteriaforthedefinitionoforallichenplanuswill
needtobeperformedtoresolvethisquestion.Ifthepotentialformalignanttransformationexists,thenitappearsto
besmall.Mostofthereportedcaseshavebeenconfinedtopatientswitheithertheerosiveorsocalledplaquetype
formoflichenplanus.
ChronicUlcerativeStomatitis
Chroniculcerativestomatitisisanotherimmunemediateddisorderthataffectstheoralmucosa.Thisconditionwas
initiallydescribedin1989,andslightlymorethan40caseshavebeenreported.Althoughtheprecisepathogenetic
mechanisms are unknown, these patients develop autoantibodies against a 70kD nuclear protein, Np63, an
isoform of p63, and in vitro studies suggest that these antibodies play a role in development of this disease by
interruptingthenormalmaintenanceoftheepithelium/connectivetissueinterface.
Theprevalenceofthisdiseasemaybemorecommonthanisrealized.Becauseofitsclinicalsimilaritytoerosive
lichen planus, it is possible that only a clinical diagnosis is made when an affected patient is encountered, and a
biopsyisnotperformed.Evenifabiopsyisdone,thetissueisoftensubmittedforroutinelightmicroscopyalone,
and the direct immunofluorescence studies that are required for its diagnosis are not ordered. Distinction from
lichen planus should be made because chronic ulcerative stomatitis typically does not respond as well to
corticosteroidtherapy,andjustasisthecasewithlupuserythematosus(LE),chroniculcerativestomatitisoftencan
beeffectivelytreatedusingantimalarialdrugs.
ClinicalFeatures
Chroniculcerativestomatitisusuallyaffectsadultwomen,andthemeanageatdiagnosisislateinthesixthdecade
of life. The condition may appear as desquamative gingivitis, although ulcerations or erosions of the tongue or
buccal mucosa are also quite common (Fig. 16105). 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
immunemediated conditions, the severity of the oral lesions tends to wax and wane. Fewer than 20% of affected
patientswilldevelopconcurrentlichenoidskinlesions.
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ChronicUlcerativeStomatitis.A,Gingivallesionshavingadesquamativegingivitispresentation,requiringbiopsy
withdirectimmunofluorescencestudiesfordiagnosis.B,Buccalmucosalinvolvement.Thelesionsappearsomewhatlichenoid,
althoughclassicWickhamstriaearenotevident.
FIG.16105
Although the histopathologic features of chronic ulcerative stomatitis are similar to those of lichen planus, the
epitheliumisgenerallymoreatrophicandtheinflammatoryinfiltrateusuallycontainssignificantnumbersofplasma
cellsinadditiontolymphocytes(Fig.16106).Artifactualepithelialseparationfromtheunderlyingconnectivetissue
isnotunusual.
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ChronicUlcerativeStomatitis.A,Lowpowerphotomicrographshowingepithelialatrophywithaheavychronic
inflammatorycellinfiltrateinthesuperficiallaminapropria.B,Highpowerphotomicrographshowinginterfacedegenerationofthe
basilarepitheliuminassociationwiththeinflammation.Unlikelichenplanus,thisinfiltrateincludesnumerousplasmacells,aswell
aslymphocytes.
FIG.16106
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
immunofluorescencestudies,autoantibodies(usuallyIgG)thataredirectedagainstthenucleiofstratifiedsquamous
epithelial cells in the basal and parabasal regions of the epithelium are detected (Fig. 16107). Indirect
immunofluorescencestudiesarealsopositiveforthesestratifiedepitheliumspecificantinuclearantibodies(ANAs),
and some investigators believe that confirmation of the diagnosis is necessary using serum for indirect
immunofluorescenceevaluation.AnELISAtesthasbeendeveloped,andifitbecomescommerciallyavailable,this
should make screening for this condition much more costeffective. Other immunemediated conditions (e.g.,
systemicsclerosisandLE)mayshowANAdepositionwithdirectimmunofluorescence;however,nucleithroughout
theentirethicknessoftheepitheliumarepositivewiththosediseases.
ChronicUlcerativeStomatitis.DirectimmunofluorescencestudiesshowpresenceofIgGinthebasalandparabasal
epithelialnuclei.
FIG.16107
Unlikethelesionsoferosivelichenplanus,thelesionsassociatedwithchroniculcerativestomatitismaynotrespond
aswelltotopicalorsystemiccorticosteroidtherapy.Ifthelesionsarenotadequatelycontrolledwithcorticosteroids,
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then management with hydroxychloroquine, an antimalarial drug, should be considered. Hydroxychloroquine

therapy, however, requires both periodic ophthalmologic evaluation to monitor for drugrelated retinopathy and
periodichematologicevaluation.
GraftVersusHostDisease
Graftversushost disease (GVHD) occurs mainly in recipients of allogeneic bone marrow transplantation, a
procedureperformedonapproximately8000patientsintheUnitedStateseachyear.Suchtransplantsareperformed
atmajormedicalcenterstotreatlifethreateningdiseasesofthebloodorbonemarrow,suchasleukemia,lymphoma,
multiple myeloma, aplastic anemia, thalassemia, sickle cell anemia, or disseminated metastatic disease. Cytotoxic
drugs, radiation, or both may be used to destroy the malignant cells, but in the process the normal hematopoietic
cellsofthepatientaredestroyed.Toprovidethepatientwithanimmunesystem,anHLAmatcheddonormustbe
found.Thedonorsupplieshematopoieticstemcellsobtainedfrombonemarrow,peripheralblood,orumbilicalcord
blood. These stem cells are transfused into the patient, whose own hematopoietic and immune cells have been
destroyed. The transfused hematopoietic cells make their way to the recipients bone marrow and begin to
reestablishnormalfunction.
Unfortunately, the HLA match is not always exact, and despite the use of immunomodulating and
immunosuppressivedrugs(suchas,cyclosporine,methotrexate,andprednisone),theengraftedcellsoftenrecognize
thattheyarenotintheirnativeenvironment.Whenthishappens,thesecellsstartattackingwhattheyperceiveasa
foreignbody.TheresultofthisattackisGVHD,anditcanbequitedevastatingtothepatient.
In recent years, oncologists have taken advantage of this type of immunologic attack when treating leukemia
patients, and often a beneficial graftversusleukemia effect is seen when the donor cells interpret the leukemic
cellsasbeingforeign.Forolderpatients,whotendtohavemoresignificantsideeffectswithtraditionalbonemarrow
transplantation, the concept of a miniallograft has been developed. Not all of the patients white blood cells
(WBCs) are destroyed in this procedure, which is also known as nonmyeloablative allogenic hematopoietic cell
transplantation,toallowthedonorcellstomountamoreaggressiveassaultonthepatientsleukemiccells.
Autologous stem cell transplantation has also become an increasingly popular method of treatment for some of
these lifethreatening diseases. Because these cells are derived from the patient, there is no risk of GVHD in this
setting.
ClinicalFeatures
ThesystemicsignsofGVHDarevaried,dependingontheorgansysteminvolvedandwhethertheproblemisacute
orchronic.TheseverityofGVHDdependsonseveralfactors,withmilderdiseaseseeninpatientswhohaveabetter
histocompatibilitymatch,areyounger,havereceivedcordblood,andarefemale.
AcuteGVHDistypicallyobservedwithinthefirstfewweeksafterbonemarrowtransplantation.Althoughacute
GVHDhasarbitrarilybeendefinedasoccurringwithin100daysaftertheprocedure,mostinvestigatorsmakethis
diagnosis based on the clinical features rather than a specific time point. The disease affects about 50% of bone
marrowtransplantpatients.Theskinlesionsthatdevelopmayrangefromamildrashtoadiffuseseveresloughing
that resembles toxic epidermal necrolysis (see page 725). These signs may be accompanied by diarrhea, nausea,
vomiting,abdominalpain,andliverdysfunction.
ChronicGVHDmayrepresentacontinuationofapreviouslydiagnosedcaseofacuteGVHD,oritmaydevelop
later than 100 days after bone marrow transplantation, sometimes not appearing for several years after the
procedure.ChronicGVHDcanbeexpectedtodevelopin30%to70%ofbonemarrowtransplantrecipients,andit
oftenmimicsanyoneofavarietyofautoimmuneconditions,suchassystemiclupuserythematosus(SLE),Sjgren
syndrome,orprimarybiliarycirrhosis.Skininvolvement,whichisthemostcommonmanifestation,mayresemble
lichenplanusorevensystemicsclerosis.
TheoralmucosalmanifestationsofGVHDcanalsovary,dependingonthedurationandseverityoftheattackand
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.InmostpatientswithoralGVHD,thereisafine,reticularnetworkofwhitestriaethatresemblesorallichen
planus,althoughamorediffusepatternofpinpointwhitepapuleshasalsobeendescribed(Figs.16108to16110).
Thetongue,thelabialmucosa,andthebuccalmucosaaretheoralmucosalsitesmostfrequentlyinvolved.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.
Ulcerationsthatarerelatedtothechemotherapeuticconditioningandneutropenicstateofthepatientoftendevelop
duringthefirst2weeksafterbonemarrowtransplantation.Ulcersthatpersistlongerthan2weeksmayrepresent
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acute GVHD, and these should be differentiated from intraoral herpesvirus infection or bacterial infection. Bone
marrowtransplantpatientshaveasmallbutincreasedriskforthedevelopmentofbothoralandcutaneousepithelial
dysplasiaandsquamouscellcarcinoma.Demarcatedwhiteorredplaquesoftheoralmucosathatdonothavethe
characteristiclichenoidfeaturesshouldbebiopsiedtoruleoutpreneoplasticorneoplasticchanges(Fig.16111).
GraftVersusHostDisease(GVHD).Confluent,interlacingwhitelinearlesionsofthevermilionzonesuperficially
resembleorallichenplanus.
FIG.16108
FIG.16109
GraftVersusHostDisease(GVHD).Lichenoidlesionsoftheleftbuccalmucosa.
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GraftVersusHostDisease(GVHD).Involvementofthetongueshowingerosionsandulcerationsthatresemble
erosivelichenplanus.
FIG.16110
SquamousCellCarcinomaArisinginGraftVersusHostDisease(GVHD).Erythematous,ulceratedmassarisingonthe
lateralborderofthetongue.Notethesurroundingmucosalerosions,whichrepresentGVHD.
FIG.16111
Xerostomiaisalsoacommoncomplaint.Ifthepatientisnottakingdrugsthatdrythemouth,itislikelythatthe
immunologic response is destroying the salivary gland tissue. Other evidence of salivary gland involvement
includesthedevelopmentofsmallsuperficialmucoceles,particularlyonthesoftpalate.
ThehistopathologicfeaturesofGVHDresemblethoseoforallichenplanustoacertaindegree.Bothlesionsdisplay
hyperorthokeratosis, short and pointed rete ridges, and degeneration of the basal cell layer. The inflammatory
response in GVHD is usually not as intense as in lichen planus. With advanced cases, an abnormal deposition of
collagenispresent,similartothepatterninsystemicsclerosis.Minorsalivaryglandtissueusuallyshowsperiductal
inflammationintheearlystages,withgradualacinardestructionandextensiveperiductalfibrosisappearinglater.
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Diagnosis
ThediagnosisofGVHDmaybedifficultbecauseofthevariedclinicalmanifestations.Suchadiagnosisisofgreat
clinicalsignificancetothepatientbecausecomplicationsoftheconditionanditstreatmentmaybelethal.Although
the diagnosis of GVHD is based on the clinical and histopathologic findings, each patient may have a different
constellationofsignsandsymptoms.Orallesionsappeartohavevalueasahighlypredictiveindexofthepresence
ofGVHD.
TheprimarystrategyfordealingwithGVHDistoreduceorpreventitsoccurrence.Carefultissuehistocompatibility
matching is performed, and the patient is given prophylactic therapy with immunomodulatory and
immunosuppressive agents, such as prednisone in combination with either cyclosporine or tacrolimus. If GVHD
develops,thenthedosesofthesedrugsmaybeincreasedorsimilarpharmacologicagents,suchasmycophenolate
mofetil,orazathioprine,maybeadded.ThedrugthalidomidehasshownsomepromiseforcasesofchronicGVHD
thathavebeenresistanttostandardtherapy.
TopicalcorticosteroidsmayfacilitatethehealingoffocaloralulcerationsassociatedwithGVHD,andsomereports
havesuggestedthattopicaltacrolimusmaybeusefulinmanagingulcersthatareresistanttocorticosteroids.Topical
anesthetic agents are administered to provide patient comfort while the lesions are present, although narcotic
analgesics may be required in some cases. The use of psoralen and ultraviolet A (PUVA) therapy also has been
shown to improve the cutaneous and oral lesions of patients with the lichenoid form of GVHD. If significant
xerostomia is present in a dentulous patient, then topical fluorides should be used daily to prevent xerostomia
relatedcaries.Ifsignificantamountsofsalivaryacinartissueremain,thentreatmentwithpilocarpinehydrochloride
or cevimeline hydrochloride may improve the salivary flow. Current recommendations are to evaluate the oral
statusofpatientsbeforebonemarrowtransplantationandeliminateanypotentialsourcesofinfection.Interestingly,
onestudyshowednodifferencesinposttransplantinfectionsorsurvivalbetweenagroupofpatientswhoreceived
dentaltreatmentbeforetheirtransplantandagroupwhodidnot.
Ingeneral,somedegreeofGVHDisexpectedinmostallogeneicbonemarrowtransplantrecipients.Theprognosis
dependsontheextenttowhichtheconditionprogressesandwhetherornotitcanbecontrolled.Thesignificanceof
this complication is reflected in the survival of more than 70% of patients with relatively mild GVHD at 6 years
posttransplant,comparedwithapproximately15%ofpatientswithsevereGVHD.
Psoriasis
Psoriasisisacommonchronicskindiseaseaffectingapproximately2%ofpeopleintheUnitedStates.Accordingto
someestimates,roughly6millionpeopleinthiscountryhavepsoriasis,andupto250,000newcasesarediagnosed
eachyear.
Psoriasisischaracterizedbyanincreasedproliferativeactivityofthecutaneouskeratinocytes.Recentadvancesin
cell kinetics, immunology, and molecular biology have increased the understanding of the etiopathogenesis of the
keratinocyte proliferation in this disorder. Although the triggering agent has yet to be identified, activated T
lymphocytes appear to orchestrate a complex scenario that includes abnormal production of cytokines, adhesion
molecules,chemotacticpolypeptides,andgrowthfactors.Geneticfactorsalsoseemtoplayarole,becauseasmany
asonethirdofthesepatientshaveaffectedrelatives.Currentlyninedifferentgeneticlocihavebeenidentifiedthat
mayberelatedtothedevelopmentofpsoriasis.Ifonetwininasetofidenticaltwinshaspsoriasis,thereisa35%to
72% chance that the other twin will have it. This suggests that genetic factors are not entirely responsible for the
condition,andthatoneormoreunidentifiedenvironmentalagentsmustinfluenceitspathogenesis.
ClinicalFeatures
Psoriasisoftenhasitsonsetduringthesecondorthirddecadeoflifeandtendstopersistforyears,withperiodsof
exacerbation and quiescence. Patients frequently report that the lesions improve during the summer and worsen
during the winter, an observation that may be related to lesional exposure to UV light. The lesions are typically
symmetricallydistributedincertainfavoredlocations,suchasthescalp,elbows,andknees.Theclassicdescriptionis
a welldemarcated, erythematous plaque with a silvery scale on its surface (Fig. 16112). The lesions are often
asymptomatic,butitisnotunusualforapatienttocomplainofitchinginfact,thetermpsoriasisisderivedfromthe
Greek word for itching. An unfortunate complication affecting approximately 11% of these patients is psoriatic
arthritis,whichmayinvolvetheTMJ.
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FIG.16112
Psoriasis.Characteristiccutaneouslesion,characterizedbyanerythematousplaquesurmountedbysilverykeratotic
scales.
Orallesionsmayoccurinpatientswithpsoriasis,buttheyaredistinctlyuncommon.Becausedescriptionsofthese
lesionshaverangedfromwhiteplaquestoredplaquestoulcerations,itisdifficulttodeterminethetruenatureof
intraoralpsoriasis(Fig.16113).Torenderadiagnosisofintraoralpsoriasis,someinvestigatorssaythattheactivity
oftheorallesionsshouldparallelthatofthecutaneouslesions.Someauthorsrefertoerythemamigrans(seepage
726)asintraoralpsoriasis,andtheprevalenceoferythemamigransinpsoriaticpatientsappearstobeslightlygreater
than that seen in the rest of the population. It is difficult, however, to prove a direct correlation of that common
mucosalalterationwithpsoriasis.
Psoriasis.Thisisanexampleofrelativelyrareinvolvementoftheoralmucosabypsoriasis.Theerythematouslinear
patchestendedtoflarewiththepatient'scutaneouslesions.(CourtesyofDr.GeorgeBlozis.)
FIG.16113
Microscopically,psoriasishasacharacteristicpattern.Thesurfaceepitheliumshowsmarkedparakeratinproduction,
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and the epithelial rete ridges are elongated (Fig. 16114). The connective tissue papillae, which contain dilated
capillaries,approachclosetotheepithelialsurface,andaperivascularchronicinflammatorycellinfiltrateispresent.
Inaddition,collectionsofneutrophils(Munroabscesses),areseenwithintheparakeratinlayer.
Psoriasis.Lowpowerphotomicrographshowingelongationofthereteridges,hyperkeratosis,andinflammationof
thepapillarydermis.
FIG.16114
With respect to oral lesions, good correlation with skin disease activity should be seen in addition to the
characteristichistopathologicfeatures,becauseotherintraorallesions,suchaserythemamigransandoralmucosal
cinnamonreaction(seepage322),exhibitapsoriasiformmicroscopicappearance.
The treatment of psoriasis depends on the severity of the disease activity. For mild lesions, no treatment may be
necessary.
For moderate involvement, topical corticosteroids are commonly prescribed in the United States. Coal tar
derivativesandkeratolyticagentsalsomaybeused.Othertopicaldrugsthathaveproveneffectiveincludevitamin
D3 analogues (calcipotriene, calcipotriol, and calcitriol), and tazarotene, a retinoid (vitamin A) compound. Newer
topical biologic agents include the calcineurin inhibitors, tacrolimus and pimecrolimus, although these are usually
reservedforrecalcitrantlesions.ExposuretoUVradiationmayalsobehelpfulformildtomoderatedisease.
For severe cases, psoralen and ultraviolet A (PUVA) therapy or ultraviolet B (UVB) therapy may be needed.
Methotrexateorcyclosporinemayalsobeusedassystemictreatmentsforseveredisease;however,thesedrugshave
significant side effects. Newer systemic biologic agents that target specific diseaserelated components include
infliximab,adalimumab,andetanercept(directedagainsttumornecrosisfactoralpha[TNF]);alefacept(directed
againstTcellreceptors);orustekinumab(directedagainstIL12andIL23).
Althoughthemortalityrateisnotincreasedinpatientswithpsoriasis,theconditionoftenpersistsforyearsdespite
therapy. A recent 30year prospective study has shown a definite increase in the risk for cutaneous squamous cell
carcinoma in psoriasis patients who have received over 350 lifetime PUVA treatments, but those who received
fewerthan150hadaverymodestincrease.Interestingly,theriskfordevelopmentofbasalcellcarcinomadidnot
seemtobesignificantlyelevated.
LupusErythematosus
Lupuserythematosus(LE)isaclassicexampleofanimmunologicallymediatedcondition,andisthemostcommon
of the socalled collagen vascular or connective tissue diseases in the United States, with more than 1.5 million
peopleaffected.Itmayexhibitanyoneofseveralclinicopathologicforms.
Systemic lupus erythematosus (SLE) is a serious multisystem disease with a variety of cutaneous and oral
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manifestations. There is an increase in the activity of the humoral limb (B lymphocytes) of the immune system in
conjunction with abnormal function of the T lymphocytes. Although genetic factors probably play a role in the
pathogenesis of SLE, the precise cause is unknown. Undoubtedly, interplay between genetic and environmental
factors occurs, for if SLE develops in one monozygotic (identical) twin, then the other twin has a 24% chance of
havingSLEaswell.Incontrast,ifonedizygotic(fraternal)twinhasSLE,thentheothertwinhasonlya2%chanceof
beingaffected.
Chronic cutaneous lupus erythematosus (CCLE) may represent a different, but related, process. It primarily
affectstheskinandoralmucosa,andtheprognosisisgood.
Subacute cutaneous lupus erythematosus (SCLE) is a third form of the disease, which has clinical features
intermediatebetweenthoseofSLEandCCLE.
ClinicalFeatures
SystemicLupusErythematosus
SLE can be a very difficult disease to diagnose in its early stages because it often appears in a nonspecific, vague
fashion, frequently with periods of remission or disease inactivity. Women are affected nearly 8 to 10 times more
frequentlythanmen.Theaverageageatdiagnosisis31years.Commonfindingsincludefever,weightloss,arthritis,
fatigue, and general malaise. In 40% to 50% of affected patients, a characteristic rash, having the pattern of a
butterfly,developsoverthemalarareaandnose(Fig.16115),typicallysparingthenasolabialfolds.Sunlightoften
makesthelesionsworse.
FIG.16115
SystemicLupusErythematosus(SLE).Theerythematouspatchesseeninthemalarregionsareacharacteristicsign.
Thekidneysareaffectedinapproximately40%to50%ofSLEpatients.Thiscomplicationmayultimatelyleadto
kidneyfailure;thusitistypicallythemostsignificantaspectofthedisease.
Cardiacinvolvementisalsocommon,withpericarditisbeingthemostfrequentcomplication.Atautopsynearly
50% of SLE patients display warty vegetations affecting the heart valves (LibmanSacks endocarditis). Its
significance is debatable, although some patients may develop superimposed subacute bacterial endocarditis on
theseotherwisesterileoutgrowthsoffibrinoidmaterialandconnectivetissuecells.
OrallesionsofSLEdevelopin5%to25%ofthesepatients,althoughsomestudiesindicateprevalenceashighas
40%.Thelesionsusuallyaffectthepalate,buccalmucosa,andgingivae.Sometimestheyappearaslichenoidareas,
but they may also look nonspecific or even somewhat granulomatous (Fig.16116). Involvement of the vermilion
zone of the lower lip (lupus cheilitis) is sometimes seen. Varying degrees of ulceration, pain, erythema, and
hyperkeratosis may be present. Other oral complaints such as xerostomia, stomatodynia, candidiasis, periodontal
disease, and dysgeusia have been described, but the direct association of these problems with SLE remains to be
proven.
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SystemicLupusErythematosus(SLE).Thisulcerationofthebuccalmucosaexhibitsfineradiatingwhitestriaeatits
periphery,clinicallyappearingsimilartoerosivelichenplanus.
FIG.16116
Confirming the diagnosis of SLE can often be difficult, particularly in the early stages. Criteria for making the
diagnosis of SLE have been established by the American Rheumatism Association, and these include both clinical
andlaboratoryfindings(Table164).
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TABLE164
PrevalenceofClinicalandLaboratoryManifestationsofSystemicLupusErythematosus
Findings
AffectedPatients(%)
SystemicSignsandSymptoms:Fatigue,Malaise,Fever,Anorexia,WeightLoss 95%
MUSCULOSKELETALSYMPTOMS
95%
Arthralgia/myalgia
95%
Nonerosivepolyarthritis
60%
CUTANEOUSSIGNS
80%
Photosensitivity
70%
Malarrash
50%
Oralulcers
40%
Discoidrash
20%
HEMATOLOGICSIGNS
85%
Anemia(chronicdisease)
70%
Leukopenia(
65%
Lymphopenia(
50%
Thrombocytopenia(
15%
Hemolyticanemia
10%
NEUROLOGICSIGNSANDSYMPTOMS
60%
Cognitivedisorder
50%
Headache
25%
Seizures
20%
CARDIOPULMONARYSIGNS
60%
Pleurisy,pericarditis,effusions
30%50%
Myocarditis,endocarditis
10%
RENALSIGNS
30%50%
Proteinuria>500mg/24hours,cellularcasts
30%50%
Nephroticsyndrome
25%
Endstagerenaldisease
5%10%
AdaptedfromHahnBH:Systemiclupuserythematosus.InLongoDL,FauciAS,KasperDL,etal,editors:Harrison'sprinciplesofinternal
medicine,ed18,NewYork,2012,McGrawHill,pp27242735.ReproducedwithpermissionofTheMcGrawHillCompanies.
ChronicCutaneousLupusErythematosus
Patients with CCLE usually have few or no systemic signs or symptoms, with lesions being limited to skin or
mucosalsurfaces.TheskinlesionsofCCLEmostcommonlypresentasdiscoidlupuserythematosus.Theybeginas
scaly,erythematouspatchesthatarefrequentlydistributedonsunexposedskin,especiallyintheheadandneckarea
(Fig.16117).Patientsmayindicatethatthelesionsareexacerbatedbysunexposure.Withtime,thelesionsmayheal
spontaneouslyinonearea,onlytoappearinanotherarea.Thehealingprocessusuallyresultsincutaneousatrophy
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.
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ChronicCutaneousLupusErythematosus(CCLE).Theskinlesionsarecharacterizedbyscaling,atrophy,and
pigmentarydisturbances,whicharemostevidentonsunexposedskin.
FIG.16117
InmostcasestheoralmanifestationsofCCLEessentiallyappearclinicallyidenticaltothelesionsoferosivelichen
planus.Unliketheorallesionsoflichenplanus,however,theorallesionsofCCLEseldomoccurintheabsenceof
skin lesions. An ulcerated or atrophic, erythematous central zone, surrounded by white, fine, radiating striae,
characterizestheorallesionofCCLE(Figs.16118and16119).Sometimestheerythematous,atrophiccentralregion
ofalesionmayshowafinestipplingofwhitedots.Aswitherosivelichenplanus,theulcerativeandatrophicoral
lesionsofCCLEmaybepainful,especiallywhenexposedtoacidicorsaltyfoods.
ChronicCutaneousLupusErythematosus(CCLE).Radiatingkeratoticstriaesurrounderythematouszonesofthe
buccalmucosa.Thesefeaturesaresimilartothoseoferosivelichenplanus.
FIG.16118
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ChronicCutaneousLupusErythematosus(CCLE).Oralinvolvementmayalsoincluderelativelynondescript
erythematouspatches,suchasthisoneinthepalate.
FIG.16119
SubacuteCutaneousLupusErythematosus
PatientswithSCLEhaveclinicalmanifestationsintermediatebetweenthoseofSLEandCCLE.Theskinlesionsare
themostprominentfeatureofthisvariation.Theyarecharacterizedbyphotosensitivityandare,therefore,generally
presentinsunexposedareas.Theselesionsdonotshowtheindurationandscarringseenwiththeskinlesionsof
CCLE.OrallesionssimilartothoseofCCLEhavebeendescribedinthisvariantoflupusaswell.Usually,therenal
or neurologic abnormalities associated with SLE are not present, although most patients will have arthritis or
musculoskeletalproblems.SCLEmaybetriggeredbyanyoneofavarietyofmedications(seepage317).
ThehistopathologicfeaturesoftheskinandorallesionsofthevariousformsofLEshowsomefeaturesincommon
butaredifferentenoughtowarrantseparatediscussions.
TheskinlesionsofCCLEarecharacterizedbyhyperkeratosis,oftendisplayingkeratinpackedintotheopeningsof
hair follicles (follicular plugging). In all forms of LE, degeneration of the basal cell layer is frequently observed,
andtheunderlyingconnectivetissuesupportspatchytodenseaggregatesofchronicinflammatorycells(Figs.16120
and16121).Inthedeeperconnectivetissue,theinflammatoryinfiltrateoftensurroundsthesmallbloodvessels.
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LupusErythematosus(LE).Lowpowerphotomicrographshowinghyperparakeratosiswithinterfacemucositisand
perivascularinflammation.
FIG.16120
FIG.16121
LupusErythematosus(LE).Highpowerphotomicrographoftheinterfacemucositis.
The oral lesions demonstrate hyperkeratosis, alternating atrophy and thickening of the spinous cell layer,
degeneration of the basal cell layer, and subepithelial lymphocytic infiltration. These features may also be seen in
oral lichen planus; however, the two conditions can usually be distinguished by the presence in LE of patchy
deposits of a periodic acidSchiff (PAS)positive material in the basement membrane zone, subepithelial edema
(sometimes to the point of vesicle formation), and a more diffuse, deep inflammatory infiltrate, often in a
perivascularorientation.Someauthorities,however,feelthatdifferentiatinglichenplanusfromLEisbestdoneby
directimmunofluorescencestudiesorhistopathologicexaminationofthecutaneouslesions.
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Diagnosis
Inadditiontotheclinicalandmicroscopicfeatures,anumberofadditionalimmunologicstudiesmaybehelpfulin
makingthediagnosisofLE.
Directimmunofluorescencetestingoflesionaltissueshowsdepositionofoneormoreimmunoreactants(usually
IgM, IgG, or C3) in a shaggy or granular band at the basement membrane zone. In addition, direct
immunofluorescencetestingofclinicallynormalskinofSLEpatientsoftenshowsasimilardepositionofIgG,IgM,or
complementcomponents.Thisfindingisknownasapositivelupusbandtest.Althoughapositivelupusbandtest
isconsistentwiththediagnosisofLE,itisnowknownthatotherconditions,suchasrheumatoidarthritis,Sjgren
syndrome,andsystemicsclerosis,mayalsohavesimilarpositivefindings.Furthermore,somepatientswithLEmay
nothaveapositivelupusbandtest;therefore,thisstudymustalwaysbeinterpretedinthecontextofotherclinical
signs.
EvaluationofserumobtainedfromapatientwithSLEshowsvariousimmunologicabnormalities.Approximately
95% of these patients have antibodies directed against multiple nuclear antigens (i.e., antinuclear antibodies
[ANAs]). Although this is a nonspecific finding that may be seen in other autoimmune diseases, as well as in
otherwise healthy older individuals, it is nevertheless useful as a screening study. Furthermore, if results are
negativeonmultipleoccasions,thenthediagnosisofSLEshouldprobablybedoubted.Antibodiesdirectedagainst
doublestrandedDNAarenotedin70%ofpatientswithSLE,andthesearemorespecificforthedisease.Another
30% of patients show antibodies directed against Sm, a protein that is complexed with small nuclear RNA. This
findingisveryspecificforSLE.
AsummaryofselectedimmunologicfindingsinLEisshowninTable165.
TABLE165
SelectedAbnormalImmunologicFindingsinLupusErythematosus
Findings
Frequency
Significance
Directimmunofluorescence,lesional
skin
CCLE:90%
SLE:95%
MayhelpdistinguishamongthevarioustypesofLE
Directimmunofluorescence,normal
skin
CCLE:0%
SLE:
25%60%
Lupusbandtest
Antinuclearantibodies(ANAs)
CCLE:0%10%
SLE:95%
VerysensitiveforSLE,butnotveryspecific;notusefulforCCLE
diagnosis
AntidoublestrandedDNAantibodies
CCLE:0%
SLE:
70%80%
SpecificforSLE;mayindicatediseaseactivityorkidneyinvolvement
AntiSmantibodies
CCLE:0%
SLE:
10%30%
SpecificforSLE
CCLE,ChroniccutaneouslupuserythematosusSLE,systemiclupuserythematosusLE,lupuserythematosus.
Patients with SLE should avoid excessive exposure to sunlight because UV light may precipitate disease activity.
Mild active disease may be effectively managed using NSAIDs combined with antimalarial drugs, such as
hydroxychloroquine. For more severe, acute episodes that involve arthritis, pericarditis, thrombocytopenia, or
nephritis, systemic corticosteroids are generally indicated; these may be combined with other immunosuppressive
andimmunomodulatingagents.Iforallesionsarepresent,theytypicallyrespondtothesystemictherapy.
As with SLE patients, patients with CCLE should avoid excessive sunlight exposure. Because most of the
manifestations of CCLE are cutaneous, topical corticosteroids are often reasonably effective. Topical calcineurin
inhibitors(tacrolimusorpimecrolimus)mayalsobeused,althoughthesemedicationsarerelativelyexpensive.For
cases that are resistant to topical therapy, systemic antimalarial drugs, immunosuppressive drugs,
immunomodulating drugs, or lowdose thalidomide may produce a response. Topical corticosteroids are also
helpfulintreatingtheorallesionsofCCLE.
TheprognosisforthepatientwithSLEisvariable.Forpatientsundergoingtreatmenttoday,the5yearsurvival
rateisapproximately95%;however,by20years,thesurvivalratefallsto75%.Ultimately,theprognosisdependson
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whichorgansareaffectedandhowfrequentlythediseaseisreactivated.Themostcommoncauseofdeathisrenal
failure; however, chronic immunosuppression also predisposes these patients to increased mortality because of
infectionanddevelopmentofmalignancy.Forreasonsthatarepoorlyunderstood,theprognosisisworseformen
thanforwomen.Inaddition,blackstendtofaremorepoorlythanwhites.
The prognosis for patients with CCLE is considerably better than that for patients with SLE, although
transformationtoSLEmaybeseeninapproximately5%ofCCLEpatients.Usually,CCLEremainsconfinedtothe
skin,butitmaypersistandbequiteanuisance.Forabout50%ofCCLEpatients,theproblemeventuallyresolves
afterseveralyears.
SystemicSclerosis(ProgressiveSystemicSclerosis
SclerodermaHideBoundDisease)
Systemic sclerosis is a relatively rare condition that probably has an immunologically mediated pathogenesis
involving abnormal interactions among vascular tissue, connective tissue, and immune cells in genetically
predisposedindividuals.Forreasonsthatarenotunderstood,densecollagenisdepositedinthetissuesofthebody
in extraordinary amounts. Although its most dramatic effects are seen in association with the skin, the disease is
oftenquiteserious,withmostorgansofthebodyaffected.
ClinicalandRadiographicFeatures
Systemic sclerosis affects approximately 10 to 20 persons per million population each year. Women have the
condition three to five times more frequently than do men. Most patients are adults. The onset of the disease is
generallyinsidious,withthecutaneouschangesoftenresponsibleforbringingtheproblemtothepatientsattention.
Often one of the first signs of the disease is Raynaud phenomenon, a vasoconstrictive event triggered by
emotionaldistressorexposuretocold.Raynaudphenomenon(seeCRESTsyndrome,onpage747)isnotspecificfor
systemicsclerosis,however,becauseitmaybepresentinotherimmunologicallymediateddiseasesandinotherwise
healthypeople.Resorptionoftheterminalphalanges(acroosteolysis)andflexioncontracturesproduceshortened,
clawlikefingers(Fig.16122).Thevasculareventsandtheabnormalcollagendepositioncontributetotheproduction
ofulcerationsonthefingertips(Fig.16123).
SystemicSclerosis.Thetense,shinyappearanceoftheskinisevident.Notethatthefingersarefixedinaclawlike
position,withsomeshowingshorteningasaresultofacroosteolysis.
FIG.16122
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FIG.16123
SystemicSclerosis.Ulcerationsofthefingertips.
The skin develops a diffuse, hard texture (sclero = hard; derma = skin), and its surface is usually smooth.
Involvement of the facial skin by subcutaneous collagen deposition results in the characteristic smooth, taut,
masklike facies (Fig.16124). Similarly, the nasal alae become atrophied, resulting in a pinched appearance to the
nose, called a mousefacies. When the skin changes are confined to the hands, face, feet, and lower portions of the
limbs,thedesignationoflimitedcutaneoussystemicsclerosisisapplied.Ifthesechangesprogressrapidlytoinvolvethe
skin of the trunk and the proximal limbs, or if the changes begin in these areas, then the process is termed diffuse
cutaneoussystemicsclerosis.Thesetwopresentationsseemtohavedifferentprognoses.
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SystemicSclerosis.Theinvolvementofthefacialskinwithabnormalcollagendepositionproducesamasklikefacies.
Notethelossofthealaeofthenose.
FIG.16124
Involvementofotherorgansmaybesubtleatfirst,buttheresultsaremoreserious.Fibrosisofthelungs,heart,
kidneys,andgastrointestinaltractareseenprimarilyinpatientswithdiffusecutaneoussystemicsclerosis,andthe
abnormal collagen deposition leads to organ failure, typically within the first 3 years after the diagnosis is made.
Pulmonaryfibrosisisparticularlysignificant,leadingtopulmonaryhypertensionandheartfailure,aprimarycause
of death for these patients. Patients with limited cutaneous systemic sclerosis tend to develop pulmonary
hypertensionlaterthanthosewithadiffusepresentation.
Theoralmanifestationsoccurinvaryingdegrees.Microstomiaoftendevelopsasaresultofcollagendepositionin
the perioral tissues. This causes a limitation of opening the mouth in nearly 70% of these patients (Fig. 16125).
Characteristic furrows radiating from the mouth produce a purse string appearance. Loss of attached gingival
mucosaandmultipleareasofgingivalrecessionmayoccurinsomepatients.Dysphagiaoftendevelopsasaresultof
depositionofcollageninthelingualandesophagealsubmucosa,producingafirm,hypomobile(boardlike)tongue
andaninelasticesophagus,thushinderingswallowing.Xerostomiaisfrequentlyidentifiedinthesepatients,andthe
possibilityofconcurrentsecondarySjgrensyndromemayrequireconsideration.
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SystemicSclerosis.SamepatientasdepictedinFig.16124.Becauseoftheassociatedmicrostomia,thisisthe
patient'smaximalopening.
FIG.16125
On dental radiographs, diffuse widening of the periodontal ligament space is often present throughout the
dentition.Theextentofthewideningmayvary,withsomeexamplesbeingsubtleandothersquitedramatic(Fig.16
126).Varyingdegreesofresorptionoftheposteriorramusofthemandible,thecoronoidprocess,thechin,andthe
condylemaybedetectedonpanoramicradiographs,affectingapproximately10%to20%ofpatients(Fig.16127).In
theory,theseareasareresorbedbecauseoftheincreasedpressureassociatedwiththeabnormalcollagenproduction.
Individualtoothresorptionhasalsobeenreportedtooccuratahigherfrequencyinthesepatients.
SystemicSclerosis.Diffusewideningoftheperiodontalligamentspaceisoftenidentifiedonevaluationofperiapical
radiographs.
FIG.16126
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SystemicSclerosis.Panoramicradiographicevaluationmayshowacharacteristicresorptionoftheramus,coronoid
process,orcondyle.
FIG.16127
Amilderconditionthatresemblescutaneoussystemicsclerosishasbeencalledlocalizedsclerodermaormorphea,
and it usually affects only a solitary patch of skin. Because these lesions often look like scars, the name en coup de
sabre(strikeofthesword)isusedtodescribethem(Fig.16128). This problem is primarily cosmetic and, unlike
systemicsclerosis,itisrarelylifethreatening.Forthisreason,manyauthoritiesnowfeelthatthisdisordermaybe
unrelatedtosystemicsclerosis.
LocalizedScleroderma(Morphea).Thecutaneousalterationonthepatient'sforeheadrepresentsalimitedformof
sclerodermacalledencoupdesabre,becausethelesionresemblesascarthatmightresultfromacutwithasword.
FIG.16128
Microscopicexaminationoftissueinvolvedbysystemicsclerosisshowsdiffusedepositionofdensecollagenwithin
and around the normal structures (Fig. 16129). This abnormal collagen replaces and destroys the normal tissue,
causingthelossofnormaltissuefunction.
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SystemicSclerosis.Mediumpowerphotomicrographofanoralbiopsyspecimen.Diffusedepositionofcollagenis
apparentthroughoutthelaminapropria.
FIG.16129
Diagnosis
Duringtheearlyphases,itmaybedifficulttomakeadiagnosisofsystemicsclerosis.Generally,theclinicalsignsof
stiffenedskintexturealongwiththedevelopmentofRaynaudphenomenonaresuggestiveofthediagnosis.Askin
biopsymaybesupportiveofthediagnosisifabundantcollagendepositionisobservedmicroscopically.
Laboratory studies may be helpful to the diagnostic process if anticentromere antibodies or antiScl 70
(topoisomeraseI)isdetected.AntitopoisomeraseIantibodiesareseenmoreoftenwithdiffusecutaneoussystemic
sclerosis and development of pulmonary fibrosis; anticentromere antibodies are usually associated with limited
cutaneous systemic sclerosis (including CRESTsyndromesee next topic), as well as development of pulmonary
hypertension.
The management of systemic sclerosis is difficult. Unfortunately, many of the recommended treatments have not
been examined in controlled trials, and the natural waxing and waning course of the disease makes it difficult to
assesstheeffectivenessofagiventreatmentinanopenlabeltrial.Systemicmedications,suchaspenicillamine,are
prescribedinanattempttoinhibitcollagenproduction.Onedoubleblindstudy,however,showednodifferencein
measuredpatientoutcomeswithhighdoseversuslowdosepenicillamine,suggestingthatperhapsthismedication
haslimitedefficacy.Surprisingly,corticosteroidsareoflittlebenefit,andsomestudieshavesuggestedthattheiruse
mayincreasetheriskofrenaldisease.Extracorporealphotochemotherapyhasshownsomebeneficialeffectonthe
skinlesions;however,noimprovementofthepulmonaryfunctiontestsisobserved.
Other management strategies are directed at controlling symptoms. Such techniques as esophageal dilation are
used, for example, to temporarily correct the esophageal dysfunction and dysphagia. Calcium channel blocking
agentshelptoincreaseperipheralbloodflowandlessenthesymptomsofRaynaudphenomenon,butmanypatients
can reduce episodes by keeping warm (especially their hands and feet) or by stopping cigarette smoking.
Angiotensinconverting 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
insertionandremovalofdentures.Microstomiaandinelasticsofttissuealsohamperthemaintenanceofgoodoral
hygiene,andaffectedpatientshaveadecreasedabilitytomanipulateatoothbrushasaresultofscleroticchangesin
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the fingers and hands. Surgical correction of open bite associated with condylar resorption has been described.
Infrequently,theresorptionofthemandiblemaybecomesogreatastocauseapathologicfracture.
The prognosis is poor, although the outlook is better for patients with limited cutaneous involvement than for
thosewithdiffuseinvolvement.Iftheheartisaffected,thentheprognosisisparticularlypoor,butmostpatientsdie
because of pulmonary involvement. Overall survival figures are difficult to calculate due to a variety of factors,
including the rarity of the disease, the inherent variability of its natural course, and the variation in treatments
providedatmedicalcentersaroundtheworld.Withcurrenttreatmentregimens,itisestimatedthat10yearsurvival
ratesforpatientswithlimitedcutaneoussystemicsclerosisapproach75%to80%,whereassurvivaldropsto55%to
60%forpatientswithdiffusecutaneoussystemicsclerosis.
CRESTSyndrome(AcrosclerosisLimitedScleroderma)
CREST syndrome is an uncommon condition that some authorities now believe represents a variant of limited
cutaneoussystemicsclerosis.ThetermCRESTisanacronymforCalcinosiscutis,Raynaudphenomenon,Esophageal
dysfunction,Sclerodactyly,andTelangiectasia.
ClinicalFeatures
As with all types of systemic sclerosis, most patients with CREST syndrome are women in the sixth or seventh
decadeoflife.Thecharacteristicsignsmaynotappearsynchronouslybutinsteadmaydevelopsequentiallyovera
periodofmonthstoyears.
Calcinosiscutisoccursintheformofmovable,nontender,subcutaneousnodules,0.5to2.0cminsize,whichare
usually multiple (Fig. 16130). Larger, more numerous or superficial calcifications may occasionally become
bothersomeandrequireremoval.
CRESTSyndrome.Thesubcutaneousnodulesonthispatient'sarmrepresentdepositionofcalciumsalts(calcinosis
cutis).(CourtesyofDr.RomnCarlos.)
FIG.16130
Raynaudphenomenon may be observed when a persons hands or feet are exposed to cold temperatures. The
initial clinical sign is a dramatic blanching of the digits, which appear deadwhite in color as a result of severe
vasospasm. A few minutes later, the affected extremity takes on a bluish color because of venous stasis. After
warming, increased blood flow results in a duskyred hue with the return of hyperemic blood flow. This may be
accompaniedbyvaryingdegreesofthrobbingpain.
Esophageal dysfunction, caused by abnormal collagen deposition in the esophageal submucosa, may not be
noticeable in the early phases of CREST syndrome. Often the subtle initial signs of this problem must be
demonstratedbybariumswallowradiologicstudies.
The sclerodactyly of CREST syndrome is rather remarkable. The fingers become stiff, and the skin takes on a
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smooth, shiny appearance. Often the fingers undergo permanent flexure, resulting in a characteristic claw
deformity (Fig. 16131). As with other forms of cutaneous systemic sclerosis, this change is due to abnormal
depositionofcollagenwithinthedermisintheseareas.
FIG.16131
CRESTSyndrome.Clawlikedeformityaffectingthehands(sclerodactyly).
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AllergiesandImmunologicDiseases
TransientLingualPapillitis
Transient lingual papillitis (lie bumps,tongue torches) represents a common oral pathosis that rarely has been
documented.Affectedpatientsexperienceclinicalalterationsthatinvolveavariablenumberoffungiformpapillaeof
the tongue. The pathogenesis currently is unknown, but the lesions most likely arise from a variety of influences.
Suggested causes include local irritation, stress, gastrointestinal disease, hormonal fluctuation, upper respiratory
tractinfection,viralinfection,andtopicalhypersensitivitytofoods,drinks,ororalhygieneproducts.
ClinicalFeatures
Threepatternsoftransientlingualpapillitishavebeendocumented.Thefirstpatternislocalizedandinvolvesoneto
severalfungiformpapillaethatbecomeenlargedandpresentaselevatedpapulesthatareredbutmaydemonstratea
yellow,ulceratedcap(Fig.91).Thelesionsappearmostfrequentlyontheanteriorportionofthedorsalsurface,are
associatedwithmildtomoderatepain,andresolvespontaneouslywithinhourstoseveraldays.Inasurveyof163
dental school staff members, 56% reported previous episodes of transient lingual papillitis. There was a female
predominance,andthevastmajorityreportedasingleaffectedpapilla.Inonereport,theoccurrenceofthelesions
appearedtobeassociatedwithafoodallergy.
FIG.91
TransientLingualPapillitis.Tender,yellowpinkpapuleonthedorsumofthetongue.
Inthesecondpattern,theinvolvementismoregeneralizedandaffectsalargepercentageofthefungiformpapillae
on the tip and lateral portions of the dorsal surface (Fig. 92). Individual papillae are very sensitive, enlarged,
https://bookshelf.vitalsource.com/#/books/9781455770526/cfi/6/34!/4/2/2@0:0.00
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erythematous,andoccasionallydisplayfocalsurfaceerosion.Feverandcervicallymphadenopathyarenotrare.In
thesecases,spreadoftheprocessamongfamilymembershasbeenreported,suggestingapossiblecorrelationtoan
unknownvirus.Spontaneousresolutionoccursinabout7dayswithoccasionalrecurrencesreported.
FIG.92
TransientLingualPapillitis.Multiplepainfulwhitepapulesonthelateraldorsumandtipoftongue.
Thethirdpatternoftransientlingualpapillitisalsodemonstratesmorediffuseinvolvement.Thealteredpapillae
are asymptomatic, appear as elevated white to yellow papules, and have been termed the papulokeratotic variant
becauseofathickenedparakeratoticcap(Fig.93).Althoughtheselesionscouldbetheresultofatopicalallergy,the
histopathologydemonstratesfeaturessimilartochronicnibblingandsuggeststhepossibilityofanunusualpattern
offrictionalhyperkeratosis.
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TransientLingualPapillitis.Clustersofasymptomatic,elevated,yellowpapulesonthedorsolateralsurfaceofthe
tongue.(CourtesyofDr.CraigFowler.)
FIG.93
On histopathologic examination of the first two variants, affected papillae demonstrate normal surface epithelium
that may reveal focal areas of exocytosis or ulceration. The underlying lamina propria exhibits a proliferation of
numeroussmallvascularchannelsandamixedinflammatorycellularinfiltrate.Investigationforevidenceofhuman
papillomavirus (HPV), herpes simplex, and fungal infestation has been negative. The papulokeratotic variant
demonstratesmarkedhyperparakeratosisinwhichthesurfaceisraggedandrevealsbacterialcolonization.Achronic
lymphocyticinfiltrateisnotedinthesuperficiallaminapropriawithextensionintothebasilarportionoftheadjacent
epithelium.
Althoughtransientlingualpapillitisresolveswithouttherapy,topicalcorticosteroids,anesthetics,andcoatingagents
havebeenusedtoreducethepainorduration.Inanattempttoeliminatethepain,occasionalpatientshavereported
removingtheaffectedpapillaewithdevicessuchasfingernailclippers.Thepapulokeratoticvariantisasymptomatic
and requires no therapy. Although frequently unsuccessful, search for a local or systemic triggering event seems
prudent.
RecurrentAphthousStomatitis(RecurrentAphthous
UlcerationsCankerSores)
Recurrentaphthousstomatitis is one of the most common oral mucosal pathoses. The reported prevalence in the
general population varies from 5% to 66%, with a mean of 20%. Different subgroups of patients appear to have
differentcausesfortheoccurrenceofaphthae.Thesefactorssuggestacommondiseaseprocessthatmaybeinitiated
byavarietyofcausativeagents,eachofwhichiscapableofproducingthediseaseincertainsubgroupsofpatients.
Tostateitsimply,thecauseappearstobedifferentthingsindifferentpeople.
Althoughnosingletriggeringagentisresponsible,themucosaldestructionappearstorepresentaTcellmediated
immunologicreactionwithproductionoftumornecrosisfactoralpha(TNF).Thisfactorisamajorinflammatory
cytokineandassistsintheultimatetargetingofthesurfaceepitheliumfordestructionbycytotoxicTcells(CD8+).
Evidenceofthedestructionoftheoralmucosamediatedbytheselymphocytesisstrong,buttheinitiatingcausesare
elusiveandmostlikelyhighlyvariable.
Thefollowingallhavebeenreportedtoberesponsibleincertainsubgroupsofpatients(andeachdiscountedin
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othersubgroups!):
Allergies
Geneticpredisposition
Hematologicabnormalities
Hormonalinfluences
Immunologicfactors
Infectiousagents
Nutritionaldeficiencies
Smokingcessation
Stress(mentalandphysical)
Trauma
Investigatorshavetheorizedthataphthousulcerationsdevelopfromanimmunologicreactiontoanoralantigen.
This reaction may arise due the presence of a highly antigenic reagent, a decrease in the mucosal barrier that
previously masked the antigen, or immunodysregulation resulting in an abnormal response to a normally present
antigen.Allpreviouslydescribedtriggerscanbegroupedintooneofthesethreecategories.Oneormoreofthese
threefactorsmaybeinvolvedinsubgroupsofpatients.
Anantigenicstimulusappearstobetheprimaryinitiatingfactorintheimmunemediatedcytotoxicdestructionof
themucosainmanypatients.Thelistseemsendless,andeveryitemonthelistmaybeimportantinsmallsubsetsof
patients. Commonly mentioned potential antigens include sodium lauryl sulfate in toothpaste, many systemic
medications (e.g., nonsteroidal antiinflammatory drugs [NSAIDs], various beta blockers, and nicorandil),
microbiologic agents (e.g., L forms of streptococci, Helicobacterpylori, herpes simplex virus [HSV], varicellazoster
virus[VZV],adenovirus,andcytomegalovirus[CMV]),andmanyfoods(e.g.,cheese,chocolate,coffee,cowsmilk,
gluten,nuts,strawberries,tomatoes,dyes,flavoringagents,andpreservatives).
The mucosal barrier appears to be important in the prevention of aphthous stomatitis and might explain the
almost exclusive presence of aphthous stomatitis on nonkeratinized mucosa. Numerous factors that decrease the
mucosalbarrierincreasethefrequencyofoccurrence(e.g.,trauma,nutritionaldeficiencies,andsmokingcessation);
conversely,thoseassociatedwithanincreasedmucosalbarrierhavebeencorrelatedwithdecreasedulcerations(e.g.,
smoking,hormonalchanges,andmarkedabsenceofaphthaeonmucosaboundtobone).
Anincreasedprevalenceofaphthouslikeulcerationshasbeennotedinavarietyofsystemicdisorders(Box91).
These ulcerations typically are identical clinically and histopathologically to those noted in otherwise healthy
individuals.Inmanycases,resolutionofthesystemicdisorderproducesadecreasedfrequencyandseverityofthe
mucosalulcerations.
Box91
SystemicDisordersAssociatedwithRecurrentAphthousStomatitis
Behetsyndrome
Celiacdisease
Cyclicneutropenia
Nutritionaldeficiencies(iron,folate,zinc,B1,B2,B6,andB12)
ImmunoglobulinA(IgA)deficiency
Immunocompromisedconditions,includinghumanimmunodeficiencyvirus(HIV)disease
Inflammatoryboweldisease
MAGICsyndrome(mouthandgenitalulcerswithinflamedcartilage)
PFAPAsyndrome(periodicfever,aphthousstomatitis,pharyngitis,cervicaladenitis)
Reactivearthritis
Sweetsyndrome
Ulcusvulvaeacutum
Threeclinicalvariationsofaphthousstomatitisarerecognized:
1.Minor
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2.Major
3.Herpetiform
Minoraphthousulcerations(Mikuliczaphthae)arethemostcommonandrepresentthepatternpresentinmore
than80%ofthoseaffected.Majoraphthousulcerations(Suttondiseaseorperiadenitismucosanecroticarecurrens
[PMNR]) occur in approximately 10% of the patients referred for treatment. The remaining patients have
herpetiformaphthousulcerations.Theminorandmajorformsmostlikelyrepresentvariationsofthesameprocess,
although herpetiform aphthae demonstrate a unique pattern. Some investigators differentiate the herpetiform
variantbecauseofsupposedevidenceofaviralcause,buttheproofisweakanddoesnotjustifyitsdistinctionfrom
the other aphthous ulcerations. Some authors include Behet syndrome as an additional variation of aphthous
stomatitis,butthismultisystemdisorderismorecomplexandisconsideredlaterinthischapter.
ClinicalFeatures
Aphthousulcerationsarenotedmorefrequentlyinchildrenandyoungadults,withapproximately80%ofaffected
individualsreportingtheirfirstulcerationbeforetheageof30.
MinorAphthousUlcerations
Patients with minor aphthous ulcerations experience the fewest recurrences, and the individual lesions exhibit the
shortest duration of the three variants. The ulcers arise almost exclusively on nonkeratinized mucosa and may be
precededbyanerythematousmaculeinassociationwithprodromalsymptomsofburning,itching,orstinging.The
ulcerationdemonstratesayellowwhite,removablefibrinopurulentmembranethatisencircledbyanerythematous
halo (Fig. 94). Classically, the ulcerations measure between 3 and 10 mm in diameter, demonstrate a variable
recurrencerate,andhealwithoutscarringin7to14days(Fig.95).Althoughscoresofulcerationsmaybepresentat
once,fromonetofivelesionstypicallyarepresentduringasingleepisode,andthepainoftenisoutofproportionfor
thesizeoftheulceration.Thebuccalandlabialmucosaeareaffectedmostfrequently,followedbytheventralsurface
of the tongue, mucobuccal fold, floor of the mouth, and soft palate (Fig.96). Involvement of keratinized mucosa
(e.g., hard palate, gingiva, dorsal surface of the tongue, and vermilion border) is rare and usually represents
extensionfromadjacentnonkeratinizedepithelium.
FIG.94
MinorAphthousUlceration.Erythematoushaloencirclingayellowishulcerationofthesoftpalateontheleftside.
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FIG.95
MinorAphthousUlcerations.Twoulcerationsofdifferentsizeslocatedonthemaxillarylabialmucosa.
FIG.96
MinorAphthousUlceration.Singleulcerationoftheanteriorbuccalmucosa.
MajorAphthousUlcerations
Major aphthous ulcerations are larger than minor aphthae and demonstrate the longest duration per episode. The
ulcerationsaredeeperthantheminorvariant,measurefrom1to3cmindiameter,takefrom2to6weekstoheal,
andmaycausescarring(Fig.97).Thenumberoflesionsvariesfrom1to10.Anyoralsurfaceareamaybeaffected,
but the labial mucosa, soft palate, and tonsillar fauces are involved most commonly (Fig.98). The onset of major
aphthaeisafterpuberty,andrecurrentepisodesmaycontinuetodevelopforupto20yearsormore.Withtime,the
associatedscarringcanbecomesignificant,andinrareinstancesmayleadtoarestrictedmouthopening.
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MajorAphthousUlceration.Large,deep,andirregularulcerationoftheposteriorbuccalmucosa.Noteextensivescarring
oftheanteriorbuccalmucosafrompreviousulcerations.
FIG.97
FIG.98
MajorAphthousUlceration.Large,irregularulcerationofthesoftpalate.
HerpetiformAphthousUlcerations
Herpetiform aphthous ulcerations demonstrate the greatest number of lesions and the most frequent recurrences.
The individual lesions are small, averaging 1 to 3 mm in diameter, with as many as 100 ulcers present in a single
recurrence.Becauseoftheirsmallsizeandlargenumber,thelesionsbearasuperficialresemblancetoaprimaryHSV
infection, leading to the confusing designation, herpetiform. It is common for individual lesions to coalesce into
largerirregularulcerations(Fig.99).Theulcerationshealwithin7to10days,buttherecurrencestendtobeclosely
spaced.Althoughthenonkeratinized,movablemucosaisaffectedmostfrequently,anyoralmucosalsurfacemaybe
involved.Thereisafemalepredominance,andtypicallytheonsetisinadulthood.
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HerpetiformAphthousUlcerations.Numerouspinheadulcerationsoftheventralsurfaceofthetongue,severalofwhich
havecoalescedintolarger,moreirregularareasofulceration.
FIG.99
Furtherclassificationofallthreetypesisvaluablewhenplanningthemostappropriatediagnosticevaluationand
therapy. The lesions are diagnosed as simpleaphthosis when they appear in patients with few lesions that heal
within 1 to 2 weeks and recur infrequently. In contrast, patients with complexaphthosis have multiple (three or
more)andalmostconstantoralulcerationsthatoftendevelopasolderlesionsresolve.Severepainandlargesizeare
common. Although associated genital or perianal lesions also may be present, there is no other evidence of an
associatedsystemicdisease.
The histopathologic picture of aphthous stomatitis is characteristic but not pathognomonic. The early ulcerative
lesionsdemonstrateacentralzoneofulceration,whichiscoveredbyafibrinopurulentmembrane.Deeptothearea
ofulceration,theconnectivetissueexhibitsanincreasedvascularityandamixedinflammatorycellularinfiltratethat
consistsoflymphocytes,histiocytes,andpolymorphonuclearleukocytes.Theepitheliumatthemarginofthelesion
demonstrates spongiosis and numerous mononuclear cells in the basilar onethird. A band of lymphocytes
intermixedwithhistiocytesispresentinthesuperficialconnectivetissueandsurroundingdeeperbloodvessels.
Diagnosis
No laboratory procedure provides definitive diagnosis. The diagnosis is made from the clinical presentation and
from exclusion of other diseases that produce ulcerations that closely resemble aphthae (see Box91). 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 deficiency, gastrointestinal disease, immunodeficiency, and drug reaction) was
discoveredinalmost60%.Becausethehistopathologicfeaturesarenonspecific,abiopsyisusefulonlyineliminating
differentialpossibilitiesandisnotbeneficialinarrivingatthedefinitivediagnosis.
The patients medical history should be reviewed for signs and symptoms of any systemic disorder that may be
associated with aphthouslike ulcerations. Most patients with mild aphthosis receive either no treatment, therapy
withanumberofoverthecounteranestheticsorprotectivebioadhesiveproducts,orperiodictopicalmedicaments
thatminimizethefrequencyandseverityoftheattacks.
Inpatientswithmilddisease,themainstayoftherapyistheuseoftopicalcorticosteroids,andthelistofpossible
choices is long. Most patients with diffuse minor or herpetiform aphthae respond well to dexamethasone solution
(0.5mg/5mL)usedinarinseandexpectoratemethod.Patientswithlocalizedulcerationscanbetreatedsuccessfully
with 0.05% augmented betamethasone dipropionate gel or 0.05% fluocinonide gel. Adrenal suppression does not
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occurwithappropriateuseofthesemedications.Majoraphthousulcerationsaremoreresistanttotherapyandoften
warrantmorepotentcorticosteroids(Fig.910).Theindividuallesionsmaybeinjectedwithtriamcinoloneacetonide
or covered with 0.05% clobetasol propionate gel or 0.05% halobetasol propionate ointment. Triamcinolone tablets
alsocanbedissolveddirectlyoverthelesions.Inhardtoreachareas,suchasthetonsillarpillars,beclomethasone
dipropionateaerosolspraycanbeused.Inresistantcases,systemiccorticosteroidsmayberequiredtosupplement
the topical medications and gain control. In such instances, prednisolone oral suspension in a swishandswallow
methodispreferabletoprednisonetablets.Inthisway,theulcerationsreceivebothtopicalandsystemictherapy.
MajorAphthousUlceration.A,Largeulcerationoftheleftanteriorbuccalmucosa.B,Samelesionafter5daysoftherapy
withbetamethasonesyrupusedinaswishandswallowmethod.Thepatientwasfreeofpainbytheseconddayoftherapy.The
ulcerationhealedcompletelyduringthenextweek.
FIG.910
An almost endless list of alternatives to corticosteroid agents has been used to treat patients suffering from
aphthousulcerations.Cautionshouldbeexercised,however,becausemanyoftheseagentshavenotbeenexamined
in a doubleblind, placebocontrolled fashion to assess the degree of effectiveness compared with placebo.
Furthermore,someofthesetreatmentsmayhavesignificantsideeffectsormaybequiteexpensive.Widelyaccepted
topicalalternativesincludeamlexanoxpaste,chlorhexidine,tetracyclineoralsuspension,andtriclosanmouthrinse.
InarecentCochranmetaanalysis,nosinglesystemictherapywasfoundtobeeffectiveinawidevarietyofpatients.
Frequently mentioned systemic therapies include a number of immunomodulatory agents, such as adalimumab,
colchicine,dapsone,levamisole,pentoxifylline,andthalidomide.
Although laser ablation shortens the duration and decreases associated symptoms, its use is of very limited
practicalbenefitbecausepatientscannotreturnoneachrecurrence.Chemicalcauterywithsilvernitratecontinuesto
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 265) and systemic argyria (see page 288). A
cauterythatusessulfuricacidandphenolicagentsisindicatedincertainsituations,butmustbeusedwithcaution
duetothepotentialforsignificantlocaltissuenecrosisrelatedtoitsmisuse.
The success of these different therapeutic approaches is variable from patient to patient. In addition, these
interventions do not resolve the underlying problem and are merely an attempt to beat back brush fires.
Recurrences often continue, although breaking up the cycle may induce longer diseasefree intervals between
attacks.Surgicalremovalofaphthousulcerationshasbeenusedbutisaninappropriatetherapy.
Patientswithcomplexaphthosisrequireamoreextensiveevaluationforoccultsystemicdiseaseandasearchfor
possible triggers of the immunemediated mucosal destruction. To go beyond the management of individual
recurrences is difficult, expensive, and often frustrating. In spite of this, patients with severe disease should be
offeredtheopportunitytoinvestigatetheunderlyingcauses.
BehetSyndrome(BehetDiseaseAdamantiadesSyndrome)
Thecombinationofchronicocularinflammationandorogenitalulcerationswasreportedasearlyastheeraofthe
ancient Greeks and later described in 1931 by a Greek ophthalmologist, Benedict Adamantiades. The classic triad
wasnotdelineateduntil1937,whenaTurkishdermatologist,HulusiBehet,definedthediseasethatbearshisname.
Althoughthediseasetraditionallyhasbeenthoughtprimarilytoaffecttheoral,genital,andocularregions,itnowis
recognizedtobeasystemicvasculitis.
Although no clear causation has been established, Behetsyndrome appears to represent an abnormal immune
process triggered by an infectious or environmental antigen in a genetically predisposed individual. Investigators
have correlated attacks to a number of environmental agents, including bacteria (especially streptococci), viruses,
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pesticides,andheavymetals.Interestingly,reductionoforalbacterialloadviaperiodontaltherapyhasbeenshown
toreducetheprevalenceofassociatedoralulcerationsinpatientswithBehetsyndrome.
HistocompatibilityantigenB51(HLAB51)hasbeenlinkedcloselytoBehetsyndrome,andthefrequencyofboth
thediseaseandthehaplotypeishighinTurkey,Japan,andtheEasternMediterraneancountries.Thisdistribution
appears correlated to the ancient Silk Route that extended from China to Rome and was traveled by the Turks.
Sexualreproductionbetweenimmigrantsandlocalsalongtherouteappearstohavespreadthegeneticvulnerability.
Interestingly,whenpredisposedpopulationsmigratetonon
endemiclocations,theprevalencedecreases,suggesting
environmentalfactorsalsoareinvolved.
ClinicalFeatures
Behetsyndromeisuncommoninblacksandusuallyarisesinthethirdandfourthdecadeswiththediseaserarely
presentingbeforepubertyorbeyondtheageof50.Menexhibitaslightlyincreasedprevalenceandtendtohavea
worseclinicalcourse.
Virtually all affected patients demonstrate oral ulcerations that often herald the onset of the disease. Other less
frequentlyassociatedfeaturesinorderofprevalenceincludegenitalulcerations,cutaneouslesions,arthritis,uveitis,
thrombophlebitis,gastrointestinalmanifestations,andcentralnervoussystem(CNS)involvement.
Theorallesionsaresimilartoaphthousulcerationsoccurringinotherwisehealthyindividualsanddemonstrate
thesamedurationandfrequency.Theindividuallesionsvaryinsizeandaresurroundedbyalargerzoneofdiffuse
erythema (Fig. 911). All three forms of oral aphthous stomatitis may be seen. Although the majority of affected
patients have lesions that resemble minor aphthous ulcerations, some reports have documented a prevalence of
major aphthae that approaches 40% in patients affected with Behet syndrome. The herpetiform variant remains
uncommonandisnotedinapproximately3%.
FIG.911
BehetSyndrome.Diffuseerythemasurroundingnumerousirregularulcerationsofthesoftpalate.
Thegenitallesionsoccurin75%ofthepatients.Inmales,approximately90%ofthelesionsinvolvethescrotum,
whereas those in females are most frequent on the vulva, vagina, or uterine cervix. Perineal, perianal, and groin
involvementisseeninbothgenders(Fig.912).Theselesionsrecurlessfrequentlythandotheoralulcerations,but
theyaredeeperandtendtohealwithscarring.
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FIG.912
BehetSyndrome.Numerousirregularulcerationsofthelabiamajoraandperineum.(FromHelmTN,CamisaC,AllenC,etal:Clinical
featuresofBehet'sdisease,OralSurgOralMedOralPathol72:30,1991.)
Common cutaneous lesions include erythematous papules, vesicles, pustules, pyoderma, folliculitis, acneiform
eruptions,anderythemanodosumlikelesions.Inadditiontothetypicaldistributionseeninadolescence,theacne
like lesions also involve unusual sites, such as the extremities. From a diagnostic standpoint, one of the most
importantskinmanifestationsisthepresenceofpositivepathergy.Oneor2daysaftertheobliqueinsertionofa
20gaugeorsmallerneedleundersterileconditions,atuberculinlikeskinreactionorsterilepustuledevelops(Fig.9
13).Positivepathergyisgeographicallyvariablewithaprevalenceof60%inMiddleEasternpatientsbutseeninonly
approximately3%ofaffectedCaucasianpatients.
BehetSyndrome.Sterilepustuleoftheskinthatdeveloped1dayafterinjectionofsaline.Thisreactionistermed
cutaneouspathergy.
FIG.913
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Arthritis is one of the more common minor manifestations of the disease and is usually selflimiting and
nondeforming.Theknees,wrists,elbows,andanklesareaffectedmostfrequently.
Ocularinvolvementoccursinupto70%ofthecasesandismorefrequentandsevereinmales.Themostcommon
findings are posterior uveitis, conjunctivitis, corneal ulceration, papilledema, and arteritis. The most common
secondary ocular complications are cataracts, glaucoma, and neovascularization of the iris and retina. Despite
therapy,blindnessoccursin25%ofpatientswithocularinvolvement.
Althoughthevasculardiseasemayinvolvearteries,veinsareaffectedmorefrequentlyandpresentassuperficial
and deep thrombophlebitis. The thrombi tend to be adherent to the diseased veins without a tendency toward
embolism.
Gastrointestinal disease is variable and includes abdominal pain, anorexia, diarrhea, dyspepsia, and vomiting.
CNSinvolvementisnotcommonbut,whenpresent,isassociatedwithapoorprognosis.From10%to25%ofthe
patients demonstrate CNS involvement, and the alterations produced result in a number of changes that include
paralysisandseveredementia.
Diagnosis
NolaboratoryfindingisdiagnosticofBehetsyndrome.Inanattempttostandardizediagnoses,definitivecriteria
havebeendeveloped.Table91delineatestherequirementsproposedbytheBehetInternationalStudyGroup.
TABLE91
InternationalStudyGroupCriteriafortheDiagnosisofBehetDisease
Criteria
Recurrentoral
ulceration
Description
Minor,major,orherpetiformaphthae
Plustwoofthe
following:
Recurrentgenital
ulcerations
Aphthaelikeulcerations
Eyelesions
Anteriororposterioruveitis,cellsinvitreousonslitlampexamination,orretinalvasculitis
Skinlesions
Erythemanodosum,pseudofolliculitisorpapulopustularlesions,oracneiformnodulesnotedin
postadolescentpatientsnotreceivingcorticosteroids
Positivepathergy
test
Readbyphysicianat24to48hours
The histopathologic features are not specific for Behet syndrome and can be seen in many disorders, including
aphthousstomatitis.Thepatternmostfrequentlyseeniscalledleukocytoclasticvasculitis.Theulcerationissimilarin
appearance to that seen in aphthous stomatitis, but the small blood vessels classically demonstrate intramural
invasionbyneutrophils,karyorrhexisofneutrophils,extravasationofredbloodcells,andfibrinoidnecrosisofthe
vesselwall.
Therapyistailoredtothediseaseseverityandprognosticfactors.Manypatientsaretreatedsymptomatically,with
thediseaseoftengoingintoremissionasthepatientages.Femalesandolderpatientshaveabetterprognosisthan
males or young patients. Ocular lesions and CNS involvement are associated with significant morbidity and
mandatemoreaggressivetherapy.
Nosinglemedicationisuniversallyeffectivewithvariableresponsesseenindifferentgroupsofpatients.Systemic
medications include azathioprine, colchicine, corticosteroids, cyclosporine, dapsone, interferon, methotrexate,
pentoxifylline, sulfasalazine, thalidomide, and antiTNF medications (adalimumab, etanercept, and infliximab).
The oral and genital ulcerations typically respond well to potent topical or intralesional corticosteroids or topical
tacrolimus.
Behetsyndromehasahighlyvariablecourse.Arelapsingandremittingpatternistypical,withattacksbecoming
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more intermittent after 5 to 7 years. In the absence of CNS disease or significant vascular complications, the
prognosisgenerallyisgood.
Sarcoidosis
Sarcoidosisisamultisystemgranulomatousdisorderofunknowncause.JonathanHutchinsoninitiallydescribedthe
disease in 1875, but Boeck coined the term sarcoidosis (Greek meaning fleshlike condition) 14 years later. The
evidenceimplicatesimproperdegradationofantigenicmaterialwiththeformationofnoncaseatinggranulomatous
inflammation. The nature of the antigen is unknown, and probably several different antigens may be responsible.
Possible involved antigens include infectious agents (e.g., mycobacterium, propionibacteria, EpsteinBarr virus,
human herpesvirus 8 [HHV8]) and a number of environmental factors (e.g., wood dust, pollen, clay, mold, and
silica). Several investigators have confirmed a genetic predisposition and positive associations with certain HLA
types.
ClinicalFeatures
Sarcoidosis has a worldwide distribution, tends to arise prior to age 50, and exhibits an increased prevalence in
femalesandblacks.Thediseasemaypresentacutelyordemonstrateachroniccoursewithperiodsofremissionand
exacerbation.Acutecasesoftenexhibitfever,fatigue,anorexia,orweightlosscombinedwithothermanifestations,
such as respiratory symptoms, polyarthritis, visual problems, and skin lesions. In chronic cases, pulmonary
symptomsarecommonandincludedrycough,dyspnea,andchestdiscomfort.Approximately20%ofpatientshave
nosymptoms,andthediseaseisdiscoveredonroutinechestradiographs.
Althoughanyorganmaybeaffected,thelungs,lymphnodes,skin,eyes,andsalivaryglandsarethepredominant
sites.Lymphoidtissueisinvolvedinalmostallcases.Themediastinalandparatracheallymphnodesareinvolved
commonly,andchestradiographsfrequentlyrevealbilateralhilarlymphadenopathy.Approximately90%ofaffected
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. 914). Scattered, nonspecific, tender
erythematousnodules,knownaserythemanodosum,frequentlyoccuronthelowerlegs.
FIG.914
Sarcoidosis.Violaceousinduratedplaquesoftherightmalarareaandbridgeofnose.(CourtesyofDr.GeorgeBlozis.)
Ocular involvement is noted in 25% of the cases and most often appears as anterior uveitis. Lesions of the
conjunctivaandretinamayoccur.Involvementofthelacrimalglandsoftenproduceskeratoconjunctivitissicca;the
salivary glands can be altered similarly, with resultant clinical enlargement and xerostomia. The salivary gland
enlargement,xerostomia,andkeratoconjunctivitissiccacancombinetomimicSjgrensyndrome(seepage434).
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Althoughlymphoid,pulmonary,cutaneous,andocularlesionsaremostcommon,virtuallyanyorgansystemmay
beaffected.Otherpotentialsitesincludetheendocrinesystem,gastrointestinaltract,heart,kidneys,liver,nervous
system, and spleen. Intraosseous lesions may occur and most commonly involve the phalanges, metacarpals, and
metatarsals.Lessfrequently,theskull,nasalbones,ribs,andvertebraeareaffected.
Twodistinctiveclinicalsyndromesareassociatedwithacutesarcoidosis.Lfgrensyndromeconsistsoferythema
nodosum,bilateralhilarlymphadenopathy,andarthralgia.PatientswithHeerfordtsyndrome(uveoparotidfever)
haveparotidenlargement,anterioruveitisoftheeye,facialparalysis,andfever.
Ifsalivaryglandandlymphnodeinvolvementareexcluded,clinicallyevidentoralmanifestationsinsarcoidosis
are uncommon. Any oral mucosal site can be affected, most often appearing as a submucosal mass, an isolated
papule,anareaofgranularity,orulceration.Themucosallesionsmaybenormalincolor,brownred,violaceous,or
hyperkeratotic (Figs. 915 and 916). The most frequently affected intraoral soft tissue site is the buccal mucosa,
followedbythegingiva,lips,tongue,andpalate.Lesionsofthefloorofthemouthoccurbutusuallyaresecondaryto
salivary gland involvement. Intraosseous lesions affect either jaw and represent approximately onefourth of all
reported intraoral cases. Of these cases, most appeared as illdefined radiolucencies that occasionally eroded the
cortexbutnevercreatedexpansion.Inthepreviouslyreportedintraoralcases,themajorityofpatientsdemonstrated
multisysteminvolvement,buttheorallesionwastheinitialmanifestationintwothirdsofthepatients.
FIG.915
Sarcoidosis.Multipleerythematousmaculesofthehardpalate.(CourtesyofDr.GeorgeBlozis.)
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FIG.916
Sarcoidosis.Erythematousmaculeswithcentralhyperkeratosisofthelowerlabialmucosa.
Microscopicexaminationofsarcoidosisexhibitsaclassicpictureofgranulomatousinflammation.Tightlyclustered
aggregates of epithelioid histiocytes are present, with a surrounding rim of lymphocytes. Intermixed with the
histiocytes are scattered Langhans or foreign body type giant cells (Fig. 917). The granulomas often contain
laminated basophilic calcifications, known as Schaumann bodies (degenerated lysosomes), or stellate inclusions,
known as asteroidbodies (entrapped fragments of collagen) (Fig. 918). None of these structures are specific for
sarcoidosis.Specialstainsforfungalandbacterialorganismsarenegative.Nopolarizable,dissolvable,orpigmented
foreignmaterialcanbedetected.
Sarcoidosis.Photomicrographofalabialminorsalivaryglanddemonstratinggranulomatousinflammation
characterizedbycircumscribedcollectionsofhistiocytes,lymphocytes,andmultinucleatedgiantcells.
FIG.917
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FIG.918
Sarcoidosis.Photomicrographillustratingmultinucleatedgiantcellwithintracytoplasmicasteroidbody.
Diagnosis
Thediagnosisisestablishedbytheclinicalandradiographicpresentations,thehistopathologicappearance,andthe
presence of negative findings 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. In spite of this, elevated ACE is reported in only 60% of patients with sarcoidosis and in a minority of
those with oral involvement. Other laboratory abnormalities that may be seen include eosinophilia; leukopenia;
anemia; thrombocytopenia; and elevation of the serum alkaline phosphatase level, erythrocyte sedimentation rate,
serumcalciumconcentration,andurinarycalciumlevel.
In the past, a skin test for sarcoidosis, the Kveim test, was performed by intradermal injection of a sterilized
suspension of human sarcoid tissue. However, this procedure is no longer used because of difficulty in obtaining
materialforthetest,concernrelatedtoitsaccuracy,andtheinabilitytoguaranteetheabsenceofcontamination(e.g.,
prions)inthishumantissue.
Minorsalivaryglandbiopsyhasbeenpromotedasadiagnosticaidinsuspectedcasesofsarcoidosis(seeFig.917)
but is less effective than a parotid biopsy. Previously, biopsy of the parotid was avoided because of the fear of
salivaryfistulaformationanddamagetothefacialnerve.Theseconcernshavebeenreducedthroughbiopsyofthe
posteriorsuperficiallobeoftheparotidgland,andconfirmationofsarcoidosishasbeenreportedin93%ofpatients
fromthisprocedure.
In approximately 60% of patients with sarcoidosis, the symptoms resolve spontaneously within 2 years without
treatment.Mostinitialdiagnosesarefollowedbya3to12monthperiodofobservationtodefinethegeneralcourse
ofthedisease.Activeinterventionisrecommendedforprogressivediseaseandpatientswithcardiacorneurologic
involvement,hypercalcemia,disfiguringskindisease,orseriousocularlesionsthatdonotrespondtolocaltherapy.
In patients requiring treatment, corticosteroids remain firstline therapy, but resistance and relapses are common.
Medicationsusedinpatientswithrefractorydiseaseincludemethotrexate,azathioprine,chlorambucil,chloroquine,
andcyclophosphamide.SeveralstudieshaveshownpromisingresultswithTNFantagonistssuchasetanercept,
infliximab,pentoxifylline,andthalidomide.In10%to20%ofthoseaffectedbysarcoidosis,resolutiondoesnotoccur
evenwithtreatment.Approximately4%to10%ofpatientsdieofpulmonary,cardiac,orCNScomplications.
OrofacialGranulomatosis
Since Wiesenfeld introduced it 1985, orofacial granulomatosis has become a wellaccepted and unifying term
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encompassing a variety of clinical presentations that, on biopsy, reveal the presence of nonspecific granulomatous
inflammation.
Thedisorderisidiopathicbutappearstorepresentanabnormalimmunereactiontoavarietyofincitingagents.In
addition,similarlesionscanbeseeninassociationwithanumberofsystemicdiseases.Table92delineatessystemic
diseasesthatmaymimicorofacialgranulomatosis,andTable93listsanumberofadditionalpossibletriggers.
TABLE92
SystemicEvaluationofPatientswithOrofacialGranulomatosis
SystemicCause
PreliminaryScreeningProcedure
Chronic
Neutrophilnitrobluetetrazoliumreductiontest(performifmedicalhistoryofchronicinfectionsisnoted)
granulomatous
disease
Crohndisease
Hematologicevaluationforevidenceofgastrointestinalmalabsorption(e.g.,lowalbumin,calcium,folate,iron,
andredbloodcellcount;elevatederythrocytesedimentationrate)orleukocytescintigraphyusing99mTc
HMPAO(hexamethylpropyleneamineoxime);ifinitialscreenispositive,thenrecommend
esophagogastroduodenoscopy,ileocolonoscopy,andsmallbowelradiographs
Sarcoidosis
Serumangiotensinconvertingenzymeandchestradiograph(hilarlymphadenopathy)
Tuberculosis
Skintestandchestradiograph(negativeacidfastbacteria[AFB]stainonbiopsyspecimendoesnotruleout
mycobacterialinfection)
TABLE93
InterventionstoRuleOutLocalCausesforOrofacialGranulomatosis
LocalCause Intervention
Chronic
Eliminatealloralfociofinfection.
oral
infection
Foreign
material
Theforeigndebrisnotediniatrogenicgingivitisisoftensubtleanddifficulttoassociatedefinitivelywiththediffuse
inflammatoryprocess.Iflesionsarenonmigratingandisolatedtogingiva,thenresponsetolocalexcisionofa
singlefocusshouldbeevaluated.
Allergy
Cosmetics,foodsandfoodadditives(benzoate,carbonepiperitone,carmoisine,carvone,chocolates,cinnamon,cocoa,
dairyproducts,eggs,monosodiumglutamate,peanuts,sunyellowdye,andwheat)flavorings,oralhygiene
products(e.g.,toothpasteandmouthrinses),anddentalrestorativemetalshavebeenimplicated.Patchtesting
(i.e.,contactdermatitisstandardserieswithoralbattery)oreliminationdietmaydiscovertheoffendingantigen.
ClinicalFeatures
Theclinicalpresentationoforofacialgranulomatosisishighlyvariable.Themajorityofpatientsareadults;however,
the process may occur at any age. 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.919). When these signs are
combined with facial paralysis and a fissured tongue, the clinical presentation is called MelkerssonRosenthal
syndrome (Figs. 920 and 921). Involvement of the lips alone is called cheilitis granulomatosa (of Miescher).
Neitherofthesetwoclinicalpresentationsrepresentsaspecificdisease,anditappearsbesttoincludebothofthese
underthetermorofacialgranulomatosis.
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FIG.919
OrofacialGranulomatosis(CheilitisGranulomatosa).Nontender,persistentenlargementoftheupperlip.(FromAllenCM,
CamisaC:Diseasesofthemouthandlips.InSamsWM,LynchP,editors:Principlesofdermatology,NewYork,1990,ChurchillLivingstone.)
FIG.920
OrofacialGranulomatosis(MelkerssonRosenthalSyndrome).Persistentenlargementofthelowerlip.(CourtesyofDr.Richard
Ziegler.)
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OrofacialGranulomatosis(MelkerssonRosenthalSyndrome).SamepatientasdepictedinFig.920.Notenumerous
furrowsonthedorsalsurfaceofthetongue.(CourtesyofDr.RichardZiegler.)
FIG.921
Intraoralsitesalsocanbeaffected,andthepredominantlesionsareedema,ulcers,andpapules.Thetonguemay
developfissures,edema,paresthesia,erosions,ortastealteration.Thegingivacandevelopswelling,erythema,pain,
or erosions. The buccal mucosa often exhibits a cobblestone appearance of edematous mucosa or focal areas of
submucosalenlargement.Linearhyperplasticfoldsmayoccurinthesulcus,oftenwithelongatedulcerationsinthe
base of these folds (Fig.922). The palate may have papules or large areas of hyperplastic tissue. Hyposalivation
rarelyisreported.
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FIG.922
OrofacialGranulomatosis.Hyperplasticmucosanotedbilaterallyinthemandibularmucobuccalfold.(CourtesyofDr.StevenA.
Anderson.)
In classic cases of cheilitis granulomatosa, edema is present in the superficial lamina propria with dilation of
lymphatic vessels and scattered lymphocytes seen diffusely and in clusters. Fibrosis may be present in longterm
lesions. Scattered aggregates of noncaseating granulomatous inflammation, consisting of lymphocytes and
epithelioidhistiocytes,arepresent,withorwithoutmultinucleatedgiantcells.Typically,thegranulomasappearto
clusteraroundscatteredvesselsandarenotaswellformedordiscreteasthoseseeninsarcoidosis(Fig.923).
OrofacialGranulomatosis.Clustersofgranulomatousinflammationaroundscatteredvessels.Theinsetillustratesthe
histiocytesandmultinucleatedgiantcellswithinthegranulomas.
FIG.923
Specialstainsforfungalorganismsandacidfastbacteriaarenegative.Nodissolvable,pigmented,orpolarizable
foreignmaterialshouldbepresent.Whenthelesionsareconfinedtothegingiva,athoroughsearchshouldbemade,
becausemanycasesofgranulomatousgingivitisareduetosubtlecollectionsofforeignmaterial(seepage146).
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Diagnosis
The initial diagnosis of orofacial granulomatosis is made on histopathologic demonstration of granulomatous
inflammationthatisassociatedwithnegativespecialstainsfororganismsandnoforeignmaterial.Becauseclinical
and histopathologic features of orofacial granulomatosis can be produced by a variety of underlying causes, this
diagnosis is the beginning, not the end, of the patients evaluation. Prior to administering any medication or
consideringsurgicalintervention,thepatientshouldbeevaluatedforthesystemicdiseasesandlocalprocesses(see
Tables92and93)thatmayberesponsibleforsimilarorallesions.Iffeaturesdiagnosticofoneofthesemorespecific
disorders are discovered, then the oral lesions presumably would be related to that disease. If a specific diagnosis
cannotbemade,thenpotentialfociofinfectionshouldbeeliminated.Ifnoresolutionisnotedafterreducinglocal
inflammatoryfactors,thenreferralofthepatientforallergytestingshouldbeconsidered.
Patients ultimately discovered to have Crohn disease often present at a younger age and have less lip swelling,
althoughlesionsofthebuccalvestibulearemorelikely.Becausegastrointestinalinvolvementhasbeendiscoveredin
up to 60% of patients with orofacial granulomatosis who have no intestinal symptoms, several investigators have
suggested thorough gastrointestinal evaluation of all children and young adults presenting with orofacial
granulomatosis.
The worldwide prevalence of allergy is estimated to be 22%, whereas the frequency noted in patients with
orofacial granulomatosis is well over 50% in several studies. Although allergy testing has been useful in many
patients, diet restriction has been successful irrespective of patch test results in occasional individuals. Several
investigatorshavesuggestedacinnamonandbenzoatefreedietinallpatientsinwhomanobvioustriggercannot
befound.
Thefirstgoalofmanagementshouldbediscoveryoftheinitiatingcause,althoughthismaybedifficultbecausethe
triggerofteniselusive.
Oral lesions have been treated with a variety of interventions, with variable results. Topical or intralesional
corticosteroids, topical tacrolimus, radiotherapy, sulfasalazine, hydroxychloroquine sulfate, azathioprine,
cyclosporine A, methotrexate, danazol, dapsone, TNF antagonists (infliximab and thalidomide), clofazimine,
metronidazole, and numerous other antibiotics have been tried. Currently, most investigators administer
intralesionaldelayedreleasehighconcentratetriamcinolonetocontroltheprogressionofthisdisease(Figs.924and
925). In the absence of a response to other treatments, surgical recontouring has been used by some but carries a
considerableriskofrecurrenceandrarelyappearstobewarranted.
FIG.924
OrofacialGranulomatosis.A,Diffuseenlargementoftheupperlip.B,Samepatientafterintralesionaltriamcinolone
injections.
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OrofacialGranulomatosis.SamepatientdepictedinFig.924.A,Clinicalappearancebeforelocaltherapy.B,Significant
resolutionafterintralesionalcorticosteroidtherapy.
FIG.925
The prognosis is highly variable. No therapy has proved to be the silver bullet in resolving the individual
lesions.Insomecases,lesionsresolvespontaneously,withorwithouttherapy;inothers,theycontinuetoprogressin
spiteofamyriadoftherapeuticattemptstostoptheprogression.
WegenerGranulomatosis
Wegener granulomatosis is a wellrecognized, although uncommon, disease process of unknown cause. Initially
describedintheGermanliteraturein1936byFriedrichWegener,thedisorderincludesnecrotizinggranulomatous
lesions of the respiratory tract, necrotizing glomerulonephritis, and systemic vasculitis of small arteries and veins.
Thepathogenesisofthediseaseisthoughttobeduetoanabnormalimmunereactiontoaninhaledenvironmental
antigenorinfectiousagent.Apossiblehereditarypredispositionhasbeenmentionedinsomecases.
ClinicalFeatures
Wegenergranulomatosisdemonstratesawideagerangefromchildhoodtooldage,withameanofageof41years
andnosexpredilection.Althoughmostfrequentlypresentinginadults,approximately15%ofthecasesarisepriorto
age20.Aprevalenceof3outof100,000hasbeenreported,and90%ofthecasesariseinCaucasians.Thediseasecan
involve almost every organ system in the body. With classic Wegener granulomatosis, patients initially show
involvement of the upper and lower respiratory tract; if the condition remains untreated, then renal involvement
oftenrapidlydevelops(generalizedWegenergranulomatosis).
LimitedWegenergranulomatosisisdiagnosedwhenthereisinvolvementoftherespiratorysystemwithoutrapid
developmentofrenallesions.Onesubsetofpatientsexhibitslesionsprimarilyoftheskinandmucosa,acondition
termed superficial Wegener granulomatosis. In this form of the disease, systemic involvement develops slowly.
Thesethreedifferentclinicalpatternshighlightthevariabilityoftheclinicalaggressivenessthatcanoccurinpatients
withWegenergranulomatosis.
Purulent nasal drainage, chronic sinus pain, nasal ulceration, congestion, and fever are frequent findings from
upper respiratory tract involvement. Persistent otitis media, sore throat, and epistaxis also are reported. With
progression,destructionofthenasalseptumcanresultinasaddlenosedeformity.Patientswithlowerrespiratory
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tract involvement may be asymptomatic, or they may have dry cough, hemoptysis, dyspnea, or chest pain. Renal
involvement usually occurs late in the disease process and is the most frequent cause of death. The
glomerulonephritis results in proteinuria and red blood cell casts. Occasionally, the eyes, ears, and skin also are
involved.
Thereportedprevalenceoforallesionsvarieswidelywithoralinvolvementrepresentingtheinitialpresentationin
2% of affected patients. The most characteristic oral manifestation is strawberry gingivitis. This distinctive but
uncommonpatternofgingivalalterationappearstobeanearlymanifestationofWegenergranulomatosisandhas
beendocumentedbeforerenalinvolvementinmostcases.Theaffectedgingivademonstratesafloridandgranular
hyperplasia. The surface forms numerous short bulbous projections, which are hemorrhagic and friable; this red,
bumpysurfaceisresponsibleforthestrawberrylikeappearance(Fig.926and927). At the time of diagnosis, the
involvementmaybelocalizedorgeneralizedtomultiplequadrants.
FIG.926
WegenerGranulomatosis.Hemorrhagicandfriablegingiva(strawberrygingivitis).(CourtesyofDr.SamMcKenna.)
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WegenerGranulomatosis.Hyperplasticandhemorrhagicmucosaofthefacialmandibulargingivaontheleft
side.(CourtesyofDr.JamesWilson.)
FIG.927
Oral ulceration also may be a manifestation of Wegener granulomatosis. These lesions are clinically nonspecific
and may occur on any mucosal surface (Fig. 928). In contrast to the gingival changes, the oral ulcerations are
diagnosed at a later stage of the disease, with more than 60% of the affected patients demonstrating renal
involvement.Otherlesscommonorofacialmanifestationsincludefacialparalysis,labialmucosalnodules,sinusitis
related toothache, arthralgia of the temporomandibular joint (TMJ), jaw claudication, palatal ulceration from nasal
extension,oralantralfistulae,andpoorlyhealingextractionsites.
FIG.928
WegenerGranulomatosis.Deep,irregularulcerationofthehardpalateontheleftside.(FromAllenCM,CamisaC,SalewskiC,etal:
Wegener'sgranulomatosis:reportofthreecaseswithorallesions,JOralMaxillofacSurg49:294298,1991.)
Enlargementofoneormoremajorsalivaryglandsfromprimaryinvolvementofthegranulomatousprocessalso
hasbeenreported.Theglandularinvolvementalsoappearsearlyinthecourseofthediseaseandmayleadtoearly
diagnosisandtreatment.
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Wegener granulomatosis appears as a pattern of mixed inflammation centered around blood vessels. Involved
vessels demonstrate transmural inflammation, often with areas of heavy neutrophilic infiltration, necrosis, and
nucleardust(leukocytoclasticvasculitis).Theconnectivetissueadjacenttothevesselhasaninflammatorycellular
infiltrate,whichcontainsavariablemixtureofhistiocytes,lymphocytes,eosinophils,andmultinucleatedgiantcells
(Fig.929).Specialstainsfororganismsarenegative,andnoforeignmaterialcanbefound.Inoralbiopsyspecimens,
theoralepitheliummaydemonstratepseudoepitheliomatoushyperplasiaandsubepithelialabscesses.Becauseofthe
paucity of large vessels in many oral mucosal biopsies, vasculitis may be difficult to demonstrate, and the
histopathologic presentation may be one of illdefined collections of epithelioid histiocytes intermixed with
eosinophils,lymphocytes, and multinucleated giant cells. In addition, the lesions of strawberry gingivitis typically
demonstrateprominentvascularitywithextensiveredbloodcellextravasation(Fig.930).
WegenerGranulomatosis.Connectivetissuecontainingproliferationofnumerousvascularchannelsandaheavy
inflammatoryinfiltrateconsistingoflymphocytes,neutrophils,eosinophils,andmultinucleatedgiantcells.
FIG.929
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WegenerGranulomatosis.Gingivalbiopsyspecimenshowingamixedinflammatorycellularinfiltrateobscuredby
extensiveextravasationofredbloodcells.
FIG.930
Diagnosis
The diagnosis of Wegener granulomatosis is made from the combination of the clinical presentation and the
microscopicfindingofnecrotizingandgranulomatousvasculitis.TheAmericanCollegeofRheumatologyproposed
four diagnostic criteria with a minimum of two required for a diagnosis of Wegener granulomatosis (Box 92).
Radiographicevaluationofthechestandsinusesisrecommendedtodocumentpossibleinvolvementoftheseareas.
Theserumcreatinineandurinalysisresultsareusedtoruleoutsignificantrenalalterations.
Box92
AmericanCollegeofRheumatologyCriteriaforDiagnosisof
WegenerGranulomatosis
Oralulcerationsornasaldischarge
Nodules,fixedinfiltrates,orcavitiesonchestradiograph
Abnormalurinarysediment(redbloodcellcastsormorethanfiveredbloodcells/highpowerfield)
Granulomatousinflammationuponbiopsy
A laboratory marker for Wegener granulomatosis has been identified. Indirect immunofluorescence for serum
antibodiesdirectedagainstcytoplasmiccomponentsofneutrophilshasbeenusedtosupportadiagnosisofWegener
granulomatosis.Therearetworeactionpatternsoftheseantineutrophilcytoplasmantibodies(ANCA).Antibodies
against proteinase3, a component of neutrophilic azurophilic cytoplasmic granules, are designated PR3ANCA
(previouslytermedcANCA).Likewise,antibodiesagainstmyeloperoxidase,aneutrophiliclysosomalgranule,are
designatedMPOANCA(previouslytermedpANCA).
PR3ANCA is the most useful in the diagnosis of Wegener granulomatosis and is seen in 90% to 95% of
generalizedWegenergranulomatosisand60%oftheearlyorlocalizedcases.ImmunofluorescenceforPR3ANCA
shouldbeorderedalongwiththespecificenzymelinkedimmunosorbentassay(ELISA)testforantibodiesagainst
proteinase3(PR3).Thesecombinedtestsareassociatedwithasensitivityof73%andadiagnosticspecificityof99%
forWegenergranulomatosis.Falsepositivesareuncommonandmaybeassociatedwithavarietyofotherdiseases.
Incontrast,MPOANCAsaredetectedinseveralvasculitidesthattypicallydonotpresentintheoralcavity.
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ThemeansurvivalofuntreatedpatientswithdisseminatedclassicWegenergranulomatosisis5months;80%ofthe
patientsaredeadat1yearand90%within2years.Theprognosisisbetterforthelimitedandsuperficialformsofthe
disease, although a proportion of patients with localized disease eventually will develop classic Wegener
granulomatosis.
The first line of therapy is oral prednisone and cyclophosphamide. On remission, the prednisone is gradually
discontinued,withcontinuationofthecyclophosphamideforatleast1year.Althoughhighresponseratesarenoted,
serious side effects related to the therapy are not rare, especially those related to the cyclophosphamide.
Trimethoprim/sulfamethoxazolehasbeenusedsuccessfullyinlocalizedcases.Whenaddedtothestandardregimen,
this antibiotic combination seems to reduce associated infections and to lower the relapse rate. Lowdose
methotrexateandcorticosteroidsalsohavebeenusedinpatientswhosediseaseisnotimmediatelylifethreateningor
has not responded appropriately to cyclophosphamide. Alternatives for cyclophosphamide include cyclosporine,
rituximab, and infliximab. For maintenance therapy, cyclophosphamide often is replaced with methotrexate or
azathioprine.
Treatmenthasaprofoundeffectontheprogressionofthedisease.Withappropriatetherapy,prolongedremission
isnotedinupto75%ofaffectedpatients;acureoftenisattainablewhenthediseaseisdiagnosedandappropriately
treatedwhiletheinvolvementislocalized.Becauseofarelapserateupto30%,maintenancetherapyisnecessaryin
manypatients.ThePR3ANCAlevelscanbeusedtomonitorthediseaseactivity.Patientsappearlesslikelytohave
relapses if their antineutrophilic antibodies disappear during treatment; in contrast, patients whose levels of
antibodiespersistareatgreaterriskforrelapse.
MucosalReactionstoSystemicDrugAdministration
Thefutureofdentistryandmedicinewillinvolveahighvolumeofpatientssufferingfromadversedrugreactions.
By 2030, 20% of the population will be more than 65 years old. As the population ages and those affected with
chronicdiseasesincrease,patientstakingmultiplemedicationsmostlikelywillescalate.IntheUnitedStatesduring
theyear2000,morethan2.8billionprescriptionswerefilled,enoughtosupplyeachinhabitantwithtenprescriptions
annually.Althoughuseoftwomedicationsisassociatedwitha6%riskofanadversereaction,thefrequencyrisesto
50%withfivedrugsandalmost100%wheneightormoremedicationsareusedsimultaneously.
Two types of adverse drug reactions are seen. Type A (augmented reactions) arise from an exaggerated but
otherwiseexpectedpharmacologicactionoftheprescribedmedication(suchas,bleedingassociatedwithwarfarin).
Approximately 80% of the total adverse drug reactions are Type A. Type B (bizarre reactions) are idiosyncratic
reactionsthatarenotexpected,themajorityofwhicharisefromimmunemediatedeffects,suchashypersensitivity
reactions.
Listsofmedicationsrelatedtoseveralpatternsofdrugrelatedmucosalalterationareprovided.Becausenewdrug
reactionsarebeingreportedonaregularbasisandlargenumbersofnewmedicationscontinuetoappear,theselists
should be considered incomplete and additional investigation is prudent. When presented with a patient with a
possible drug reaction, all utilized medications, both prescribed and overthecounter, that the patient is taking
shouldberesearchedwithareputableonlinepharmaceuticalreference.Thisshouldincludenotonlytheinformation
withinthedruginsertbutalsotheconstantlyupdatedresultsofacompletesearchofthehealthcareliterature.
In addition to drugrelated problems, such as angioedema (see page326), medicationrelated osteonecrosis (see
page 271), cleft lip/palate (see page 1), erythema multiforme (see page 723), gingival hyperplasia (see page 148),
methemoglobinemia, mucosal discolorations (see page 290), burning mouth disorder (see page 807), tardive
dyskinesia,tastedisturbances(seepage809),sialorrhea(seepage431),andxerostomia(seepage432),medications
can induce a wide variety of mucosal ulcerations and erosions. A reaction of the oral mucosa to the systemic
administrationofamedicationiscalledstomatitismedicamentosa.Severaldifferentpatternsoforalmucosaldisease
canbeseen:
Anaphylacticstomatitis
Intraoralfixeddrugeruptions
Lichenoiddrugreactions
Pemphigoidlikedrugreactions
Pemphiguslikedrugreactions
Lupuserythematosuslikeeruptions
Nonspecificerosive,ulcerative,oraphthouslikelesions
AnaphylacticstomatitisarisesaftertheallergenentersthecirculationandbindstoimmunoglobulinE(IgE)mast
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cell complexes. Although systemic anaphylactic shock can result, localized alterations also occur. Fixed drug
eruptionsareinflammatoryalterationsofthemucosaorskinthatrecuratthesamesiteaftertheadministrationof
anyallergen,oftenamedication.MedicationsreportedtobeassociatedwithfixeddrugeruptionsarelistedinBox9
3, lichenoid drug eruptions in Box94, lupus erythematosuslike drug eruptions in Box95, pemphiguslike drug
reactions in Box96, and mucosal pemphigoidlike eruptions in Box97. In addition, a long list of medications is
knowntobeassociatedwithnonspecificerosive,ulcerative,oraphthouslikelesions,butisnotincludedduetoits
length.
Box93
MedicationsImplicatedinFixedDrugEruptions
Analgin
Barbiturates
Chlorhexidine
Cotrimoxazole
Dapsone
Goldsalts
Indomethacin
Lidocaine
Penicillamine
Phenazonederivatives
Phenolphthalein
Salicylates
Sulfonamides
Tetracycline
Box94
MedicationsImplicatedinLichenoidEruptions
Allopurinol
Amiphenazole
Amphotericin
Angiotensinconvertingenzyme(ACE)inhibitors
Antimalarials
Arsenicals
Barbiturates
Betaadrenoceptorblockers
Bismuth
Carbamazepine
Carbimazole
Chloralhydrate
Chlorpropamide
Cimetidine
Clofibrate
Colchicine
Cyanamide
Dapsone
Dipyridamole
Ethionamide
Flunarizine
Furosemide
Goldsalts
Griseofulvin
Interferonalpha
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Ketoconazole
Levamisole
Lincomycin
Lithium
Lorazepam
Mepacrine
Metformin
Methyldopa
Metronidazole
Niridazole
Nonsteroidalantiinflammatorydrugs(NSAIDs)
Oralcontraceptives
Palladium
Paraaminosalicylicacid
Penicillins
Penicillamine
Phenindione
Phenothiazines
Phenylbutazone
Phenytoin
Prazosin
Procainamide
Propylthiouracil
Proteaseinhibitors
Protionamide
Pyrimethamine
Pyritinol
Quinidine
Rifampicin
Spironolactone
Streptomycin
Sulfonamides
Sulfonylureas
Tetracycline
Thiazidediuretics
Tocainide
Tolbutamide
Triprolidine
Box95
MedicationsImplicatedinLupusErythematosuslikeEruptions
Carbamazepine
Chlorpromazine
Etanercept
Ethosuximide
Gold
Griseofulvin
Hydantoins
Hydralazine
Infliximab
Isoniazid
Lithium
Methyldopa
Penicillamine
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Primidone
Procainamide
Quinidine
Reserpine
Streptomycin
Thiouracil
Trimethadione
Box96
MedicationsImplicatedinPemphiguslikeEruptions
Alphamercaptopropionylglycine
Ampicillin
Benzylpenicillin
Captopril
Cefadroxil
Cephalexin
Diclofenac
Ethambutol
Glibenclamide
Gold
Heroin
Ibuprofen
Interleukin2
Interferonbeta
Oxyphenbutazone
Penicillamine
Phenobarbital
Phenylbutazone
Piroxicam
Practolol
Probenecid
Procainepenicillin
Propranolol
Pyritinolchlorhydrate
Rifampin
Thioproline
Box97
MedicationsImplicatedinMucosalPemphigoidlikeEruptions
Amoxicillin
Azapropazone
Clonidine
Furosemide
Ibuprofen
Isoniazid
Mefenamicacid
Nadolol
Penicillamine
PenicillinV
Phenacetin
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Practolol
Salicylicacid
Sulfonamides
Sulfasalazine
ClinicalFeatures
Thepatternsofmucosalalterationsassociatedwiththesystemicadministrationofmedicationsarevaried,almostas
muchasthenumberofdrugsthatresultinthesechanges.Anaphylacticstomatitismayoccuraloneorinconjunction
withurticarialskinlesionsorothersignsandsymptomsofanaphylaxis(e.g.,hoarseness,respiratorydistress,and
vomiting). The affected mucosa may exhibit multiple zones of erythema or numerous aphthouslike ulcerations.
Mucosal fixed drug eruptions appear as localized areas of erythema and edema, which can develop into
vesiculoerosivelesionsandarelocatedmostfrequentlyonthelabialmucosa.Lichenoid,lupuslike,pemphigoidlike,
and pemphiguslike drug reactions resemble their namesakes clinically, histopathologically, and immunologically
(Fig.931).Theselatterchronicdrugreactionsmayinvolveanymucosalsurface,butthemostcommonsitesarethe
posteriorbuccalmucosaandthelateralbordersofthetongue(Figs.932and933).Bilateralandsymmetricallesions
arefairlycommon.
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AllergicMucosalReactiontoSystemicDrugAdministration.A,Bilateralerosionsoflowerlabialmucosawithintermixed
striae.Biopsyrevealedlichenoidpatternofmucositisbutwithnumerousplasmacellsintermixedwiththelymphocytes.The
erosionsultimatelywereproventobeassociatedwithsimvastatin.B,SamepatientdepictedinAafterdiscontinuationof
simvastatin.
FIG.931
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LichenoidDrugReactiontoAllopurinol.Irregularareaofsuperficialerosionoftheleftbuccalmucosa.Lesionswere
alsopresentonthecontralateralbuccalmucosaandbilaterallyonthelateralbordersofthetongue.
FIG.932
AllergicMucosalReactiontoSystemicDrugAdministration.Largeirregularerosionoftherightventralsurfaceofthe
tongue.Thelesionarosesecondarytouseofoxaprozin,anonsteroidalantiinflammatorydrug(NSAID).
FIG.933
Anaphylactic stomatitis typically reveals a nonspecific pattern of subacute mucositis that contains lymphocytes
intermixed with eosinophils and neutrophils. Fixed drug eruptions also reveal a mixed inflammatory cellular
infiltratethatconsistsoflymphocytes,eosinophils,andneutrophils,oftencombinedwithspongiosisandexocytosis
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.Thehistopathologicandimmunologicfeaturesofthesechronicdrugreactionscannotbeusedreliablyto
separatethemfromtheirassociatedprimaryimmunologicdisease.
Immunofluorescencehasbeenusedinanattempttoseparatedrugreactionsfromprimaryvesiculoerosivedisease.
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In most instances, this technique has proven to be unsatisfactory. In spite of these findings, a unique pattern of
reaction has been seen when indirect immunofluorescence for IgG has been performed in patients with lichenoid
drugreactions.Inmanyofthesepatients,adistinctiveannularfluorescentpattern,termedstringofpearls,hasbeen
noted along the cell membrane of the basal cell layer of stratified squamous epithelium. The detected circulating
antibodyhasbeentermedbasalcellcytoplasmicantibody.Althoughfurtherstudyisdesirable,thistechniquemay
provetobeausefuladjunctduringevaluationoforallichenoidlesions.
Diagnosis
Adetailedmedicalhistorymustbeobtained,andthepatientshouldbequestionedcloselyconcerningtheuseofboth
prescription and overthecounter medications. 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, the most
recentlyadministratedmedicationoftenistheculprit.Ifthelasttobeintroduceddrugdoesnotappearresponsible,
serial elimination of the medications can be performed in collaboration with the patients physician until the
offendingagentisdiscovered.
Inchronicdrugreactions,definitivediagnosiscanbemadeifthemucosalalterationsresolveafterdiscontinuation
ofthemedicationandrecuronreintroductionoftheagent.Presumptivediagnosisusuallyissufficientandjustified
whenthemucosalalterationsclearaftercessationoftheoffendingmedication.
Inpossiblelupuslikedrugreactions,serumevaluationforgenericantinuclearantibodies(ANAs)andantibodies
againstdoublestrandedDNAandhistonesoftencanbebeneficial.Lupuslikedrugreactionstypicallyareassociated
withcirculatinggenericANAsandantibodiesagainsthistones,whereaslupuserythematosusalsorevealsantibodies
to doublestranded DNA (a finding not typically noted in drug reactions). This pattern does not hold true in
reactions associated with the TNF antagonists, infliximab and etanercept, which simulate systemic lupus
erythematosus(SLE)verycloselyandareassociatedwithantibodiestodoublestrandedDNA.
The responsible medication should be discontinued and, if necessary, replaced with another drug that provides a
similar therapeutic result. Localized acute reactions can be resolved with topical corticosteroids. When systemic
manifestations are present, anaphylactic stomatitis often warrants systemic administration of adrenaline
(epinephrine), corticosteroids, or antihistamines. Chronic oral lesions often resolve on cessation of the offending
drug,buttopicalcorticosteroidsmaysometimesberequiredforcompleteresolution.
If discontinuation of the medication is contraindicated, palliative care can be provided; however, corticosteroids
oftenareineffectiveaslongastheoffendingmedicationiscontinued.
AllergicContactStomatitis(StomatitisVenenata)
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,topicalanesthetics,restorativemetals,acrylicdenturematerials,dentalimpressionmaterials,anddenture
adhesivepreparationshavebeenmentioned.Twotypesofallergens,cinnamon(seepage322)anddentalrestorative
materials (see page 324), demonstrate clinical and histopathologic patterns that are sufficiently unique to justify
separatedescriptions.
Althoughtheoralcavityisexposedtoawidevarietyofantigens,thefrequencyofatrueallergicreactiontoany
oneantigenfromthiscontactappearstoberare.Thiswasverifiedinaprospectivestudyof13,325dentalpatients,in
whichonlysevenacuteand15chroniccasesofadverseeffectswereattributedtodentalmaterials.Theoralmucosa
ismuchlesssensitivethanthesurfaceoftheskin;thisismostlikelybecauseofthefollowing:
Theperiodofcontactisoftenbrief.
Thesalivadilutes,digests,andremovesmanyantigens.
Thelimitedkeratinizationoforalmucosamakeshaptenbindingmoredifficult,andthehighvascularitytendsto
removeanyantigenquickly.
Theallergenmaynotberecognized(becauseofthelowerdensityofLangerhanscellsandTlymphocytes).
Iftheskinhasbeensensitizedoriginally,themucosamayormaynotdemonstratefutureclinicalsensitization.In
contrast, if the mucosa is sensitized initially, then the skin usually demonstrates similar changes with future
exposure.Longtermoralexposuremayinducetoleranceandreducetheprevalenceofcutaneoussensitivityinsome
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instances. For example, exposure to nickelcontaining orthodontic hardware has been associated with a reduced
prevalenceoffuturecutaneoussensitivitytonickeljewelry.
In addition to oral lesions, allergic contact reactions may produce exfoliative cheilitis (see page278) or perioral
dermatitis (see next section). As mentioned in Chapter8, most cases of chronic cheilitis represent local irritation,
usuallyfromchronicliplicking.Inspiteofthis,investigationhasrevealedthatapproximately25%ofaffectedcases
are allergic contact cheilitis from a variety of antigens that include medications, lipsticks, sunscreens, toothpaste,
dentalfloss,nailpolishes,andcosmetics.
ClinicalFeatures
Allergiccontactstomatitiscanbeacuteorchronic.Ofthosecasesdiagnosed,thereisadistinctfemalepredominance
in both forms. After eliminating focal trauma, localized signs and symptoms suggest mucositis from an isolated
allergen(e.g.,dentalmetal);incontrast,widespreadmouthpainsuggestsanassociationwithamorediffusetrigger,
suchasfood,drink,flavorings,ororalhygienematerials.
Inpatientswithacutecontactstomatitis,burningisthemostfrequentsymptom.Theappearanceoftheaffected
mucosa is variable, from a mild and barely visible redness to a brilliantly erythematous lesion with or without
edema.Vesiclesarerarelyseenand,whenpresent,rapidlyrupturetoformareasoferosion(Fig.934).Superficial
ulcerationsthatresembleaphthaeoccasionallyarise.Itching,stinging,tingling,andedemamaybenoted.
AllergicContactStomatitistoAluminumChloride.Mucosalerythemaandvesiclesofthelowerlabialmucosacausedby
useofaluminumchlorideongingivalretractioncord.
FIG.934
Inchroniccasestheaffectedmucosaistypicallyincontactwiththecausativeagentandmaybeerythematousor
whiteandhyperkeratotic.Periodically,erosionsmaydevelopwithintheaffectedzones.Someallergens,especially
toothpastes,cancausewidespreaderythema,withdesquamationofthesuperficiallayersoftheepithelium(Fig. 9
35).Allergiccontactcheilitisdemonstratesclinicalfeaturesidenticaltothosecasescreatedthroughchronicirritation,
anditmostfrequentlyappearsaschronicdryness,scaling,fissuring,orcrackingofthevermilionborderofthelip.
Rarely, symptoms identical to orolingual paresthesia can be present without any clinically evident signs. One
distinctivepattern,plasmacellgingivitis,isdiscussedelsewhere(seepage145).
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FIG.935
AllergicContactStomatitistoToothpaste.Erythematousmucosawithsuperficialepithelialdesquamation.
Diagnosis
Usually,thediagnosisofacutecontactstomatitisisstraightforwardbecauseofthetemporalrelationshipbetweenthe
useoftheagentandtheresultanteruption.Ifanacuteoralorcircumoralreactionisnotedwithin30minutesofa
dentalvisit,thenallergytoalluseddentalmaterials,localanesthetics,andglovesshouldbeinvestigated.
The diagnosis of chronic contact stomatitis is much more difficult. Most investigators require good oral health,
elimination of all other possible causes, and visible oral signs, together with a positive history of allergy and a
positive skin test result to the suspected allergen. If allergic contact stomatitis is strongly suspected but skin test
results are negative, then direct testing of the oral mucosa can be attempted. The antigen can be placed on the
mucosainamixturewithOrabaseorinarubbercupthatisfixedtothemucosa.
In mild cases of acute contact stomatitis, removal of the suspected allergen is all that is required. In more severe
cases, antihistamine therapy, which is combined with topical anesthetics, usually is beneficial. Chronic reactions
respondtoremovaloftheantigenicsourceandapplicationofatopicalcorticosteroidgelororalsuspension.
Whenattemptingtodiscoverthesourceofadiffuseallergicmucositis,useofplainbakingsodaortoothpastethat
is free of flavoring or preservatives is recommended. The patient also should be instructed to avoid mouthwash,
gum, mints, chocolate, cinnamoncontaining products, carbonated drinks, and excessively salty, spicy, or acidic
foods.Ifanassociationcannotbefound,thencutaneouspatchtestingmayprovidehelpfulinformation.
PerioralDermatitis(PeriorificialDermatitis)
Perioral dermatitis does not refer to every rash that occurs around the mouth but is specific for a unique
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inflammatoryskindiseasethatinvolvesthecutaneoussurfacessurroundingthefacialorifices.Becausethedisorder
alsoofteninvolvestheparanasalandperiorbitalskin,periorificialdermatitisisthemostappropriatedesignation.
Although the process is idiopathic, the dermatitis is associated strongly with uncritical use of potent topical
corticosteroids on the facial skin. Fluorinated toothpaste and overuse of heavy facial cosmetics, creams, and
moisturizersalsoareimplicatedinmanypatients.Weakercorrelationshavebeenseenwithsystemiccorticosteroids,
corticosteroid inhalers, and nasal corticosteroids. Heavy exposure to ultraviolet light, heat, and wind appears to
worsen the dermatitis. Some of these substances may initially induce an irritant or allergic contact dermatitis,
whereasothersarethoughttoproduceinappropriateocclusionoftheskinsurfacewithsubsequentproliferationof
skinflora.
ClinicalFeatures
Perioraldermatitisappearswithpersistenterythematouspapules,papulovesicles,andpapulopustulesthatinvolve
theskinsurroundingthevermilionborderoftheupperandlowerlips.Inaddition,involvementoftheperinasalskin
isseeninapproximately40%ofaffectedpatients,and25%haveperiorbitaldermatitis(Fig.936).Classically,thereis
a zone of spared skin immediately adjacent to the vermilion border. Pruritus and burning are variable. The vast
majority of the cases are diagnosed in women between the ages of 20 to 45 years, lending further support to the
associationwithcosmeticuse.Inspiteofthis,theprocessdoesoccurinmenandinchildrenofeithersex.
PerioralDermatitis.Multipleerythematouspapulesoftheskinsurroundingthevermilionborderofthelips.Notesimilar
involvementaroundthenasalorifices(periorificialdermatitis).(CourtesyofDr.BillyMillay.)
FIG.936
Biopsy of perioral dermatitis demonstrates a variable pattern. In many cases there is a chronic lymphohistiocytic
dermatitisthatoftenexhibitsspongiosisofthehairfollicles.Inotherpatientsarosacealikepatternisnotedinwhich
thereisperifolliculargranulomatousinflammation.Onoccasion,thishistopathologicpatternhasbeenmisdiagnosed
assarcoidosis.
Most cases resolve with zero therapy, which includes discontinuation of corticosteroids, cosmetics, and facial
creams.Discontinuationofpotenttopicalcorticosteroiduseoftenisfollowedbyaperiodofexacerbation,whichcan
beminimizedbysubstitutionofalesspotentcorticosteroidbeforetotalcessation.Oraltetracyclineisconsideredthe
therapeuticgoldstandardforperioraldermatitisbutmustbeavoidedduringchildhoodandpregnancy.Inaddition,
ashortageoftetracyclineintheUnitedStateshasmadeitsuseproblematic.Nostrongevidencehasbeenpresented
todemonstratethatdoxycyclineorminocyclineisequivalentorsuperiortotetracycline.Luckily,perioraldermatitis
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alsorespondswelltotopicalpimecrolimusortopicalerythromycin.Weakertherapeuticrecommendationsinclude
topicalmetronidazole,clindamycin,tacrolimus,tetracycline,adapalene,orazelaicacid,plussystemicerythromycin
or isotretinoin. The pathosis typically demonstrates significant improvement within several weeks and total
resolutioninafewmonths.Recurrenceisuncommon.
ContactStomatitisFromArtificialCinnamonFlavoring
Mucosal abnormalities secondary to the use of artificially flavored cinnamon products are fairly common, but the
range of changes was not recognized widely until the late 1980s. Cinnamon oil is used as a flavoring agent in
confectionery, ice cream, soft drinks, alcoholic beverages, processed meats, gum, candy, toothpaste, breath
fresheners, mouthwashes, and even dental floss. Concentrations of the flavoring 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 tartarcontrol
toothpastes have a strong bitter flavor and require a significant concentration of flavoring agents including
cinnamon to hide the taste, resulting in a greater chance these formulations will cause oral mucosal lesions.
Althoughmuchlesscommon,reactionstocinnamoninitsnaturalspiceformhavebeendocumented.
ClinicalFeatures
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
burningarecommonsymptomsinallcases.
Thegingivaisthemostfrequentsiteaffectedbytoothpaste,oftenresemblingplasmacellgingivitis(seepage145);
enlargement,edema,anderythemaarecommon.Sloughingofthesuperficialoralepitheliumwithoutcreationofan
erosionisseencommonly.Erythematousmucositis,occasionallycombinedwitherosion,hasbeenreportedonthe
buccalmucosaandtongue.Exfoliativecheilitisandcircumoraldermatitisalsomayoccur.
Reactionsfromchewinggumandcandyaremorelocalizedandtypicallydonotaffectthelipvermilionorperioral
skin.Mostofthelesionsappearonthebuccalmucosaandlateralbordersofthetongue.Buccalmucosallesionsoften
areoblongpatchesthatarealignedalongtheocclusalplane(Fig.937).Individuallesionshaveanerythematousbase
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 259). Lingual involvement may become extensive and spread to the dorsal
surface(Fig.938).Significantthickeningofthesurfaceepitheliumcanoccurandmayraiseclinicalconcernfororal
hairyleukoplakia(OHL)(seepage242)orcarcinoma(Fig.939).
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FIG.937
ContactStomatitisfromCinnamonFlavoring.Oblongareaofsensitiveerythemawithoverlyingshaggyhyperkeratosis.
ContactStomatitisfromCinnamonFlavoring.Sensitiveandthickenedhyperkeratosisofthelateralanddorsalsurfaceof
thetongueontherightside.
FIG.938
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ContactStomatitisfromCinnamonFlavoring.Leftlateralborderofthetonguedemonstratinglinearrowsof
hyperkeratosisthatresembleoralhairyleukoplakia(OHL).
FIG.939
Usually, the epithelium in contact stomatitis from artificial cinnamon flavoring is acanthotic, often with elongated
reteridgesandthinningofthesuprapapillaryplates.Hyperkeratosisandextensiveneutrophilicexocytosismaybe
present. The superficial lamina propria demonstrates a heavy inflammatory cell infiltrate that consists
predominantlyoflymphocytesthatmaybeintermixedwithplasmacells,histiocytes,oreosinophils.Thisinfiltrate
often obscures the epithelium and connective tissue interface (Fig.940). A characteristic feature in localized cases
caused by gum, mints, or candies is the frequent presence of an obvious perivascular inflammatory infiltrate that
extendswellbelowtheinterfacezone(Fig.941).
ContactStomatitisfromCinnamonFlavoring.Oralmucosademonstratingsignificantinterfacemucositisanddeeper
perivascularinflammation.
FIG.940
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ContactStomatitisfromCinnamonFlavoring.Perivascularinflammatoryinfiltrateconsistingpredominantlyof
lymphocytesandplasmacells.
FIG.941
Diagnosis
With a high index of suspicion and knowledge of the variations of the clinical pattern, the diagnosis of localized
contactstomatitisoftencanbemadefromtheclinicalappearanceandthehistoryofcinnamonuse.Oftenbiopsiesare
performed for atypical or extensive cases because of the differential diagnosis, which includes several significant
vesiculoerosive and neoplastic conditions. The histopathologic features are not specific, but they are sufficient to
raise a high index of suspicion in an oral and maxillofacial pathologist who is familiar with the pattern. Use of
cinnamoncontainingtoothpasteshouldbeinvestigatedineverypatientwithanatypicalpatternofgingivitis.Diet
related examples often are the most difficult to diagnose and may necessitate cutaneous allergy patch testing or a
dietdiarytoisolatethecause.
Typically,thesignsandsymptomsdisappearwithin1weekafterthediscontinuationofthecinnamonproduct.Ifthe
patientresumesintakeoftheproduct,thenthelesionsreappear,usuallywithin24hours.Onoccasion,resolutionis
moregradualandthepatientmaybenefitfromshorttermuseofatopicalcorticosteroid.
LichenoidContactReactionFromDentalRestorativeMaterials
Dentalamalgamhasbeeninactiveuseforover180yearsandhasproventobeadurableandrelativelyinexpensive
material that remains one of the most commonly placed dental restorations. Because of an associated lowlevel
releaseofmercuryfromthesefillings(anamountsignificantlylessthanthedailycontributionfromfoodandnon
dentalsources),itsusehasbeenblamedforawidevarietyofhealthconcerns.Duetothecontroversy,anumberof
controlledstudieswereperformed,showingnoassociationbetweenthepresenceofdentalamalgamsandsystemic
disease.Twooralpathoses,burningmouthsyndromeandorofacialgranulomatosis,alsohavebeencorrelatedwith
thepresenceofamalgamsbysomeinvestigators,butnoconclusiveevidenceexiststoassociatethesedisorderswith
the dental restorative material. The primary adverse effects that are well documented include acute and chronic
hypersensitivityreactions.
Dental amalgams contain mercury, silver, tin, and copper, with some variations also including zinc, indium,
palladium,orplatinum.Thevastmajorityofhypersensitivityreactionstodentalrestorativematerialsaretodental
amalgam, usually associated with the mercury content. Reactions have been seen much less frequently to other
dentalrestorationscontainingmaterialssuchasgold,beryllium,chromium,cobalt,orcompositeresins.
Although rare acute reactions to mercury may be seen following placement of amalgam, the vast majority of
adversealterationsrepresentchronictypeIVhypersensitivityreactionsthatareseenmostcommonlyassociatedwith
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olderandcorrodedamalgams.Itisbelievedthemetalionsreleasedbycorrosionhaptenizewithoralkeratinocyte
surfaceproteinsandinitiateacellmediatedautoimmuneresponsedirectedatthebasalcelllayeroftheepithelium.
Some investigators have called these chronic alterations galvanic lesions, but neither clinical nor experimental
studiessupporttheelectrogalvanichypothesisoforigin.
Thesechroniccontactreactionsappearclinicallyandhistopathologicallysimilartolichenplanus(seepage729)but
demonstrateadifferentmucosaldistribution.Whenpatientswithtrueorallichenplanusareexamined,thelesions
migrateandexhibitnodirectcorrelationtocontactwithdentalmaterials.Inaddition,patientswithlichenplanusdo
notdemonstrateasignificantlyincreasedpositivepatchtestingtodentalrestorativematerialsandexhibitminimal
tonoclinicalimprovementonremovaloftheiramalgams.
However, there is a subgroup of patients whose lichenoid lesions do not migrate and usually involve only the
mucosaadjacenttoadentalmetal.Onpatchtesting,thevastmajorityofthesepatientsreacttotheoffendingmetal,
andthelesionsresolverapidlyafterremovalofadjacentamalgams.Suchlesionsshouldbediagnosedasalichenoid
contactreactiontoadentalrestorativematerial,notastruelichenplanus.
ClinicalFeatures
Acute reactions to dental amalgams are extremely rare and related to an immediate hypersensitivity reaction to
mercury. The signs tend to arise within hours after placement of an amalgam and present with erythematous,
pruritic, and urticarial lesions of the ipsilateral oral mucosa and facial skin. In severe reactions, soft tissue edema,
tachycardia,andbreathingdifficultiesalsoareseen.
Thevastmajorityoflichenoidcontactreactionsaffecttheposteriorbuccalmucosaandtheventralsurfaceofthe
lateral borders of the tongue. The lesions usually are confined to the area of contact and may be white or
erythematous,withorwithoutperipheralstriae(Fig.942).Mostpatientshavenosymptoms,butperiodicerosion
maybenoted.Inalllikelihood,manyofthelesionspreviouslyreportedasthesocalledplaquetypeoflichenplanus
were,inreality,lichenoidcontactreactions.
OralMucosalContactReactiontoDentalAmalgam.A,Hyperkeratoticlesionwithaperipheralradiatingpatternonthe
lateralborderofthetongueontherightsidethealteredmucosacontactedtheamalgamsoftheadjacentmandibularmolarteeth.
Thelesionremainedinthesamelocationfor5yearsandperiodicallybecameerosiveandsymptomatic.Smoothingandpolishing
oftheadjacentrestorationshadnoeffect.B,Appearanceofpreviouslyalteredareaofthetongue14daysafterremovalofadjacent
amalgams.Notetotalresolutionofthemucosalalterations.
FIG.942
Diagnosis
Thediagnosisofalichenoidcontactreactionismadefromtheclinicalappearanceofthelesion,thelackoflesional
migration, and the correlation to adjacent dental metal (Fig. 943). Although the histopathologic features may be
indistinguishablefromlichenplanus,biopsyoccasionallyisperformedtoconfirmtheclinicalimpressionandtorule
out other pathoses such as epithelial dysplasia. Although patch testing is positive in up to 70% of patients with
contactreactionsandsimilarlyreactiveinlessthan4%ofpatientswithtruelichenplanus,theclinicalpresentation
hasproventobeamorereliablediagnosticindicatorthanpatchtesting.
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OralMucosalContactReactiontoDentalAmalgam.Radiatingpatternofhyperkeratoticstriaeontheposteriorbuccal
mucosathatcontactsalargedistobuccalamalgamofthepermanentmandibularsecondmolar.
FIG.943
Biopsyofallergiccontactstomatitisfromdentalmaterialsexhibitsnumerousfeaturesoflichenplanus.Thesurface
epitheliummaybehyperkeratotic,atrophic,orulcerated.Areasofhydropicdegenerationofthebasalcelllayeroften
are present. The superficial lamina propria contains a dense bandlike chronic inflammatory cellular infiltrate
consisting predominantly of lymphocytes, but there may be scattered plasma cells. On occasion, deeper lymphoid
aggregatesmaybenoted,ofteninaperivascularorientation.
Inpatientswithacutehypersensitivityreactionstothemercuryinanamalgam,theprocessusuallyisselflimiting
and resolves spontaneously within 2 to 3 days. In spite of this, systemic symptoms, such as significant breathing
difficulties,maynecessitateremovalofthenewlyplacedamalgam.
For chronic lichenoid reactions, local measures, such as improved oral hygiene, smoothing, polishing, and
recontouringoftheamalgamrestoration,shouldbeattemptedbeforemoreaggressivemeasures,becauseclinically
similarlesionshavebeennotedasaresultofsurfaceplaqueaccumulation.Ifthisisunsuccessful,thentheamalgam
inquestionshouldbereplaced.Becausepatientsrarelymayexhibithypersensitivitytocompositeresins,useofinert
materials(suchas,glassionomer,porcelain,orporcelainfusedtometal)isrecommended.Likelichenplanus,some
investigatorsbelieveuntreatedlichenoidcontactreactionsrarelymayevolveintocarcinoma,althoughthepossibility
thatsomepreneoplasticleukoplakiasaremistakenforlichenoidcontactreactionscannotberuledout.Althoughthis
association is far from proven, removal of amalgams adjacent to possible lichenoid contact reactions appears
prudent.Lichenoidlesionsthatfailtoresolvefollowingremovaloftheadjacentmetalshouldbeevaluatedfurther.
Angioedema(AngioneuroticEdemaQuinckeDisease)
Angioedemaisadiffuseedematousswellingofthesofttissuesthatmostcommonlyinvolvesthesubcutaneousand
submucosalconnectivetissuesbutmayaffectthegastrointestinalorrespiratorytract,occasionallywithfatalresults.
The disorder has been referred to as Quincke disease, after the clinician who initially related the changes to an
alteration in vascular permeability. The outdated term angioneuroticedema also has been used, because affected
patientsoftencomplainedofachokingsensationandwerelabeledneurotic.
The most common cause is mast cell degranulation, which leads to histamine release and the typical clinical
alterations. IgEmediated 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
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stimuli,suchasheat,cold,exercise,emotionalstress,solarexposure,andsignificantvibration.
AnunusualpatternofdrugreactionthatcanproducesevereformsofangioedemathatarenotmediatedbyIgEis
the type associated with use of drugs called angiotensinconverting enzyme (ACE) inhibitors. These medications
represent one of the most frequently prescribed drugs, with 35 to 40 million patients currently taking these
antihypertensives. Some of the most popular are 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
degradesbradykinin).Inanattempttoavoidthisangioedema,asecondgenerationofmedicationscalledangiotensin
II receptor blockers (e.g., losartan and valsartan) was developed specifically to avoid any inhibition of bradykinin
degradation.Thesenewermedicationslowerthefrequencyofangioedemabutdonoteliminatetheadversereaction.
Theprevalenceofthispatternofangioedemaisestimatedtobe0.1%to0.2%ofthosewhouseACEinhibitors.Inthe
majorityofaffectedpatients,theangioedemaariseswithinhoursofinitialuseofthedrug.Inupto30%ofthecases,
theangioedemaisdelayed,withthelongestreportedintervalbetweendruguseinitiationandtheinitialattackbeing
10years.AttacksprecipitatedbydentalprocedureshavebeenreportedinlongtermusersofACEinhibitors.Many
cliniciansoverlooktheassociationbetweenangioedemaandACEinhibitors,withstudiesdemonstratingcontinued
administrationofthemedicationinmorethan50%ofaffectedpatients.
Angioedemaalsocanresultfromactivationofthecomplementpathway.Thismaybehereditaryoracquired.Two
rareautosomaldominanthereditaryformsareseen.TypeI,comprising85%ofthehereditarycases,iscausedbya
quantitativereductionintheinhibitorthatpreventsthetransformationofC1toC1esterase.Withoutadequatelevels
ofC1esteraseinhibitor(C1INH),C1esterasecleavesC4andC2andresultsinangioedema.TypeIIexhibitsnormal
levelsofC1INH,buttheinhibitorisdysfunctional.
TheacquiredtypeofC1INHdeficiencyisseeninassociationwithcertaintypesoflymphoproliferativediseases
(Caldwell syndrome) or in patients who develop specific autoantibodies. In lymphoproliferative diseases,
monoclonal antibodies directed against the tumor cells activate C1 and lead to consumption of C1INH. In the
autoimmunevariant,theantibodyattachestotheC1receptorontheC1INHmolecule,leadingtodysfunctionalC1
INH and consumption of C1. In both the acquired and the hereditary forms of abnormal C1INH activity, minor
trauma,suchasadentalprocedure,canprecipitateanattack.
Finally, angioedema has been seen in the presence of high levels of antigenantibody complexes (e.g., lupus
erythematosus and viral or bacterial infections) and in patients with grossly elevated peripheral blood eosinophil
counts.
ClinicalFeatures
Angioedemaischaracterizedbytherelativelyrapidonsetofsoft,nontendertissueswelling,whichmaybesolitary
ormultiple(Fig.944).Inthehereditaryforms,theinitialonsettypicallyisnotedinchildhoodoradolescence.The
episodesareunpredictableandintermixedwithedemafreeintervals.Recurrentskinswellingandabdominalpain
arethemostfrequentpresentations.Theextremitiesarethemostcommoncutaneoussitesofinvolvement,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 monitored for extended periods (and may be
associated with respiratory distress). A deeper voice, hoarseness, aphonia, and dyspnea are important warning
signs. Recurrent snoringinduced 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
enlargementsthatmaymeasureuptoseveralcentimetersindiameter(Fig.945).Althoughpainisunusual,itching
iscommonanderythemamaybepresent.Theenlargementtypicallyresolvesover24to72hours.Incontrasttothe
hereditary variants, allergic, acquired, and ACE inhibitorassociated angioedema demonstrate significant
involvement of the head and neck, such as the face, lips, tongue, floor of mouth, pharynx, and larynx. The risk of
angioedemaassociatedwithACEinhibitorsissignificantlygreaterinblacks(threetofourtimesthatofotherraces),
andthispatternisthetypemostfrequentlyencounteredbyoralhealthpractitioners.
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FIG.944
Angioedema.Diffuseupperlipswellingthataroserapidly.
Angioedema.A,Soft,nontendertissueswellingofthefacearoserelativelyrapidlyafterdentaltreatment.B,Facial
appearanceafterresolutionofedematousfacialenlargement.
FIG.945
Diagnosis
Incasesofallergiccausation,thediagnosisofangioedemaoftenismadefromtheclinicalpresentationinconjunction
withtheknownantigenicstimulus.Whenmultipleantigenicexposuresoccur,thediagnosisoftheoffendingagent
canbedifficultandinvolvesdietarydiariesandantigenictesting.
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Thosepatientswhoseconditionscannotberelatedtoantigenicexposureormedicationsshouldbeevaluatedfor
the presence of adequate functional C1INH. In the hereditary types, both forms exhibit normal levels of C1 and
decreasedlevelsoffunctionalC1INH.TypeIdemonstratesadecreasedquantityofC1INH;typeIIexhibitsnormal
levels of the inhibitor, but it is dysfunctional. The acquired type associated with lymphoproliferative diseases
demonstrateslowC1andlowC1INH,whereastheautoimmunevariantexhibitslowC1anddysfunctionalC1INH.
Thetreatmentofallergicangioedemausuallyconsistsoforalantihistaminetherapy.Iftheattackisnotcontrolledor
iflaryngealinvolvementispresent,thenintramuscularepinephrineshouldbeadministered.Iftheepinephrinedoes
notstoptheattack,thenintravenouscorticosteroidsandantihistaminesshouldbegiven.
CasesofangioedemarelatedtoACEinhibitorsarenotIgEmediatedandoftendonotrespondtoantihistamines
andcorticosteroids.Inspiteofthis,someinvestigatorsbelieveuseofcorticosteroidsandhistamineblockersshortens
the time of intubation in patients who require airway support. Although the mechanism is unclear, some patients
withACEinhibitorassociatedangioedemaalsohaverespondedtoC1INHconcentrate.Inmanypatients,noform
ofpharmaceuticalinterventioniseffective,andthepatientsmustbekeptundercloseobservationuntiltheairwayis
nolongeratrisk.PatientsexperiencingACEinhibitorassociatedangioedemashouldavoidallmedicationsinthis
classofdrugs,andtheirphysiciansshouldconsideralternativehypertensionmanagementstrategies.AngiotensinII
receptorblockersdonotappeartobesafealternatives.
Those cases related to C1INH deficiency also do not respond to antihistamine, corticosteroid, or adrenergic
therapy. Intubation and tracheostomy may be required for laryngeal involvement. Fresh freezedried plasma has
beenused;however,someinvestigatorsdonotrecommenditsusebecausethereisariskoftransmittinginfection,
anditreplacesnotonlyC1INHbutalsopotentiallyharmfulC1esterase,C1,C2,andC4.C1INHconcentrateand
esteraseinhibitingdrugs(aprotininortranexamicacid)arethetreatmentsofchoiceforacuteattacks.Becauseacute
attacks of hereditary angioedema are not only unpleasant but also potentially life threatening, prevention is
paramount.Allpatientsshouldcarrymedicalwarningcardsthatstatethediagnosisandlistelementaryprecautions.
ProphylaxisforC1INHdeficiencyisrecommendedinpatientswhohavemorethanthreeattacksperyear.Patients
should avoid violent physical activity and trauma. Medical prophylaxis is recommended before any dental or
surgicalprocedure.Inthehereditarytypes,suchprophylaxistypicallyincludesacombinationof:1)anattenuated
androgen, such as danazol or stanozolol (androgens induce hepatic synthesis of C1INH); 2) tranexamic acid or
aprotinin;and3)oneormoreinfusionsofC1INH.Theautoimmuneacquiredtypeisbestpreventedthroughtheuse
ofcorticosteroids.
Bibliography
TransientLingualPapillitis
BrannonRB,FlaitzCM.Transientlingualpapillitis:apapulokeratoticvariant.OralSurgOralMedOralPathol
OralRadiolEndod.2003;96:187191.
FlaitzCM,ChavarriaC.Painfultonguelesionsassociatedwithafoodallergy.PediatrDent.2001;23:506507.
GiuntaJL.Transientlingualpapillitis.JMassDentAssoc.2009;58:2627.
LacourJP,PerrinC.Eruptivefamiliallingualpapillitis:anewentity.PediatrDermatol.1997;14:1316.
RouxO,LacourJP.Eruptivelingualpapillitiswithhouseholdtransmission:aprospectiveclinicalstudy.BrJ
Dermatol.2004;150:299303.
WhitakerSB,KrupaJJ,SinghBB.Transientlingualpapillitis.OralSurgOralMedOralPatholOralRadiolEndod.
1996;82:441445.
RecurrentAphthousStomatitis
BaccagliniL,LallaRV,BruceAJ,etal.Urbanlegends:recurrentaphthousstomatitis.OralDis.2011;17:755770.
BrocklehurstP,TickleM,GlennyAM,etal.Systemicinterventionsforrecurrentaphthousstomatitis(mouth
ulcers).CochraneDatabaseSystRev.2012;(9)[CD005411].
LiuC,ZhouZ,LiuG,etal.Efficacyandsafetyofdexamethasoneointmentonrecurrentaphthousulceration.
AmJMed.2012;125:292301.
PedersenA,HougenHP,KenradB.Tlymphocytesubsetsinoralmucosaofpatientswithrecurrentaphthous
ulceration.JOralPatholMed.1992;21:176180.
RogersRS.Complexaphthosis.AdvExpMedBiol.2003;528:311316.
ScullyC,PorterS.Oralmucosaldisease:recurrentaphthousstomatitis.BrJOralOralMaxillofacSurg.
2008;46:198206.
ShipJA.Recurrentaphthousstomatitis:anupdate.OralSurgOralMedOralPatholOralRadiolEndod.
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thismistakenimpression.Inmostcases,however,thesquamousproliferationhasabland
cytologicappearance.Inexamplesthataredifficulttodistinguishfromcarcinoma,low
immunoreactivityforp53proteinandKi67mayhelptosupportadiagnosisofnecrotizing
sialometaplasia.
FIG.1131
NecrotizingSialometaplasia.Necroticmucousacini(left)andadjacentductalsquamousmetaplasia(right).
Becauseoftheworrisomeclinicalpresentationofnecrotizingsialometaplasia,biopsyusuallyisindicatedtoruleout
the possibility of malignant disease. Once the diagnosis has been established, no specific treatment is indicated or
necessary.Thelesiontypicallyresolvesonitsownaccord,withanaveragehealingtimeof5to6weeks.
SalivaryGlandTumors
GeneralConsiderations
Tumorsofthesalivaryglandsconstituteanimportantareainthefieldoforalandmaxillofacialpathology.Although
suchtumorsareuncommon,theyarebynomeansrare.Theannualincidenceofsalivaryglandtumorsaroundthe
world ranges from about 1.0 to 6.5 cases per 100,000 people. Although soft tissue neoplasms (e.g., hemangioma),
lymphoma,andmetastatictumorscanoccurwithinthesalivaryglands,thediscussioninthischapterislimitedto
primaryepithelialneoplasms.
Anoftenbewilderingarrayofsalivarytumorshasbeenidentifiedandcategorized.Inaddition,theclassification
scheme is a dynamic one that changes as clinicians learn more about these lesions. As an example, since the last
editionofthistext,mammaryanaloguesecretorycarcinomahasbeennewlyrecognizedasanimportantlowgrade
salivary malignancy that may occur in both major and minor glands. Box 115 includes most of the currently
recognized tumors. Some of the tumors on this list are not specifically discussed because their rarity places them
outsidethescopeofthistext.
https://bookshelf.vitalsource.com/#/books/9781455770526/cfi/6/42!/4/2/8/2/28/2/14/2/6/2/2@0:48.2
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Box115
ClassificationofSalivaryGlandTumors
Benign
Pleomorphicadenoma(mixedtumor)
Myoepithelioma
Basalcelladenoma
Canalicularadenoma
Warthintumor(papillarycystadenomalymphomatosum)
Oncocytoma
Sebaceousadenoma
Sebaceouslymphadenoma
Ductalpapillomas
Sialadenomapapilliferum
Intraductalpapilloma
Invertedductalpapilloma
Papillarycystadenoma
Malignant
Malignantmixedtumors
Carcinomaexpleomorphicadenoma
Carcinosarcoma
Metastasizingmixedtumor
Mucoepidermoidcarcinoma
Aciniccelladenocarcinoma
Adenoidcysticcarcinoma
Polymorphouslowgradeadenocarcinoma
Basalcelladenocarcinoma
Epithelialmyoepithelialcarcinoma
Mammaryanaloguesecretorycarcinoma
Salivaryductcarcinoma
Myoepithelialcarcinoma
Cystadenocarcinoma
Sebaceousadenocarcinoma
Sebaceouslymphadenocarcinoma
Clearcelladenocarcinoma
Oncocyticcarcinoma
Squamouscellcarcinoma
Malignantlymphoepitheliallesion(lymphoepithelialcarcinoma)
Smallcellcarcinoma
Sialoblastoma
Adenocarcinoma,nototherwisespecified(NOS)
Anumberofinvestigatorshavepublishedtheirfindingsonsalivaryglandneoplasia,butacomparisonofthese
studiesisoftendifficult.Somestudieshavebeenlimitedtoonlythemajorglandsorhavenotincludedalltheminor
salivaryglandsites.Inaddition,theeverevolvingclassificationsystemmakesanevaluationofsomeolderstudies
difficult, especially when researchers attempt to compare them with more recent analyses. Notwithstanding these
difficulties,itisstillhelpfultocomparethesestudiesbecausetheyprovideagoodoverviewofsalivaryneoplasiain
general. An evaluation of various studies shows fairly consistent trends (with minor variations) with regard to
salivaryglandtumors.
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Tables113and114summarizefivelargeseriesofprimaryepithelialsalivaryglandtumors,analyzedbysitesof
occurrenceandfrequencyofmalignancy,respectively.Somevariationsbetweenstudiesmayrepresentdifferencesin
diagnostic criteria, geographic differences, or referral bias in the cases seen. (Some centers may tend to see more
malignanttumorsonreferralfromothersources.)
TABLE113
SitesofOccurrenceofPrimaryEpithelialSalivaryGlandTumors
Author(Year)
NumberofCases Parotid Submandibular Sublingual
Minor
EvesonandCawson(1985) 2,410
73%
11%
0.3%
14%
Seifertetal.(1986)
2,579
80%
10%
1.0%
9%
Spiro(1986)
2,807
70%
8%
(includedwithminorglandtumors) 22%
Ellisetal.(1991)
13,749
64%
10%
0.3%
23%
Tianetal.(2010)
6,982
61%
10%
1.0%
28%
TABLE114
FrequencyofMalignancyforSalivaryTumorsatDifferentSites
Author(Year)
NumberofCases Parotid Submandibular Sublingual
Minor
EvesonandCawson(1985) 2,410
15%
37%
86%
46%
Seifertetal.(1986)
2,579
20%
45%
90%
45%
Spiro(1986)
2,807
25%
43%
(includedwithminorglandtumors) 82%
Ellisetal.(1991)
13,749
32%
41%
70%
49%
Tianetal.(2010)
6,982
18%
26%
95%
62%
The most common site for salivary gland tumors is the parotid gland, accounting for 61% to 80% of all cases.
Fortunately,arelativelylowpercentageofparotidtumorsaremalignant,rangingfrom15%to32%.Overall,itcanbe
stated that twothirds to threequarters of all salivary tumors occur in the parotid gland, and twothirds to three
quartersoftheseparotidtumorsarebenign.
Table115summarizesfourlargeseriesofparotidneoplasms.Thepleomorphicadenomaisoverwhelminglythe
most common tumor (50% to 77% of all cases in the parotid gland). Warthin tumors are also fairly common; they
accountfor5%to22%ofcases.Avarietyofmalignanttumorsoccur,withthemucoepidermoidcarcinomaappearing
to be the most frequent overall. Although previous studies suggested that the United Kingdom may have a lower
frequencyofthistumor,amorerecentseriesshowedprevalencenumbersequivalenttoothercountries.
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TABLE115
ParotidTumors
Tianetal.(China,
2010)
Totalnumberofcases
Ellisetal.(UnitedStates,
1991)
Eveson&Cawson(GreatBritain, Eneroth(Sweden,
1985)
1971)
4264
8222
1756
2158
Pleomorphicadenoma
49.9%
53.0%
63.3%
76.8%
Warthintumor
22.4%
7.7%
14.0%
4.7%
Oncocytoma
0.5%
1.9%
0.9%
1.0%
Basalcelladenoma
5.8%
1.4%
Otherbenigntumors
3.4%
3.7%
7.1%*
Total
82.1%
67.7%
85.3%
82.5%
Mucoepidermoid
carcinoma
4.3%
9.6%
1.5%
4.1%
Aciniccellcarcinoma
3.2%
8.6%
2.5%
3.1%
Adenoidcystic
carcinoma
1.8%
2.0%
2.0%
2.3%
Malignantmixed
tumor
2.3%
2.5%
3.2%
1.5%
Squamouscell
carcinoma
0.7%
2.1%
1.1%
0.3%
Othermalignant
tumors
5.6%
7.5%
4.4%
6.3%
Total
17.9%
32.3%
14.7%
17.5%
BenignTumors
MalignantTumors
Includesallothermonomorphicadenomas.
From8%to11%ofallsalivarytumorsoccurinthesubmandibulargland,butthefrequencyofmalignancyinthis
glandismuchgreaterthanthatoftheparotidgland,rangingfrom26%to45%.However,asshowninTable116,the
pleomorphic adenoma is still the most common tumor and makes up 53% to 72% of all neoplasms. Unlike its
occurrenceintheparotidgland,theWarthintumorisunusualinthesubmandibulargland,makingupnomorethan
1%to2%ofalltumors.Adenoidcysticcarcinomaisthemostcommonmalignancy,rangingfrom11%to17%ofall
cases.
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TABLE116
SubmandibularTumors
Tianetal.(China,
2010)
Totalnumberofcases
Ellisetal.(UnitedStates,
1991)
Eveson&Cawson(GreatBritain, Eneroth(Sweden,
1985)
1971)
663
1235
257
170
Pleomorphicadenoma
72.2%
53.3%
59.5%
60.0%
Warthintumor
0.6%
1.3%
0.8%
2.4%
Oncocytoma
0.2%
1.5%
0.4%
0.6%
Basalcelladenoma
0.3%
1.0%
Otherbenigntumors
0.6%
1.7%
1.9%*
Total
73.9%
58.8%
62.6%
62.9%
Mucoepidermoid
carcinoma
4.2%
9.1%
1.6%
3.5%
Aciniccellcarcinoma
1.1%
2.7%
0.4%
0.6%
Adenoidcystic
carcinoma
11.2%
11.7%
16.8%
15.3%
Malignantmixed
tumor
4.1%
3.5%
7.8%
1.8%
Squamouscell
carcinoma
1.1%
3.4%
1.9%
7.1%
Othermalignant
tumors
4.5%
10.8%
8.9%
8.8%
Total
26.1%
41.2%
37.4%
37.1%
BenignTumors
MalignantTumors
Includesallothermonomorphicadenomas.
Tumorsofthesublingualglandarerare,comprisingnomorethan1%ofallsalivaryneoplasms.However,70%to
95%ofsublingualtumorsaremalignant.
Tumorsofthevarioussmallerminorsalivaryglandsmakeup9%to28%ofalltumors,whichmakesthisgroup
the second most common site for salivary neoplasia. Table117 summarizes the findings of five large surveys of
minorglandtumors.Unfortunately,relativelyhighproportions(38%to49%)ofthesehavebeenmalignantinmost
studies.Excludingraresublingualtumors,itcanbestatedthatthesmallertheglandis,thegreateristhelikelihood
ofmalignancyforasalivaryglandtumor.
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TABLE117
MinorSalivaryGlandTumors
Jonesetal.
Buchneretal.
(United
(UnitedStates,
Kingdom,2008)
2007)
Totalnumberofcases
Piresetal.
(United
States,2007)
Ellisetal.
(United
States,1991)
Waldronetal.
(UnitedStates,
1988)
455
380
546
3355
426
Pleomorphicadenoma
40.4%
39.2%
33.2%
38.1%
40.8%
Monomorphicadenoma
(canalicularandbasalcell
adenoma)
15.2%
7.6%
9.2%
4.5%
10.8%
Otherbenigntumors
6.6%
12.1%
13.5%
8.8%
5.9%
Total
62.2%
58.9%
55.9%
51.3%
57.5%
Mucoepidermoidcarcinoma
13.0%
21.8%
22.9%
21.5%
15.3%
Aciniccellcarcinoma*
1.3%
1.6%
3.8%
3.5%
3.5%
Adenoidcysticcarcinoma
11.4%
6.3%
6.4%
7.7%
9.4%
Malignantmixedtumor
2.4%
0.5%
0.4%
1.7%
1.4%
Polymorphouslowgrade
adenocarcinoma
6.2%
7.1%
5.1%
2.2%
11.0%
Othermalignanttumors
3.5%
3.7%
5.5%
12.1%
1.9%
Total
37.8%
41.1%
44.1%
48.7%
42.5%
BenignTumors
MalignantTumors
Incidencenumbersforaciniccellcarcinomaareprobablyhighbecausetheypredaterecognitionofmammaryanaloguesecretorycarcinoma,
whichhassimilarfeatures.
Asobservedinthemajorglands,thepleomorphicadenomaisthemostcommonminorglandtumorandaccounts
for about 40% of all cases. Mucoepidermoid carcinoma is the most frequent malignancy of minor gland origin,
comprising13%to23%ofalltumors.Adenoidcysticcarcinomaandpolymorphouslowgradeadenocarcinomaare
alsorecognizedasrelativelycommonmalignanttumorsarisingfromtheminorsalivaryglands.
The palate is the most frequent site for minor salivary gland tumors, with 42% to 54% of all cases found there
(Table118).Mostoftheseoccurontheposteriorlateralhardorsoftpalate,whichhavethegreatestconcentrationof
glands. Table 119 shows the relative prevalence of various tumors on the palate. The lips are the second most
commonlocation for minor gland tumors (21% to 24% of cases), followed by the buccal mucosa (12% to 15% of
cases). Labial tumors are significantly more common in the upper lip, which accounts for 74% to 87% of all lip
tumors(Table1110).Althoughmucocelesarecommonlyfoundonthelowerlip,thisisasurprisinglyraresitefor
salivaryglandtumors.
TABLE118
LocationofMinorSalivaryGlandTumors
Author(Year)
NumberofCases Palate Lips Buccal Retromolar FloorofMouth Tongue Other
Waldronetal.(1988) 426
42%
22% 15%
5%
5%
1%
9%
Ellisetal.(1991)
3355
44%
21% 12%
2%
3%
5%
12%
Buchneretal.(2007)
380
54%
22% 14%
5%
3%
1%
0%
Jonesetal.(2008)
455
51%
24% 12%
2%
2%
2%
8%
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TABLE119
PalatalSalivaryGlandTumors
Buchneretal.
(UnitedStates,
2007)
Totalnumberofcases
Piresetal.
(UnitedStates,
2007)
Ellisetal.
Waldronetal.
(UnitedStates,
(UnitedStates,
1991)
1988)
Eveson&Cawson
(GreatBritain,1985)
206
181
1478
181
183
Pleomorphicadenoma
46.6%
39.8%
48.2%
51.9%
47.0%
Otherbenigntumors
10.2%
13.2%
5.0%
6.0%
6.0%
Total
56.8%
53.0%
53.2%
58.0%
53.0%
Mucoepidermoid
carcinoma
18.9%
23.8%
20.7%
9.9%
9.3%
Aciniccellcarcinoma*
0.0%
2.2%
1.4%
1.7%
1.1%
Adenoidcystic
carcinoma
8.7%
7.7%
8.3%
10.5%
15.3%
Malignantmixedtumor 0.5%
0.0%
2.4%
2.2%
8.2%
Polymorphouslow
grade
adenocarcinoma
10.2%
6.1%
3.0%
16.0%
Othermalignant
tumors
4.9%
7.2%
11.0%
1.7%
13.1%
Total
43.2%
47.0%
46.8%
42.0%
47.0%
BenignTumors
MalignantTumors
Incidencenumbersforaciniccellcarcinomaareprobablyhighbecausetheypredaterecognitionofmammaryanaloguesecretorycarcinoma,
whichhassimilarfeatures.
TABLE1110
LocationofLabialSalivaryGlandTumors
Author(Year)
NumberofCases UpperLip LowerLip
Waldronetal.(1988) 93
85%
15%
Nevilleetal.(1988)
103
84%
16%
Ellisetal.(1991)
536
77%
23%
Piresetal.(2007)
144
74%
26%
Buchneretal.(2007)
82
78%
22%
Jonesetal.(2008)
107
87%
13%
Significantdifferencesinthepercentageofmalignanciesandtherelativefrequencyofvarioustumorscanbenoted
fordifferentminorsalivaryglandsites.AsshowninTable1111,41%to47%ofpalataltumorsand30%to50%of
buccalmucosatumorsaremalignant,similartotheoverallprevalenceofmalignancyinallminorsalivaryglandsites
combined.Intheupperlip,however,only9%to25%oftumorsaremalignantbecauseofthehighprevalenceofthe
canalicular adenoma, which has a special affinity for this location. In contrast, although lower lip tumors are
uncommon,43%to86%aremalignant(mostlymucoepidermoidcarcinomas).Upto95%ofretromolartumorsare
malignant,alsobecauseofapredominanceofmucoepidermoidcarcinomas.Unfortunately,mosttumorsinthefloor
ofthemouthandtonguearealsomalignant.
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TABLE1111
IntraoralMinorSalivaryGlandTumors:PercentageMalignantbySite
Author(Year)
Palate UpperLip LowerLip Buccal Retromolar FloorofMouth Tongue
Eveson&Cawson(1985) 47%
25%
50%
50%
60%
92%
Waldronetal.(1988)
42%
14%
86%
46%
91%
80%
75%
Ellisetal.(1991)
47%
22%
60%
50%
90%
88%
86%
Buchneretal.(2007)
43%
9%
56%
37%
95%
69%
60%
Jonesetal.(2008)
41%
15%
43%
30%
88%
75%
71%
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PleomorphicAdenoma(BenignMixedTumor)
Thepleomorphicadenoma,orbenignmixedtumor,iseasilythemostcommonsalivaryneoplasm.Itaccountsfor
50%to77%ofparotidtumors,53%to72%ofsubmandibulartumors,and33%to41%ofminorglandtumors.
Pleomorphic adenomas are derived from a mixture of ductal and myoepithelial elements. A remarkable
microscopicdiversitycanexistfromonetumortothenext,aswellasindifferentareasofthesametumor.Theterms
pleomorphic adenoma and mixed tumor both represent attempts to describe this tumors unusual histopathologic
features, but neither term is entirely accurate. Although the basic tumor pattern is highly variable, rarely are the
individual cells actually pleomorphic. (However, focal minor atypia is acceptable.) Likewise, although the tumor
oftenhasaprominentmesenchymeappearingstromalcomponent,itisnottrulyamixedneoplasmthatisderived
from more than one germ layer. Cytogenetic analysis has shown translocations in approximately 70% of
pleomorphicadenomas,primarilyinvolvingpleomorphicadenomagene1(PLAG1)locatedatchromosomeregion8q12.
Regardlessofthesiteoforigin,thepleomorphicadenomatypicallyappearsasapainless,slowlygrowing,firmmass
(Figs.1132to1134).Thepatientmaybeawareofthelesionformanymonthsoryearsbeforeseekingadiagnosis.
Thetumorcanoccuratanyagebutismostcommoninyoungandmiddleagedadultsbetweentheagesof30and
60. Pleomorphic adenoma is also the most common primary salivary gland tumor to develop during childhood.
Thereisaslightfemalepredilection.
FIG.1132
PleomorphicAdenoma.Small,firmnodulelocatedbelowtheleftearintheparotidgland.(CourtesyofDr.MikeHansen.)
https://bookshelf.vitalsource.com/#/books/9781455770526/cfi/6/44!/4/2/2/2/2/4/10/2/18/2/2@0:0
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FIG.1133
Pleomorphicadenoma.Slowlygrowingtumoroftheparotidgland.
FIG.1134
PleomorphicAdenoma.Tumorofthesubmandibulargland.(CourtesyofDr.RomnCarlos.)
Mostpleomorphicadenomasoftheparotidglandoccurinthesuperficiallobeandpresentasaswellingoverlying
the mandibular ramus in front of the ear. Facial nerve palsy and pain are rare. Initially, the tumor is movable but
becomeslessmobileasitgrowslarger.Ifneglected,thenthelesioncangrowtogrotesqueproportions.About10%of
parotid mixed tumors develop within the deep lobe of the gland beneath the facial nerve (Fig.1135). Sometimes
theselesionsgrowinamedialdirectionbetweentheascendingramusandstylomandibularligament,resultingina
dumbbellshaped tumor that appears as a mass of the lateral pharyngeal wall or soft palate. On rare occasions,
bilateral pleomorphic adenomas of the parotid glands have been reported, developing in either a synchronous or
metachronousfashion.
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PleomorphicAdenoma.A,Largetumorfromthedeeplobeoftheparotidgland,whichhasresultedinafirmmassof
thelateralsoftpalate.B,Contrastenhancedaxialmagneticresonanceimage(MRI)ofatumorofthedeeplobeoftheparotid
gland.(CourtesyofDr.TerryDay.)
FIG.1135
Thepalateisthemostcommonsiteforminorglandmixedtumors,accountingforapproximately50%to65%of
intraoralexamples.Thisisfollowedbytheupperlip(19%to27%)andbuccalmucosa(13%to17%).Palataltumors
almostalwaysarefoundontheposteriorlateralaspectofthepalate,presentingassmoothsurfaced,domeshaped
masses(Figs.1136 and 1137). If the tumor is traumatized, then secondary ulceration may occur. Because of the
tightlyboundnatureofthehardpalatemucosa,tumorsinthislocationarenotmovable,althoughthoseinthelipor
buccalmucosafrequentlyaremobile.
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FIG.1136
PleomorphicAdenoma.Firmmassofthehardpalatelateraltothemidline.
FIG.1137
PleomorphicAdenoma.Tumorofthepterygomandibulararea.
Thepleomorphicadenomaistypicallyawellcircumscribed,encapsulatedtumor(Fig.1138).However,thecapsule
may be incomplete or show infiltration by tumor cells. This lack of complete encapsulation is more common for
minorglandtumors,especiallyalongthesuperficialaspectofpalataltumorsbeneaththeepithelialsurface.
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PleomorphicAdenoma.Lowpowerviewshowingawellcircumscribed,encapsulatedtumormass.Evenatthispower,
thevariablemicroscopicpatternofthetumorisevident.
FIG.1138
The tumor is composed of a mixture of glandular epithelium and myoepithelial cells within a mesenchymelike
background. The ratio of the epithelial elements and the mesenchymelike component is highly variable among
differenttumors.Sometumorsmayconsistalmostentirelyofbackgroundstroma.Othersarehighlycellularwith
littlebackgroundalteration.
The epithelium often forms ducts and cystic structures or may occur as islands or sheets of cells. Keratinizing
squamouscellsandmucusproducingcellsalsocanbeseen.Myoepithelialcellsoftenmakeupalargepercentageof
thetumorcellsandhaveavariablemorphology,sometimesappearingangularorspindled.Somemyoepithelialcells
areroundedanddemonstrateaneccentricnucleusandeosinophilichyalinizedcytoplasm,thusresemblingplasma
cells(Fig.1139).Thesecharacteristicplasmacytoidmyoepithelialcellsaremoreprominentintumorsarisinginthe
minorglands.
FIG.1139
PleomorphicAdenoma.Plasmacytoidmyoepithelialcells.
The highly characteristic stromal changes are believed to be produced by the myoepithelial cells. Extensive
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accumulationofmucoidmaterialmayoccurbetweenthetumorcells,resultinginamyxomatousbackground(Fig.
1140). Vacuolar degeneration of cells in these areas can produce a chondroid appearance (Fig. 1141). In many
tumors,thestromaexhibitsareasofaneosinophilic,hyalinizedchange(Fig.1142). At times, fat or osteoid also is
seen.
FIG.1140
PleomorphicAdenoma.Ductalstructures(left)withassociatedmyxomatousbackground(right).
FIG.1141
PleomorphicAdenoma.Chondroidmaterial(right)withadjacentductalepitheliumandmyoepithelialcells.
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PleomorphicAdenoma.Manyoftheductsandmyoepithelialcellsaresurroundedbyahyalinized,eosinophilic
backgroundalteration.
FIG.1142
Occasionally, salivary tumors are seen that are composed almost entirely of myoepithelial cells with no ductal
elements.Suchtumorsoftenarecalledmyoepitheliomas,althoughtheyprobablyrepresentoneendofthespectrum
ofmixedtumors.
Pleomorphicadenomasarebesttreatedbysurgicalexcision.Forlesionsinthesuperficiallobeoftheparotidgland,
superficialparotidectomywithidentificationandpreservationofthefacialnerveisrecommended.Localenucleation
shouldbeavoidedbecausetheentiretumormaynotberemovedorthecapsulemaybeviolated,resultinginseeding
of the tumor bed. For tumors of the deep lobe of the parotid, total parotidectomy is usually necessary, also with
preservation of the facial nerve, if possible. Submandibular tumors are best treated by total removal of the gland
withthetumor.Tumorsofthehardpalateusuallyareexciseddowntoperiosteum,includingtheoverlyingmucosa.
Inotheroralsitesthelesionoftenenucleateseasilythroughtheincisionsite.
With adequate surgery the prognosis is excellent, with a cure rate of more than 95%. The risk of recurrence
appears to be lower for tumors of the minor glands. Conservative enucleation of parotid tumors often results in
recurrence, with management of these cases made difficult as a result of multifocal seeding of the primary tumor
bed. In such cases, multiple recurrences are not unusual and may necessitate adjuvant radiation therapy. Tumors
withapredominantlymyxoidappearancearemoresusceptibletorecurthanthosewithothermicroscopicpatterns.
Malignantdegenerationisapotentialcomplication,resultinginacarcinomaexpleomorphicadenoma(seepage
460).Theriskofmalignanttransformationisprobablysmall,butitmayoccurinasmanyas3%to4%ofallcases.
Thisriskincreaseswiththedurationofthetumor.
Oncocytoma(OxyphilicAdenoma)
Theoncocytomaisabenignsalivaryglandtumorcomposedoflargeepithelialcellsknownasoncocytes.Theprefix
oncoisderivedfromtheGreekwordonkoustai,whichmeanstoswell.Theswollengranularcytoplasmofoncocytesis
due to excessive accumulation of mitochondria. Focal oncocytic metaplasia of salivary ductal and acinar cells is a
commonfindingthatisrelatedtopatientage;oncocytesareuncommoninpersonsyoungerthan50,buttheycanbe
foundinalmostallindividualsbyage70.Inadditiontosalivaryglands,oncocyteshavebeenidentifiedinanumber
ofotherorgans,especiallythethyroid,parathyroid,andkidney.Theoncocytomaisarareneoplasm,representing
approximately1%ofallsalivarytumors.
ClinicalFeatures
Theoncocytomaispredominantlyatumorofolderadults,withpeakprevalenceinthesixthtoeighthdecadesoflife.
No significant sex predilection has been observed. Oncocytomas occur primarily in the major salivary glands,
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especiallytheparotidgland,whichaccountsforabout85%to90%ofallcases.Oncocytomasoftheminorsalivary
glandsareexceedinglyrare.
The tumor appears as a firm, slowly growing, painless mass that rarely exceeds 4 cm in diameter. Parotid
oncocytomasusuallyarefoundinthesuperficiallobeandareclinicallyindistinguishablefromotherbenigntumors.
On occasion, bilateral tumors can occur, although these may represent examples of oncocytosis (multinodular
oncocytichyperplasia)(seenexttopic).
The oncocytoma is usually a wellcircumscribed tumor that is composed of sheets of large polyhedral cells
(oncocytes),withabundantgranular,eosinophiliccytoplasm(Fig.1143).Sometimesthesecellsformanalveolaror
glandularpattern.Thecellshavecentrallylocatednucleithatcanvaryfromsmallandhyperchromatictolargeand
vesicular. Little stroma is present, usually in the form of thin fibrovascular septa. An associated lymphocytic
infiltratemaybenoted.
FIG.1143
Oncocytoma.Sheetoflarge,eosinophiliconcocytes.
The granularity of the cells corresponds to an overabundance of mitochondria, which can be demonstrated by
electronmicroscopy.Thesegranulesalsocanbeidentifiedonlightmicroscopicexaminationwithaphosphotungstic
acid hematoxylin (PTAH) stain. The cells also contain glycogen, as evidenced by their positive staining with the
periodicacidSchiff(PAS)techniquebutbynegativePASstainingafterdigestionwithdiastase.
Oncocytomasmaycontainvariablenumbersofcellswithaclearcytoplasm.Inrareinstances,theseclearcellsmay
compose most of the lesion and create difficulty in distinguishing the tumor from lowgrade salivary clear cell
adenocarcinomaormetastaticrenalcellcarcinoma.
Oncocytomas are best treated by surgical excision. In the parotid gland, this usually entails partial parotidectomy
(lobectomy) to avoid violation of the tumor capsule. The facial nerve should be preserved whenever possible. For
tumorsinthesubmandibulargland,treatmentconsistsoftotalremovalofthegland.Oncocytomasoftheoralminor
salivaryglandsshouldberemovedwithasmallmarginofnormalsurroundingtissue.
Theprognosisafterremovalisgood,withalowrateofrecurrence.However,oncocytomasofthesinonasalglands
can be locally aggressive and have been considered to be lowgrade malignancies. Rare examples of
histopathologicallymalignantoncocytomas(oncocyticcarcinoma)alsohavebeenreported.Thesecarcinomashavea
relativelypoorprognosis.
Oncocytosis(MultinodularOncocyticHyperplasia)
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Oncocyticmetaplasiaisthetransformationofductalandacinarcellstooncocytes.Suchcellsareuncommonbefore
theageof50;however,aspeoplegetolder,occasionaloncocytesarecommonfindingsinthesalivaryglands.Focal
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PleomorphicAdenoma.Manyoftheductsandmyoepithelialcellsaresurroundedbyahyalinized,eosinophilic
backgroundalteration.
FIG.1142
Occasionally, salivary tumors are seen that are composed almost entirely of myoepithelial cells with no ductal
elements.Suchtumorsoftenarecalledmyoepitheliomas,althoughtheyprobablyrepresentoneendofthespectrum
ofmixedtumors.
Pleomorphicadenomasarebesttreatedbysurgicalexcision.Forlesionsinthesuperficiallobeoftheparotidgland,
superficialparotidectomywithidentificationandpreservationofthefacialnerveisrecommended.Localenucleation
shouldbeavoidedbecausetheentiretumormaynotberemovedorthecapsulemaybeviolated,resultinginseeding
of the tumor bed. For tumors of the deep lobe of the parotid, total parotidectomy is usually necessary, also with
preservation of the facial nerve, if possible. Submandibular tumors are best treated by total removal of the gland
withthetumor.Tumorsofthehardpalateusuallyareexciseddowntoperiosteum,includingtheoverlyingmucosa.
Inotheroralsitesthelesionoftenenucleateseasilythroughtheincisionsite.
With adequate surgery the prognosis is excellent, with a cure rate of more than 95%. The risk of recurrence
appears to be lower for tumors of the minor glands. Conservative enucleation of parotid tumors often results in
recurrence, with management of these cases made difficult as a result of multifocal seeding of the primary tumor
bed. In such cases, multiple recurrences are not unusual and may necessitate adjuvant radiation therapy. Tumors
withapredominantlymyxoidappearancearemoresusceptibletorecurthanthosewithothermicroscopicpatterns.
Malignantdegenerationisapotentialcomplication,resultinginacarcinomaexpleomorphicadenoma(seepage
460).Theriskofmalignanttransformationisprobablysmall,butitmayoccurinasmanyas3%to4%ofallcases.
Thisriskincreaseswiththedurationofthetumor.
Oncocytoma(OxyphilicAdenoma)
Theoncocytomaisabenignsalivaryglandtumorcomposedoflargeepithelialcellsknownasoncocytes.Theprefix
oncoisderivedfromtheGreekwordonkoustai,whichmeanstoswell.Theswollengranularcytoplasmofoncocytesis
due to excessive accumulation of mitochondria. Focal oncocytic metaplasia of salivary ductal and acinar cells is a
commonfindingthatisrelatedtopatientage;oncocytesareuncommoninpersonsyoungerthan50,buttheycanbe
foundinalmostallindividualsbyage70.Inadditiontosalivaryglands,oncocyteshavebeenidentifiedinanumber
ofotherorgans,especiallythethyroid,parathyroid,andkidney.Theoncocytomaisarareneoplasm,representing
approximately1%ofallsalivarytumors.
ClinicalFeatures
Theoncocytomaispredominantlyatumorofolderadults,withpeakprevalenceinthesixthtoeighthdecadesoflife.
No significant sex predilection has been observed. Oncocytomas occur primarily in the major salivary glands,
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especiallytheparotidgland,whichaccountsforabout85%to90%ofallcases.Oncocytomasoftheminorsalivary
glandsareexceedinglyrare.
The tumor appears as a firm, slowly growing, painless mass that rarely exceeds 4 cm in diameter. Parotid
oncocytomasusuallyarefoundinthesuperficiallobeandareclinicallyindistinguishablefromotherbenigntumors.
On occasion, bilateral tumors can occur, although these may represent examples of oncocytosis (multinodular
oncocytichyperplasia)(seenexttopic).
The oncocytoma is usually a wellcircumscribed tumor that is composed of sheets of large polyhedral cells
(oncocytes),withabundantgranular,eosinophiliccytoplasm(Fig.1143).Sometimesthesecellsformanalveolaror
glandularpattern.Thecellshavecentrallylocatednucleithatcanvaryfromsmallandhyperchromatictolargeand
vesicular. Little stroma is present, usually in the form of thin fibrovascular septa. An associated lymphocytic
infiltratemaybenoted.
FIG.1143
Oncocytoma.Sheetoflarge,eosinophiliconcocytes.
The granularity of the cells corresponds to an overabundance of mitochondria, which can be demonstrated by
electronmicroscopy.Thesegranulesalsocanbeidentifiedonlightmicroscopicexaminationwithaphosphotungstic
acid hematoxylin (PTAH) stain. The cells also contain glycogen, as evidenced by their positive staining with the
periodicacidSchiff(PAS)techniquebutbynegativePASstainingafterdigestionwithdiastase.
Oncocytomasmaycontainvariablenumbersofcellswithaclearcytoplasm.Inrareinstances,theseclearcellsmay
compose most of the lesion and create difficulty in distinguishing the tumor from lowgrade salivary clear cell
adenocarcinomaormetastaticrenalcellcarcinoma.
Oncocytomas are best treated by surgical excision. In the parotid gland, this usually entails partial parotidectomy
(lobectomy) to avoid violation of the tumor capsule. The facial nerve should be preserved whenever possible. For
tumorsinthesubmandibulargland,treatmentconsistsoftotalremovalofthegland.Oncocytomasoftheoralminor
salivaryglandsshouldberemovedwithasmallmarginofnormalsurroundingtissue.
Theprognosisafterremovalisgood,withalowrateofrecurrence.However,oncocytomasofthesinonasalglands
can be locally aggressive and have been considered to be lowgrade malignancies. Rare examples of
histopathologicallymalignantoncocytomas(oncocyticcarcinoma)alsohavebeenreported.Thesecarcinomashavea
relativelypoorprognosis.
Oncocytosis(MultinodularOncocyticHyperplasia)
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Oncocyticmetaplasiaisthetransformationofductalandacinarcellstooncocytes.Suchcellsareuncommonbefore
theageof50;however,aspeoplegetolder,occasionaloncocytesarecommonfindingsinthesalivaryglands.Focal
oncocytic metaplasia also may be a feature of other salivary gland tumors. Oncocytosis refers to both the
proliferationandtheaccumulationofoncocyteswithinsalivaryglandtissue.Itmaymimicatumor,bothclinically
andmicroscopically,butitalsoisconsideredtobeametaplasticprocessratherthananeoplasticone.
ClinicalFeatures
Oncocytosisisfoundprimarilyintheparotidgland;however,inrareinstances,itmayinvolvethesubmandibularor
minor salivary glands. It can be an incidental finding in otherwise normal salivary gland tissue, but it may be
extensiveenoughtoproduceclinicalswelling.Usuallytheproliferationismultifocalandnodular,butsometimesthe
entireglandcanbereplacedbyoncocytes(diffusehyperplasticoncocytosis).Aswithotheroncocyticproliferations,
oncocytosisoccursmostfrequentlyinolderadults.
Microscopic examination usually reveals focal nodular collections of oncocytes within the salivary gland tissue.
These enlarged cells are polyhedral and demonstrate abundant granular, eosinophilic cytoplasm as a result of the
proliferation of mitochondria. On occasion, these cells may have a clear cytoplasm from the accumulation of
glycogen(Fig.1144). The multifocal nature of the proliferation may be confused with that of a metastatic tumor,
especiallywhentheoncocytesareclearinappearance.
FIG.1144
Oncocytosis.Multifocalcollectionsofclearoncocytes(arrows)intheparotidgland.
Oncocytosis is a benign condition and often is discovered only as an incidental finding. No further treatment is
necessary,andtheprognosisisexcellent.
WarthinTumor(PapillaryCystadenomaLymphomatosum)
Warthintumorisabenignneoplasmthatoccursalmostexclusivelyintheparotidgland.Althoughitismuchless
commonthanthepleomorphicadenoma,itrepresentsthesecondmostcommonbenignparotidtumor,accounting
for5%to22%ofallparotidneoplasms.Thenameadenolymphomaalsohasbeenusedforthistumor,butthisterm
shouldbeavoidedbecauseitoveremphasizesthelymphoidcomponentandmaygivethemistakenimpressionthat
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thelesionisatypeoflymphoma.AnalysesoftheepithelialandlymphoidcomponentsoftheWarthintumorusually
haveshownbothtobepolyclonal;thissuggeststhatthislesionmaynotrepresentaneoplasmbutwouldbebetter
classifiedasatumorlikeprocess.However,asmallpercentageofWarthintumorshavebeenshowntodemonstratea
chromosomal translocation and fusion gene transcript similar to that seen in mucoepidermoid carcinoma. This
findingmayindicatethatsubsetsofthesetumorsaretrueneoplasms,althoughsuchexamplesalsocouldrepresent
evidenceofanearlymucoepidermoidcarcinomadevelopingwithinaWarthintumor.
ThepathogenesisofWarthintumorisuncertain.Thetraditionalhypothesissuggeststhatitarisesfromheterotopic
salivary gland tissue found within parotid lymph nodes. However, researchers have also suggested that these
tumors may develop from a proliferation of salivary gland ductal epithelium that is associated with secondary
formation of lymphoid tissue. A number of studies have demonstrated a strong association between the
development of this tumor and smoking. Smokers have an eightfold greater risk for Warthin tumor than do
nonsmokers.
ClinicalFeatures
TheWarthintumorusuallyappearsasaslowlygrowing,painless,nodularmassoftheparotidgland(Fig.1145).It
maybefirmorfluctuanttopalpation.Thetumormostfrequentlyoccursinthetailoftheparotidneartheangleof
themandible,anditmaybenotedformanymonthsbeforethepatientseeksadiagnosis.Oneuniquefeatureisthe
tendencyofWarthintumortooccurbilaterally,whichhasbeennotedin5%to17%ofreportedcases.Mostofthese
bilateraltumorsdonotoccursimultaneouslybutaremetachronous(occurringatdifferenttimes).
FIG.1145
WarthinTumor.Massinthetailoftheparotidgland.(CourtesyofDr.GeorgeBlozis.)
Inrareinstances,theWarthintumorhasbeenreportedwithinthesubmandibularglandorminorsalivaryglands.
However, because the lymphoid component is often less pronounced in these extraparotid sites, the pathologist
shouldexercisecautiontoavoidoverdiagnosisofalesionbetterclassifiedasapapillarycystadenomaorasalivary
ductcystwithoncocyticductalmetaplasia.
Warthintumormostoftenoccursinolderadults,withpeakprevalenceinthesixthandseventhdecadesoflife.
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The observed frequency of this tumor is much lower in blacks than in whites. Most studies show a decided male
predilection, with some early studies demonstrating a maletofemale ratio up to 10:1. However, more recent
investigations show a more balanced sex ratio. Because Warthin tumors have been associated with cigarette
smoking,thischangingsexratiomaybeareflectionofamoreequalprevalenceofsmokinginwomenoverthepast
fewdecades.Thisassociationwithsmokingalsomayhelpexplainthefrequentbilateralityofthetumor,becauseany
tumorigeniceffectsofsmokingwouldbemanifestedinbothparotids.
TheWarthintumorhasoneofthemostdistinctivehistopathologicpatternsofanytumorinthebody.Althoughthe
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.1146 and 1147). The
epitheliumisoncocyticinnature,forminguniformrowsofcellssurroundingcysticspaces.Thecellshaveabundant,
finely granular eosinophilic cytoplasm and are arranged in two layers. The inner luminal layer consists of tall
columnarcellswithcentrallyplaced,palisaded,andslightlyhyperchromaticnuclei.Beneaththisisasecondlayerof
cuboidal or polygonal cells with more vesicular nuclei. The lining epithelium demonstrates multiple papillary
infoldingsthatprotrudeintothecysticspaces.Focalareasofsquamousmetaplasiaormucouscellprosoplasiamay
beseen.Theepitheliumissupportedbyalymphoidstromathatfrequentlyshowsgerminalcenterformation.
FIG.1146
WarthinTumor.Lowpowerviewshowingapapillarycystictumorwithalymphoidstroma.
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FIG.1147
WarthinTumor.Highpowerviewofepithelialliningshowingdoublerowofoncocyteswithadjacentlymphoidstroma.
Surgical removal is the treatment of choice for most patients with Warthin tumor. The procedure usually is easily
accomplished because of the superficial location of the tumor. Some surgeons prefer local resection with minimal
surrounding tissue; others opt for superficial parotidectomy to avoid violating the tumor capsule and because a
tentative diagnosis may not be known preoperatively. If a confident diagnosis of Warthin tumor can be made by
fineneedleaspirationcytologyofanonsuspiciousparotidgrowth,someclinicianswillelecttomanagethepatient
conservativelywithregularfollowupvisitsratherthansurgery.
A2%to6%recurrenceratehasbeenreportedfollowingsurgery.Manyauthors,however,believethatthetumoris
frequently multicentric in nature; therefore, it is difficult to determine whether these are true recurrences or
secondary tumor sites. Malignant Warthin tumors (carcinoma ex papillary cystadenoma lymphomatosum) have
beenreportedbutareexceedinglyrare.
MonomorphicAdenoma
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
classification schemes, a variety of tumors were included under the broad heading of monomorphic adenoma,
includingWarthintumor,oncocytoma,basalcelladenoma,andcanalicularadenoma.Otherauthorshaveusedthis
term more specifically as a synonym just for the basal cell adenoma or canalicular adenoma. Because of its
ambiguousnature,thetermmonomorphicadenoma probably should be avoided, and each of the tumors mentioned
shouldbereferredtobyitsmorespecificname.
CanalicularAdenoma
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
avoidedbecauseitreferstoaseparatetumorwithdifferentclinicalfeatures(seenexttopic).
ClinicalFeatures
Thecanalicularadenomashowsastrikingpredilectionfortheupperlip,withnearly75%occurringinthislocation.
Itrepresentsthefirstorsecondmostcommontumor(alongwithpleomorphicadenoma)oftheupperlip.Thebuccal
mucosaisthesecondmostcommonsite.Occurrenceinotherminorsalivaryglandsisuncommon,andcanalicular
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adenomasoftheparotidglandarerare.
The tumor nearly always occurs in older adults, with peak prevalence in the seventh decade of life. There is a
definitefemalepredominance,rangingfrom1.2to1.8femalesforeachmale.
Thecanalicularadenomaappearsasaslowlygrowing,painlessmassthatusuallyrangesfromseveralmillimeters
to 2 cm (Fig.1148). It may be firm or somewhat fluctuant to palpation. The overlying mucosa may be normal in
colororbluishandcanbemistakenforamucocele.However,mucocelesoftheupperliparerare.Insomeinstances,
the lesion has been noted to be multifocal, with multiple separate tumors discovered in the upper lip or buccal
mucosa.
FIG.1148
CanalicularAdenoma.Massintheupperlip.(CourtesyofDr.JohnFantasia.)
Themicroscopicpatternofcanalicularadenomaismonomorphicinnature.Thispatternischaracterizedbysingle
layered cords of columnar or cuboidal epithelial cells with deeply basophilic nuclei (Fig. 1149). 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
epitheliummaydemonstratepapillaryprojectionsintothecysticlumina.Thetumorcellsaresupportedbyaloose
connective tissue stroma with prominent vascularity. Unlike the appearance in pleomorphic adenomas, stromal
alterations,suchaschondroidmetaplasia,donotoccur.Athin,fibrouscapsuleoftensurroundsthetumor,although
satelliteislandsareobservedinthesurroundingsalivaryglandtissueinapproximately22%to24%ofcases,which
explainsthetendencyformultifocaltumors.
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FIG.1149
CanalicularAdenoma.Uniformcolumnarcellsformingcanallikeductalstructures.
The canalicular adenoma is best treated by local surgical excision. Recurrence is uncommon and actually may
representcasesthataremultifocalinnature.
BasalCellAdenoma
Thebasalcelladenomaisabenignsalivarytumorthatderivesitsnamefromthebasaloidappearanceofthetumor
cells. It is an uncommon neoplasm that represents only 1% to 4% of all salivary tumors. Because of its uniform
histopathologic appearance, it often has been classified as one of the monomorphic adenomas. However, as
mentioned previously, this term probably should be avoided because of its imprecise and frequently confusing
definition. 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
myoepithelialcells.Thebasalcelladenomashowssomehistopathologicsimilaritytothecanalicularadenoma;inthe
past,thesetwotermshavebeenusedsynonymously.However,histopathologicandclinicaldifferenceswarrantthat
theybeconsideredasdistinctentities.
ClinicalFeatures
Unlikethecanalicularadenoma,thebasalcelladenomaisprimarilyatumoroftheparotidgland,witharound75%
of all cases occurring there. However, the minor glands represent the second most common site, specifically the
glandsoftheupperlipandbuccalmucosa.Thetumorcanoccuratanyagebutismostcommoninmiddleagedand
olderadults,withpeakprevalenceintheseventhdecadeoflife.Thetumorappearstobemorecommoninwomen,
withsomestudiesshowingashighasa2:1femaletomaleratio.
Clinically, the basal cell adenoma appears as a slowly growing, freely movable mass similar to a pleomorphic
adenoma.Mosttumorsarelessthan3cmindiameter.Parotidtumorsusuallyarelocatedwithinthesuperficiallobe
ofthegland.
Onesubtype,themembranousbasalcelladenoma,deservesseparatemention.Thisformofthetumorappearsto
be hereditary, often occurring in combination with skin appendage tumors, such as dermal cylindromas and
trichoepitheliomas.Multiplebilateraltumorsmaydevelopwithintheparotids.Becausethesetumorsoftenbeara
histopathologicresemblancetotheskintumors,theyalsohavebeencalleddermalanaloguetumors.
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
fibrousstroma.Theperipheralcellsoftheseislandsarepalisadedandcuboidaltocolumnarinshape,similartothe
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microscopic appearance of basal cell carcinoma. These peripheral cells are frequently hyperchromatic; the central
cellsoftheislandstendtohavepalerstainingnuclei.Thecentralcellsoccasionallyformeddiesorkeratinpearls.
The trabecular subtype demonstrates narrow cordlike epithelial strands (Fig. 1150). The tubular subtype is
characterized by the formation of small, round, ductlike structures. Some basal cell adenomas demonstrate zones
withacribriformpatternthatcanmimicadenoidcysticcarcinoma.Frequently,amixtureofhistopathologicsubtypes
isseen.
FIG.1150
BasalCellAdenoma.Parotidtumorshowingcordsofbasaloidcellsarrangedinatrabecularpattern.
Themembranousbasalcelladenomaexhibitsmultiplelargelobularislandsoftumorthataremoldedtogetherina
jigsaw puzzle fashion. These islands are surrounded by a thick layer of hyaline material, which represents
reduplicated basement membrane. Similar hyaline droplets also are often found among the epithelial cells. The
microscopic appearance is similar to that of a dermal cylindroma, one of the skin tumors with which it is often
associated.
The treatment of basal cell adenoma is similar to that of pleomorphic adenoma and consists of complete surgical
removal.Recurrenceisrareformosthistopathologicsubtypes.However,themembranoussubtypehasa25%to37%
recurrencerate,possiblyrelatedtoitsmultifocalnature.
The malignant counterpart of the basal cell adenoma is the basal cell adenocarcinoma. Most basal cell
adenocarcinomasarisedenovo,butsomeexamplesdevelopfrommalignantdegenerationofapreexistingbasalcell
adenoma. Fortunately, these tumors have a relatively good prognosis; although local recurrence is common, the
tumorrarelymetastasizesorresultsindeath.
DuctalPapillomas(SialadenomaPapilliferumIntraductalPapilloma
InvertedDuctalPapilloma)
A number of salivary gland tumors can be characterized microscopically by a papillomatous pattern, the most
common being Warthin tumor (papillary cystadenoma lymphomatosum). The sialadenoma papilliferum,
intraductal papilloma, and inverted ductal papilloma are three rare salivary tumors that also show unique
papillomatousfeatures.
Italsoshouldbementionedthat,onoccasion,thecommonsquamouspapilloma(seepage332)oftheoralmucosa
willariseatthesitewhereaminorsalivaryglandductmergeswiththesurfaceepithelium.Becauseofthislocation,
such squamous papillomas may contain scattered mucous cells within the exophytic papillary growth, and these
lesionshavesometimesbeencalledductalpapillomas.However,itshouldbeemphasizedthattheselesionsaresurface
papillomasandnotprimarysalivaryglandtumors.
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ClinicalFeatures
The sialadenoma papilliferum most commonly arises from the minor salivary glands, especially on the palate,
althoughitalsohasbeenreportedintheparotidgland.Itusuallyisseeninolderadultsandhasa1.5:1.0maleto
femaleratio.Thetumorappearsasanexophytic,papillarysurfacegrowththatisclinicallysimilartothecommon
squamouspapilloma(Fig.1151).
FIG.1151
SialadenomaPapilliferum.Exophyticpapillarymassonthepalate.(CourtesyofDr.PeterLyu.)
Theintraductalpapillomaisanilldefinedlesionthatoftenhasbeenconfusedwithothersalivaryglandlesions,
such as the papillary cystadenoma. It usually occurs in adults and is most common in the minor salivary glands,
whereitappearsasasubmucosalswelling.
Theinvertedductalpapillomaisararetumorthathasbeendescribedonlyintheminorsalivaryglandsofadults.
The lower lip and mandibular vestibule are the most common locations. The lesion usually appears as an
asymptomaticnodule,whichsometimesmayshowapitorindentationintheoverlyingsurfacemucosa(Fig.1152).
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FIG.1152
InvertedDuctalPapilloma.Exophyticmasswithcentralpapillaryprojectionsonthelowerlabialmucosa.(CourtesyofDr.
AmyBogardus.)
At lowpower magnification, the sialadenoma papilliferum is somewhat similar to the squamous papilloma,
exhibiting multiple exophytic papillary projections that are covered by stratified 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. 1153). Multiple ductal lumina are formed, which
characteristicallyarelinedbyadoublerowedlayerofcellsconsistingofaluminallayeroftallcolumnarcellsanda
basilar layer of smaller cuboidal cells. These ductal cells often have an oncocytic appearance. An inflammatory
infiltrate of plasma cells, lymphocytes, and neutrophils is characteristically present. Because of their microscopic
similarity,thistumorhasbeenconsideredtobeananalogueofthecutaneoussyringocystadenomapapilliferum.
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SialadenomaPapilliferum.A,Lowpowerviewshowingapapillarysurfacetumorwithassociatedductalstructuresin
thesuperficiallaminapropria.B,Highpowerviewofcysticareaslinedbypapillary,oncocyticepithelium.
FIG.1153
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
projectionsintothecysticlumen.Incontrast,theinvertedductalpapillomaiscomposedprimarilyofaproliferation
ofsquamoidepitheliumwithmultiplethick,bulbouspapillaryprojectionsthatfilltheductallumen(Fig.1154).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 mucusproducing cells. In situ
hybridizationanalysishasshownpositivityforhumanpapillomavirus(HPV)types6and11inboththesurfaceand
invertedepitheliumofsomeinvertedductalpapillomas.
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InvertedDuctalPapilloma.Papillaryintraductalproliferationlocatedbeneaththemucosalsurface.Higherpowerview
showsbothsquamouscellsandmucouscells(inset).(CourtesyofDr.DeanK.White.)
FIG.1154
Allthreeformsofductalpapillomaarebesttreatedbyconservativesurgicalexcision.Recurrenceisrare.
MucoepidermoidCarcinoma
Mucoepidermoidcarcinomaisthemostcommonsalivaryglandmalignancy.Becauseofitshighlyvariablebiologic
potential,itwasoriginallycalledmucoepidermoidtumor.Thetermrecognizedonesubsetthatactedinamalignant
fashion and a second group that appeared to behave in a benign fashion with favorable prognosis. However,
researcherslaterrecognizedthatevenlowgradetumorsoccasionallywillexhibitmalignantbehavior;therefore,the
termmucoepidermoidcarcinomaisthepreferreddesignation.
Thepathogenesisofthistumorisuncertain,althoughradiationexposuremaybeoneriskfactor.Publishedseries
havereportedthat38%to82%ofmucoepidermoidcarcinomaswillshowat(11;19)reciprocaltranslocation,which
resultsintheproductionoftheCRTC1MAML2fusiononcogene.Thistranslocationisidentifiedmorefrequentlyin
lowandintermediategradetumors.
ClinicalFeatures
Most large series show mucoepidermoid carcinoma to be the most common malignant salivary gland neoplasm,
comprising 4% to 10% of all major gland tumors and 13% to 23% of minor gland tumors. 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 first
decade of life. However, mucoepidermoid carcinoma is the most common malignant salivary gland tumor in
children.
Themucoepidermoidcarcinomaismostcommonintheparotidglandandusuallyappearsasanasymptomatic
swelling. Most patients are aware of the lesion for 1 year or less, although some report a mass of many years
duration.Painorfacialnervepalsymaydevelop,usuallyinassociationwithhighgradetumors.Theminorglands
constitutethesecondmostcommonsite,especiallythepalate(Fig.1155).Minorglandtumorsalsotypicallyappear
as asymptomatic swellings, which are sometimes fluctuant and have a blue or red color that can be mistaken
clinicallyforamucocele.Althoughthelowerlip,floorofmouth,tongue,andretromolarpadareasareuncommon
locationsforsalivaryglandneoplasia,themucoepidermoidcarcinomaisthemostcommonsalivarytumorineachof
thesesites(Fig.1156).Intraosseoustumorsalsomaydevelopinthejaws(seepage457).
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FIG.1155
MucoepidermoidCarcinoma.Bluepigmentedmassoftheposteriorlateralhardpalate.(CourtesyofDr.JamesF.Drummond.)
FIG.1156
MucoepidermoidCarcinoma.Massofthetongue.
Asitsnameimplies,themucoepidermoidcarcinomaiscomposedofamixtureofmucusproducingcellsandsquamous
(epidermoid)cells(Figs.1157to1159).Themucouscellsvaryinshapebutcontainabundantfoamycytoplasmthat
stains positively with mucin stains. The epidermoid cells are characterized by squamoid features, often
demonstratingapolygonalshape,intercellularbridges,and,rarely,keratinization.Inaddition,athirdtypeofcell
theintermediatecellistypicallypresentandisbelievedtobeaprogenitorofboththemucousandtheepidermoid
cells.Intermediatecellsvaryinappearancefromsmall,basaloid(maternal)cellstoslightlylargerovoidcellswith
scant, pale eosinophilic cytoplasm. Some tumors also show variable numbers of clear cells, which sometimes can
predominate the microscopic picture (Fig.1160). An associated lymphoid infiltrate is not unusual and may be so
prominentinsomecasesthatthelesioncanbemistakenforametastatictumorwithinalymphnode.Othervariants
ofmucoepidermoidcarcinomacandemonstratenumerousoncocytesorprominentsclerosisofthetumorstroma.
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MucoepidermoidCarcinoma.Lowpowerviewofamoderatelywelldifferentiatedtumorshowingductalandcystic
spacessurroundedbymucousandsquamouscells.
FIG.1157
FIG.1158
MucoepidermoidCarcinoma.Thislowgradetumorshowsnumerouslargemucouscellssurroundingacysticspace.
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FIG.1159
MucoepidermoidCarcinoma.Highpowerviewshowingasheetofsquamouscellswithfocalmucusproducingcells
(left).
FIG.1160
MucoepidermoidCarcinoma.Clearcellmucoepidermoidcarcinoma.
Traditionally,mucoepidermoidcarcinomashavebeencategorizedintooneofthreehistopathologicgradesbased
onthefollowing:
1.Amountofcystformation
2.Degreeofcytologicatypia
3.Relativenumbersofmucous,epidermoid,andintermediatecells
Lowgrade tumors show prominent cyst formation, minimal cellular atypia, and a relatively high proportion of
mucouscells.Highgradetumorsconsistofsolidislandsofsquamousandintermediatecells,whichcandemonstrate
considerable pleomorphism and mitotic activity (Fig. 1161). Mucusproducing cells may be infrequent, and the
tumorsometimescanbedifficulttodistinguishfromsquamouscellcarcinoma.
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MucoepidermoidCarcinoma.Highpowerviewshowingasheetofpleomorphicsquamousepithelialcellsintermixed
withmucousandintermediatecells.
FIG.1161
Intermediategrade tumors show features that fall between those of the lowgrade and highgrade neoplasms.
Cystformationoccursbutislessprominentthanthatobservedinlowgradetumors.Allthreemajorcelltypesare
present,buttheintermediatecellsusuallypredominate.Cellularatypiamayormaynotbeobserved.
However, some authors have found that the relative proportion of the three different cell types does not
necessarilycorrelatewithprognosis.Toovercomethis,twoexpertgroupshaveproposedevaluationschemesbased
onsignificantmicroscopicparameters,towhichrelativepointvalueshavebeenassignedtodeterminethegradeof
thetumor(Table1112).
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TABLE1112
MucoepidermoidCarcinoma:ComparisonofTwoGradingSystems
Parameter
PointValue
Auclairetal.(1992)
Intracysticcomponent
Neuralinvasionpresent
Necrosispresent
Fourormoremitosesper10highpowerfields
Anaplasiapresent
Grade
TotalPointScore
Low
04
Intermediate
56
High
714
Brandweinetal.(2001)
Intracysticcomponent
Tumorfrontinvadesinsmallnestsandislands
Pronouncednuclearatypia
Lymphaticorvascularinvasion
Bonyinvasion
Greaterthanfourmitosesper10highpowerfields 3
Perineuralspread
Necrosis
Grade
TotalPointScore
II
23
III
4ormore
FromAuclairPL,GoodeRK,EllisGL:Mucoepidermoidcarcinomaofintraoralsalivaryglands:evaluationandapplicationofgradingcriteriain
143cases,Cancer69:20212030,1992BrandweinMS,IvanovK,WallaceDI,etal:Mucoepidermoidcarcinoma:aclinicopathologicstudyof
80patientswithspecialreferencetohistologicalgrading,AmJSurgPathol25:835845,2001.
Thetreatmentofmucoepidermoidcarcinomaispredicatedbythelocation,histopathologicgrade,andclinicalstage
ofthetumor.Earlystagetumorsoftheparotidoftencanbetreatedbysubtotalparotidectomywithpreservationof
the facial nerve. Advanced tumors may necessitate total removal of the parotid gland, with sacrifice of the facial
nerve.Submandibularglandtumorsaretreatedbytotalremovalofthegland.Mucoepidermoidcarcinomasofthe
minor glands usually are treated by assured surgical excision. For lowgrade neoplasms, only a modest margin of
surroundingnormaltissuemayneedtoberemoved,buthighgradeorlargetumorswarrantwiderresection,similar
tothatrequiredforsquamouscellcarcinomas.Ifthereisunderlyingbonedestruction,thentheinvolvedbonemust
beexcised.
Neckdissectionisindicatedforpatientswithclinicalevidenceofmetastaticdiseaseandalsomaybeconsidered
forpatientswithlargerorhighgradetumors.Postoperativeradiationtherapyalsomaybeusedformoreaggressive
tumors.
The prognosis depends on the grade and stage of the tumor. Patients with lowgrade tumors generally have a
goodprognosis.Formostprimarysites,localrecurrencesorregionalmetastasesareuncommon,andaround90%to
98% of patients are cured. The prognosis for those with intermediategrade tumors is slightly worse than that for
lowgrade tumors. The outlook for patients with highgrade tumors is more guarded, with only 30% to 54% of
patientssurviving.Tumorsthatexhibitthet(11;19)translocationandCRTC1MAML2fusiongenetranscripthavea
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betterprognosisthantumorswithoutthistranslocation.
Forunknownreasons,submandibularglandtumorsareassociatedwithapooreroutlookthanthoseintheparotid
gland. Mucoepidermoid carcinomas of the oral minor salivary glands generally have a good prognosis, probably
becausetheyaremostlylowtointermediategradetumors.However,tumorsofthetongueandfloorofthemouth
arelesspredictableandmayexhibitmoreaggressivebehavior.
IntraosseousMucoepidermoidCarcinoma(CentralMucoepidermoid
Carcinoma)
On rare occasions, salivary gland tumors arise centrally within the jaws. The most common and bestrecognized
intrabony salivary tumor is the intraosseous mucoepidermoid carcinoma. However, other salivary tumors have
beenreportedtodevelopwithinthejaws,includingadenoidcysticcarcinoma,benignandmalignantmixedtumors,
adenocarcinoma,aciniccelladenocarcinoma,epithelialmyoepithelialcarcinoma,andmonomorphicadenoma.
Severalhypotheseshavebeenproposedtoexplainthepathogenesisofintraosseoussalivarytumors.Onetheory
suggeststhattheymayarisefromectopicsalivaryglandtissuethatwasdevelopmentallyentrappedwithinthejaws.
However, the discovery of ectopic salivary tissue is uncommon in biopsy specimens from the jaws; therefore, this
seemsanunlikelysourceformostintrabonysalivarytumors.Somemaxillarytumorsmayarisefromglandsofthe
sinuslining,butthisisoftendifficulttoproveordisprove.Themostlikelysourceformostintraosseoustumorsis
odontogenic epithelium. Mucusproducing cells are common in odontogenic cyst linings, especially dentigerous
cysts (see page 632). In addition, many intraosseous mucoepidermoid carcinomas develop in association with
impactedteethorodontogeniccysts.
Intraosseousmucoepidermoidcarcinomasaremostcommoninmiddleagedadultsanddemonstrateaslightfemale
predilection.Theyaremorecommoninthemandiblethaninthemaxillaandaremostoftenseeninthemolarramus
area. The most frequent presenting symptom is cortical swelling, although some lesions may be discovered as
incidentalfindingsonradiographs.Pain,trismus,andparesthesiaarereportedlessfrequently.
Radiographsusuallyrevealeitheraunilocularormultilocularradiolucencywithwelldefinedborders(Fig.1162).
However,someexamplesarecharacterizedbyamoreirregularandilldefinedareaofbonedestruction.Somecases
areassociatedwithanuneruptedtoothand,therefore,clinicallymaysuggestanodontogeniccystortumor.
FIG.1162
IntraosseousMucoepidermoidCarcinoma.Multilocularlesionoftheposteriormandible.(CourtesyofDr.JosephF.Finelli.)
The microscopic appearance of intraosseous mucoepidermoid carcinoma is similar to that of its soft tissue
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counterpart.Mosttumorsarelowgradelesions,althoughhighgrademucoepidermoidcarcinomasalsohavebeen
reportedwithinthejaws.
The primary treatment modality for patients with intraosseous mucoepidermoid carcinoma is surgery; adjunctive
radiation therapy also sometimes is used. Radical surgical resection offers a better chance for cure than do more
conservativeprocedures,suchasenucleationorcurettage.Thelocalrecurrenceratewithconservativetreatmentis
40%,incontrastto13%formoreradicaltreatment.Metastasishasbeenreportedinabout12%ofcases.Theoverall
prognosisisfairlygood;around10%ofpatientsdie,usuallyasaresultoflocalrecurrenceofthetumor.
AcinicCellCarcinoma
Theaciniccellcarcinomaisasalivaryglandmalignancywithcellsthatshowserousacinardifferentiation.Because
many of these tumors act in a nonaggressive fashion and are associated with a good prognosis, this neoplasm
formerlywascalledaciniccelltumor,anonspecificdesignationthatdidnotindicatewhetherthelesionwasbenign
ormalignant.However,becausesomeofthesetumorsdometastasizeorrecurandcausedeath,itisgenerallyagreed
todaythataciniccellcarcinomashouldbeconsideredalowgrademalignancy.
Many cases previously reported as acinic cell carcinoma, but which are poor in zymogen granules, would be
reclassified today as examples of a newly delineated salivary neoplasmmammary analogue secretory carcinoma
(seenexttopic).Thisisespeciallytrueforpurportedaciniccellcarcinomasinnonparotidsites.Therefore,evaluation
oftheliteratureanddataonaciniccellcarcinomapriorto2010ismademoredifficult.
ClinicalFeatures
Around 85% to 90% of all acinic cell carcinomas occur in the parotid gland, a logical finding because this is the
largestglandandonethatiscomposedentirelyofserouselements(Fig.1163).Mostsurveyshaveshownthatthis
neoplasmmakesup2%to3%ofallparotidtumors,althoughonestudyshoweditrepresented8.6%ofallparotid
tumors(seeTable114).Itismuchlesscommoninthesubmandibulargland,whichisthesiteforonly2.7%to5%of
thesetumors.About9%ofallaciniccellcarcinomasreportedlydevelopintheoralminorsalivaryglands,withthe
buccal mucosa, lips, and palate being the most common sites. Overall, around 1.3% to 3.8% of all minor salivary
glandtumorshavebeenreportedtobeaciniccellcarcinomas,althoughitislikelythatmanyofthesecaseswouldbe
reclassifiedtodayasmammaryanaloguesecretorycarcinoma.
FIG.1163
AcinicCellCarcinoma.Large,firmmassoftherightparotidgland.
Thetumoroccursoverabroadagerange,witharelativelyevenpeakprevalencestretchingfromthesecondtothe
seventh decades of life; the mean age is in the middle 40s to early 50s. The tumor usually appears as a slowly
growingmass,andthelesionoftenispresentformanymonthsoryearsbeforeadiagnosisismade.Thetumormay
beotherwiseasymptomatic,althoughassociatedpainortendernesssometimesisreported.Facialnerveparalysisis
aninfrequentbutominoussignforparotidtumors.
Acinic cell carcinomas are highly variable in their microscopic appearance. The tumor often is well circumscribed
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and sometimes may even appear encapsulated; however, some tumors exhibit an infiltrative growth pattern. The
mostcharacteristiccellisonewithfeaturesoftheserousacinarcell,withabundantgranularbasophiliccytoplasm
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,
vacuolatedcytoplasm.Onrareoccasions,thetumormaydemonstratehighgradefeatures,includingpleomorphism,
increasedmitoticactivity,andnecrosis.
Several growth patterns have been described. The solid variety consists of numerous welldifferentiated acinar
cells arranged in a pattern that resembles normal parotid gland tissue (Figs. 1164 and 1165). In the microcystic
variety, multiple small cystic spaces are created that may contain some mucinous or eosinophilic material. In the
papillarycysticvariety,largercysticareasareformedthatarelinedbyepitheliumhavingpapillaryprojectionsinto
the cystic spaces. The follicular variety has an appearance similar to that of thyroid tissue. A lymphoid infiltrate,
sometimeswithgerminalcenterformation,isnotunusual.
FIG.1164
AcinicCellCarcinoma.Parotidtumordemonstratingsheetofgranular,basophilicserousacinarcells.
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FIG.1165
AcinicCellCarcinoma.Highpowerviewofserouscellswithbasophilic,granularcytoplasm.
Aciniccellcarcinomasconfinedtothesuperficiallobeoftheparotidglandarebesttreatedbylobectomy;forthosein
thedeeplobe,totalparotidectomyisusuallynecessary.Thefacialnervemayneedtobesacrificedifitisinvolvedby
tumor.Submandibulartumorsaremanagedbytotalremovalofthegland,andminorglandtumorsaretreatedwith
assured surgical excision. Lymph node dissection is not indicated unless there is clinical evidence of metastatic
disease.Adjunctiveradiationtherapymaybeconsideredforuncontrolledlocaldisease.
The acinic cell carcinoma is associated with one of the better prognoses of any of the malignant salivary gland
tumors. Approximately 10% to 20% of patients have recurrences locally, and metastases develop in 8% to 11% of
patients.About10%ofpatientswilldieoftheirdisease,withhighgradetumorsshowingamuchworseprognosis
than that for lowgrade tumors. The outcome for minor gland tumors is better than that for tumors arising in the
majorglands.
MammaryAnalogueSecretoryCarcinoma
Mammaryanaloguesecretorycarcinomaisanewlyrecognizedsalivaryglandmalignancywithhistopathologicand
molecular features that are similar to secretory carcinoma of the breast. Both of these tumors harbor a balanced
chromosomaltranslocation,t(12;15)(p13;q25),whichresultsintheformationofanETV6NTRK3fusiongene.Priorto
its recognition in 2010, many examples of mammary analogue secretory carcinoma probably were diagnosed as
aciniccellcarcinoma,whichhasoverlappinglightmicroscopicfeatures(seelegendforFig.1166).
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MammaryAnalogueSecretoryCarcinoma.Bluishswellingoftheanteriorbuccalmucosa,whichcouldbemistaken
clinicallyforamucocele.(Thistumororiginallywasdiagnosedasaciniccellcarcinomabeforemammaryanaloguesecretory
carcinomawasrecognizedasadistinctentity.Thissameimagewasusedtoillustrateanaciniccellcarcinomaintheprevious
editionofthistext!)
FIG.1166
ClinicalFeatures
Themostcommonsiteoforiginforthemammaryanaloguesecretorycarcinomaistheparotidgland,whichaccounts
for 58% of reported cases. The minor salivary glands (31%) and submandibular gland (9%) are less frequent sites.
The lips, soft palate, and buccal mucosa are the most common intraoral subsites (Fig.1166). The mean age is 47
years, and the tumor has been reported to occur slightly more often in males than in females. The lesion usually
presents as a slowly growing, painless mass, which the patient may have noticed for months or many years.
Occasionalexampleshavebeenassociatedwithsomedegreeofdiscomfort.
Mammaryanaloguesecretorycarcinomashowsmicroscopicfeaturesthataresimilartothoseofsecretorycarcinoma
of the breast. The tumor cells exhibit bland, vesicular nuclei surrounded by slightly granular or vacuolated
cytoplasm. These cells are variably arranged as solid, tubular, microcystic, or macrocystic structures. Larger cystic
spaces may exhibit papillary infolding of tumor cells with a hobnail appearance (Fig.1167). Mitotic figures are
rare.
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FIG.1167
MammaryAnalogueSecretoryCarcinoma.Mediumpowerviewshowingpapillarycysticspacesandsmallsolid
islands.
ThetumorcellsshowdiffuseimmunoreactivityforS100protein,vimentin,andmammaglobin.Thechromosomal
translocationcanbeconfirmedviafluorescentinsituhybridization(FISH)usingtheETV6breakapartprobe,orby
detectionoftheETV6NTRK3fusiongenebyreversetranscriptionpolymerasechainreaction(RTPCR).
Althoughdataontreatmentandoutcomearelimited,mammaryanaloguesecretorycarcinomaappearstobealow
grade malignancy with a generally favorable prognosis. However, local tumor recurrence and metastases
occasionally have been documented, including several patients who died of tumor. Treatment most often has
consistedofsurgicalresection,sometimessupplementedbyadjuvantradiationtherapy.
MalignantMixedTumors(CarcinomaExPleomorphicAdenomaCarcinoma
ExMixedTumorCarcinosarcomaMetastasizingMixedTumor)
Malignant mixed tumors represent malignant counterparts to the benign mixed tumor or pleomorphic adenoma.
Theseuncommonneoplasmsconstitute2%to4%ofallsalivarytumorsandcanbedividedintothreecategories:
1.Carcinomaexpleomorphicadenoma(carcinomaexmixedtumor)
2.Carcinosarcoma
3.Metastasizingmixedtumor
The most common of these is the carcinoma ex pleomorphic adenoma, which is characterized by malignant
transformationoftheepithelialcomponentofapreviouslybenignpleomorphicadenoma.Thecarcinosarcomaisa
raremixedtumorinwhichbothcarcinomatousandsarcomatouselementsarepresent.Themetastasizingmixed
tumorhashistopathologicfeaturesthatareidenticaltothecommonpleomorphicadenoma(mixedtumor).Inspite
of its benign appearance, however, the lesion metastasizes. The metastatic tumor also has a benign microscopic
appearance,usuallysimilartothatoftheprimarylesion.
ClinicalFeatures
CarcinomaExPleomorphicAdenoma
There is fairly convincing evidence that the carcinoma ex pleomorphic adenoma represents a malignant
transformationwithinwhatwaspreviouslyabenignneoplasm.Firstofall,themeanageofpatientswiththistumor
isabout15yearsolderthanthatforthebenignpleomorphicadenoma.Itismostcommoninmiddleagedandolder
adults,withpeakprevalenceinthesixthtoeighthdecadesoflife.Inaddition,patientsmayreportthatamasshas
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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
supportmalignanttransformationofabenignpleomorphicadenoma.Ithasbeennotedthattheriskformalignant
changeinapleomorphicadenomaincreaseswiththedurationofthetumor.
More than 80% of cases of carcinoma ex pleomorphic adenoma are seen within the major glands, primarily the
parotidgland(Fig.1168).Nearlytwothirdsofminorsalivaryglandcasesoccuronthepalate(Fig.1169).Although
painorrecentrapidgrowthisnotunusual,manycasespresentasapainlessmassthatisindistinguishablefroma
benigntumor.Parotidtumorsmayproducefacialnervepalsy.
FIG.1168
CarcinomaExPleomorphicAdenoma.Massoftheparotidgland.
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FIG.1169
CarcinomaExPleomorphicAdenoma.Granularexophyticandulceratedmassfillingthevaultofthepalate.
Carcinosarcoma
Thecarcinosarcomaisanextremelyraretumor.Mostcaseshavebeenreportedintheparotidgland,butthelesion
also has been seen in the submandibular gland and minor salivary glands. The clinical signs and symptoms are
similar to those of the carcinoma ex pleomorphic adenoma. Some patients have a previous history of a benign
pleomorphicadenoma,althoughothercasesappeartoarisedenovo.
MetastasizingMixedTumor
Themetastasizingmixedtumorisalsoquiterare.Aswithothermalignantmixedtumors,mostcasesoriginateinthe
parotid gland, but the primary tumor also may occur in the submandibular gland or minor salivary glands.
Metastases have been found most frequently in the bones or lung, but they also can occur in other sites, such as
regionallymphnodes,skin,ortheliver.Mostpatientshaveahistoryofabenignmixedtumor,whichmayhavebeen
excisedmanyyearsearlier.Manytimestheprimarytumorexhibitsmultiplerecurrencesbeforemetastasisoccurs.
The carcinoma ex pleomorphic adenoma shows a variable microscopic appearance. Areas of typical benign
pleomorphicadenomausuallycanbefoundandmayconstitutemostoronlyasmallportionofthelesion.However,
extensivesamplingmayberequiredtoidentifythebenigncomponentinsomecases.Withinthetumorareareasof
malignantdegenerationoftheepithelialcomponent,characterizedbycellularpleomorphismandabnormalmitotic
activity (Fig. 1170). This change is most often in the form of a poorly differentiated adenocarcinoma (such as,
salivary duct carcinoma), but other patterns also can develop, including myoepithelial carcinoma, polymorphous
lowgradeadenocarcinoma,mucoepidermoidcarcinoma,andadenoidcysticcarcinoma.
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CarcinomaExPleomorphicAdenoma.A,Mediumpowerviewofthebenignportionofthetumorshowingsheetsof
plasmacytoidmyoepithelialcellswithinamyxoidbackground.B,Malignantportionofthetumorshowingepithelialcellswith
pleomorphicnuclei.
FIG.1170
Based on the pattern of growth, carcinoma ex pleomorphic adenoma can be divided into three subcategories:
invasive, minimally invasive, or noninvasive. Invasive carcinoma ex pleomorphic adenoma shows malignant cells
penetrating greater than 1.5 mm from the tumor capsule into adjacent tissues. Minimally invasive tumors show
extracapsularinvasionthatmeasures1.5mmorless.Noninvasivetumorsmaybediscoveredasasmallmalignant
focus within the center of an encapsulated pleomorphic adenoma but without violation of the tumor capsule.
Because such tumors have a markedly better prognosis than invasive tumors, they also have been designated as
carcinomainsituexmixedtumororintracapsularcarcinomaexpleomorphicadenoma.
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
sarcomatousportionoftenpredominatesthetumorandisusuallyintheformofchondrosarcomabutalsomayshow
characteristicsofosteosarcoma,fibrosarcoma,liposarcoma,rhabdomyosarcoma,ormalignantfibroushistiocytoma.
Somelesionshaveevidenceofanoriginfromabenignmixedtumor.
Themetastasizingmixedtumorhasmicroscopicfeaturesofabenignpleomorphicadenoma,withinboththeprimary
andthemetastaticsites.Malignanthistopathologicchangesarenotobserved.
Invasivecarcinomaexpleomorphicadenomausuallyisbesttreatedbywideexcision,possiblyinconjunctionwith
locallymphnodedissectionandadjunctiveradiationtherapy.Theprognosisisguarded;theoverall5yearsurvival
rate ranges from 25% to 65%, but this rate drops to 10% to 35% at 15 years. The prognosis is related to the
histopathologicsubtypeofthemalignantcomponent.Onestudyshowedthatwelldifferentiatedcarcinomas,suchas
polymorphous lowgrade adenocarcinoma, have nearly a 90% 5year survival rate. However, the outlook is much
worse for patients with tumors that are poorly differentiated or that have invaded more than 8 mm beyond the
residual capsule or benign residual tumor. In contrast, the prognosis for noninvasive or minimally invasive
carcinomaexpleomorphicadenomaapproachesthatforbenignmixedtumor.However,rareexamplesofmetastasis
ortumordeathhavebeendocumentedintheselattergroups.
Carcinosarcoma
Carcinosarcomas are treated by radical surgical excision, which may be combined with radiation therapy and
chemotherapy. The prognosis is poor, with around 75% of patients either dying from their disease or developing
recurrentlocaltumorormetastases.
The treatment for a metastasizing mixed tumor consists of surgical excision of both the primary tumor and the
metastaticsites.Amortalityrateof40%hasbeenreported.
AdenoidCysticCarcinoma
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hybridization(FISH)usingtheETV6breakapartprobe,orbydetectionoftheETV6NTRK3
fusiongenebyreversetranscriptionpolymerasechainreaction(RTPCR).
Althoughdataontreatmentandoutcomearelimited,mammaryanaloguesecretorycarcinomaappearstobealow
grade malignancy with a generally favorable prognosis. However, local tumor recurrence and metastases
occasionally have been documented, including several patients who died of tumor. Treatment most often has
consistedofsurgicalresection,sometimessupplementedbyadjuvantradiationtherapy.
MalignantMixedTumors(CarcinomaExPleomorphicAdenomaCarcinoma
ExMixedTumorCarcinosarcomaMetastasizingMixedTumor)
Malignant mixed tumors represent malignant counterparts to the benign mixed tumor or pleomorphic adenoma.
Theseuncommonneoplasmsconstitute2%to4%ofallsalivarytumorsandcanbedividedintothreecategories:
1.Carcinomaexpleomorphicadenoma(carcinomaexmixedtumor)
2.Carcinosarcoma
3.Metastasizingmixedtumor
The most common of these is the carcinoma ex pleomorphic adenoma, which is characterized by malignant
transformationoftheepithelialcomponentofapreviouslybenignpleomorphicadenoma.Thecarcinosarcomaisa
raremixedtumorinwhichbothcarcinomatousandsarcomatouselementsarepresent.Themetastasizingmixed
tumorhashistopathologicfeaturesthatareidenticaltothecommonpleomorphicadenoma(mixedtumor).Inspite
of its benign appearance, however, the lesion metastasizes. The metastatic tumor also has a benign microscopic
appearance,usuallysimilartothatoftheprimarylesion.
ClinicalFeatures
There is fairly convincing evidence that the carcinoma ex pleomorphic adenoma represents a malignant
transformationwithinwhatwaspreviouslyabenignneoplasm.Firstofall,themeanageofpatientswiththistumor
isabout15yearsolderthanthatforthebenignpleomorphicadenoma.Itismostcommoninmiddleagedandolder
adults,withpeakprevalenceinthesixthtoeighthdecadesoflife.Inaddition,patientsmayreportthatamasshas
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
supportmalignanttransformationofabenignpleomorphicadenoma.Ithasbeennotedthattheriskformalignant
changeinapleomorphicadenomaincreaseswiththedurationofthetumor.
More than 80% of cases of carcinoma ex pleomorphic adenoma are seen within the major glands, primarily the
parotidgland(Fig.1168).Nearlytwothirdsofminorsalivaryglandcasesoccuronthepalate(Fig.1169).Although
painorrecentrapidgrowthisnotunusual,manycasespresentasapainlessmassthatisindistinguishablefroma
benigntumor.Parotidtumorsmayproducefacialnervepalsy.
https://bookshelf.vitalsource.com/#/books/9781455770526/cfi/6/44!/4/2/2/2/26/2/10/2/12/2
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FIG.1168
CarcinomaExPleomorphicAdenoma.Massoftheparotidgland.
FIG.1169
CarcinomaExPleomorphicAdenoma.Granularexophyticandulceratedmassfillingthevaultofthepalate.
Carcinosarcoma
Thecarcinosarcomaisanextremelyraretumor.Mostcaseshavebeenreportedintheparotidgland,butthelesion
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also has been seen in the submandibular gland and minor salivary glands. The clinical signs and symptoms are
similar to those of the carcinoma ex pleomorphic adenoma. Some patients have a previous history of a benign
pleomorphicadenoma,althoughothercasesappeartoarisedenovo.
Themetastasizingmixedtumorisalsoquiterare.Aswithothermalignantmixedtumors,mostcasesoriginateinthe
parotid gland, but the primary tumor also may occur in the submandibular gland or minor salivary glands.
Metastases have been found most frequently in the bones or lung, but they also can occur in other sites, such as
regionallymphnodes,skin,ortheliver.Mostpatientshaveahistoryofabenignmixedtumor,whichmayhavebeen
excisedmanyyearsearlier.Manytimestheprimarytumorexhibitsmultiplerecurrencesbeforemetastasisoccurs.
The carcinoma ex pleomorphic adenoma shows a variable microscopic appearance. Areas of typical benign
pleomorphicadenomausuallycanbefoundandmayconstitutemostoronlyasmallportionofthelesion.However,
extensivesamplingmayberequiredtoidentifythebenigncomponentinsomecases.Withinthetumorareareasof
malignantdegenerationoftheepithelialcomponent,characterizedbycellularpleomorphismandabnormalmitotic
activity (Fig. 1170). This change is most often in the form of a poorly differentiated adenocarcinoma (such as,
salivary duct carcinoma), but other patterns also can develop, including myoepithelial carcinoma, polymorphous
lowgradeadenocarcinoma,mucoepidermoidcarcinoma,andadenoidcysticcarcinoma.
CarcinomaExPleomorphicAdenoma.A,Mediumpowerviewofthebenignportionofthetumorshowingsheetsof
plasmacytoidmyoepithelialcellswithinamyxoidbackground.B,Malignantportionofthetumorshowingepithelialcellswith
pleomorphicnuclei.
FIG.1170
Based on the pattern of growth, carcinoma ex pleomorphic adenoma can be divided into three subcategories:
invasive, minimally invasive, or noninvasive. Invasive carcinoma ex pleomorphic adenoma shows malignant cells
penetrating greater than 1.5 mm from the tumor capsule into adjacent tissues. Minimally invasive tumors show
extracapsularinvasionthatmeasures1.5mmorless.Noninvasivetumorsmaybediscoveredasasmallmalignant
focus within the center of an encapsulated pleomorphic adenoma but without violation of the tumor capsule.
Because such tumors have a markedly better prognosis than invasive tumors, they also have been designated as
carcinomainsituexmixedtumororintracapsularcarcinomaexpleomorphicadenoma.
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
sarcomatousportionoftenpredominatesthetumorandisusuallyintheformofchondrosarcomabutalsomayshow
characteristicsofosteosarcoma,fibrosarcoma,liposarcoma,rhabdomyosarcoma,ormalignantfibroushistiocytoma.
Somelesionshaveevidenceofanoriginfromabenignmixedtumor.
Themetastasizingmixedtumorhasmicroscopicfeaturesofabenignpleomorphicadenoma,withinboththeprimary
andthemetastaticsites.Malignanthistopathologicchangesarenotobserved.
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Invasivecarcinomaexpleomorphicadenomausuallyisbesttreatedbywideexcision,possiblyinconjunctionwith
locallymphnodedissectionandadjunctiveradiationtherapy.Theprognosisisguarded;theoverall5yearsurvival
rate ranges from 25% to 65%, but this rate drops to 10% to 35% at 15 years. The prognosis is related to the
histopathologicsubtypeofthemalignantcomponent.Onestudyshowedthatwelldifferentiatedcarcinomas,suchas
polymorphous lowgrade adenocarcinoma, have nearly a 90% 5year survival rate. However, the outlook is much
worse for patients with tumors that are poorly differentiated or that have invaded more than 8 mm beyond the
residual capsule or benign residual tumor. In contrast, the prognosis for noninvasive or minimally invasive
carcinomaexpleomorphicadenomaapproachesthatforbenignmixedtumor.However,rareexamplesofmetastasis
ortumordeathhavebeendocumentedintheselattergroups.
Carcinosarcoma
Carcinosarcomas are treated by radical surgical excision, which may be combined with radiation therapy and
chemotherapy. The prognosis is poor, with around 75% of patients either dying from their disease or developing
recurrentlocaltumorormetastases.
The treatment for a metastasizing mixed tumor consists of surgical excision of both the primary tumor and the
metastaticsites.Amortalityrateof40%hasbeenreported.
AdenoidCysticCarcinoma
Theadenoidcysticcarcinomaisoneofthemorecommonandbestrecognizedsalivarymalignancies.Becauseofits
distinctivehistopathologicfeatures,itwasoriginallycalledacylindroma,andthistermstillisheardsometimesasa
synonymforthisneoplasm.However,useofthetermcylindromashouldbeavoidedbecauseitdoesnotconveythe
malignantnatureofthetumor,andalsobecausethissametermisusedforaskinadnexaltumorthathasamarkedly
differentclinicalpresentationandprognosis.
Theadenoidcysticcarcinomacanoccurinanysalivaryglandsite,butapproximately40%to45%developwithinthe
minor salivary glands. The palate is the most common site for minor gland tumors (Fig. 1171). The remaining
tumorsarefoundmostlyintheparotidandsubmandibularglands,withafairlyevendistributionbetweenthesetwo
sites. On an individual basis, however, a striking difference can be seen among the various glands. In the parotid
gland, the adenoid cystic carcinoma is relatively rare, constituting only 2% of all tumors. In the submandibular
gland, this tumor accounts for 11% to 17% of all tumors and is the most common malignancy. It is also relatively
commonamongpalatalsalivaryneoplasms;itrepresents8%to15%ofallsuchtumors.Thelesionismostcommon
in middleaged adults and is rare in people younger than age 20. Surveillance, Epidemiology, and End Results
(SEER)datafrom1973to2007intheUnitedStatesshowedamale:femaleratioof1:1.4.
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FIG.1171
AdenoidCysticCarcinoma.Painfulmassofthehardpalateandmaxillaryalveolarridge.(CourtesyofDr.GeorgeBlozis.)
Theadenoidcysticcarcinomausuallyappearsasaslowlygrowingmass.Painisacommonandimportantfinding,
occasionallyoccurringearlyinthecourseofthediseasebeforethereisanoticeableswelling.Patientsoftencomplain
ofaconstant,lowgrade,dullache,whichgraduallyincreasesinintensity.Facialnerveparalysismaydevelopwith
parotidtumors.Palataltumorscanbesmoothsurfacedorulcerated.Tumorsarisinginthepalateormaxillarysinus
oftenshowradiographicevidenceofbonedestruction(Fig.1172).
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AdenoidCysticCarcinoma.Computedtomography(CT)scanofthismassivepalataltumorshowsextensive
destructionofthehardpalatewithextensionofthetumorintothenasalcavityandbothmaxillarysinuses.(CourtesyofDr.KevinRiker.)
FIG.1172
Theadenoidcysticcarcinomaiscomposedofamixtureofmyoepithelialcellsandductalcellsthatcanhaveavaried
arrangement (Fig. 1173). Three major patterns are recognized: 1) cribriform, 2) tubular, and 3) solid. Usually a
combinationoftheseisseen,andthetumorisclassifiedbasedonthepredominantpattern.
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AdenoidCysticCarcinoma.Islandsofhyperchromaticcellsformingcribriformandtubularstructures.Insetshowsa
highpowerviewofasmallcribriformisland.
FIG.1173
Thecribriformpattern is the most classic and bestrecognized appearance, characterized by islands of basaloid
epithelialcellsthatcontainmultiplecylindrical,cystlikespacesresemblingSwisscheese.Thesespacesoftencontain
a mildly basophilic mucoid material, a hyalinized eosinophilic product, or a combined mucoidhyalinized
appearance.Sometimesthehyalinizedmaterialalsosurroundsthesecribriformislands(Fig.1174),orsmallstrands
oftumorarefoundembeddedwithinthishyalinizedstroma.Thetumorcellsaresmallandcuboidal,exhibiting
deeply basophilic nuclei and little cytoplasm. These cells are fairly uniform in appearance, and mitotic activity is
rarely seen. The pathologist should be mindful that other salivary tumors, especially polymorphous lowgrade
adenocarcinoma,alsomayexhibitareaswithacribriformpattern.
FIG.1174
AdenoidCysticCarcinoma.Thetumorcellsaresurroundedbyhyalinizedmaterial.
Inthetubularpattern,thetumorcellsaresimilarbutoccurasmultiplesmallductsortubuleswithinahyalinized
stroma.Thetubularluminacanbelinedbyonetoseverallayersofcells,andsometimesbothalayerofductalcells
andmyoepithelialcellscanbediscerned.
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Thesolidvariantconsistsoflargerislandsorsheetsoftumorcellsthatdemonstratelittletendencytowardductor
cyst formation. Unlike the cribriform and tubular patterns, cellular pleomorphism and mitotic activity, as well as
focalnecrosisinthecenterofthetumorislands,maybeobserved.
Ahighlycharacteristicfeatureofadenoidcysticcarcinomaisitstendencytoshowperineuralinvasion(Fig.1175),
whichprobablycorrespondstothecommonclinicalfindingofpaininthesepatients.Sometimesthecellsappearto
have a swirling arrangement around nerve bundles. However, perineural invasion is not pathognomonic for
adenoid cystic carcinoma; it also may be seen in other salivary malignancies, especially polymorphous lowgrade
adenocarcinomas.
FIG.1175
AdenoidCysticCarcinoma.Perineuralinvasion.
PositiveimmunostainingreactionsforCD43andckit(CD117)inadenoidcysticcarcinomahavebeenreportedto
beusefuldiagnosticfeaturesthatcanhelptodistinguishthistumorfrompolymorphouslowgradeadenocarcinoma,
basal cell adenoma, and canalicular adenoma. In addition, the patterns of expression of a variety of other
immunohistochemical markers have been suggested to be diagnostically relevant, including stains for vimentin,
collagenIV,laminin,integrins,Ki67,smoothmuscleactin,andvariouscytokeratins.
Adenoid cystic carcinoma is a relentless tumor that is prone to local recurrence and eventual distant metastasis.
Surgical resection is usually the treatment of choice. Adjuvant radiation therapy may slightly improve patient
survival in some cases, although recent SEER data suggest that radiation therapy does little to improve prognosis
overall.Becausemetastasistoregionallymphnodesisuncommon(6%to10%ofcases),neckdissectionusuallyis
notindicated.
Becausethetumorispronetolaterecurrenceandmetastasis,the5yearsurvivalratehaslimitedsignificanceand
doesnotequatetoacure.The5yearsurvivalratemaybeashighas77%to82%,butthisratecontinuestodecrease
overtime.The10yearsurvivalcurrentlyrangesfrom60%to68%,andby20years,only35%to52%ofpatientsare
still alive. Tumors with a solid histopathologic pattern are associated with a worse outlook than those with a
cribriformortubulararrangement.Withrespecttosite,theprognosisispoorestfortumorsarisinginthemaxillary
sinusandsubmandibulargland.Bettersurvivalisobservedinfemales,youngerpatients,andpatientswithlocalized
diseaseatthetimeofdiagnosis.Moststudieshaveshownthatmicroscopicidentificationofperineuralinvasionhas
little effect on the prognosis. Tumor DNA ploidy analysis may help to predict the prognosis of adenoid cystic
carcinoma;patientswithdiploidtumorshavebeenshowntohaveasignificantlybetteroutcomethanpatientswith
aneuploidtumors.
Death usually results from local recurrence or distant metastases. Tumors of the palate or maxillary sinus
eventually may invade upward to the base of the brain. Metastases occur in approximately 35% of patients, most
frequentlyinvolvingthelungs,bone,andbrain.
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PolymorphousLowGradeAdenocarcinoma(LobularCarcinomaTerminal
DuctCarcinoma)
Thepolymorphouslowgradeadenocarcinomaisamorerecentlyrecognizedtypeofsalivarymalignancythatwas
first described in 1983. Before its identification as a distinct entity, examples of this tumor were categorized as
pleomorphic adenoma, an unspecified form of adenocarcinoma, or sometimes as adenoid cystic carcinoma. Once
recognizedasaspecificentity,however,itwasrealizedthatthistumorpossessesdistinctclinicopathologicfeatures
andisoneofthemorecommonminorsalivaryglandmalignancies.
ClinicalFeatures
Thepolymorphouslowgradeadenocarcinomaisalmostexclusivelyatumoroftheminorsalivaryglands.However,
rareexamplesalsohavebeenreportedinthemajorglands,eitherarisingdenovoorasthemalignantcomponentofa
carcinomaexpleomorphicadenoma.Sixtyfivepercentoccuronthehardorsoftpalate(Fig.1176),withtheupper
lip and buccal mucosa being the next most common locations. It is most common in older adults, having peak
prevalenceinthesixthtoeighthdecadesoflife.Twothirdsofallcasesoccurinfemales.
FIG.1176
PolymorphousLowGradeAdenocarcinoma.Slowgrowing,firmmassoftherightposteriorlateralhardpalate.(Courtesy
ofDr.KevinRiker.)
Thetumormostoftenappearsasapainlessmassthatmayhavebeenpresentforalongtimewithslowgrowth.
Occasionally,itisassociatedwithbleedingordiscomfort.Tumorcanerodeorinfiltratetheunderlyingbone.
The tumor cells of polymorphous lowgrade 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,orspindled;thesenucleiusuallyarepalestaining,althoughtheycanbemorebasophilicinsomeareas.
Thecellscanexhibitdifferentgrowthpatterns,hence,thepolymorphousterm.Thecellsmaygrowinasolidpatternor
formcords,ducts,orlargercysticspaces.Insometumors,acribriformpatterncanbeproducedthatmimicsadenoid
cysticcarcinoma(Fig.1177).Mitoticfiguresareuncommon.
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PolymorphousLowGradeAdenocarcinoma.Thismediumpowerviewshowsacribriformarrangementofuniform
tumorcellswithpalestainingnuclei.
FIG.1177
At low power, the tumor sometimes appears well circumscribed. However, the peripheral cells are usually
infiltrative, invading the adjacent tissue in a singlefile fashion (Fig. 1178). 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 commonanother feature that may cause the tumor to be mistaken for adenoid cystic
carcinoma (Fig. 1179). However, a distinction between these two tumors is important because of their vastly
differentprognoses.
FIG.1178
PolymorphousLowGradeAdenocarcinoma.Palestainingcellsthatinfiltrateassinglefilecords.
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FIG.1179
PolymorphousLowGradeAdenocarcinoma.Perineuralinvasion.
Immunohistochemical staining can be helpful in distinguishing polymorphous lowgrade adenocarcinoma from

othersalivaryglandtumorsthatitmaymimic.Whencomparedwithadenoidcysticcarcinoma,polymorphouslow
gradeadenocarcinomaexhibitssignificantlyweakerexpressionofCD43andckit(CD117).Likewise,lackofstaining
for glial fibrillary acidic protein (GFAP) can help to differentiate this tumor from pleomorphic adenoma, which is
almostalwaysstronglypositiveforGFAP.
The polymorphous lowgrade adenocarcinoma is best treated by wide surgical excision, sometimes including
resection of the underlying bone. Metastasis to regional lymph nodes is relatively uncommon, occurring in 9% to
17% of patients. Therefore, neck dissection seems unwarranted in most cases unless there is clinical evidence of
cervical metastases. However, tumors arising at the base of the tongue show a greater risk of regional metastasis.
Distantmetastasisisrare.
Theoverallprognosisisrelativelygood.Recurrentdiseasehasbeenreportedin9%to29%ofallpatients,butthis
usuallycanbecontrolledwithreexcision.Deathfromtumorisrarebutmayoccursecondarytodirectextensioninto
vitalstructures.Microscopicidentificationofperineuralinvasiondoesnotappeartoaffecttheprognosis.
SalivaryAdenocarcinoma,NotOtherwiseSpecified
In spite of the wide variety of salivary gland malignancies that have been specifically identified and categorized,
some tumors still defy the existing classification schemes. These tumors usually are designated as salivary
adenocarcinomas,nototherwisespecified(NOS).
ClinicalandHistopathologicFeatures
Becausetheseadenocarcinomasrepresentsuchadiversegroupofneoplasms,itisdifficulttogeneralizeabouttheir
clinicalandmicroscopicfeatures.Likemostsalivarytumors,theyappeartobemostcommonintheparotidgland,
followed by the minor glands and the submandibular gland (Figs. 1180 and 1181). They may present as
asymptomatic masses or cause pain or facial nerve paralysis. The microscopic appearance is highly variable but
demonstrates features of a glandular malignancy with evidence of cellular pleomorphism, an infiltrative growth
pattern, or both. These tumors exhibit a wide spectrum of differentiation, ranging from welldifferentiated, low
gradeneoplasmstopoorlydifferentiated,highgrademalignancies.
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FIG.1180
SalivaryAdenocarcinoma.Clearcelladenocarcinomaofthesubmandibulargland.
FIG.1181
SalivaryAdenocarcinoma.Massoftheposteriorlateralhardpalate.
Asthesetumorsarestudiedmore,itshouldbepossibletoclassifysomeofthemintoseparate,specificcategories
andallowmoredefinitiveanalysesoftheirclinicalandmicroscopicfeatures.
Becauseoftheirdiversity,itisdifficulttopredicttheprognosisforsalivaryadenocarcinoma(NOS),butpatientswith
earlystage,welldifferentiatedtumorsappeartohaveabetteroutcome.Thesurvivalrateisbetterfortumorsofthe
oralcavitythanforthoseinthemajorsalivaryglands.Thereported10yearsurvivalrateforparotidtumorsranges
from26%to55%;incontrast,onestudyreporteda10yearsurvivalrateof76%forintraoraltumors.
Bibliography
SalivaryGlandAplasia
DangNP,PicardM,MondiJM,etal.Completecongenitalagenesisofallmajorsalivaryglands:acasereport
andreviewoftheliterature.OralSurgOralMedOralPatholOralRadiolEndod.2010;110:e23e27.
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16
DermatologicDiseases
EctodermalDysplasia
Ectodermal dysplasia represents a group of inherited conditions in which two or more ectodermally derived
anatomicstructuresfailtodevelop.Thusdependingonthetypeofectodermaldysplasia,hypoplasiaoraplasiaof
tissues (e.g., skin, hair, nails, teeth, and sweat glands) may be seen. The various types of this disorder may be
inheritedinanyoneofseveralgeneticpatterns,includingautosomaldominant,autosomalrecessive,andXlinked
patterns.Eventhoughbysomeaccountsalmost200differentsubtypesofectodermaldysplasiacanbedefined,these
disordersareconsideredtoberelativelyrare,withanestimatedfrequencyofsevencasesoccurringinevery10,000
births.Forfewerthan20%oftheseconditions,thespecificgeneticmutationsandtheirchromosomallocationshave
beenidentified.Systematicallyclassifyingtheseconditionscanbechallengingbecauseoftheirwiderangingclinical
features; however, some investigators have suggested that a classification scheme based on the molecular genetic
alterationassociatedwitheachtypemightbeappropriate.Thusgroupsofectodermaldysplasiasyndromescouldbe
categorizedasbeingcausedbymutationsingenesencodingcellcellsignals,genesencodingadhesionmolecules,or
genesregulatingtranscription.
ClinicalFeatures
Perhaps the best known of the ectodermal dysplasia syndromes is hypohidrotic ectodermal dysplasia. In most
instances, this disorder seems to show an Xlinked inheritance pattern, with the gene mapping to Xq12q13.1;
therefore,amalepredominanceisusuallyseen.However,afewfamilieshavebeenidentifiedthatshowautosomal
recessiveorautosomaldominantpatternsofinheritance.
Affected individuals typically display heat intolerance because of a reduced number of eccrine sweat glands.
Sometimesthediagnosisismadeduringinfancybecausethebabyappearstohaveafeverofundeterminedorigin;
however, the infant simply cannot regulate body temperature appropriately because of the decreased number of
sweat glands. Uncommonly, death results from the markedly elevated body temperature, although this generally
happensonlywhentheconditionisnotidentified.Sometimes,asadiagnosticaid,aspecialimpressioncanbemade
ofthepatientsfingertipsandthenexaminedmicroscopicallytocountthedensityofthesweatglands.Suchfindings
shouldbeinterpretedinconjunctionwithappropriateagematchedcontrols.
Othersignsofthisdisorderincludefine,sparsehair,includingareduceddensityofeyebrowandeyelashhair(Fig.
161).Theperiocularskinmayshowafinewrinklingwithhyperpigmentation(Fig.162),andmidfacehypoplasiais
frequentlyobserved,oftenresultinginprotuberantlips.Becausethesalivaryglandsareectodermallyderived,these
glands may be hypoplastic or absent, and patients may exhibit varying degrees of xerostomia. The nails may also
appeardystrophicandbrittle.
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EctodermalDysplasia.Thesparsehair,periocularhyperpigmentation,andmildmidfacialhypoplasiaarecharacteristic
featuresevidentinthisaffectedpatient.
FIG.161
EctodermalDysplasia.CloserviewofthesamepatientdepictedinFig.161.Fineperiocularwrinkling,aswellassparse
eyelashandeyebrowhair,canbeobserved.
FIG.162
The teeth are usually markedly reduced in number (oligodontia or hypodontia), and their crown shapes are
characteristicallyabnormal(Fig.163).Theincisorcrownsusuallyappeartapered,conical,orpointed,andthemolar
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crownsarereducedindiameter.Completelackoftoothdevelopment(anodontia)hasalsobeenreported,butthis
appearstobeuncommon.
FIG.163
EctodermalDysplasia.Oligodontiaandconicalcrownformsaretypicaloralmanifestations.(CourtesyofDr.CharlesHookandDr.
BobGellin.)
Femalepatientsmayshowpartialexpressionoftheabnormalgene;thatis,theirteethmaybereducedinnumber
ormayhavemildstructuralchanges.ThisincompletepresentationcanbeexplainedbytheLyonhypothesis,with
halfofthefemalepatientsXchromosomesexpressingthenormalgene,andtheotherhalfexpressingthedefective
gene.
Histopathologicexaminationoftheskinfromapatientwithhypohidroticectodermaldysplasiashowsadecreased
numberofsweatglandsandhairfollicles.Theadnexalstructuresthatarepresentarehypoplasticandmalformed.
Managementofhypohidroticectodermaldysplasiawarrantsgeneticcounselingfortheparentsandthepatient.The
dentalproblemsarebestmanagedbyprostheticreplacementofthedentitionwithcompletedentures,overdentures,
or fixed appliances, depending on the number and location of the remaining teeth. With careful site selection,
endosseousdentalimplantsmaybeconsideredforfacilitatingprostheticmanagementofpatientsolderthan6years
ofage.
WhiteSpongeNevus(CannonDiseaseFamilialWhiteFolded
Dysplasia)
Whitespongenevusisarelativelyraregenodermatosis(ageneticallydeterminedskindisorder)thatisinheritedas
anautosomaldominanttraitdisplayingahighdegreeofpenetranceandvariableexpressivity.Thisconditionisdue
toadefectinthenormalkeratinizationoftheoralmucosa.Inthe30memberfamilyofkeratinfilaments,thepairof
keratinsknownaskeratin4andkeratin13isspecificallyexpressedinthespinouscelllayerofmucosalepithelium.
Mutationsineitherofthesekeratingeneshavebeenshowntoberesponsiblefortheclinicalmanifestationsofwhite
spongenevus.
ClinicalFeatures
The lesions of white sponge nevus usually appear at birth or in early childhood, but sometimes the condition
developsduringadolescence.Symmetrical,thickened,white,corrugatedorvelvety,diffuseplaquesaffectthebuccal
mucosa bilaterally in most instances (Fig.164). Other common intraoral sites of involvement include the ventral
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tongue,labialmucosa,softpalate,alveolarmucosa,andfloorofthemouth,althoughtheextentofinvolvementcan
vary from patient to patient. Extraoral mucosal sites, such as the nasal, esophageal, laryngeal, and anogenital
mucosa,appeartobelesscommonlyaffected.Patientsareusuallyasymptomatic.
FIG.164
WhiteSpongeNevus.Diffuse,thickenedwhiteplaquesofthebuccalmucosa.
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
commonfeatures(Figs.165and166); however, similar microscopic findings may be associated with leukoedema
andhereditarybenignintraepithelialdyskeratosis(HBID).Insomeinstances,aneosinophiliccondensationisnoted
in the perinuclear region of the cells in the superficial layers of the epithelium, a feature that is unique to white
sponge nevus. Ultrastructurally, this condensed material can be identified as tangled masses of keratin
tonofilaments.
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WhiteSpongeNevus.Thislowpowerphotomicrographshowsprominenthyperparakeratosis,markedthickening
(acanthosis),andvacuolationofthespinouscelllayer.
FIG.165
WhiteSpongeNevus.Thishighpowerphotomicrographshowsvacuolationofthecytoplasmofthecellsofthespinous
layer,withnoevidenceofepithelialatypia.Perinuclearcondensationofkeratintonofilamentscanalsobeobservedinsomecells.
FIG.166
Exfoliativecytologicstudiesmayprovidemoredefinitivediagnosticinformation.Acytologicpreparationstained
withthePapanicolaoumethodoftenshowstheeosinophilicperinuclearcondensationoftheepithelialcellcytoplasm
toagreaterextentthandoesthehistopathologicsection(Fig.167).
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WhiteSpongeNevus.ThishighpowerphotomicrographofaPapanicolaoustainedcytologicpreparationshowsthe
pathognomonicperinuclearcondensationofkeratintonofilaments.
FIG.167
Becausethisisabenigncondition,notreatmentisnecessary.Theprognosisisgood.
HereditaryBenignIntraepithelialDyskeratosis(WitkopVon
SallmannSyndrome)
Hereditary benign intraepithelial dyskeratosis (HBID) is a rare autosomal dominant genodermatosis primarily
affecting descendants of a triracial isolate (Native American, black, and white) of people who originally lived in
NorthCarolina.ExamplesofHBIDhavesporadicallybeenreportedfromotherareasoftheUnitedStatesbecauseof
migration of affected individuals, and descriptions of affected patients with no apparent connection to North
Carolinahavealsoappearedintheliterature.
ClinicalFeatures
ThelesionsofHBIDusuallydevelopduringchildhood,inmostinstancesaffectingtheoralandconjunctivalmucosa.
Theorallesionsaresimilartothoseofwhitespongenevus,withbothconditionsshowingthick,corrugatedwhite
plaques involving the buccal and labial mucosa (Fig.168). Milder cases may exhibit the opalescent appearance of
leukoedema.Otheroralmucosalsites,suchasthefloorofthemouthandlateraltongue,mayalsobeaffected.These
orallesionsmayexhibitasuperimposedcandidalinfectionaswell.
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HereditaryBenignIntraepithelialDyskeratosis(HBID).Orallesionsappearascorrugatedwhiteplaquesofthebuccal
mucosa.(CourtesyofDr.JohnMcDonald.)
FIG.168
ThemostinterestingfeatureofHBIDistheocularlesions,whichbegintodevelopveryearlyinlife.Theseappear
asthick,opaque,gelatinousplaquesaffectingthebulbarconjunctivaadjacenttothecornea(Fig.169)andsometimes
involvingthecorneaitself.Whenthelesionsareactive,patientsmayexperiencetearing,photophobia,anditchingof
theeyes.Inmanypatients,theplaquesaremostprominentinthespringandtendtoregressduringthesummeror
autumn.Sometimesblindnessmayresultfromtheinductionofvascularityofthecorneasecondarytotheshedding
process.
HereditaryBenignIntraepithelialDyskeratosis(HBID).Ocularlesionsappearasgelatinousplaques(arrow)ofthebulbar
conjunctivae.(CourtesyofDr.CarlWitkop.)
FIG.169
ThehistopathologicfeaturesofHBIDincludeprominentparakeratinproductioninadditiontomarkedacanthosis.A
peculiardyskeratoticprocess,similartothatofDarierdisease,isscatteredthroughouttheupperspinouslayerofthe
surface oral epithelium (Fig.1610). With this dyskeratotic process, an epithelial cell appears to be surrounded or
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engulfedbyanadjacentepithelialcell,resultinginthesocalledcellwithinacellphenomenon.
HereditaryBenignIntraepithelialDyskeratosis(HBID).A,Mediumpowerphotomicrographexhibiting
hyperparakeratosis,acanthosis,anddyskeratosis.B,Highermagnificationshowingdyskeratoticcells.
FIG.1610
Because HBID is a benign condition, no treatment is generally required or indicated for the oral lesions. If
superimposed candidiasis develops, then an antifungal medication can be used. Patients with symptomatic ocular
lesions should be referred to an ophthalmologist. Typically, the plaques that obscure vision must be surgically
excised.Thisprocedure,however,isrecognizedasatemporarymeasurebecausethelesionsoftenrecur.
PachyonychiaCongenita(JadassohnLewandowskyType
JacksonLawlerType)
Pachyonychiacongenita is a group of rare genodermatoses that are usually inherited as an autosomal dominant
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PeutzJeghersSyndrome
PeutzJegherssyndromeisarelativelyrarebutwellrecognizedcondition,havingaprevalenceofapproximately1
in50,000to200,000births.Itischaracterizedbyfrecklelikelesionsofthehands,perioralskin,andoralmucosa,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.
Mutationofthetumorsuppressorgene,STK11(alsoknownasLKB1)isresponsibleformostcasesofPeutzJeghers
syndrome.Thisgene,whichencodesforaserine/threoninekinase,islocatedonchromosome19p13.3.
ClinicalFeatures
The skin lesions of PeutzJeghers syndrome usually develop early in childhood and involve the periorificial areas
(e.g.,mouth,nose,anus,andgenitalregion).Theskinoftheextremitiesisaffectedinabout50%ofpatients(Fig.16
27).Thelesionsresemblefreckles,buttheydonotwaxandwanewithsunexposure,asdotruefreckles.
PeutzJeghersSyndrome.Cutaneouslesionsappearasbrown,macular,frecklelikeareas,oftenconcentratedaround
themouthoronthehands.(CourtesyofDr.AhmedUthman.)
FIG.1627
The intestinal polyps, generally considered to be hamartomatous growths, are scattered throughout the mucus
producingareasofthegastrointestinaltract.Thejejunumandileumaremostcommonlyaffected.Patientsoftenhave
problemswithintestinalobstructionbecauseofintussusception(telescopingofaproximalsegmentofthebowel
intoadistalportion),aproblemthatusuallybecomesevidentduringthethirddecadeoflife.Mostoftheseepisodes
areselfcorrecting,butsurgicalinterventionissometimesnecessarytopreventischemicnecrosisofthebowel,with
subsequent peritonitis. Gastrointestinal adenocarcinoma develops in a significant percentage of affected patients,
althoughthepolypsthemselvesdonotappeartobepremalignant.Inonelargeseriesofcases,9%ofthepatientshad
developed gastrointestinal malignancy by 40 years of age and 33% by 60 years of age. This compares to 0.1% and
1.0%, respectively, in the general population. Other tumors affecting the pancreas, male and female genital tract,
breast,andovarymayalsodevelop.Inwomen,theriskofdevelopingbreastcancerapproaches50%by60yearsof
age.Theincreasedfrequencyofmalignancyinthesepatientsoverallisestimatedtobeapproximately10to18times
greaterthannormal.
Theorallesionsessentiallyrepresentanextensionoftheperioralfreckling.These1to4mmbrowntobluegray
macules primarily affect the vermilion zone, the labial and buccal mucosa, and the tongue; they are seen in more
than90%ofthesepatients(Fig.1628).Thenumberoflesionsandtheextentofinvolvementcanvarymarkedlyfrom
patienttopatient.Somedegreeoffadingofthepigmentedlesionsmaybenotedduringadolescence.
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FIG.1628
PeutzJeghersSyndrome.Oralmanifestationsincludemultiple,dark,frecklelikelesionsofthelips.(CourtesyofDr.Ahmed
Uthman.)
The gastrointestinal polyps of PeutzJeghers syndrome histopathologically represent benign overgrowths of
intestinalglandularepitheliumsupportedbyacoreofsmoothmuscle.Epithelialatypiaisnotusuallyaprominent
feature,unlikethepolypsofGardnersyndrome(seepage606).
Microscopic evaluation of the pigmented cutaneous lesions shows slight acanthosis of the epithelium with
elongationofthereteridges.Noapparentincreaseinmelanocytenumberisdetectedbyelectronmicroscopy,butthe
dendriticprocessesofthemelanocytesareelongated.Furthermore,themelaninpigmentappearstoberetainedin
themelanocytesratherthanbeingtransferredtoadjacentkeratinocytes.
PatientswithPeutzJegherssyndromeshouldbemonitoredfordevelopmentofintussusceptionortumorformation.
Geneticcounselingisalsoappropriate.
HereditaryHemorrhagicTelangiectasia(OslerWeberRendu
Syndrome)
Hereditary hemorrhagic telangiectasia (HHT) is an uncommon mucocutaneous disorder that is inherited as an
autosomal dominant trait, and epidemiologic studies suggest a prevalence that ranges from 1 in 5,000 to 18,000
people, depending on the geographic region. Mutation of either one of two different genes at two separate loci is
responsibleforthecondition.HHT1iscausedbyamutationoftheendoglin(ENG)geneonchromosome9,whereas
mutation of activin receptorlike kinase1 (ALK1; ACVRL1), a gene located on chromosome 12, produces HHT2. The
proteinsproducedbythesegenesmayplayaroleinbloodvesselwallintegrity.WithbothtypesofHHT,numerous
vascular hamartomas develop, affecting the skin and mucosa; however, other vascular problems, such as
arteriovenous fistulas, may also be seen. Patients affected with HHT1 tend to have more pulmonary and cerebral
involvement,whereasthosewithHHT2generallyhavealateronsetoftheirtelangiectasiasandagreaterdegreeof
hepaticinvolvement.Amuchlesscommonmutation,involvingtheMADH4gene,hasalsobeenidentified,andthese
patients exhibit an overlap syndrome characterized by HHT and juvenile polyposis. The polyps involve both the
upperandlowergastrointestinaltract,andthesepatientshaveanincreasedriskfordevelopingcolorectalcarcinoma
atanearlyage.TheclinicianshouldbefamiliarwithHHTbecausetheorallesionsareoftenthemostdramaticand
mosteasilyidentifiedcomponentofthissyndrome.
ClinicalFeatures
PatientswithHHTareoftendiagnosedinitiallybecauseoffrequentepisodesofepistaxis.Onfurtherexamination,
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thenasalandoropharyngealmucosaeexhibitnumerousscatteredredpapules,1to2mminsize,whichblanchwhen
diascopyisused.Thisblanchingindicatesthattheredcolorisduetobloodcontainedwithinbloodvessels(inthis
case, small collections of dilated capillaries [telangiectasias] that are close to the surface of the mucosa). These
telangiectatic vessels are most frequently found on the vermilion zone of the lips, tongue, and buccal mucosa,
although any oral mucosal site may be affected (Figs. 1629 and 1630). With aging, the telangiectasias tend to
becomemorenumerousandslightlylarger.
HereditaryHemorrhagicTelangiectasia(HHT).Thetongueofthispatientshowsmultipleredpapules,whichrepresent
superficialcollectionsofdilatedcapillaryspaces.
FIG.1629
FIG.1630
HereditaryHemorrhagicTelangiectasia(HHT).Redmaculessimilartothetonguelesionsareobservedonthebuccal
mucosa.
Inmanypatients,telangiectasiasareseenonthehandsandfeet.Thelesionsareoftendistributedthroughoutthe
gastrointestinalmucosa,thegenitourinarymucosa,andtheconjunctivalmucosa.Thegastrointestinaltelangiectasias
have a tendency to rupture, which may cause significant blood loss. Chronic irondeficiency anemia is often a
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problem for such individuals. Significantly, arteriovenous fistulas may develop in the lungs (15% to 45% of HHT
patients),liver(30%),orbrain(10%to20%).Thepulmonaryarteriovenousmalformationsseemtopredisposethese
patientstothedevelopmentofbrainabscessesduetorighttoleftshuntingofbacteriathatmightbeintroducedinto
the bloodstream. In at least one instance, periodontal vascular malformations were felt to be the cause of septic
pulmonaryembolithatresolvedonlyafterseveralteethwithperiodontalabscesseswereextracted.
AdiagnosisofHHTcanbemadeifapatienthasthreeofthefollowingfourcriteria:
1.Recurrentspontaneousepistaxis
2.Telangiectasiasofthemucosaandskin
3.Arteriovenousmalformationinvolvingthelungs,liver,orCNS
4.FamilyhistoryofHHT
In some instances, CREST syndrome (Calcinosis cutis, Raynaud phenomenon, Esophageal dysfunction,
Sclerodactyly, and Telangiectasia) (see page 747) must be considered in the differential diagnosis. In these cases,
serologic studies for anticentromere autoantibodies often help to distinguish between the two conditions because
theseantibodiestypicallywouldbepresentonlyinCRESTsyndrome.
Ifoneofthetelangiectasiasissubmittedforbiopsy,themicroscopicfeaturesessentiallyshowasuperficiallylocated
collectionofthinwalledvascularspacesthatcontainerythrocytes(Fig.1631).
HereditaryHemorrhagicTelangiectasia(HHT).Thislowpowerphotomicrographshowsmultipledilatedvascular
spaceslocatedimmediatelysubjacenttotheepithelium.
FIG.1631
FormildcasesofHHT,notreatmentmayberequired.Moderatecasesmaybemanagedbyselectivecryosurgeryor
electrocauteryofthemostbothersomeofthetelangiectaticvessels.Laserablationofthetelangiectaticlesionshasalso
beenused,althoughthisapproachappearstobemostsuccessfulforpatientswithmildtomoderatedisease.More
severely affected patients, particularly those troubled by repeated episodes of epistaxis, may require a surgical
procedureofthenasalseptum(septaldermoplasty).Theinvolvednasalmucosaisremovedandreplacedbyaskin
graft;however,somelongtermfollowupstudiessuggestthatthegraftseventuallybecomerevascularized,resulting
inrecurrenceoftheproblem.Nasalclosureisanothersurgicaltechniquethathasbeenperformedforpatientswith
severeepistaxisinwhomothermethodshavefailed.
Combined progesterone and estrogen therapy may benefit some patients, but because of the potentially serious
side effects, this should be limited to the most severely affected individuals. Bevacizumab, an antibody directed
against vascular endothelial growth factor, has shown some promise in controlling epistaxis, but this is a costly
medication.Ironreplacementtherapyisindicatedfortheirondeficientpatient,andoccasionallybloodtransfusions
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maybenecessarytocompensateforbloodloss.
Fromadentalstandpoint,someauthorsrecommendtheuseofprophylacticantibioticsbeforedentalprocedures
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
ruledoutbecauseofthe1%prevalenceofbrainabscessesinaffectedindividuals.Researchersbelievethatantibiotic
coverage,similartothatforendocarditisprophylaxis,maypreventthisseriouscomplication.Patientswithahistory
of HHT should be screened for arteriovenous malformations, which can be eliminated by embolization or other
vasodestructive techniques using interventional radiologic methods. The decision to treat such a lesion often
dependsontheanatomicsiteandtheseverityofthemalformation.
The prognosis is generally good, although a 1% to 2% mortality rate is reported from complications related to
bloodloss.Forpatientswithbrainabscesses,themortalityratecanrangeupto10%,evenwithearlydiagnosisand
appropriatetherapy.
EhlersDanlosSyndromes
TheEhlersDanlossyndromes, a group of inherited connective tissue disorders, are relatively heterogeneous. At
least ten types have been described over the years, but recent clinical and molecular evidence suggests that seven
categoriesofthisdiseasemaybemoreappropriate.Thepatientexhibitsproblemsthatareusuallyattributedtothe
productionofabnormalcollagen,theproteinthatisthemainstructuralcomponentoftheconnectivetissue.Because
the production of collagen necessitates many biochemical steps that are controlled by several genes, the potential
existsforanyoneofthesegenestomutate,producingselectivedefectsincollagensynthesis.Thevariousformsof
abnormalcollagenresultinmanyoverlappingclinicalfeaturesforeachofthetypesoftheEhlersDanlossyndrome
(Table161).Thisdiscussionconcentratesonthemostcommonandsignificantformsofthisgroupofconditions.
TABLE161
EhlersDanlosSyndromes
Type
ClinicalFeatures
Inheritance Defect
Classical(severe)
Hyperextensibleskin,easybruising,
hypermobilejoints,papyraceousscarring
ofskin
AD
CollagentypeVmutations
Classical(mild)
Lesssevereclassicalmanifestations
AD
CollagentypeVmutations
Hypermobility
Softskin,noscarring,markedjoint
hyperextensibility
AD
Notknown
Vascular
Severebruising;riskforarterial,bowel,and
uterinerupture
AD
CollagentypeIIImutations
Kyphoscoliosis
Ocularglobefragility,hyperextensibleskin,
hypermobilejoints,scoliosis
AR
Lysylhydroxylasepointmutations
Arthrochalasis
Congenitalhipdislocation,joint
hypermobility,normalscarring,
mandibularhypoplasia
AD
CollagentypeImutations
Dermatosparaxis
Severeskinfragility,saggingskin
AR
Procollagenpeptidasedeficiency
Other(includesXlinked,
periodontal,and
fibronectintypes)
Xlinkedandperiodontalsimilartomild
classictype;fibronectinhasplateletdefect
XLR,AD,
AR
Notknown;possiblecollagentypeI
andIIIdefect;possibledefectin
fibronectin
AD,AutosomaldominantAR,autosomalrecessiveXLR,Xlinkedrecessive.
Typical clinical findings include hypermobility of the joints, easy bruisability, and marked elasticity of the skin.
Someaffectedindividualshaveworkedincircussideshowsastherubbermanandthecontortionistasaresult
oftheirpronouncedjointmobilityandabilitytostretchtheskin.
ClinicalFeatures
The pattern of inheritance and the clinical manifestations vary with the type of EhlersDanlos syndrome being
examined.About80%ofpatientshavetheclassicaltypeineitherthemildorsevereform.ClassicalEhlersDanlos
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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 identified in others, suggesting genetic heterogeneity.
Hyperelasticityoftheskin(Fig.1632) and cutaneous fragility can be observed. An unusual healing response that
oftenoccurswithrelativelyminorinjurytotheskinistermedpapyraceousscarringbecauseitresemblescrumpled
cigarettepaper(Fig.1633).
EhlersDanlosSyndrome.Thehyperelasticityoftheskinisevidentinthispatientaffectedbythemildformofclassical
EhlersDanlossyndrome.
FIG.1632
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EhlersDanlosSyndrome.Scarringthatresemblescrumpledcigarettepaper(papyraceousscarring)isassociatedwith
minimaltraumainpatientswithEhlersDanlossyndromes.Theselesionsinvolvetheskinoftheknee.
FIG.1633
Patients with the hypermobilitytype of EhlersDanlos syndrome exhibit remarkable joint hypermobility but no
evidenceofunusualscarring.
Thevasculartype of EhlersDanlos used to be known as the ecchymotic type because of the extensive bruising
that occurs with everyday trauma. Defects in type III collagen have been identified in this disorder. This form is
inheritedinanautosomaldominantpattern,andayoungpatientmaybemistakenforavictimofchildabuse.The
lifeexpectancyofthesepatientsisoftengreatlyreducedbecauseofthetendencyforaorticaneurysmformationand
rupture.
One rare form of EhlersDanlos syndrome (type VIII) has dental manifestations as a hallmark feature, with
patients showing marked periodontal disease activity at a relatively early age. Although these patients may have
overlapping features with either the classical or vascular forms of the disease, studies of five affected families in
SwedenhavesuggestedthatthisformofEhlersDanlossyndromeislinkedtoaspecificmutationofagenethathas
beenmappedtochromosome12p13.
TheoralmanifestationsofEhlersDanlossyndromeincludetheabilityof50%ofthesepatientstotouchthetipof
theirnosewiththeirtongue(Gorlinsign),afeatthatcan be achieved by less than 10% of the general population.
Someauthorshavenotedeasybruisingandbleedingduringminormanipulationsoftheoralmucosa;othersstate
that oral mucosal friability is present. A tendency for recurrent subluxation of the temporomandibular joint (TMJ)
andthedevelopmentofotherTMJdisordershasalsobeenreported.
Most patients with EhlersDanlos syndrome have normal teeth. A variety of dental abnormalities have been
described,however,includingmalformed,stuntedtoothroots,largepulpstones,andhypoplasticenamel.Although
mostofthesefindingshavenotbeenconsistentlycorrelatedwithanyparticulartypeofthesyndrome,pulpstones
seemtooccurmorecommonlyinpatientsaffectedbyclassicalEhlersDanlossyndrome.
TheprognosisforthepatientwithEhlersDanlossyndromedependsonthetype.Someforms,suchasthevascular
type, can be very serious, with sudden death occurring from rupture of the aorta secondary to the weakened,
abnormalcollagenthatconstitutesthevesselwall.Themildclassicaltypeisgenerallycompatiblewithanormallife
span,althoughaffectedwomenmayhaveproblemswithplacentaltearingandhemorrhageduringgestation.
Accurate diagnosis is important because it affects the prognosis heavily. Similarly, because the various types of
thissyndromeshowavarietyofinheritancepatterns,anaccuratediagnosisisrequiredsothatappropriategenetic
counselingcanbeprovided.
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TuberousSclerosis(EpiloiaBournevillePringleSyndrome)
Tuberous sclerosis is an uncommon syndrome that is classically characterized by intellectual disability, seizure
disorders,andangiofibromasoftheskin.Theconditionisofteninheritedasanautosomaldominanttrait,buttwo
thirdsofthecasesaresporadicandappeartorepresentnewmutations.Thesemutationsinvolveeitheroneoftwo
genes:TSC1 (found on chromosome 9) or, more commonly, TSC2 (found on chromosome 16). Both of these gene
products are believed to contribute to the same intracellular biochemical pathway that seems to have a tumor
suppressorfunction.Themultiplehamartomatousgrowthsthatareseeninthisdisorderarethoughttoarisefrom
disruptionofthenormaltumorsuppressorfunctionofthesegenes.Tuberoussclerosishasawiderangeofclinical
severity,althoughpatientswhohavetheTSC2mutationhaveamoresevereexpressionofthediseasethanpatients
whohavetheTSC1mutation.Milderformsoftuberoussclerosismaybedifficulttodiagnose.
Theprevalenceisatleast1in10,000inthegeneralpopulation,althoughinsomelongtermcarefacilitiestuberous
sclerosis accounts for as high as 1% of the intellectually disabled patients. Nevertheless, average intelligence is
presentinoverhalfoftuberoussclerosispatients.
ClinicalFeatures
Several clinical features characterize tuberous sclerosis. The first of these, facialangiofibromas, used to be called
adenoma sebaceum. Because these lesions are neither adenomas nor sebaceous, the use of that term should be
discontinued. Facial angiofibromas appear as multiple, smoothsurfaced papules and occur primarily in the
nasolabial fold area (Fig.1634).Similarlesions,calledungual or periungualfibromas, are seen around or under the
marginsofthenails(Fig.1635).
FIG.1634
TuberousSclerosis.Patientstypicallyhavemultiplepapularfaciallesionsthatmicroscopicallyareangiofibromas.
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FIG.1635
TuberousSclerosis.Examinationofthefingersoftenshowsperiungualfibromas.
Twoothercharacteristicskinlesionsareconnectivetissuehamartomascalledshagreenpatchesandovoidareasof
hypopigmentationcalledashleafspots.Eventhoughapproximately5%ofthegeneralpopulationmayhaveanash
leaf spot, studies have reported that 90% to 98% of children with tuberous sclerosis display these lesions. The
shagreenpatches,sonamedbecauseoftheirresemblancetosharkskinderivedshagreencloth,affecttheskinofthe
trunk.TheashleafspotsmayappearonanycutaneoussurfaceandmaybebestvisualizedusingUV(Woodslamp)
illumination.
CNS manifestations include seizure disorders in 70% to 80% of affected patients and intellectual disability in
approximately 30%. In addition, hamartomatous proliferations in the CNS develop into the potatolike growths
(tubers)seenatautopsy,fromwhichthetermtuberoussclerosisisderived(Fig.1636). The tuberous hamartomas
canbestbevisualizedusingT2weightedmagneticresonanceimaging(MRI)andarepresentin80%to95%ofthese
patients.Also,approximately10%oftuberoussclerosispatientswilldevelopatypeofbenignbraintumorknownas
subependymalgiantcellastrocytoma.
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TuberousSclerosis.Patchycalcifications(arrows)associatedwithintracranialhamartomaformationareseenonthis
lateralskullradiograph.(CourtesyofDr.RegMunden.)
FIG.1636
A relatively rare tumor of the heart muscle, called cardiacrhabdomyoma, is also typically associated with this
syndrome. This lesion, which probably represents a hamartoma rather than a true neoplasm, occurs in
approximately 30% to 50% of affected patients and is typically identified in early childhood. Problems with
myocardial function may develop as a result of this process, but many of these tumors undergo spontaneous
regression.
Anotherhamartomatoustypeofgrowthrelatedtothisdisorderistheangiomyolipoma.Thisisabenignneoplasm
composed of vascular smooth muscle and adipose tissue and occurs primarily in the kidney, typically bilaterally.
Even though the angiomyolipoma is benign, the tumors are often associated with large dilated blood vessels, and
significantclinicalproblemscanariseifthesevesselsrupturespontaneously.
Oralmanifestationsoftuberoussclerosisincludedevelopmentalenamelpittingonthefacialaspectoftheanterior
permanent dentition in 50% to 100% of patients. These pits are more readily appreciated after applying a dental
plaquedisclosingsolutiontotheteeth.Multiplefibrouspapulesaffect11%to56%ofpatients.Thefibrouspapules
areseenpredominantlyontheanteriorgingivalmucosa(Fig.1637), although the lips, buccal mucosa, palate, and
tonguemaybeinvolved.Diffusefibrousgingivalenlargementisreportedinaffectedpatientseventhosewhoare
not taking phenytoin; however, most cases of gingival hyperplasia in these individuals are probably related to
medication taken to control seizures. Some patients with tuberous sclerosis may also exhibit radiolucencies of the
jawsthatrepresentdensefibrousconnectivetissueproliferations(Fig.1638).
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TuberousSclerosis.Patientsoftenexhibitgingivalhyperplasia,whichmaybesecondarytophenytoinmedications
usedtocontrolseizuresinsomecases.Fibrouspapulesofthegingiva(arrows)mayalsobepresent.
FIG.1637
TuberousSclerosis.Periapicalradiographexhibitingawelldefinedradiolucencyapicaltothemaxillaryleftlateral
incisor.Biopsyrevealedanintraosseousfibrousproliferation.
FIG.1638
Thediagnosisoftuberoussclerosiscanbebasedonfindingatleasttwoofthefollowingmajorfeatures:
Facialangiofibromas
Ungualorperiungualfibromas
Hypomelanoticmacules(threeormore)
Shagreenpatch
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CNShamartomas
Subependymalgiantcellastrocytoma
Cardiacrhabdomyoma
Renalangiomyolipoma
Multipleretinalnodularhamartomas
Thepresenceofonemajorandtwominorfeaturesmayalsoconfirmthediagnosis.Theminorfeaturesincludethe
following:
Multiple,randomlydistributedenamelpits
Gingivalfibromas
Bonecysts(actuallyfibrousproliferations)
Multiplerenalcysts
Hamartomatousrectalpolyps
Microscopic examination of the fibrous papules of the oral mucosa or the enlarged gingivae shows a nonspecific
fibroushyperplasia.Similarly,theradiolucentjawlesionsconsistofdensefibrousconnectivetissuethatresembles
desmoplastic fibroma or the simple type of central odontogenic fibroma. The angiofibroma of the skin is a benign
aggregation of delicate fibrous connective tissue characterized by plump, uniformly spaced fibroblasts with
numerousinterspersedthinwalledvascularchannels.
For patients with tuberous sclerosis, most of the treatment is directed toward the management of the seizure
disorder with anticonvulsant agents. Periodic MRI of the head may be done to screen for intracranial lesions,
whereas ultrasound evaluation is performed for evaluation of kidney involvement. Intellectually disabled patients
mayhaveproblemswithoralhygieneprocedures,andpoororalhygienecontributestophenytoininducedgingival
hyperplasia. Recent studies examining medications (such as, everolimus) that block the metabolic pathway that
causes tuberous sclerosis have shown significant shrinkage of several tumor types associated with this disorder,
includingrenalangiomyolipoma,facialangiofibroma,andsubependymalgiantcellastrocytoma.Patientsaffectedby
tuberous sclerosis have a slightly reduced life span compared with the general population, with death usually
relatedtoCNSorkidneydisease.Geneticcounselingisalsoappropriateforaffectedpatients,andgenetictestingis
availableforbothTSC1andTSC2mutationsifprenatalorpreimplantationfamilyplanningisdesired.
MultipleHamartomaSyndrome(CowdenSyndromePTEN
HamartomaTumorSyndrome)
Multiplehamartomasyndromeisarareconditionthathasimportantimplicationsfortheaffectedpatient,because
malignancies,inadditiontothebenignhamartomatousgrowths,developinahighpercentageoftheseindividuals.
Usually,thesyndromeisinheritedasanautosomaldominanttraitshowingahighdegreeofpenetranceandarange
ofexpressivity.Thegeneresponsibleforthisdisorderhasbeenmappedtochromosome10,andamutationofthe
phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene has been implicated in its pathogenesis. The
estimatedprevalenceofthisconditionisapproximately1in200,000,andmorethan300affectedpatientshavebeen
described in the literature. In recent years, overlapping clinical features of multiple hamartoma syndrome with
LhermitteDuclos disease, BannayanRileyRuvalcaba syndrome, and Proteuslike syndrome have been noted,
andallofthesedisordershavedemonstratedmutationsofthePTENgene.
ClinicalFeatures
Cutaneousmanifestationsarepresentinalmostallpatientswithmultiplehamartomasyndrome,usuallydeveloping
duringtheseconddecadeoflife.Themajorityoftheskinlesionsappearasmultiple,small(lessthan1mm)papules,
primarilyonthefacialskin,especiallyaroundthemouth,nose,andears(Fig.1639).Microscopically,mostofthese
papules represent hair follicle hamartomas called trichilemmomas. Other commonly noted skin lesions are acral
keratosis,awartyappearinggrowththatdevelopsonthedorsalsurfaceofthehand,andpalmoplantarkeratosis,a
prominent calluslike lesion on the palms or soles. Cutaneous hemangiomas,neuromas,xanthomas, and lipomas
havealsobeendescribed.
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MultipleHamartomaSyndrome.Thesetinycutaneousfacialpapulesrepresenthairfolliclehamartomas
(trichilemmomas).
FIG.1639
Otherproblemscanappearinthesepatientsaswell.Thyroiddiseaseusuallyappearsaseitheragoiterorathyroid
adenoma, but papillary or follicular adenocarcinoma may develop. In one large series, thyroid malignancy was
identifiedin14%ofpatientswiththiscondition.Inwomen,fibrocysticdiseaseofthebreastisfrequentlyobserved.
Unfortunately,breastcanceroccurswitharelativelyhighfrequency(25%to50%)inthesepatients.Themeanageat
diagnosisofbreastmalignancyis40years,whichismuchyoungerthanusual.Inthegastrointestinaltract,multiple
benign hamartomatous polyps may be present. In addition, several types of benign and malignant tumors of the
femalegenitourinarytractoccurmoreoftenthaninthenormalpopulation.
The oral lesions vary in severity from patient to patient and usually consist of multiple papules affecting the
gingivae,dorsaltongue,andbuccalmucosa(Figs.1640and1641).Theselesionshavebeenreportedinmorethan
80% of affected patients and generally produce no symptoms. Other possible oral findings include a higharched
palate, periodontitis, and extensive dental caries, although it is unclear whether the latter two conditions are
significantlyrelatedtothesyndrome.
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FIG.1640
MultipleHamartomaSyndrome.Multiple,irregularfibroepithelialpapulesinvolvethetongue(center)andalveolarridge
mucosa.
FIG.1641
MultipleHamartomaSyndrome.Multiplepapulesontheleftbuccalmucosa.
The histopathologic features of the oral lesions are rather nonspecific, essentially representing fibroepithelial
hyperplasia. Other lesions associated with this syndrome have their own characteristic histopathologic findings,
dependingonthehamartomatousorneoplastictissueorigin.
Diagnosis
Thediagnosiscanbebasedonthefindingoftwoofthefollowingthreepathognomonicsigns:
1.Multiplefacialtrichilemmomas
2.Multipleoralpapules
3.Acralkeratoses
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A variety of other major and minor diagnostic criteria, as well as a positive family history, are also helpful in
confirmingthediagnosis.GenetictestingformutationsofthePTENgeneareclinicallyavailable,but20%ofpatients
who otherwise have characteristic multiple hamartoma syndrome will not demonstrate a genetic abnormality;
therefore,anegativetestdoesnotnecessarilyprecludethediagnosisofmultiplehamartomasyndrome.
Treatmentofmultiplehamartomasyndromeiscontroversial.Althoughmostofthetumorsthatdeveloparebenign,
the prevalence of malignancy is higher than in the general population; therefore, annual physical examinations
should be performed that focus specifically on anatomic sites of increased tumor prevalence, particularly breast,
uterus,andthyroid.Someinvestigatorsrecommendbilateralprophylacticmastectomiesasearlyasthethirddecade
oflifeforfemalepatientsbecauseoftheassociatedincreasedriskofbreastcancer.
EpidermolysisBullosa
Thetermepidermolysisbullosadescribesaheterogeneousgroupofinheritedblisteringmucocutaneousdisorders.
Each has a specific defect in the attachment mechanisms of the epithelial cells, either to each other or to the
underlying connective tissue. Recent advances in the understanding of the clinical features, epidemiology,
immunofluorescencemapping,andmoleculargeneticabnormalitiesoftheseconditionshaveledtotheidentification
of approximately 34 different forms. Depending on the defective mechanism of cellular cohesion, there are four
broadcategories:
1.Simplex
2.Junctional
3.Dystrophic
4.Kindlersyndrome
Eachcategoryconsistsofseveralformsofthedisorder.Avarietyofinheritancepatternsmaybeseen,depending
ontheparticularform.Thedegreeofseveritycanrangefromrelativelymild,annoyingforms,suchasthesimplex
types,throughaspectrumthatincludessevere,fataldisease.Forexample,manycasesofjunctionalepidermolysis
bullosa result in death at birth because of the significant sloughing of the skin during passage through the birth
canal.Specificmutationsinthegenesencodingkeratin5andkeratin14havebeenidentifiedasbeingresponsiblefor
most of the simplex types, whereas mutations in the genetic codes of laminin332, type XVII collagen, or 64
integrinhavebeendocumentedforthejunctionaltypes.Mostofthedystrophictypesarecausedbymutationsin
thegenesresponsiblefortypeVIIcollagenproduction,withover300distinctlydifferentmutationsidentifiedtodate.
Kindlersyndromeisthemostrecentlycharacterizedpatternofthisgroupofdisorders,andmutationsofthegene
thatencodesforahemidesmosomalattachmentprotein,kindlin1,areresponsibleforthisrarecondition.
AfewrepresentativeexamplesofthetypesofepidermolysisbullosaaresummarizedinTable162.Becauseoral
lesions are most commonly observed in the dystrophic forms, this discussion centers on these forms. Dental
abnormalities,suchasanodontia,enamelhypoplasia,pittingoftheenamel,neonatalteeth,severeperiodontitis,and
severe dental caries, have been variably associated with several of the different types of epidermolysis bullosa,
althoughstudieshavesuggestedthattheprevalenceofdentalabnormalitiesissignificantlyincreasedonlywiththe
junctional type. A disorder termed epidermolysis bullosa acquisita is mentioned because of the similarity of its
name;however,thisisanunrelatedcondition,havinganautoimmune(ratherthanagenetic)origin(seepage721).
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TABLE162
ExamplesofEpidermolysisBullosa
Form
Inheritance ClinicalFeatures
Defect
EBsimplex
AD
Blisteringofthehandsandfeet;mucosalinvolvementuncommon;
blistershealwithoutscarring;prognosisusuallygood
Keratingenedefects
JunctionalEB,
generalizedgravis
variant
AR
Severeblisteringatbirth;granulationtissuearoundthemouth;oral
erosionscommon;pittedenamelhypoplasia;oftenfatal
(previouslycalledEBletalis)
Defectsof
hemidesmosomes
Dominant,dystrophic
EB,Pasinitype
AD
Generalizedblistering,whitepapules
DefectintypeVII
collagen
Dominant,dystrophic
EB,Cockayne
Tourainetype
AD
Extremitiesprimarilyaffected
DefectintypeVII
collagen
Recessive,dystrophic
EB,generalized
gravistype
AR
Severemucosalinvolvement;mittenlikescarring;deformitiesof
handsandfeet;patientsusuallydonotsurvivepastearly
adulthood
DefectintypeVII
collagen
Recessive,dystrophic
EB,inversetype
AR
Involvementofgroinandaxilla;severeoralandesophageallesions
DefectintypeVII
collagen
EB,EpidermolysisbullosaAD,autosomaldominantAR,autosomalrecessive.
ClinicalFeatures
DominantDystrophicTypes
Thedystrophicformsofepidermolysisbullosathatareinheritedinanautosomaldominantfashionarenotusually
lifethreatening,althoughtheymaycertainlybedisfiguringandposemanyproblems.Theinitiallesionsarevesicles
or bullae, which are seen early in life and develop on areas exposed to lowgrade, chronic trauma, such as the
knuckles or knees (Fig. 1642). The bullae rupture, resulting in erosions or ulcerations that ultimately heal with
scarring.Intheprocess,appendagessuchasfingernailsmaybelost.
EpidermolysisBullosa.Ayounggirl,affectedbythedominantdystrophicformofepidermolysisbullosa,showsthe
characteristichemorrhagicbullae,scarring,anderosionassociatedwithminimaltraumatothehands.
FIG.1642
Theoralmanifestationsaretypicallymild,withsomegingivalerythemaandtenderness.Gingivalrecessionand
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reductioninthedepthofthebuccalvestibulemaybeobserved(Fig.1643).
EpidermolysisBullosa.Ateenagedboy,affectedbydominantdystrophicepidermolysisbullosa,showsareduced
depthofthelabialvestibulecausedbyrepeatedmucosaltearingandhealingwithscarring.
FIG.1643
RecessiveDystrophicTypes
Generalizedrecessivedystrophicepidermolysisbullosarepresentsoneofthemoredebilitatingformsofthedisease.
Vesicles and bullae form with even minor trauma. Secondary infections are often a problem because of the large
surfaceareasthatmaybeinvolved.Ifthepatientmanagestosurviveintotheseconddecade,thenhandfunctionis
often greatly diminished because of the repeated episodes of cutaneous breakdown and healing with scarring,
resultinginfusionofthefingersintoamittenlikedeformity(Fig.1644).
EpidermolysisBullosa.A19yearoldman,affectedbyrecessivedystrophicepidermolysisbullosa,showsthetypical
mittenlikedeformityofthehandcausedbyscarringofthetissueafterdamageassociatedwithnormalactivity.
FIG.1644
Theoralproblemsarenolesssevere.Bullaandvesicleformationisinducedbyvirtuallyanyfoodhavingsome
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degreeoftexture.Evenwithasoftdiet,therepeatedcyclesofscarringoftenresultinmicrostomia(Fig.1645)and
ankyloglossia.Similarmucosalinjuryandscarringmaycauseseverestrictureoftheesophagus.Becauseasoftdietis
usuallyhighlycariogenic,cariousdestructionofthedentitionatanearlyageiscommon.
EpidermolysisBullosa.SamepatientasdepictedinFig.1644.Microstomiahasbeencausedbyrepeatedtraumaand
healingwithscarring.Notetheseveredentalcariesactivityassociatedwithasoftcariogenicdiet.
FIG.1645
Thehistopathologicfeaturesofepidermolysisbullosavarywiththetypebeingexamined.Thesimplexformshows
intraepithelial clefting by light microscopy. Junctional,dystrophic, and Kindler forms show subepithelial clefting
(Fig. 1646). Electron microscopic examination reveals clefting at the level of the lamina lucida of the basement
membraneinthejunctionalformsandbelowthelaminadensaofthebasementmembraneinthedystrophicforms.
In contrast, the Kindler form shows clefting just below the basal cell layer, at its interface with the lamina lucida.
Immunohistochemical evaluation of perilesional tissue is now typically used to identify specific defects to classify
and subtype the condition further. Molecular genetic analysis may also be helpful for confirming the diagnosis in
someinstances.
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EpidermolysisBullosa.Completeseparationoftheepitheliumfromtheconnectivetissueisseeninthis
photomicrographofatissuesectionobtainedfromapatientaffectedbyajunctionalformofepidermolysisbullosa.
FIG.1646
Treatmentofepidermolysisbullosavarieswiththetype.Formildercases,notreatmentotherthanlocalwoundcare
may be needed. Sterile drainage of larger blisters and the use of topical antibiotics are often indicated in these
situations. For the more severe cases, intensive management with oral antibiotics may be necessary if cellulitis
develops;despiteintensivemedicalcare,somepatientsdieasaresultofinfectiouscomplications.
The mitten deformity of the hands, seen in recessive dystrophic epidermolysis bullosa, can be corrected with
plasticsurgery,buttheproblemusuallyrecursafteraperiodoftime,andsurgicalinterventionisrequiredevery2
yearsonaverage.Withesophagealinvolvement,dysphagiamaybeasignificantproblem,resultinginmalnutrition
andweightloss.Placementofagastrostomytubemaybenecessaryattimes.Patientswiththerecessivedystrophic
formsarealsopredisposedtodevelopmentofcutaneoussquamouscellcarcinoma.Thismalignancyoftendevelops
inareasofchroniculcerationduringthesecondthroughthirddecadesoflifeandrepresentsasignificantcauseof
death for these patients. Infrequently, the lingual mucosa of affected patients has been reported to undergo
malignanttransformationaswell.
Managementoftheoralmanifestationsalsodependsonthetypeofthedisease.Forpatientswhoaresusceptibleto
mucosal bulla formation, dental manipulation should be kept to a minimum. To achieve this, topical 1% neutral
sodiumfluoridesolutionshouldbeadministereddailytopreventdentalcaries.Asoftdietthatisasnoncariogenicas
possible,aswellasatraumaticoralhygieneprocedures,shouldbeencouraged.Maintainingadequatenutritionfor
affectedpatientsiscriticaltoensureoptimalwoundhealing.Endosseousdentalimplants,followedbyfixeddental
prostheses,havebeensuccessfullyplacedinsomepatientswithrecessivedystrophicepidermolysisbullosa.
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
extensivedentalcare,endotrachealanesthesiamaybeperformedwithoutsignificantproblemsinmostcases.
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.
ImmuneMediatedDiseasesandTheirEvaluation
Severalconditionsdiscussedinthischapteraretheresultofinappropriateproductionofantibodiesbythepatient
(autoantibodies).Theseautoantibodiesaredirectedagainstvariousconstituentsofthemolecularapparatusthathold
epithelialcellstogetherorthatbindthesurfaceepitheliumtotheunderlyingconnectivetissue.Theensuingdamage
producedbytheinteractionoftheseautoantibodieswiththehosttissueisseenclinicallyasadiseaseprocess,often
termed an immunobullous disease. Because each disease is characterized by production of specific types of
autoantibodies, identification of the antibodies and the tissues against which they are targeted is important
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partofthisbookmaybereproducedortransmiedwithoutpublisherspriorpermission.
17
OralManifestationsofSystemic
Diseases
Mucopolysaccharidosis
The mucopolysaccharidoses are a heterogeneous group of metabolic disorders that are usually inherited in an
autosomalrecessivefashion.Thesedisordersareallcharacterizedbythelackofanyoneofseveralnormalenzymes
neededtoprocesstheimportantintercellularsubstancesknownasglycosaminoglycans.Thesesubstancesusedtobe
known as mucopolysaccharides, thus the term mucopolysaccharidosis. Examples of glycosaminoglycans include the
following:
Heparansulfate
Dermatansulfate
Keratansulfate
Chondroitinsulfate
Thetypeofmucopolysaccharidosisthatisseenclinicallydependsonwhichofthesesubstrateslacksitsparticular
enzyme.Themucopolysaccharidosesasagroupoccurwithafrequencyofapproximately1in15,000to29,000live
births,althoughsometypesaremuchlesscommon.
The clinical features of the mucopolysaccharidoses vary, depending on the particular syndrome that is examined
(Table 171). Furthermore, aected patients with a particular type of this disorder often exhibit a wide range of
severity of involvement. Most types of mucopolysaccharidosis are associated with some degree of intellectual
disability.Oftenthefacialfeaturesofaectedpatientsaresomewhatcoarse,withheavybrowridges(Fig.171),and
thereareotherskeletalchanges,suchasstijoints.Cloudydegenerationofthecorneas,aproblemthatfrequently
leadstoblindness,isseeninseveralformsofmucopolysaccharidosis.
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TABLE171
FeaturesofSelectedMucopolysaccharidosisSyndromes
Inheritance EnzymeDeciency
Stored
ClinicalFeatures
Substrate
Type
Eponym
IH
Hurler
AR
LIduronidase
HSandDS
Appearsininfancy;cloudycorneas,growth
impairment,reducedintelligence,coronary
arterydisease;rarelylive10years
IS
Scheie
AR
LIduronidase
HSandDS
Onsetinlatechildhood;cloudycorneas,normal
intelligence,aorticregurgitation;surviveto
adulthood
II
Hunter
XlinkedR
Iduronate2sulfatase
HSandDS
Appearsat1to2yearsofage;clearcorneas,
reducedintelligence,growthimpairment,sti
joints
IIIA
SanlippoA
AR
HeparanNsulphatase
HS
Appearsat4to6yearsofage;clearcorneas,
reducedintelligence,mildskeletalchanges;
deathinadolescence
IIIB
SanlippoB
AR
N
HS
acetylglucosaminidase
GenerallysameasSanlippoA
IVA
MorquioA
AR
Galactose6sulfatase
KSandCS
Appearsat1to2yearsofage;cloudycorneas,
normalintelligence,laxjoints;maysurviveto
middleage
IVB
MorquioB
AR
galactosidase
KS
GenerallysimilartoMorquioA
VI
Maroteaux
Lamy
AR
ArylsulphataseB
DSandCS
Appearsat2to6yearsofage;cloudycorneas,
normalintelligence,growthimpairment,sti
joints;maysurvivetoadulthood
AR,AutosomalrecessiveCS,chondroitinsulfateDS,dermatansulfateHS,heparansulfateKS,keratansulfateR,recessive
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FIG.171
Mucopolysaccharidosis.ThispatientaffectedbyHuntersyndromeexhibitsthecharacteristicfacialfeaturesofthis
disorder.
The oral manifestations vary according to the particular type of mucopolysaccharidosis. Most types show some
degreeofmacroglossia.Gingivalhyperplasiamaybepresent,particularlyintheanteriorregions,asaresultofthe
dryingandirritatingeectsofmouthbreathing.Thedentalchangesincludethinenamelwithpointedcuspsonthe
posterior teeth, although this seems to be a feature unique to mucopolysaccharidosis type IVA. Other dental
manifestationsincludenumerousimpactedteethwithprominentfollicularspaces(Fig.172),possiblycausedbythe
accumulation of glycosaminoglycans in the follicular connective tissue. Some investigators have reported the
occurrence of multiple impacted teeth that are congregated in a single large follicle, forming a rosee paern
radiographically.
Mucopolysaccharidosis.RadiographicexaminationofthedentitionofachildaffectedbyHuntersyndrometypically
showsradiolucencies(arrows)associatedwiththecrownsofuneruptedteeth.
FIG.172
Although the clinical ndings may suggest that a patient is aected by one of the mucopolysaccharidoses, the
diagnosisisconrmedbyndingelevatedlevelsofglycosaminoglycansintheurine,aswellasdecienciesofthe
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specicenzymesinthepatientsleukocytesandbroblasts.
No satisfactory systemic treatment of the mucopolysaccharidoses exists at this time. Several forms of
mucopolysaccharidosisareassociatedwithamarkedlyreducedlifespanandwithintellectualdisability.Aemptsto
improvethesurvivalandqualityoflifeofthesepatientsusinghematopoieticstemcelltransplantationhavemetwith
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
replacementtherapycurrentlyisavailableformucopolysaccharidosistypesI,II,andVI.Initiationoftherespective
recombinanthumanenzymeslaronidase,idursulfase,andgalsulfaseearlyinthepatientslifeappearstoimprove
signicantlymanyoftheaspectsofthedisease,althoughcompleteresolutiondoesnotoccur.Becauseoftherarityof
these conditions and the expense of developing the treatments, the annual cost for such therapy can range from
$176,000 for laronidase to $657,000 for idursulfase, which currently has the dubious distinction of being the most
expensiveprescriptionmedication.Geneticcounselingisindicatedfortheparentsandsiblingsofapatientaected
byoneofthemucopolysaccharidosissyndromes.Prenataldiagnosisisavailableforfamilyplanningaswell.
Management of the dental problems of these patients is essentially no dierent from that of other patients.
However,severalfactorsmayhavetobetakenintoaccount:
Degreeofintellectualdisability(ifany)
Presenceorabsenceofaseizuredisorder
Degreeofjointstiening
Extentofotherrelatedmedicalproblems
Dependingonwhichofthesefactorsispresentandtheextentofinvolvement,dentalcaremaywarrantsedation,
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 aected patients, general anesthesia probably should be considered only in lifethreatening
situations.
LipidReticuloendothelioses
The lipid reticuloendothelioses are a relatively rare group of inherited disorders. These include the following
conditions:
Gaucherdisease
NiemannPickdisease
TaySachsdisease
TheseconditionsareseenwithincreasedfrequencyinpatientswithAshkenaziJewishheritage.Aectedpatients
lack certain enzymes necessary for processing specic lipids; this results in an accumulation of the lipids within a
variety of cells. Because of this accumulation, it appeared that cells were aempting to store these substances;
therefore,thetermstoragediseasewascommonlyusedforthesedisorders.
InGaucherdisease (the most common of the reticuloendothelioses), a lack of glucocerebrosidase results in the
accumulation of glucosylceramide, particularly within the lysosomes of cells of the macrophage and monocyte
lineage. Three types of Gaucher disease are now recognized: type 1 (nonneuronopathic) is seen primarily in the
AshkenaziJewishpopulation,andtypes2and3(neuronopathic)haveapanethnicdistribution.
NiemannPickdiseaseischaracterizedbyadeciencyofacidsphingomyelinase,resultingintheaccumulationof
sphingomyelin,alsowithinthelysosomesofmacrophages.
TaySachsdiseaseiscausedbyalackofhexosaminidaseA,whichresultsintheaccumulationofaganglioside,
principallywithinthelysosomesofneurons.
All these disorders are inherited as autosomal recessive traits. The genetic mutation known to cause Gaucher
diseasehasbeenevaluatedfortheAshkenaziJewishpopulation,andapproximately1in12to17personscarrythe
defective gene. Most of the individuals identied as having the gene, however, were heterozygous and, therefore,
asymptomatic.
GaucherDisease
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The clinical features of Gaucher disease are generally the result of the eects of the abnormal storage of
glucosylceramide. Macrophages laden with this glucocerebroside are typically rendered relatively nonfunctional,
and they tend to accumulate within the liver, spleen, and bone marrow of the aected patient. Bone marrow
accumulation displaces the normal hematopoietic cells and produces anemia and thrombocytopenia. In addition,
these patients are susceptible to bone infarctions. The resulting bone pain is often the presenting complaint.
Characteristic Erlenmeyer ask deformities of the long bones, particularly of the femur, are often identied.
Accumulations of the macrophages in the spleen and liver result in visceral enlargement. Many aected patients
showasignicantdegreeofgrowthimpairment.Neurologicdeteriorationoccursinpatientswiththelesscommon
types 2 and 3 Gaucher disease. Jaw lesions typically appear as illdened radiolucencies that usually aect the
mandible, producing thinning of the cortical bone without causing devitalization of the teeth or signicant
resorption of the lamina dura. The walls of the mandibular canal may also be obliterated by the disease process.
Decreased salivary ow has been documented for patients with Gaucher disease compared with an age and sex
matchedpopulation,althoughthisdecreasemaynotbeclinicallyimportant.
NiemannPickDisease
NiemannPick disease occurs as three dierent types, each associated with a dierent clinical expression and
prognosis. Types A and B are caused by a deciency of acid sphingomyelinase, whereas type C is primarily the
result of mutations of either NPC1 or NPC2, genes involved with cholesterol processing. Types A and C have
neuronopathicfeatures,characterizedbypsychomotorimpairment,dementia,spasticity,andhepatosplenomegaly,
withdeathoccurringduringtherstorseconddecadeoflife.TypeBpatientsnormallysurviveintoadulthoodand
exhibitvisceralsigns,primarilyhepatosplenomegaly,andsometimespulmonaryinvolvement.
TaySachsDisease
TaySachsdiseasemayhaveawideclinicalrangebecausetheconditionisgeneticallyheterogeneous.Someformsare
mild, with patients surviving into adulthood. In the severe infantile form, however, rapidly progressive neuronal
degenerationdevelopsshortlyafterbirth.Signsandsymptomsincludeblindness,developmentalimpairment,and
intractableseizures.Deathusuallyoccursby3to5yearsofage.
HistopathologicexaminationofanosseouslesionofGaucherdiseaseshowssheetsoflipidengorgedmacrophages
(Gaucher cells) exhibiting abundant bluish cytoplasm, which has a ne texture resembling wrinkled silk. In
NiemannPick disease, the characteristic cell seen on examination of a bone marrow aspirate is the sea blue
histiocyte.
GaucherDisease
ForpatientswithamildexpressionofGaucherdisease,notreatmentmaybenecessary.Formoresevereformsof
Gaucherdisease,enzymereplacementtherapywithoneofthemacrophagetargetedglucocerebrosidases,including
imiglucerase, velaglucerase alfa, and taliglucerase alfa, is used. All of these medications require intravenous (IV)
infusionandarequiteexpensive,oftencostingmorethan$150,000peryearfortreatment.After9to12monthsof
therapy, patients exhibit improvement in the status of their anemia, a decrease in plasma glucocerebroside levels,
and a decrease in hepatosplenomegaly. Resolution of the radiographic bone changes takes place over a longer
period.Childrentreatedwiththisregimenmayshowsignicantgaininheight.Unfortunatelyenzymereplacement
therapy has shown minimal eect on the neuronopathic Gaucher disease types 2 and 3, primarily because the
medicationcannotcrossthebloodbrainbarrier.Bonemarrowtransplantationhasalsobeenaempted;however,the
problemsinherentingraftversushostdisease(GVHD)arestillpresentwiththatformoftherapy,andthusitisnot
recommended.AcasecontrolstudyshowedthatadultswithGaucherdiseasehaveanincreasedriskforhematologic
malignancies,particularlylymphomaandmultiplemyeloma.Geneticcounselingshouldbeprovidedtoallaected
patients.
NiemannPickandTaySachsDisease
TheneuronopathicformsofNiemannPickdiseaseandtheinfantileformofTaySachsdiseaseareassociatedwitha
poorprognosis.Geneticcounselingshouldbeprovidedforaectedfamilies.Molecularmarkersofthesedisorders
havebeendevelopedtoidentifycarriers.Suchidenticationallowsearlierinterventionintermsofcounseling,and
targeted population screening for the gene that causes TaySachs disease has resulted in a marked decrease in
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aectedpatientsduringthepastthreedecades.
LipoidProteinosis(HyalinosisCutisEtMucosaeUrbachWiethe
Syndrome)
Ararecondition,lipoidproteinosisisinheritedasanautosomalrecessivetrait.Itischaracterizedbythedeposition
of a waxy material in the dermis and submucosal connective tissue of aected patients. The earliest thorough
description of lipoid proteinosis was by Urbach and Wiethe in 1929, and more than 300 patients, most being of
European background, have been reported to date. Mutations of the ECM1 gene, which encodes a glycoprotein
knownasextracellularmatrixprotein1,havebeenidentiedasthecauseforthiscondition.
ClinicalFeatures
Thelaryngealmucosaandvocalcordsareusuallythesitesthatareinitiallyaectedbylipoidproteinosis.Therefore,
therstsignofthediseasemaybeoneofthefollowing:
Aninabilityoftheinfanttomakeacryingsound
Ahoarsecryininfancy
Thedevelopmentofahoarsevoiceduringearlychildhood
The vocal cords become thickened as the accumulation of an amorphous material begins to aect the laryngeal
mucosa.Thisinltrativemucosalprocessmayalsoinvolvethepharynx,esophagus,tonsils,vulva,andrectum.Skin
lesions also develop early in life, appearing as thickened, yellowish, waxy papules; plaques; or nodules that often
aecttheface,particularlythelipsandthemarginsoftheeyelids(Fig.173).Somelesionsmaybeginasdarkcrusted
vesiclesthathealasatrophichyperpigmentedpatches.
FIG.173
LipoidProteinosis.Thickenedpapulesarepresentalongthemarginoftheeyelid.(CourtesyofDr.MariaCopete.)
Eventually,mostpatientsexhibitathickened,furrowedappearanceoftheskin.Otherareasoftheskinthatmaybe
involved include the neck, palms, axillae, elbows, scrotum, knees, and digits. In those areas subjected to chronic
trauma,ahyperkeratotic,verrucoussurfaceoftendevelops.Inadditiontothecutaneousmanifestations,symmetrical
intracranial calcications of the medial temporal lobes have been identied in approximately 70% of aected
patients.Theselesionsareusuallyasymptomatic,althoughafewpatientswithsuchcalcicationshavebeenreported
tohaveaseizuredisorder.
Theoralmucosalabnormalitiestypicallybecomeevidentintheseconddecadeoflife.Thetongue,labialmucosa,
and buccal mucosa become nodular, diusely enlarged, and thickened because of inltration with waxy, yellow
whiteplaquesandnodules(Fig.174).Thedorsaltonguepapillaeareeventuallydestroyed,andthetonguedevelops
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asmoothsurface.Theaccumulationoftheamorphousmaterialwithinthetonguemayresultinitsbeingboundto
theoorofthemouth.Therefore,thepatientmaynotbeabletoprotrudethetongue.Gingivalenlargementappears
tobeaninfrequentnding.
FIG.174
LipoidProteinosis.Theupperlabialmucosaexhibitsyellowwhite,nodularthickening.(CourtesyofDr.MariaCopete.)
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 periodic
acidSchi(PAS)methodandisnotdigestedbydiastase.Thelocationofthismaterial,itsstainingproperties,andthe
presenceofincreasedlaminin,typeIVcollagen,andtypeVcollagensuggestabasementmembraneorigin.
Abiopsyspecimenofalesioninitslaterstagesusuallyshowsnotonlythelamellarmaterialbutalsodepositionof
anamorphoussubstancewithinthedermalconnectivetissue(Fig.175).
LipoidProteinosis.A,Thismediumpowerphotomicrographshowsperivasculardepositionofalamellar,acellular
material.B,TheperiodicacidSchiff(PAS)methodisusedtostainandhighlighttheperivasculardeposits.(CourtesyofDr.MariaCopete.)
FIG.175
Generally,nospecictreatmentisavailableforlipoidproteinosisotherthangeneticcounseling.Inrareinstances,the
inltrationofthelaryngealmucosamayproducedicultbreathingforsomeinfants,inwhichcasedebulkingofthe
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mucosallesionsmaybenecessary.Mostpatientswithlipoidproteinosishaveanormallifespan.Certainly,however,
thevocalhoarsenessandtheappearanceoftheskinmayinuencethequalityoflifeforaectedpatients.Asisthe
case with several other hyperkeratotic genodermatoses, the rough, scaly skin lesions may respond to systemic
retinoidtherapy,butthedepositsofabnormalmaterialinthedermisandsubmucosadonot.
Jaundice(Icterus)
Jaundiceisaconditioncharacterizedbyexcessbilirubininthebloodstream.Thebilirubinaccumulatesinthetissues,
whichresultsinayellowishdiscolorationoftheskinandmucosa.Tounderstandjaundice,itisimportanttoknow
something about the metabolism of bilirubin. Most bilirubin is derived from the breakdown of hemoglobin, the
oxygencarryingpigmentoferythrocytes.Theaveragelifespanofanerythrocyteinthecirculationis120days.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,
bilirubinistakenupbythehepatocytesandconjugatedwithglucuronicacid,whichproducesconjugatedbilirubin,a
solubleproductthatcanbeexcretedinthebile.
Therearenumerouscausesforincreasedserumlevelsofbilirubin;somearephysiologic,andmanyarepathologic.
Therefore, the presence of jaundice is not a specic sign and generally necessitates physical examination and
laboratorystudiestodeterminetheprecisecause.Thebasicdisturbancesassociatedwithincreasedbilirubinlevels
includeanincreasedproductionofbilirubin.Thisoccurswhentheredbloodcells(RBCs)arebeingbrokendownat
such a rapid rate that the liver cannot keep pace with processing. This breakdown is seen in such conditions as
autoimmunehemolyticanemiaorsicklecellanemia.
In addition, the liver may not be functioning correctly, resulting in decreased uptake of the bilirubin from the
circulationordecreasedconjugationofbilirubininthelivercells.Jaundiceisfrequentlypresentatbirthasaresultof
thelowlevelofactivityoftheenzymesystemthatconjugatesbilirubin.Defectsinthisenzymesystemmayalsobe
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 aect up to 5% of people in the United
States.Becausemostoftheseexamplesofjaundiceoccurwithimpairedprocessingofbilirubin,laboratorystudies
usuallyshowunconjugatedbilirubinintheserum.
The presence of conjugated bilirubinemia in jaundice can usually be explained by the reduced excretion of
bilirubinintothebileducts.Thiscanbetheresultofswellingofthehepatocytes(resultinginanocclusionofthebile
canaliculi)orhepatocytenecrosis,withdisruptionofthebilecanaliculiandliberationofconjugatedbilirubin.Thus
liverfunctionmaybedisturbedbecauseofanyoneofavarietyofinfections(e.g.,viruses)ortoxins(e.g.,alcohol).
Occlusion of the bile duct from gallstones, stricture, or cancer can also force conjugated bilirubin into the
bloodstream.
ClinicalFeatures
The patient aected by jaundice exhibits a diuse, uniform, yellowish discoloration of the skin and mucosa. The
colorvariesinintensity,dependingontheserumlevelofbilirubinandtheanatomicsite.Becauseelastinbershave
an anity for bilirubin, tissues that have a high content of elastin, including the sclera, lingual frenum, and soft
palate,areprominentlyaected.Thescleraoftheeyeisoftentherstsiteatwhichtheyellowcolorisnoted(Fig.17
6).Theyellowdiscolorationcausedbyhypercarotenemia(resultingfromexcessingestionofcarotene,avitaminA
precursorfoundinyellowvegetablesandfruits)maybeconfusedwithjaundice,butthescleraisnotinvolvedinthat
condition.
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FIG.176
Jaundice.Theyellowcolorofthesclerarepresentsacommonfinding.
Othersignsandsymptomsassociatedwithjaundicevarywiththeunderlyingcauseofthehyperbilirubinemia.For
example,patientswithviralhepatitisusuallyhaveafever,abdominalpain,anorexia,andfatigue.Thepatientwith
jaundice typically requires a complete medical evaluation to determine the precise cause of the condition so that
propertherapycanbeinstituted.
Thetreatmentandprognosisofthepatientwithjaundicevarywiththecause.Thejaundicethatiscommonlynoted
at birth often resolves spontaneously; however, if the infant is placed under special lights, then the clearing will
occur more quickly because conjugation of the bilirubin molecule is triggered by exposure to blue light. If the
episodeofjaundiceisduetosignicantliverdamage,asmaybeseenwithviralhepatitisBorhepatotoxicchemical
injury, then the prognosis will vary, depending on the extent of liver damage. The prognosis for patients with
jaundicesecondarytoliverdamageassociatedwithmetastaticmalignancyispoor.
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
becausehebelievedittobeastarchlikematerial(amyl=starch;oid=resembling).Wenowunderstandthatamyloid
can be formed in a variety of seings, each with its own specic type of amyloid protein. Many of these amyloid
proteinshavebeenidentiedpreciselywithrespecttotheirbiochemicalcomposition,andideallyanaemptshould
bemadetocategorizethetypeofamyloidspecicallywhenthisdiagnosisismade.Thevariousamyloidproteinsare
designatedwithanA,toindicateamyloid,followedbyanabbreviationforthespecicamyloidprotein.Forexample,
AL would identify amyloid composed of immunoglobulin light (L) chain molecules.Although amyloid may have
severalsources,alltypesofamyloidhavethecommonfeatureofapleatedsheetmolecularconguration,which
can be seen with xray diraction crystallographic analysis. Because of this similarity of molecular structure, the
dierenttypesofamyloidhavesimilarstainingpaernswithspecialstains.
Amyloidosiscanproduceavarietyofeects,dependingontheorganofinvolvementandtheextenttowhichthe
amyloidisdeposited.Withlimitedcutaneousformsofamyloidosis,virtuallynoeectonsurvivalisseen.Withsome
formsofsystemicamyloidosis,however,deathmayoccurwithinafewyearsofthediagnosisasaresultofcardiacor
renal failure. Furthermore, the presence of amyloid may be associated with other problems, such as multiple
myelomaorchronicinfections.
ClinicalFeatures
Severalclassicationsofamyloidosishavebeenproposedinthepastdecade,eachevolvingastheknowledgeofthis
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unusual condition increases. None of the classications is completely satisfactory, although in recent years, the
biochemicalmakeupoftheseproteinshasguredmoreprominentlyinmostclassications.Thisdiscussionaempts
to be as concise and direct as possible. Essentially, amyloidosis may be divided into organlimited and systemic
formsfromaclinicalstandpoint.
OrganLimitedAmyloidosis
Althoughorganlimitedamyloidosismayoccurinavarietyoforgans,ithasinfrequentlybeenreportedintheoral
soft tissues. An example of a limited form of amyloidosis is the amyloid nodule, which appears as a solitary,
otherwiseasymptomatic,submucosaldeposit.Mostoftheorganlimitedformsofamyloidosisconsistofaggregates
ofimmunoglobulinlightchains,whichinsomecasesareproducedbyafocalcollectionofmonoclonalplasmacells.
Bydenition,suchamyloiddepositsarenotassociatedwithanysystemicalteration.
SystemicAmyloidosis
Systemicamyloidosismayoccurinseveralforms:
Primary
Myelomaassociated
Secondary
Hemodialysisassociated
Heredofamilial
PrimaryandMyelomaAssociatedAmyloidosis
Theprimaryandmyelomaassociatedformsofamyloidosisusuallyaectolderadults(averageage,65years),anda
slight male predilection is present. These types of amyloidosis are caused by deposition of light chain molecules
(thusthedesignationAL),withmostcasesbeingidiopathic,althoughapproximately15%to20%areassociatedwith
multiple myeloma. The initial signs and symptoms may be nonspecic, often resulting in a delayed diagnosis.
Fatigue,weightloss,paresthesia,hoarseness,edema,andorthostatichypotensionareamongtherstindicationsof
thisdiseaseprocess.Eventually,carpaltunnelsyndrome,mucocutaneouslesions,hepatomegaly,andmacroglossia
developasaresultofthedepositionoftheamyloidprotein.Theskinlesionsappearassmoothsurfaced,rm,waxy
papulesandplaques.Thesemostcommonlyaecttheeyelidregion(Fig.177),theretroauricularregion,theneck,
andthelips.Thelesionsareoftenassociatedwithpetechiaeandecchymoses.Macroglossiahasbeenreportedin10%
to40%ofthesepatientsandmayappearasdiuseornodularenlargementofthetongue(Fig.178).Sometimesoral
amyloid nodules show ulceration and submucosal hemorrhage overlying the lesions. Infrequently, patients may
complainofdryeyesordrymouth,whichissecondarytoamyloidinltrationanddestructionofthelacrimaland
salivaryglands.Whensignicantbloodvesselinltrationhasoccurred,claudicationofthejawmusculaturemaybe
noticed.
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Amyloidosis.Thispatientexhibitsafirm,waxynodularlesionintheperiocularregion,afindingthatischaracteristicof
thiscondition.
FIG.177
FIG.178
Amyloidosis.Thepatientexhibitsanenlargedandcrenatedtongue.(CourtesyofDr.GregoryErena.)
SecondaryAmyloidosis
Secondary amyloidosis is so named because it characteristically develops as a result of a chronic inammatory
process,suchaslongstandingosteomyelitis,tuberculosis,orsarcoidosis.Cleavagefragmentsofacirculatingacute
phase reactant protein appear to comprise this type of amyloidosis, which is thus designated AA. The heart is
usually not aected as in other forms of amyloidosis. Liver, kidney, spleen, and adrenal involvement are typical,
however.Withtheadventofmodernantibiotictherapy,thisformofamyloidosishasbecomemuchlesscommonin
theUnitedStates.
HemodialysisAssociatedAmyloidosis
Patientswhohaveundergonelongtermrenaldialysisalsoaresusceptibletoamyloidosis,althoughinthiscasethe
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amyloid protein has been identied as 2microglobulin, and this type of amyloidosis is designated as A2M. 2
Microglobulin is a normally occurring protein that usually is not removed by the dialysis procedure, and it
accumulates in the plasma. Eventually, it forms deposits, particularly in the bones and joints. Often, carpal tunnel
syndromeoccurs,aswellascervicalspinepainanddysfunction.Tongueinvolvementhasbeenreported.Thistype
ofamyloidosismaybecomelessofaprobleminthefuturebecauseofincreaseduseofdialyzerswithlargerpores
thatpermitremovalofthelarge2microglobulinmolecule.
HeredofamilialAmyloidosis
Heredofamilial amyloidosis is an uncommon but signicant form of the disease. Several kindred have been
identiedinSwedish,Portuguese,andJapanesepopulations,andmosttypesareinheritedasautosomaldominant
traits.An autosomalrecessiveform,knownasfamilialMediterraneanfever,hasalsobeendescribed.Severalofthese
conditions appear as polyneuropathies, although other manifestations, such as cardiomyopathy, cardiac
arrhythmias,congestiveheartfailure,andrenalfailure,eventuallydevelopastheamyloiddepositioncontinues.
Biopsy of rectal mucosa has classically been used to conrm a diagnosis of primary or myelomaassociated
amyloidosis,withupto80%ofsuchbiopsyspecimensbeingpositive.Aspirationbiopsyofabdominalsubcutaneous
fat is a simpler procedure, however, and the sensitivity of this technique has been reported to range from 55% to
75%.Alternativetissuesources,however,arethegingivaandlabialsalivaryglands.Histopathologicexaminationof
gingival tissue that has been aected 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
diuselypresentthroughoutthetissue(Fig.179).Relativelylowsensitivityhasbeenreportedforgingivalbiopsies,
whereas labial salivary gland tissue shows deposition of amyloid in a periductal or perivascular location in more
than80%ofthecases.
Amyloidosis.Thismediumpowerphotomicrographshowstheeosinophilic,acellulardepositsthatarecharacteristicof
amyloiddeposition.
FIG.179
Iftheamorphouseosinophilicmaterialrepresentsamyloid,itwillbestainedbythedye,Congored,whichhasan
anity for the abnormal protein. In tissue sections stained with Congo red, the amyloid appears red. When the
tissuethattakesuptheCongoredstainisviewedwithpolarizedlight,itexhibitsanapplegreenbirefringence(Fig.
1710). This Congo red staining method is considered to be the gold standard for identifying the presence of
amyloid.Othertechniqueshavebeenused,butthesearelesssensitiveorspecic.Microscopicsectionsstainedwith
crystalvioletrevealacharacteristicmetachromasia;thisnormallypurpledyeappearsmorereddishwhenitreacts
with amyloid. Staining with thioavine T, a uorescent dye, also gives positive results if amyloid is present.
Ultrastructurally,amyloidisseenasacollectionof7.5to10nmdiameter,nonbranching,linearbrils.
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Amyloidosis.HighpowerphotomicrographofaCongoredstainedsection,demonstratingcharacteristicapplegreen
birefringencewhenviewedwithpolarizedlight.(CourtesyofDr.JohnKalmar.)
FIG.1710
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
ruledout.Immunohistochemicalstudiesareprovingtobeveryusefulindistinguishingthespecictypeofamyloid
protein.Familyhistoryandphysicalexaminationndingsarealsoimportant.
Inmostinstances,noeectivetherapyisavailableforamyloidosis.Surgicaldebulkingofamyloiddepositioninthe
tongue has met with limited success. Selected forms of amyloidosis may respond to treatment, or at least their
progressionmaybeslowed,dependingontheunderlyingcause.Incasesofsecondaryamyloidosisassociatedwith
an infectious agent, treatment of the infection and reduction of the inammation often result in clinical
improvement. Renal transplantation may arrest the progression of the bone lesions in hemodialysisassociated
amyloidosis, but this procedure apparently does not reverse the process. Liver transplantation can improve the
prognosis of several forms of inherited amyloidosis, particularly the transthyretin variant. Familial Mediterranean
fevermayrespondtosystemiccolchicinetherapy.Geneticcounselingisalsoappropriateforpatientsaectedbythe
inheritedformsofamyloidosis.Treatmentofprimaryamyloidosis(AL)withcolchicine,prednisone,andmelphalan
appearstoimprovetheprognosisofpatientswhodonothavecardiacorrenalinvolvement,althoughtheoutlookis
guardedtopoorinmostinstances.Mostpatientsdieofcardiacfailure,arrhythmia,orrenaldiseasewithinmonthsto
afewyearsafterthediagnosis.
Xanthelasma(XanthelasmaPalpebrarum)
Xanthelasma is the most common of the cutaneous xanthomas, occurring in approximately 1% of the adult
population. The condition is mentioned because these lesions appear somewhat similar to cutaneous amyloid
deposits.Inaddition,thepresenceofxanthelasmahasbeenrelatedtoanincreasedriskofatherosclerosisaswellas
elevatedserumlipids.
ClinicalFeatures
Xanthelasmaistypicallyidentiedinmiddleagedorolderadults,presentingasoneormoresoft,yellowishplaques
associatedwiththeperiocularskin(Fig.1711).Thelesionstendtodeveloponthemedialaspectoftheuppereyelid.
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Theirsoftconsistencyandyellowcolorclinicallyshouldhelpdistinguishxanthelasmafromamyloiddeposits.
Xanthelasma.Thesesoftyellowishplaquesonthemedialaspectoftheskinoftheuppereyelidarecharacteristicof
xanthelasma.
FIG.1711
Biopsyofxanthelasmashowsacollectionoflipidladenhistiocytesinthesupercialtomiddermalconnectivetissue.
Treatmentofxanthelasmaitselfisnotnecessaryandisgenerallyconsideredacosmeticprocedure.Ifthepatienthas
not been evaluated recently with respect to their cholesterol levels, referral to a primary care physician for serum
lipidassessmentwouldbeprudent.Thelesionscanbesurgicallyremoved,althoughrecurrenceisnotunusual,even
ifserumlipidsarecontrolled.
VitaminDeficiency
IntheUnitedStatestoday,signicantvitamindecienciesarenotcommon.Patientswithmalabsorptionsyndromes
oreatingdisorders,personswhofollowfaddiets,andalcoholicsarethegroupsmostcommonlyaected.
Vitamin A (retinol) is essential for the maintenance of vision, and it also plays a role in growth and tissue
dierentiation.VitaminAcanbeobtaineddirectlyfromdietarysources,suchasorganmeats(particularlyliver),or
thebodycansynthesizeitfromcarotene,whichisabundantinredandyellowvegetables.
VitaminB1 (thiamin) acts as a coenzyme for several metabolic reactions and is thought to maintain the proper
functioningofneurons.Thiaminisfoundinmanyanimalandvegetablefoodsources.
Vitamin B2 (riboavin) is necessary for cellular oxidationreduction reactions. Foods that contain signicant
amountsofriboavinincludemilk,greenvegetables,leanmeat,sh,legumes,andeggs.
VitaminB3(niacin)actsasacoenzymeforoxidationreductionreactions.Richsourcesincludefoodfromanimal
sources,especiallyleanmeatandliver,milk,eggs,wholegrains,peanuts,yeast,andcerealbranorgerm.
VitaminB6(pyridoxine)servesasacofactorassociatedwithenzymesthatparticipateinaminoacidsynthesis.Itis
foundinmanyanimalandvegetablefoodsources.
VitaminC(ascorbicacid)isnecessaryforthepropersynthesisofcollagen.Thisvitaminispresentinawidevariety
ofvegetablesandfruits,althoughitisparticularlyabundantincitrusfruits.
Vitamin D, which is now considered to be a hormone, can be synthesized in adequate amounts within the
epidermisiftheskinisexposedtoamoderatedegreeofsunlight.Mostmilkandprocessedcerealisfortiedwith
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vitamin D in the United States today, however. Appropriate levels of vitamin D and its active metabolites are
necessaryforcalciumabsorptionfromthegut.
VitaminE(tocopherol)isafatsolublevitaminthatiswidelystoredthroughoutthebody.Itprobablyfunctions
as an antioxidant. Vegetable oils, meats, nuts, cereal grains, and fresh greens and vegetables are good sources of
vitaminE.
VitaminKisafatsolublevitaminfoundinawidevarietyofgreenvegetables,aswellasmilk,buer,andliver;
intestinalbacteriaalsoproduceit.Thisvitaminisnecessaryforthepropersynthesisofvariousproteins,including
thecloingfactorsII,VII,IX,andX.
ClinicalFeatures
VitaminA
AseveredeciencyofvitaminAduringinfancymayresultinblindness.Theearlychangesassociatedwithalackof
this vitamin later in life include an inability of the eye to adapt to reduced light conditions (i.e., night blindness).
Withmoresevere,prolongeddeciency,drynessoftheskinandconjunctivadevelop,andtheocularchangesmay
progresstoulcerationofthecornea,leadingtoblindness.
Thiamin
Adeciencyofthiaminresultsinaconditioncalledberiberi,aproblemthatisrelativelyuncommonintheWestern
worldexceptinalcoholicsorotherindividualswhodonotreceiveabalanceddiet.Thiamindeciencyhasalsobeen
documentedinpatientswhohavehadgastricbypasssurgeryforweightcontrol,presumablybecauseanadequate
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
containednearlyallofthethiamin,peoplewhosubsistedonthepolishedricebecamedecientinthisvitamin.The
disorder is manifested by cardiovascular problems (e.g., peripheral vasodilation, heart failure, and edema) and
neurologic problems (including peripheral neuropathy and Wernicke encephalopathy). Patients with Wernicke
encephalopathy experience vomiting, nystagmus, and progressive mental deterioration, which may lead to coma
anddeath.
Riboflavin
A diet that is chronically decient in riboavin causes a number of oral alterations, including glossitis, angular
cheilitis,sorethroat,andswellinganderythemaoftheoralmucosa.Anormocytic,normochromicanemiamaybe
present,andseborrheicdermatitismayaecttheskin.
Niacin
A deciency of niacin causes a condition known as pellagra, a term derived from the Italian words pelle agra,
meaningroughskin.Thisconditionmayoccurinpopulationsthatusemaizeasaprincipalcomponentoftheirdiets,
becausecornisapoorsourceofniacin.PellagrawasoncecommoninthesoutheasternUnitedStatesandmaystillbe
seeninsomepartsoftheworld.Theclassicsystemicsignsandsymptomsincludethetriadofdermatitis,dementia,
anddiarrhea.Thedermatitisisdistributedsymmetrically;sunexposedareas,suchastheface,neck,andforearms,
areaectedmostseverely(Fig.1712).Theoralmanifestationshavebeendescribedasstomatitisandglossitis,with
thetongueappearingred,smooth,andraw.Withoutcorrectionoftheniacindeciency,thediseasemayevolveand
persistoveraperiodofyears,eventuallyleadingtodeath.
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Pellagra.Theskinonthefootisroughandhyperpigmented,exceptforacentralbandthatwasprotectedfromsunlight
byasandalstrap.(CourtesyofDr.SylvieBrener.)
FIG.1712
Pyridoxine
Adeciencyofpyridoxineisunusualbecauseofitswidespreadoccurrenceinavarietyoffoods.Anumberofdrugs,
such as the antituberculosis drug isoniazid, act as pyridoxine antagonists; therefore, patients who receive these
medicationsmayhaveadeciencystate.Becausethevitaminplaysaroleinneuronalfunction,patientsmayshow
weakness,dizziness,orseizuredisorders.Cheilitisandglossitis,reportedinpeoplewithpellagra,arealsoreported
inpatientswithpyridoxinedeciency.
VitaminC
AdeciencyofvitaminCisknownasscurvy, and its occurrence in the United States is usually limited to people
whosedietslackfreshfruitsandvegetables.Commonlyaectedgroupsincludeinnercityinfants(whosedietsoften
consistentirelyofmilk)andolderedentulousmen,particularlythosewholivealone.
Theclinicalsignsofscurvyaretypicallyrelatedtoinadequatecollagensynthesis.Forexample,weakenedvascular
walls may result in widespread petechial hemorrhage and ecchymosis. Similarly, wound healing is delayed, and
recentlyhealedwoundsmaybreakdown.Inchildhood,painfulsubperiostealhemorrhagesmayoccur.
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.
Thegingivallesionshavebeentermedscorbuticgingivitis(Fig.1713).Ifuntreated,scurvymayultimatelyleadto
death,oftenasaresultofintracranialhemorrhage.
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FIG.1713
Scurvy.Hemorrhagicgingivalenlargement(scorbuticgingivitis)becauseofcapillaryfragility.(CourtesyofDr.JamesHargan.)
VitaminD
AdeciencyofvitaminDduringinfancyresultsinaconditioncalledrickets;adultswhoaredecientinthisvitamin
develop osteomalacia. With the vitaminD supplementation of milk and cereal, rickets is a relatively uncommon
diseasetodayintheUnitedStates.Inpastcenturies,however,ricketswasoftenseen,particularlyinthetemperate
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 darkskinned and do not receive adequate sun exposure, as well as
solely breastfed infants, remain at risk for developing rickets. Nutritional rickets remains a problem in many
developingcountries,althoughtheconditionisthoughttobeassociatedmorewithcalciumdeciencythanvitamin
Ddeciency.
Clinical manifestations of rickets include irritability, growth impairment, and prominence of the costochondral
junctions(rachiticrosary).Asthechildagesandbeginstoputweightonthelongbonesofthelegs,signicantbowing
resultsbecauseofthepoormineralizationoftheskeleton.VitaminDdeciencyoccurringduringtheperiodoftooth
developmentwillresulthypomineralizationoftheteeth(Fig.1714).
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VitaminDDeficiency.HypocalcificationoftheteethisseeninthischildwhohadvitaminDdeficiencyrelatedtoadiet
ofbreastmilkexclusivelyandlackofadequatesunlightexposure.(CourtesyofDr.PamelaMcDonald.)
FIG.1714
A similar paern of poorly mineralized bone is seen in osteomalacia in adults. Bone normally undergoes
continuousremodelingandturnover,andtheosteoidthatisproducedduringthisprocessdoesnothavesucient
calcium to mineralize completely. Thus a weak, fragile bone structure results. Patients aected by osteomalacia
frequentlycomplainofdiuseskeletalpain,andtheirbonesaresusceptibletofracturewithrelativelyminorinjury.
VitaminE
AdeciencyofvitaminEisrareandoccursprimarilyinchildrenwhosuerfromchroniccholestaticliverdisease.
Thesepatientshaveseveremalabsorptionofallfatsolublevitamins,butparticularlyvitaminE.Multipleneurologic
signsdevelopasaresultofabnormalitiesinthecentralnervoussystem(CNS)andperipheralnervoussystem.
VitaminK
A deciency of vitamin K may be seen in patients with malabsorption syndromes or in those whose intestinal
microora has been eliminated by longterm, broadspectrum antibiotic use. Oral anticoagulants in the dicumarol
familyalsoinhibitthenormalenzymaticactivityofvitaminK.AdeciencyorinhibitionofsynthesisofvitaminK
leadstoacoagulopathybecauseoftheinadequatesynthesisofprothrombinandothercloingfactors.Intraorally,
this coagulopathy is most often manifested by gingival bleeding. If the coagulopathy is not corrected, death may
resultfromuncontrolledsystemichemorrhage.
Replacementtherapyisindicatedforvitamindeciencies.However,suchdecienciesareuncommon,exceptforthe
situations described earlier. In fact, vitamin excess is perhaps more likely to be encountered in the United States
today because so many people selfmedicate with unnecessary and potentially harmful vitamin supplements. For
example,excessvitaminAmaycauseabdominalpain,vomiting,headache,jointpain,andexostoses,whereasexcess
vitamin C may induce the formation of additional kidney stones in individuals with a history of nephrolithiasis.
Similarly,anincreasedprevalenceofkidneystonescanbeseenwithexcessoralintakeofvitaminD.
IronDeficiencyAnemia
IrondeciencyanemiaisthemostcommoncauseofanemiaintheUnitedStatesandthroughouttheworld.This
formofanemiadevelopswhentheamountofironavailabletothebodycannotkeeppacewiththeneedforironin
theproductionofredbloodcells(RBCs).Thistypeofanemiadevelopsunderfourconditions:
1.Excessivebloodloss
2.IncreaseddemandforRBCs
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3.Decreasedintakeofiron
4.Decreasedabsorptionofiron
It is estimated up to 11% 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
decientbecauseofchronicbloodloss,usuallyassociatedwithgastrointestinaldisease,suchaspepticulcerdisease,
diverticulosis,hiatalhernia,ormalignancy.
Anincreaseddemandforerythrocyteproductionoccursduringchildhoodgrowthspurtsandduringpregnancy.
Adecreasedintakeofironmaybeseenduringinfancywhenthedietconsistsofrelativelyironpoorfoods,suchas
cerealsandmilk.Likewise,thedietsofolderpeoplemaybedecientiftheirdentalconditionprohibitsthemfrom
eating the proper foods or if they cannot aord ironrich foods, such as meats and vegetables. In the developing
world,intestinalparasites(especiallyhookworms)areacommoncauseofirondeciencyinchildrenandpregnant
women.
Decreased absorption is a much less common problem; however, it can be seen in patients who have had a
complete gastrectomy or who have celiac sprue, a condition that results in severe chronic diarrhea because of
sensitivitytotheplantprotein,gluten.
ClinicalFeatures
Patientswithirondeciencyanemiathatissevereenoughtocausesymptomsmaycomplainoffatigue,easytiring,
palpitations,lightheadedness,andlackofenergy.Oralmanifestationsincludeangularcheilitisandatrophicglossitis
or generalized oral mucosal atrophy. The glossitis has been described as a diuse or patchy atrophy of the dorsal
tongue papillae, often accompanied by tenderness or a burning sensation. Such ndings are also evident in oral
candidiasis,andsomeinvestigatorshavesuggestedthatirondeciencypredisposesthepatienttocandidalinfection,
whichresultsinthechangesseenatthecornersofthemouthandonthetongue.Suchlesionsarerarelyseeninthe
UnitedStates,perhapsbecausetheanemiaisusuallydetectedrelativelyearlybeforetheoralmucosalchangeshave
hadachancetodevelop.
LaboratoryFindings
The diagnosis should be established by means of a complete blood count with RBC indices because many other
conditions, such as hypothyroidism, other anemias, or chronic depression, may elicit similar systemic clinical
complaints. The laboratory evaluation characteristically shows hypochromic microcytic RBCs, which may be
reduced in numbers. Additional supporting evidence for iron deciency includes the ndings of low serum iron
levelsandferritinconcentrationtogetherwithelevatedtotalironbindingcapacity.
Therapyformostcasesofirondeciencyanemiaconsistsofdietaryironsupplementationbymeansoforalferrous
sulfate.Forpatientswithmalabsorptionproblemsorsevereanemia,parenteralironmaybegivenperiodically.The
response to therapy is usually prompt, with red cell parameters returning to normal within 1 to 2 months. The
underlyingcauseoftheanemiashouldbeidentiedsothatitmaybeaddressed,iffeasible.
PlummerVinsonSyndrome(PatersonKellySyndrome
SideropenicDysphagia)
PlummerVinsonsyndrome is a rare condition characterized by irondeciency anemia, seen in conjunction with
glossitis and dysphagia. Its prevalence in developed countries has been declining, probably as a result of the
improvednutritionalstatusofthepopulations.Theconditionissignicantinthatithasbeenassociatedwithahigh
frequencyofbothoralandesophagealsquamouscellcarcinoma;therefore,itisconsideredapremalignantprocess.
MostreportedpatientswithPlummerVinsonsyndromehavebeenwomenofScandinavianorNorthernEuropean
background,between30and50yearsofage.Patientstypicallycomplainofaburningsensationassociatedwiththe
tongueandoralmucosa.Sometimesthisdiscomfortissoseverethatdenturescannotbeworn.Angularcheilitisis
oftenpresentandmaybesevere(Fig.1715).Markedatrophyofthelingualpapillae,whichproducesasmooth,red
appearanceofthedorsaltongue,isseenclinically(Fig.1716).
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FIG.1715
PlummerVinsonSyndrome.Patientsoftenshowangularcheilitis.
PlummerVinsonSyndrome.Thediffusepapillaryatrophyofthedorsaltongueischaracteristicoftheoral
changes.(FromNevilleBW,DammDD,WhiteDK:Coloratlasofclinicaloralpathology,ed2,Philadelphia,1999,LippincottWilliams&Wilkins.)
FIG.1716
Patients also frequently complain of diculty in swallowing (dysphagia) or pain on swallowing.An evaluation
withendoscopyoresophagealbariumcontrastradiographicstudiesusuallyshowsthepresenceofabnormalbands
oftissueintheesophagus,calledesophagealwebs.Anothersignisanalterationofthegrowthpaernofthenails,
whichresultsinaspoonshapedconguration(koilonychia).Thenailsmayalsobebrile.
Symptoms of anemia may prompt patients with PlummerVinson syndrome to seek medical care. Fatigue,
shortnessofbreath,andweaknessarecharacteristicsymptoms.
LaboratoryFindings
Hematologicstudiesshowahypochromicmicrocyticanemiathatisconsistentwithanirondeciencyanemia.
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A biopsy specimen of involved mucosa from a patient with PlummerVinson syndrome typically shows epithelial
atrophywithvaryingdegreesofsubmucosalchronicinammation.Inadvancedcases,evidenceofepithelialatypia
ordysplasiamaybeseen.
TreatmentofPlummerVinsonsyndromeisprimarilydirectedatcorrectingtheirondeciencyanemiabymeansof
dietary iron supplementation. This therapy usually resolves the anemia, relieves the glossodynia, and may reduce
the severity of the esophageal symptoms. Occasionally, esophageal dilation is necessary to help improve the
symptoms of dysphagia. Patients with PlummerVinson syndrome should be evaluated periodically for oral,
hypopharyngeal, and esophageal cancer because a 5% to 50% prevalence of upper aerodigestive tract malignancy
hasbeenreportedinaectedpersons.
PerniciousAnemia
PerniciousanemiaisanuncommonconditionthatoccurswithgreatestfrequencyamongolderpatientsofNorthern
European heritage, although recent studies have identied the disease in black and Hispanic populations as well.
Asianpopulationsseemtobeaectedmuchlessfrequently.Thediseaseisamegaloblasticanemiacausedbypoor
absorptionofcobalamin(vitaminB12,extrinsicfactor).Intrinsicfactor,whichisproducedbytheparietalcellsofthe
stomach lining, is needed for vitaminB12 absorption. Normally, when cobalamin is ingested, it binds to intrinsic
factorintheduodenum.Becausetheliningcellsoftheintestinepreferentiallytakeupthecobalaminintrinsicfactor
complex,signicantamountsofthevitamincannotbeabsorbedunlessbothcomponentsarepresent.
Inthecaseofperniciousanemia,mostpatientslackintrinsicfactorbecauseofanautoimmunedestructionofthe
parietalcellsofthestomach;thisresultsindecreasedabsorptionofcobalamin.Antibodiesdirectedagainstintrinsic
factorarealsofoundintheserumofthesepatients.VitaminB12deciencymayoccurforotherreasons,andalthough
the resulting signs and symptoms may be identical to those of pernicious anemia, these should be considered as
distinctlydierentdeciencydisorders.Forexample,adecreasedabilitytoabsorbcobalaminmayalsooccurafter
gastrointestinalbypassoperations.Inaddition,becausecobalaminisprimarilyderivedfromanimalsources,some
strictvegetarians(vegans)maydevelopvitaminB12deciency.
Because cobalamin is necessary for normal nucleic acid synthesis, anything that disrupts the absorption of the
vitamincausesproblems,especiallyforcellsthataremultiplyingrapidlyand,therefore,synthesizinglargeamounts
of nucleic acids. The cells that are the most mitotically active are aected to the greatest degree, especially the
hematopoieticcellsandthegastrointestinalliningepithelialcells.
ClinicalFeatures
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 oxygencarrying capacity of the blood. Vitamin B12 also functions to maintain myelin throughout the
nervous system; therefore, with reduced levels of the vitamin, many patients report paresthesia, tingling, or
numbness of the extremities. Diculty in walking and diminished vibratory and positional sense may be present.
Psychiatricsymptomsofmemoryloss,irritability,depression,anddementiahavealsobeendescribed.
Oral symptoms often consist of a burning sensation of the tongue, lips, buccal mucosa, or other mucosal sites.
Clinicalexaminationmayshowfocalpatchyareasoforalmucosalerythemaandatrophy(Fig.1717),ortheprocess
may be more diuse, depending on the severity and duration of the condition. The tongue may be aected in as
manyas50%to60%ofpatientswithperniciousanemia,butitmaynotshowasmuchinvolvementasotherareasof
theoralmucosainsomeinstances.Theatrophyanderythemamaybeeasiertoappreciateonthedorsaltonguethan
atothersites,however.
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FIG.1717
PerniciousAnemia.A,Thedorsaltongueshowserythemaandatrophy.B,AftertherapywithvitaminB12,themucosal
alterationresolved.
Histopathologicexaminationofanerythematousportionoftheoralmucosashowsmarkedepithelialatrophywith
loss of rete ridges, an increased nucleartocytoplasmic ratio of the surface epithelial cells, and prominent nucleoli
(Fig.1718). This paern can be misinterpreted as epithelial dysplasia at times, although the nuclei in pernicious
anemiatypicallyarepalestainingandshowperipheralchromatinclumping.Apatchydiusechronicinammatory
cellinltrateisusuallynotedintheunderlyingconnectivetissue.
PerniciousAnemia.Thismediumpowerphotomicrographshowsepithelialatrophyandatypiawithchronic
inflammationoftheunderlyingconnectivetissue.Thesefeaturesarecharacteristicofamegaloblasticanemia,suchaspernicious
anemia.
FIG.1718
LaboratoryFindings
HematologicevaluationofvitaminB12deciencyshowsamacrocyticanemiaandreducedserumcobalaminlevels.
TheSchillingtestforperniciousanemiahasbeenusedtodeterminethepathogenesisofthecobalamindeciencyby
comparing absorption and excretion rates of radiolabeled cobalamin. However, this study is rather complicated to
perform,andisnowconsideredtobeobsolete.Thepresenceofserumantibodiesdirectedagainstintrinsicfactoris
quitespecicforperniciousanemia.
Once the diagnosis of pernicious anemia is established, treatment traditionally has consisted of monthly
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intramuscularinjectionsofcyanocobalamin.Theconditionrespondsrapidlyoncetherapyisinitiated,withreportsof
clearing of oral lesions within 5 days. Highdose oral cobalamin therapy has also been shown to be an equally
eectivetreatment,however,withadvantagesbeingitscosteectivenessandtheeliminationofpainfulinjections.
Onerecentsystematicliteraturereviewhasidentiedwhatappearstobeanincreasedriskofgastriccarcinoma,with
perniciousanemiapatientsbeingseventimesmorelikelytodevelopthistumorcomparedtothegeneralpopulation.
BothvitaminB12deciencyandfolatedeciencywillcausemegaloblasticanemia,anditisimportanttodistinguish
between the two problems. Treatment of vitamin B12 deciency with folate will resolve the anemia and the oral
mucosalatrophy,butreducedmyelinproductionwillcontinue,resultinginfurtherCNSdamage.
PituitaryDwarfism
Pituitary dwarsm is a relatively rare condition that results from either the diminished production of growth
hormonebytheanteriorpituitarygland,abnormalitiesofthegrowthhormonemolecule,orareducedcapacityofthe
tissues to respond to growth hormone. Aected patients are typically much shorter than normal, although their
bodyproportionsaregenerallyappropriate.
Severalconditionsmaycauseshortstature,andacarefulevaluationofthepatientmustbeperformedtoruleout
otherpossiblecauses,suchasthefollowing:
1.Intrinsicdefectsinthepatientstissues(e.g.,certainskeletaldysplasias,chromosomalabnormalities,and
idiopathicshortstature)
2.Alterationsintheenvironmentofthegrowingtissues(e.g.,malnutrition,hypothyroidism,anddiabetesmellitus)
If a lack of growth hormone is detected, the cause should be determined. Sometimes the fault lies with the
pituitaryglanditself(e.g.,aplasiaorhypoplasia).Inotherinstances,theproblemmayberelatedtodestructionofthe
pituitaryorhypothalamusbytumors,therapeuticradiation,orinfection.
If the hypothalamus is aected, 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
hormoneandcortisol,arealsodetectedinpatientswithprimarypituitaryorhypothalamicdisorders.
Somepatientsexhibitnormalorevenelevatedlevelsofgrowthhormone,yetstillshowlileevidenceofgrowth.
These individuals usually have inherited an autosomal recessive trait, resulting in abnormal and reduced growth
hormonereceptorsonthepatientscells.Thusnormalgrowthcannotproceed.
ClinicalFeatures
Perhaps the most striking feature of pituitary dwarsm is the remarkably short stature of the aected patient.
Sometimesthisisnotnoticeduntiltheearlyyearsofchildhood,butareviewofthepatientsgrowthhistoryshould
showaconsistentpaernoffailuretoachievetheminimalheightonthestandardgrowthchart.Oftenthepatients
heightmaybeasmuchasthreestandarddeviationsbelownormalforagivenage.Unlikethebodyproportionsin
manyofthedysmorphicsyndromesandskeletaldysplasias,thebodyproportionsofpatientsaectedbyalackof
growthhormoneareusuallynormal.Onepossibleexceptionisthesizeoftheskull,whichisusuallywithinnormal
limits. Because the facial skeleton does not keep pace with the skull, however, the face of an aected patient may
appearsmallerthanitshouldbe.Mentalstatusisgenerallywithinnormallimits.
Themaxillaandmandibleofaectedpatientsaresmallerthannormal,andtheteethshowadelayedpaernof
eruption.Thedelayrangesfrom1to3yearsforteeththatnormallyeruptduringtherstdecadeoflifeandfrom3to
10yearsforteeththatnormallyeruptintheseconddecadeoflife.Oftenthesheddingofdeciduousteethisdelayed
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
proportiontotheotheranatomicstructures.Onerecentstudysuggestedthatgrowthhormonedecientpatientsmay
exhibitmoresevereperiodontaldiseasecomparedtoamatchedcontrolpopulation.
LaboratoryFindings
Radioimmunoassayforhumangrowthhormoneshowslevelsthataremarkedlybelownormal.
Replacementtherapywithhumangrowthhormoneisthetreatmentofchoiceforpatientswithpituitarydwarsmif
thedisorderisdetectedbeforeclosureoftheepiphysealgrowthplates.Inthepast,growthhormonewasextracted
from cadaveric pituitary glands; today, genetically engineered human growth hormone is produced with
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recombinant DNA technology. For patients with a growth hormone deciency caused by a hypothalamic defect,
treatmentwithgrowthhormonereleasinghormoneisappropriate.Ifpatientsareidentiedandtreatedatanearly
age,theycanbeexpectedtoachievearelativelynormalheight.Thecraniofacialbonestructurealsoassumesaless
childlike paern. Evaluation of a series of patients who had been treated for long periods with growth hormone
determinedthatuptohalfdevelopedacromegalicfeatures,includinglargerfeetandalargermandible.Forpatients
wholackgrowthhormonereceptors,notreatmentisavailable.
Gigantism
Gigantismisarareconditioncausedbyanincreasedproductionofgrowthhormone,usuallyrelatedtoafunctional
pituitaryadenoma.Theincreasedproductionofgrowthhormonetakesplacebeforeclosureoftheepiphysealplates,
andtheaectedpersongrowsatamuchmorerapidpace,becomingabnormallytall.Althoughtheaverageheightof
thepopulationoftheUnitedStateshasbeengraduallyincreasingduringthepastseveraldecades,individualswho
exceed the mean height by more than three standard deviations may be considered candidates for endocrinologic
evaluation.Familialexamplesofgigantismhavealsobeendescribed.
Patientswithgigantismusuallyshowmarkedlyacceleratedgrowthduringchildhood,irrespectiveofnormalgrowth
spurts.Radiographicevaluationoftheskulloftenshowsanenlargedsellaasaresultofthepresenceofapituitary
adenoma.Theadenomamayresultinhormonaldeciencies,suchashypothyroidismandhypoadrenocorticism,if
theremainingnormalpituitaryglandtissueiscompressedanddestroyed.McCuneAlbrightsyndrome(polyostotic
brous dysplasia and caf au lait pigmentation with associated endocrinologic disturbances) (see page 593) may
accountforasmanyas20%ofthecasesofgigantism.
If the condition remains uncorrected for a prolonged period, extreme height (more than 7 feet tall) will be
achieved, and enlargement of the facial soft tissues, the mandible, and the hands and feet will become apparent.
These changes often resemble those seen inacromegaly (discussed later).Another oral nding is true generalized
macrodontia.
Appropriatemanagementofgigantisminvolvesthesurgicalremovalofthefunctioningpituitaryadenoma,usually
by a transsphenoidal approach. Radiation therapy may also be used, as well as one of the somatostatin analogues
andagrowthhormonereceptorantagonist(discussedinthenexttopic,acromegaly).
Thelifespanofpatientswithgigantismisusuallymarkedlyreduced.Complicationsassociatedwithhypertension,
peripheralneuropathy,osteoporosis,andpulmonarydiseasecontributetoincreasedmorbidityandmortality.
Acromegaly
Acromegalyisanuncommonconditioncharacterizedbytheexcessproductionofgrowthhormoneafterclosureof
theepiphysealplatesintheaectedpatient.Usually,thisincreaseingrowthhormoneisduetoafunctionalpituitary
adenoma.Theincidenceisestimatedtobeapproximatelythreetovenewcasesdiagnosedpermillionpopulation
peryear.Theprevalenceisnowbelievedtobebetween40and130aectedpatientspermillion.
Becausemostpatientswithacromegalyhaveapituitaryadenoma,symptomsrelateddirectlytothespaceoccupying
mass of the tumor may be present. These symptoms include headaches, visual disturbances, and other signs of a
brain tumor. Sometimes pressure atrophy of the residual normal pituitary by the adenoma results in diminished
productionofotherpituitaryhormonesandcausesotherindirectendocrineproblems.Thedirecteectsofincreased
levelsofgrowthhormoneincludeavarietyofproblems,suchashypertension,heartdisease,hyperhidrosis,arthritis,
andperipheralneuropathy.
Renewedgrowthinthesmallbonesofthehandsandfeet(Fig.1719)andinthemembranousbonesoftheskull
andjawsistypicallyobserved.Patientsmaycomplainofgloves,rings,orhatsbecomingtoosmall.Thesofttissue
isalsooftenaected,producingacoarsefacialappearance(Fig.1720).Hypertrophyofthesoftpalataltissuesmay
causeoraccentuatesleepapnea.Becausethesesignsandsymptomsareslowtodevelopandarevagueattheonset,
anaveragetimeof6to10yearselapsesfromtheonsetofsymptomstothediagnosisofdisease.Theaverageageat
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diagnosisis42years,andnosexpredilectionisseen.
FIG.1719
Acromegaly.Enlargementofthebonesofthehands.(CourtesyofDr.WilliamBruce.)
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FIG.1720
Acromegaly.Thispatientshowsthetypicalcoarsefacialfeatures.(CourtesyofDr.WilliamBruce.)
Fromadentalperspective,thesepatientshavemandibularprognathismasaresultoftheincreasedgrowthofthe
mandible (Fig. 1721), which may cause apertognathia (anterior open bite). Growth of the jaws also may cause
spacing of the teeth, resulting in diastema formation. Soft tissue growth often produces uniform macroglossia in
aectedpatients.
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FIG.1721
Acromegaly.Thislateralskullfilmshowsthedramaticdegreeofmandibularenlargementthatmayoccur.
LaboratoryFindingsandDiagnosis
If acromegaly is suspected, measurement of serum growth hormone levels is done after giving the patient a
measured quantity of glucose orally. Normally, this glucose challenge will reduce the production of growth
hormone, but if the patient has acromegaly, growth hormone will not be suppressed. Usually magnetic resonance
imaging(MRI)willidentifythepituitaryadenomathatisresponsibleforinappropriategrowthhormonesecretion.
Thetreatmentofapatientwithacromegalyistypicallydirectedattheremovalofthepituitarytumormassandthe
returnofthegrowthhormonelevelstonormal.Themosteectivetreatmentwiththeleastassociatedmorbidityis
surgicalexcisionbyatranssphenoidalapproach.Theprognosisforsuchaprocedureisgood,althoughamortality
rateofapproximately1%isstillexpected.Theconditionisusuallycontrolledwiththisprocedure,butpatientswith
largertumorsandmarkedlyelevatedgrowthhormonelevelsarelesslikelytobecontrolled.
Radiationtherapymaybeusedinsomeinstances,butthereturnofthegrowthhormonelevelstonormalisnotas
rapidoraspredictableaswithsurgery.Becausesomepatientsalsoexperiencehypopituitarismcausedbyradiation
eectsontherestofthegland,somecentersmayoerradiationtherapyastreatmentonlywhensurgeryfailsoris
too risky. Pharmacotherapy with one of the somatostatin analogues (e.g., octreotide, lanreotide, and vapreotide)
helpstocontrolacromegalyifsurgicaltreatmentisunsuccessfulorifsurgeryiscontraindicated.Agrowthhormone
receptorblocking agent, pegvisomant, has also been developed and may be used in conjunction with one of the
somatostatinanaloguesorbyitselfifthepatientcannottoleratethesomatostatinanalogue.Pegvisomantisinjected
daily and acts in the peripheral tissues to inhibit the action of growth hormone. These drugs are also used as an
adjunct to radiation therapy during the prolonged period that is sometimes necessary for that treatment to take
eect.
The prognosis for untreated patients is guarded, with an increased mortality rate compared with that of the
general population. Hypertension, diabetes mellitus, coronary artery disease, congestive heart failure, respiratory
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disease,andcoloncancerareseenwithincreasedfrequencyinacromegalicpatients,andeachofthesecontributesto
theincreasedmortalityrate.Althoughtreatmentofthepatientwithacromegalyhelpstocontrolmanyoftheother
complicatingproblemsandimprovestheprognosis,thelifespanofthesepatientsstillisshortened,particularlyfor
thosewithpersistentelevatedgrowthhormonelevels,cardiomyopathy,orhypertension.
Hypothyroidism(CretinismMyxedema)
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
thyroidhormonelevelsforaprolongedperiod,thendepositionofaglycosaminoglycangroundsubstanceisseenin
thesubcutaneoustissues,producinganonpiingedema.Somecallthissevereformofhypothyroidismmyxedema;
othersusethetermsmyxedemaandhypothyroidisminterchangeably.
Hypothyroidismmaybeclassiedaseitherprimaryorsecondary.Inprimaryhypothyroidism,thethyroidgland
itself is in some way abnormal; in secondary hypothyroidism, the pituitary gland does not produce an adequate
amountofthyroidstimulatinghormone(TSH),whichisnecessaryfortheappropriatereleaseofthyroidhormone.
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
NorthAmericaisapproximately1in4000births.Usually,thisisduetohypoplasiaoragenesisofthethyroidgland.
In other areas of the world, hypothyroidism in infancy is usually due to a lack of dietary iodine. In adults,
hypothyroidismisoftencausedbyautoimmunedestructionofthethyroidgland(knownasHashimotothyroiditis)
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
hypothyroidismcanberelatedtothedecreasedmetabolicrateinthesepatients.
ClinicalFeatures
Themostcommonfeaturesofhypothyroidismincludesuchsignsandsymptomsaslethargy,dryandcoarseskin,
swelling of the face (Fig. 1722) and extremities, huskiness of the voice, constipation, weakness, and fatigue. The
heartrateisusuallyslowed(bradycardia).Reducedbodytemperature(hypothermia)maybepresent,andtheskin
oftenfeelscoolanddrytothetouch.Intheinfant,thesesignsmaynotbereadilyapparent,andthefailuretogrow
normallymaybetherstindicationofthedisease.
Hypothyroidism.A,Thefacialappearanceofthis9yearoldchildisduetotheaccumulationoftissueedemasecondary
toseverehypothyroidism.B,Samepatientafter1yearofthyroidhormonereplacementtherapy.Notetheeruptionofthemaxillary
permanentteeth.
FIG.1722
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With respect to the oral ndings, the lips may appear thickened because of the accumulation of
glycosaminoglycans. Diuse enlargement of the tongue occurs for the same reason (Fig. 1723). If the condition
developsduringchildhood,theteethmayfailtoerupt,althoughtoothformationmaynotbeimpaired(Figs.1724
and1725).
Hypothyroidism.Theenlargedtongue(macroglossia)issecondarytoedemaassociatedwithadulthypothyroidism
(myxedema).(CourtesyofDr.GeorgeBlozis.)
FIG.1723
Hypothyroidism.PhotographofthesamepatientdepictedinFig.1722beforehormonereplacementtherapy.Notethe
retaineddeciduousteeth,forwhichthepatientwasinitiallyreferred.
FIG.1724
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Hypothyroidism.PanoramicradiographofthesamepatientinFigs.1722and1724.Notetheunerupted,yetfully
developedpermanentdentition.
FIG.1725
LaboratoryFindings
Thediagnosisismadebyassayingthefreethyroxine(T4)levels.Iftheselevelsarelow,thenTSHlevelsaremeasured
todeterminewhetherprimaryorsecondaryhypothyroidismispresent.Withprimarythyroiddisease,TSHlevelsare
elevated.Withsecondarydiseasecausedbypituitarydysfunction,TSHlevelsarenormalorborderline.
Thyroidreplacementtherapy,usuallywithlevothyroxine,isindicatedforconrmedcasesofhypothyroidism.The
prognosisisgenerallygoodforadultpatients.Iftheconditionisrecognizedwithinareasonabletime,theprognosis
isalsogoodforchildren.Iftheconditionisnotidentiedinatimelymanner,however,permanentdamagetothe
CNSmayoccur,resultinginintellectualdisability.Foraectedchildren,thyroidhormonereplacementtherapyoften
resultsinadramaticresolutionofthecondition(seeFig.1722).
Hyperthyroidism(ThyrotoxicosisGravesDisease)
Hyperthyroidismisaconditioncausedbyexcessproductionofthyroidhormone.Thisexcessproductionresultsina
stateofmarkedlyincreasedmetabolismintheaectedpatient.Mostcases(60%to90%)areduetoGravesdisease,a
conditionthatwasinitiallydescribedintheearlynineteenthcentury.Itisthoughttobetriggeredbyautoantibodies
thataredirectedagainstreceptorsforthyroidstimulatinghormone(TSH)onthesurfaceofthethyroidcells.When
theautoantibodiesbindtothesereceptors,theyseemtostimulatethethyroidcellstoreleaseinappropriatethyroid
hormone.
Other causes of hyperthyroidism include hyperplastic thyroid tissue and thyroid tumors, both benign and
malignant,whichsecreteinappropriatethyroidhormone.Similarly,apituitaryadenomamayproduceTSH,which
canthenstimulatethethyroidtosecreteexcessthyroidhormone.
ClinicalFeatures
Gravesdiseaseisvetotentimesmorecommoninwomenthaninmenandisseenwithsomefrequency.Itaects
almost2%oftheadultfemalepopulation.Gravesdiseaseismostcommonlydiagnosedinpatientsduringthethird
andfourthdecadesoflife.
Most patients with Graves disease exhibit diuse thyroid enlargement. Many of the signs and symptoms of
hyperthyroidism can be aributed to an increased metabolic rate caused by the excess thyroid hormone. Patients
usuallycomplainaboutnervousness,heartpalpitations,heatintolerance,emotionallability,andmuscleweakness.
Thefollowingareoftennotedduringtheclinicalevaluation:
Weightlossdespiteincreasedappetite
Tachycardia
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Excessiveperspiration
Widenedpulsepressure(increasedsystolicanddecreaseddiastolicpressures)
Warm,smoothskin
Tremor
Ocularinvolvement,whichdevelopsin20%to40%ofaectedpatients,isperhapsthemoststrikingfeatureofthis
disease.Intheearlystagesofhyperthyroidism,patientshaveacharacteristicstarewitheyelidretractionandlidlag.
WithsomeformsofGravesdisease,protrusionoftheeyes(exophthalmosorproptosis)develops(Fig.1726).This
bulgingoftheeyesisduetoanaccumulationofglycosaminoglycansintheretroorbitalconnectivetissues.
FIG.1726
Hyperthyroidism.TheprominenteyesarecharacteristicoftheexophthalmosassociatedwithGravesdisease.
LaboratoryFindings
ThediagnosisofhyperthyroidismismadebyassayingfreeT4(thyroxine)andTSHlevelsintheserum.Inaected
patients,theT4levelsshouldbeelevatedandtheTSHconcentrationistypicallydepressed.
Diuse enlargement and hypercellularity of the thyroid gland are seen in patients with Graves disease, typically
with hyperplastic thyroid epithelium and lile apparent colloid production. Lymphocytic inltration of the
glandularparenchymaisalsooftennoted.
In the United States, radioactive iodine (131I) is the most commonly used form of therapy for adult patients with
Gravesdisease.Thethyroidglandnormallytakesupiodinefromthebloodstreambecausethiselementisacritical
componentofthyroidhormone.WhenradioactiveiodineisgiventoapatientwithGravesdisease,thethyroidgland
quickly removes it from the bloodstream and sequesters the radioactive material within the glandular tissue. The
radioactivitythendestroysthehyperactivethyroidtissue,bringingthethyroidhormonelevelsbacktonormal.Most
oftheradiationisreceivedduringtherstfewweeksbecausethehalflifeof131Iisshort.
Othertechniquesincludedrugtherapywithagentsthatblockthenormaluseofiodinebythethyroidgland,and
thisformoftherapyisinitiallyfavoredinmostEuropeancenters.Thetwodrugsthathavebeenwidelyprescribedin
theUnitedStatesarepropylthiouracil(PTU)andmethimazole.PTUhasbeenassociatedwithlivertoxicityinsome
patients, and the US Food and Drug Administration has recommended that its use should be limited to specic
circumstances,suchasmethimazoleallergyorduringthersttrimesterofpregnancy.Sometimesmethimazolemay
be administered chronically in the hope that a remission may be induced. In addition, the thyroid gland, or a
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signicantportionofit,mayberemovedsurgically,therebyreducingthyroidhormoneproduction.Methimazoleis
often given prior to either surgical removal of the thyroid or treatment with radioactive iodine in order to bring
thyroidhormonelevelsintothenormalrange.
Drug therapy alone is often unsuccessful in controlling hyperthyroidism, and approximately half of patients
treated in this way will relapse. Unfortunately, with radioactive iodine and surgery, the risk of hypothyroidism is
relativelygreat,andthyroidhormonereplacementtherapyisoftenneeded.
Inapatientwithuncontrolledhyperthyroidism,adeniteriskexistswithrespecttoaninappropriatereleaseof
largeamountsofthyroidhormoneatonetime,resultinginaconditioncalledathyroidstorm.Athyroidstormmay
be precipitated by infection, psychologic trauma, or stress. Clinically, patients may have delirium, convulsions, an
elevated temperature (up to 106 F), and tachycardia (sometimes more than 140 beats/minute). Such individuals
shouldbehospitalizedimmediatelybecausethemortalityrateassociatedwiththyroidstormisapproximately20%.
The clinician should be aware of the potential for this problem, and patients with hyperthyroidism should ideally
havetheconditionundercontrolbeforedentaltreatment.
Hypoparathyroidism
Calcium levels in extracellular tissues are normally regulated by parathyroid hormone (PTH) (parathormone) in
conjunctionwithvitaminD.Ifcalciumlevelsdropbelowacertainpoint,thenthereleaseofPTHisstimulated.The
hormonethenactsdirectlyonthekidneyandtheosteoblastsofthebonetorestorethecalciumtonormallevels.In
thekidney,calciumreabsorptionispromoted,phosphateexcretionisenhanced,andtheproductionofvitaminDis
stimulated,whichincreasestheabsorptionofcalciumfromthegut.Osteoblastsarestimulatedtoproduceavariety
ofcytokinesthatsubsequentlyincreaseosteoclasticdierentiationandmetabolicallyactivatetheosteoclaststoresorb
bone,thusliberatingcalcium.
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
glandisexcisedforotherreasons,butsometimesitistheresultofautoimmunedestructionoftheparathyroidtissue.
Rare syndromes, such as DiGeorgesyndrome and the autoimmune polyendocrinopathycandidiasisectodermal
dystrophy syndrome (endocrinecandidiasis syndrome, autoimmune polyglandular syndrome, type 1), may be
associatedwithhypoparathyroidism.
ClinicalFeatures
Withthelossofparathyroidfunction,theserumlevelsofcalciumdrop,resultinginhypocalcemia.Oftenthepatient
withchronichypoparathyroidismadaptstothepresenceofhypocalcemiaandisasymptomaticunlesssituationsthat
further reduce the calcium levels are encountered. Such situations include metabolic alkalosis, as seen during
hyperventilation,whenastateoftetanymaybecomeevident.
Chvosteksignisanoralndingofsignicance,characterizedbyatwitchingoftheupperlipwhenthefacialnerve
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 piing enamel hypoplasia and failure of
tootheruptionmayoccur(Fig.1727).Thepresenceofpersistentoralcandidiasisinayoungpatientmaysignalthe
onset of autoimmune polyendocrinopathycandidiasisectodermal dystrophy syndrome (see page 196).
Hypoparathyroidismmaybeonlyoneofseveralendocrinedecienciesassociatedwiththiscondition.
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Hypoparathyroidism.Enamelhypoplasiahasaffectedthedentitionofthispatient,whohadhypoparathyroidismwhile
theteethwereforming.
FIG.1727
LaboratoryFindings
PTHcanbemeasuredbymeansofaradioimmunoassay.IfserumPTHlevelsaredecreasedinconjunctionwitha
decreasedserumcalciumconcentration,elevatedserumphosphatelevel,andnormalrenalfunction,thenadiagnosis
ofhypoparathyroidismcanbemade.
PatientswithhypoparathyroidismareusuallytreatedwithoraldosesofanactiveformofvitaminD,calcitriol(1,25
dihydroxycholecalciferol, vitamin D3). Additional supplements of dietary calcium are also typically necessary to
maintaintheproperserumcalciumlevels.Withthisregimen,patientscanoftenliveafairlynormallife.Teriparatide,
arecombinantformoftheactivecomponentofhumanparathormone,hasbeendevelopedbutisnotapprovedinthe
United States for management of hypoparathyroidism. Clinical trials have shown that, when given twice daily as
subcutaneous injections, this drug may have promise as an alternative management strategy for
hypoparathyroidism,althoughitisrelativelyexpensive.
Pseudohypoparathyroidism(AlbrightHereditary
OsteodystrophyAcrodysostosis)
Therareconditionknownaspseudohypoparathyroidismrepresentsatleasttwobroaddisordersinwhichnormal
parathyroidhormone(PTH)ispresentinadequateamountsbutthebiochemicalpathwaysresponsibleforactivating
thetargetcellsarenotfunctioningproperly.Theclinicalresultisapatientwhoappearstohavehypoparathyroidism.
InthecaseofpseudohypoparathyroidismtypeI,threesubcategorieshavebeendened.FortypeIa,amolecular
defect of a specic intracellular binding protein known as Gs seems to prevent the formation of cyclic adenosine
monophosphate (cAMP), a critical component in the activation of cell metabolism. Because other hormones also
requirebindingwithGstocarryouttheirfunctions,patientshavemultipleproblemswithotherendocrineorgans
andfunctions.Thisconditionisusuallyinheritedasanautosomaldominanttrait.
WithrespecttopseudohypoparathyroidismtypeIb,theproblemisthoughttobecausedbydefectivereceptorsfor
thePTHonthesurfaceofthetargetcells(theproximalrenaltubules).Forthisreason,nootherendocrinetissuesor
functionsareaected.Anautosomaldominantmodeofinheritancehasbeensuggestedforafewfamiliesaectedby
type Ib pseudohypoparathyroidism, but most cases are apparently sporadic. The mechanism of action for
pseudohypoparathyroidism type Ic is less clear, but it may involve a defect in adenylate cyclase or a subtle Gs
alteration.
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PseudohypoparathyroidismtypeIIischaracterizedbytheinductionofcAMPbyPTHinthetargetcells;however,
afunctionalresponsebythecellsisnotinvoked.Allofthereportedcasesofthisformofthediseaseappeartobe
sporadic.
ClinicalFeatures
Pseudohypoparathyroidism most commonly appears as type Ia disease. Patients aected by
pseudohypoparathyroidism,eithertypeIaorIc,haveacharacteristicarrayoffeaturesthatincludesmildintellectual
disability, 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.
Subcutaneouscalcications(osteomacutis)maybeidentiedinsomepatients.Otherendocrineabnormalitiesthat
aretypicallyencounteredincludehypogonadismandhypothyroidism.
PatientswithtypeIbandIIdiseaseclinicallyappearnormal,asidefromtheirsymptomsofhypocalcemia.
Dental manifestations of pseudohypoparathyroidism include generalized enamel hypoplasia, widened pulp
chamberswithintrapulpalcalcications,oligodontia,delayederuption,andbluntingoftheapicesoftheteeth.The
pulpalcalcicationsareoftendescribedasdaggershaped.
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
necessarytodelineatethevarioussubtypes.
PseudohypoparathyroidismismanagedbytheadministrationofvitaminDandcalcium.Theserumcalciumlevels
andurinarycalciumexcretionarecarefullymonitored.Becauseofindividualpatientdierences,themedicationmay
needtobecarefullyadjusted;however,theprognosisisconsideredtobegood.
Hyperparathyroidism
Excess production of parathyroid hormone (PTH) results in the condition known as hyperparathyroidism. PTH
normallyisproducedbytheparathyroidglandsinresponsetoadecreaseinserumcalciumlevels.
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
disturbanceiscausedbyanyoneofseveralinheritedsyndromes,includingmultipleendocrineneoplasiatype1or
type2a, or hyperparathyroidismjaw tumor syndrome. In the laer condition, aected patients develop multiple
jawlesionsthathistopathologicallyareconsistentwithcentralossifyingbroma(seepage602).Therealsoappearsto
beanincreasedriskforthesepatientstodevelopparathyroidcarcinoma.
SecondaryhyperparathyroidismdevelopswhenPTHiscontinuouslyproducedinresponsetochroniclowlevels
ofserumcalcium,asituationusuallyassociatedwithchronicrenaldisease.ThekidneyprocessesvitaminD,whichis
necessaryforcalciumabsorptionfromthegut.Therefore,inapatientwithchronicrenaldisease,activevitaminDis
notproducedandlesscalciumisabsorbedfromthegut,resultinginloweredserumcalciumlevels.
Mostpatientswithprimaryhyperparathyroidismareolderthan60yearsofage.Womenhavethisconditiontwoto
fourtimesmoreoftenthanmendo.Indevelopedcountries,theconditiontypicallyisidentiedonroutineserologic
testing,andthemajorityofpatientsarerelativelyasymptomatic.
Patients with the classic triad of signs and symptoms of hyperparathyroidism are described as having stones,
bones, and abdominal groans.Aected individuals are more likely to present with these signs and symptoms in
economicallylessdevelopedcountrieswhereserologicevaluationisnotdoneonaroutinebasis.
Stones refers to the fact that these patients, particularly those with primary hyperparathyroidism, have a
marked tendency to develop renal calculi (kidney stones, nephrolithiasis) because of the elevated serum calcium
levels. Metastatic calcications are also seen, frequently involving other soft tissues, such as blood vessel walls,
subcutaneoussofttissues,thesclera,thedura,andtheregionsaroundthejoints.
Bonesreferstoavarietyofosseouschangesthatmayoccurinconjunctionwithhyperparathyroidism.Oneof
therstclinicalsignsofthisdiseaseisseenradiographicallyassubperiostealresorptionofthephalangesoftheindex
andmiddlengers.Generalizedlossofthelaminadurasurroundingtherootsoftheteethisalsoseenasanearly
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manifestation of the condition (Fig. 1728). Alterations in trabecular paern characteristically develop next. A
decrease in trabecular density and blurring of the normal trabecular paern occur; often a ground glass
appearanceresults.
Hyperparathyroidism.Thisperiapicalradiographrevealsthegroundglassappearanceofthetrabeculaeandlossof
laminadurainapatientwithsecondaryhyperparathyroidism.(CourtesyofDr.RandyAnderson.)
FIG.1728
Withpersistentdisease,otherosseouslesionsdevelop,suchasthesocalledbrowntumorofhyperparathyroidism.
Thislesionderivesitsnamefromthecolorofthetissuespecimen,whichisusuallyadarkredbrownbecauseofthe
abundanthemorrhageandhemosiderindepositionwithinthetumor.Theselesionsappearradiographicallyaswell
demarcatedunilocularormultilocularradiolucencies(Fig.1729).Theycommonlyaectthemandible,clavicles,ribs,
andpelvis.Theymaybesolitarybutareoftenmultiple,andlongstandinglesionsmayproducesignicantcortical
expansion.Typically,theotherosseouschangesareobservableifbrowntumorsarepresent.Themostsevereskeletal
manifestationofchronichyperparathyroidismhasbeencalledosteitisbrosacystica,aconditionthatdevelopsfrom
the central degeneration and brosis of longstanding brown tumors. In patients with secondary
hyperparathyroidism caused by endstage renal disease (renal osteodystrophy; chronic kidney diseasemineral
andbonedisorder),strikingenlargementofthejawshasbeenknowntooccur(Fig.1730)andproduceaground
glassradiographicpaern(seeFig.1728).
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Hyperparathyroidism.Thisocclusalradiographoftheedentulousmaxillaryanteriorregionshowsamultilocular
radiolucencycharacteristicofabrowntumorofprimaryhyperparathyroidism.(CourtesyofDr.BrianBlocher.)
FIG.1729
Hyperparathyroidism.Palatalenlargementischaracteristicoftherenalosteodystrophyassociatedwithsecondary
hyperparathyroidism.
FIG.1730
Abdominal groans refers to the tendency for the development of duodenal ulcers. In addition, changes in
mentalstatusareoftenseen,rangingfromlethargyandweaknesstoconfusionordementia.
Thebrowntumorofhyperparathyroidismishistopathologicallyidenticaltothecentralgiantcellgranulomaofthe
jaws, a benign tumorlike lesion that usually aects teenagers and young adults (see page 584). Both lesions are
characterized by a proliferation of exceedingly vascular granulation tissue, which serves as a background for
numerous multinucleated osteoclasttype giant cells (Fig. 1731). Some lesions may also show a proliferative
responsecharacterizedbyaparallelarrangementofspiculesofwovenbonesetinacellularbroblasticbackground
with variable numbers of multinucleated giant cells (Fig. 1732). This paern is often associated with secondary
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hyperparathyroidismrelatedtochronicrenaldisease(renalosteodystrophy).
Hyperparathyroidism.Thishighpowerphotomicrographofabrowntumorofhyperparathyroidismshowsscattered
multinucleatedgiantcellswithinavascularandproliferativefibroblasticbackground.
FIG.1731
Hyperparathyroidism.Thismediumpowerphotomicrographshowstrabeculaeofcellularwovenboneandclustersof
multinucleatedgiantcellswithinabackgroundofcellularfibrousconnectivetissue.Thesefeaturesarecharacteristicoftissue
changesseeninrenalosteodystrophy.
FIG.1732
In primary hyperparathyroidism, the hyperplastic parathyroid tissue or the functional tumor must be removed
surgicallytoreducePTHlevelstonormal.Localizationoftheparathyroidadenomaisoftenfacilitatedbyasestamibi
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scan,whichisanuclearmedicinetechniqueusingatechnetium99labeledsmallproteinthatispreferentiallytaken
up by the tumor. Such tumors are frequently removed by a minimally invasive surgical technique, and
intraoperativeassessmentoftheadequacyofexcisioncanbedeterminedbynotingadropinparathormonelevels
within10minutesofremovingtheadenoma.
Secondary hyperparathyroidism may evolve to produce signs and symptoms related to renal calculi or renal
osteodystrophy. Restriction of dietary phosphate, use of phosphatebinding agents, and pharmacologic treatment
withanactivevitaminDmetabolite(e.g.,calcitriol)andacalcimimeticagent,suchascinacalcet,mayavertproblems.
Cinacalcet sensitizes the calcium receptors of the parathyroid cells to extracellular calcium, causing the cells to
reduce their output of parathormone. Exposure to aluminum salts, which inhibit bone mineralization, should be
eliminated also. Patients who do not respond to medical therapy may require parathyroidectomy. Renal
transplantation may restore the normal physiologic processing of vitamin D, as well as phosphorus and calcium
reabsorptionandexcretion;however,thisdoesnotoccurineverycase.
Hypercortisolism(CushingSyndrome)
Hypercortisolismisaclinicalconditionthatresultsfromasustainedincreaseinglucocorticoidlevels.Inmostcases
this increase is due to corticosteroid therapy that is prescribed for other medical purposes. The increase is less
commonly caused by an endogenous source, such as production of adrenocorticotropic hormone (ACTH) by an
adrenaltumororpituitaryadenoma.Ifapituitaryadenomaisresponsible,thenthetermCushingdiseaseisapplied.
Thisconditionisratherrareandusuallyaectsyoungadultwomen.
ClinicalFeatures
The signs of Cushing syndrome usually develop slowly. The most consistent clinical observation is weight gain,
particularly in the central areas of the body. The accumulation of fat in the dorsocervical spine region results in a
bualo hump appearance; fay tissue deposition in the facial area results in the characteristic rounded facial
appearanceknownasmoonfacies(Fig.1733).Othercommonndingsincludethefollowing:
Redpurpleabdominalstriae
Hirsutism
Poorhealing
Osteoporosis
Hypertension
Moodchanges(particularlydepression)
Hyperglycemiawiththirstandpolyuria
Musclewastingwithweakness
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CushingSyndrome.Theroundedfacialfeatures(moonfacies)ofthispatientareduetotheabnormaldepositionof
fat,whichisinducedbyexcesscorticosteroidhormone.(CourtesyofDr.GeorgeBlozis.)
FIG.1733
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 and
symptomsdescribedearlier.Thediagnosismaybemorediculttoestablishinpatientswithafunctioningadrenal
cortical tumor or an ACTHsecreting pituitary adenoma. Evaluation of these patients should include the
measurement of free cortisol in the urine and an assay of the eect of dexamethasone (a potent articial
corticosteroid)ontheserumACTHandcortisollevels.Inanunaectedpatient,thelevelsoffreecortisolshouldbe
within normal limits, and the administration of an exogenous corticosteroid, such as dexamethasone, should
suppressthenormallevelofACTH,withaconcomitantdecreaseinthecortisollevels.Becausefunctioningtumors
donotrespondtonormalfeedbackmechanisms,theanticipateddecreasesinACTHandcortisolwouldnotbeseen
inapatientwithsuchatumor.
The clinician should be aware of the signs and symptoms of hypercortisolism to refer aected patients for
appropriateendocrinologicevaluationanddiagnosis.Oncethediagnosisisestablishedandthecauseisdetermined
tobeanadrenalorpituitarytumor,surgicalremovalofthelesionisthetreatmentofchoice.Radiationtherapyalso
maybeeective,particularlyinyoungerpatients.Forpatientswithunresectabletumors,drugsthatinhibitcortisol
synthesis (such as, ketoconazole, metyrapone, or aminoglutethimide) may be used to help control the excess
productionofcortisol.
Mostcasesofhypercortisolism,however,arecausedbysystemiccorticosteroidtherapythatisgivenforavariety
ofimmunologicreasons,includingtreatmentofautoimmunediseasesandallogeneictransplantrecipients.Certain
strategies,suchastheuseofcorticosteroidsparingagentsoralternatedaytherapy,mayminimizethecorticosteroid
doseneeded.Thegoalshouldbeforpatientstousethelowestdosepossibletomanageimmunologicdisease.
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In normal situations, cortisol is critical to the function of the body, particularly in dealing with stress. As the
hormoneismetabolizedandserumlevelsdrop,feedbacktothepituitaryglandsignalsittoproduceACTH,which
stimulatestheadrenalglandtoproduceadditionalcortisol.Unfortunately,therapeuticcorticosteroidssuppressthe
productionofACTHbythepituitaryglandtotheextentthatthepituitaryglandmaynotbeabletoproduceACTH
inresponsetostress,andanacuteepisodeofhypoadrenocorticism(addisoniancrisis)maybeprecipitated.Therefore,
theclinicianmustbeawareofthepotentialsideeectsofchronichighdosecorticosteroiduseandmustbeableto
adapt the treatment of the patient accordingly. For stressful dental and surgical procedures especially, it is often
necessarytoincreasethecorticosteroiddosebecauseofthegreaterneedofthebodyforcortisol.Consultationwith
thephysicianwhoismanagingthecorticosteroidtherapyisadvisedtodeterminetowhatextentthedoseshouldbe
adjusted.
AddisonDisease(Hypoadrenocorticism)
Insucientproductionofadrenalcorticosteroidhormonescausedbythedestructionoftheadrenalcortexresultsin
theconditionknownasAddisondisease,orprimaryhypoadrenocorticism.Theincidenceofnewcasesdiagnosed
in the Western hemisphere is approximately 4 per million population per year, while the prevalence is about 140
casespermillionpeople.Thecausesarediverseandincludethefollowing:
Autoimmunedestruction(mostcommoncauseinWesternsocieties)
Infections(e.g.,tuberculosisanddeepfungaldiseases,particularlyinpatientswithacquiredimmunodeciency
syndrome[AIDS])
Rarely,metastatictumors,sarcoidosis,hemochromatosis,oramyloidosis
If the pituitary gland is not functioning properly, secondary hypoadrenocorticism may develop because of
decreasedproductionofACTH,thehormoneresponsibleformaintainingnormallevelsofserumcortisol.
ClinicalFeatures
Theclinicalfeaturesofhypoadrenocorticismdonotactuallybegintoappearuntilatleast90%oftheglandulartissue
has been destroyed. With gradual destruction of the adrenal cortex, an insidious onset of fatigue, irritability,
depression,weakness,andhypotensionisnotedoveraperiodofmonths.Ageneralizedhyperpigmentationofthe
skinoccurs,classicallydescribedasbronzing.Thehyperpigmentationisgenerallymoreprominentonsunexposed
skin and over pressure points, such as the elbows and knees; it is caused by increased levels of betalipotropin 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, due to hyponatremia caused by
lackofthemineralocorticoid,aldosterone.Whenhypoadrenocorticismisaccompaniedbyhypoparathyroidismand
mucocutaneous candidiasis, the possibility of autoimmune polyendocrinopathycandidiasisectodermal dystrophy
syndromeshouldbeconsidered(seepage196).
The oral manifestations include diuse or patchy, brown, macular pigmentation of the oral mucosa caused by
excessmelaninproduction(Fig.1734).Oftentheoralmucosalchangesaretherstmanifestationofthedisease,with
theskinhyperpigmentationoccurringafterward.Sometimestheoralhypermelanosismaybediculttodistinguish
from physiologic racial pigmentation, but a history of a recent onset of oral pigmentation should suggest the
possibilityofAddisondisease.
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FIG.1734
AddisonDisease.DiffusepigmentationofthemaxillaryfacialgingivainapatientwithAddisondisease.(CourtesyofDr.John
Kalmar.)
LaboratoryFindings
The diagnosis of hypoadrenocorticism is conrmed by a rapidACTH stimulation test and measurement of serum
cortisol levels and plasmaACTH levels. If serum cortisol levels are below 18 g/dL, then the patient has adrenal
insuciency. In primary hypoadrenocorticism, the plasma ACTH levels are high (>100 ng/L). In secondary
hypoadrenocorticism,thelevelsarenormal(9to52ng/L)orlow,aswouldbeexpectedbecausetheconditionresults
fromdecreasedACTHproductionbythepituitarygland.
Addison disease is managed with replacement therapy, including both a glucocorticoid (such as, hydrocortisone)
and mineralocorticoid (such as, udrocortisone). The physiologic dose of glucocorticoid is considered to be
approximately30to45mgofhydrocortisoneoritsequivalentperday,usuallygivenindivideddoses.Becausethe
bodysneedforcorticosteroidhormonesincreasesduringstressfulevents,thepatientmusttakethisintoaccountand
increasethedoseaccordingly.Thisadjustmentisgenerallynotrequiredfordentalproceduresperformedusinglocal
anesthesiaandlastinglessthan1hour,butanincreaseddosemaybenecessaryforcertaindentalandoralsurgical
proceduresthataremorelengthyoraredoneundergeneralanesthesia.
Beforetheavailabilityofcorticosteroids,theprognosisforpatientswithhypoadrenocorticismwaspoor,withmost
patientssurvivinglessthan2years.Eventoday,iftheconditionisnotrecognizedpromptly,deathmayresultina
relativelyshortperiodoftime.Withproperdiagnosisandmanagement,mostpatientswithhypoadrenocorticismcan
expecttohaveanormallifespan,althougharecentpopulationbasedstudysuggestedanincreasedmortalityrate
relatedtomalignancyandcardiovasculardisease.
DiabetesMellitus
Diabetesmellitusisacommondisorderofcarbohydratemetabolismthatisthoughttohaveseveralcauses,although
thebasicproblemisoneofeitherdecreasedproductionofinsulinortissueresistancetotheeectsofinsulin.Thenet
resultofthisabnormalstateisanincreaseinthebloodglucoselevel(hyperglycemia).
Diabetesmellitusisusuallydividedintotwopresentations:
1.TypeIcharacterizedbycomplete,ornearlycomplete,lackofinsulinproduction
2.TypeIIcharacterizedbyinadequateinsulinproductionorresistanceoftargettissuestotheeectsofinsulin
TypeIdiabetesmellituswasformerlyknownasinsulindependentdiabetesmellitusorjuvenileonsetdiabetes,
but these terms are not considered to be accurate. Type II diabetics often require insulin injections in order to
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manage their disease, and from 5% to 10% of type 1 diabetics develop their disease after 30 years of age. Patients
with type 1 diabetes mellitus usually exhibit severe hyperglycemia and ketoacidosis without treatment, and they
requireexogenousinsulininjectionstosurvive.
TypeIIdiabetesmellitusissometimesmorediculttodiagnose.Itusuallyoccursinolder,obeseadults,butit
maybeseeninobeseadolescentsaswell.Forthisreason,thetermadultonsetdiabeteswasabandoned.Although
hyperglycemia is present, ketoacidosis rarely develops. Furthermore, patients can produce some endogenous
insulin.Certainpatientsmayrequireinsulintohelpcontroltheirdisease;theinsulininjections,however,areusually
notnecessaryforthepatientssurvival.
Withrespecttoepidemiology,intheUnitedStatesdiabetesmellitusaectsapproximately8%ofthepopulation,or
26millionpeople,althoughapproximately6millionofthesecasesremainundiagnosed.Morethan1.5millionnew
casesareidentiedeachyearintheUnitedStates.Oftheseaectedpatients,mosthavetypeIIdiabetes;only5%to
10%havetypeI.
Diabetesisanimportantdiseasewhenweconsiderthemanycomplicationsassociatedwithitandtheeconomic
eect it has on society. One of the main complications of diabetes is peripheral vascular disease, a problem that
resultsinkidneyfailure,aswellasischemiaandgangrenousinvolvementofthelimbs.Bysomeestimates,25%ofall
new cases of kidney failure occur in diabetic patients. Thus diabetes is the leading cause of kidney failure in the
UnitedStates.Eachyearmorethan50,000amputationsareperformedforthegangrenouscomplicationsofdiabetes.
ThisdiseaseistheleadingcauseoflowerlimbamputationsintheUnitedStates.Retinalinvolvementoftenresultsin
blindness;thustheleadingcauseofnewcasesofblindnessinworkingageadultsintheUnitedStatesisdiabetes,
withmorethan12,000peopleaectedannually.Complicationsbecauseofdiabetesareestimatedtocontributetothe
deathsofmorethan200,000Americanseachyear.
Thecauseofdiabetesmellitusisessentiallyunknown,althoughmostcasesoftypeIdiabetesappeartobecaused
byautoimmunedestructionofthepancreaticisletcells,andthisimmunologicaackmaybeprecipitatedbyaviral
infection in a genetically susceptible individual. Type II diabetes does not appear to have an autoimmune cause,
however,becausenodestructionoftheisletcellsisseenmicroscopically.Instead,geneticabnormalitieshavebeen
detectedinpatientswithcertaintypesoftypeIIdiabetes,whichmayexplainwhytheconditionoccurssooftenin
families.IfoneparentisaectedbytypeIIdiabetes,thenthechancesofachildhavingthedisorderisabout40%.
Similarly,ifoneidenticaltwinhastypeIIdiabetes,thenthechancesare90%thatthediseasewillalsodevelopinthe
othertwin.
ClinicalFeatures
Althoughacompletereviewofthepathophysiologyofdiabetesmellitusisbeyondthescopeofthistext,theclinical
signs and symptoms of a patient with this disease are easier to understand with some basic knowledge of the
process.Thehormoneinsulin,producedbythebetacellsofthepancreaticisletsofLangerhans,isnecessaryforthe
uptakeofglucosebythecellsofthebody.Wheninsulinbindstoitsspeciccellsurfacereceptor,aresultingcascade
ofintracellularmoleculareventscausestherecruitmentofintracellularglucosebindingproteins,whichfacilitatethe
uptakeofglucosebyeachcell.
TypeIDiabetesMellitus
Because patients with type I diabetes have a deciency in the amount of insulin, the bodys cells cannot absorb
glucoseanditremainsintheblood.Normalbloodglucoselevelsarebetween70and120mg/dL;indiabeticpatients,
theselevelsareoftenbetween200and400mg/dL.Above300mg/dL,thekidneyscannolongerreabsorbtheglucose;
therefore,itspillsoverintotheurine.Becauseglucoseisthemainsourceofenergyforthebody,andbecausenoneof
thisenergycanbeusedbecauseglucosecannotbeabsorbed,thepatientfeelstiredandlethargic.Thebodybeginsto
use other energy sources, such as fat and protein, resulting in the production of ketones as a byproduct of those
energyconsumptionpathways.Thepatientoftenlosesweight,despiteincreasedfoodintake(polyphagia).Withthe
hyperglycemia, the osmolarity of the blood and urine increases. The increased osmolarity results in frequent
urination(polyuria) and thirst, which leads to increased water intake (polydipsia). Clinically, most patients with
typeIdiabetesareyounger(averageageatdiagnosisbeing14years),andtheyhaveathinbodyhabitus.
TypeIIDiabetesMellitus
Bycontrast,patientswithtypeIIdiabetesareusuallyolderthan40yearsofageatdiagnosis,and80%to90%ofthem
areobese.Inthissituation,itisthoughtthatadecreaseinthenumberofinsulinreceptorsorabnormalpostbinding
moleculareventsrelatedtoglucoseuptakeresultsinglucosenotbeingabsorbedbythebodyscells.Thuspatients
aresaidtoshowinsulinresistancebecauseseruminsulinlevelsareusuallywithinnormallimitsorevenelevated.
If the hyperglycemia is taken into account, however, the amount of circulating insulin is typically not as much as
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would be present in a normal person with a similar level of blood glucose. Therefore, many of these patients are
describedashavingarelativelackofinsulin.
ThesymptomsassociatedwithtypeIIdiabetesaremuchmoresubtleincomparisontothoseseenwithtypeI.The
rstsignoftypeIIdiabetesisoftendetectedwithroutinehematologicexaminationratherthananyspecicpatient
complaint. Ketoacidosis is rarely seen in patients with type II diabetes. Nevertheless, many of the other
complicationsofdiabetesarestillassociatedwiththisformofthedisease.
Complications
Many complications of diabetes mellitus are directly related to the microangiopathy caused by the disease. The
microangiopathyresultsinocclusionofthesmallbloodvessels,producingperipheralvasculardisease.Theresultant
decreaseintissueperfusionresultsinischemia.Theischemiapredisposesthepatienttoinfection,particularlysevere
infections such as gangrene. Another contributing factor is the impairment of neutrophil function, particularly
neutrophilchemotaxis.
Amputation of the lower extremity often is necessary because of the lack of tissue perfusion and the patients
inabilitytocopewithinfection.Similarvascularocclusionmayaectthecoronaryarteries(whichplacesthepatient
at risk for myocardial infarction) or the carotid arteries and their branches (predisposing the patient to
cerebrovascular accident, or stroke). When microvascular occlusion aects the retinal vessels, blindness typically
results.Kidneyfailureistheoutcomeofrenalbloodvesselinvolvement.IftheketoacidosisisnotcorrectedintypeI
diabetes,thepatientmaylapseintoadiabeticcoma.
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. Diuse, nontender,
bilateralenlargementoftheparotidglands,calleddiabeticsialadenosis(seepage437),maybeseeninpatientswith
eitherformofdiabetes.Inuncontrolledorpoorlycontrolleddiabeticpatients,astrikingenlargementanderythema
oftheaachedgingivahasbeendescribed(Fig.1735).Inaddition,thesepatientsappeartobemoresusceptibleto
oral candidiasis in its various clinical forms (see page 191). Erythematous candidiasis, which appears as central
papillaryatrophyofthedorsaltonguepapillae,isreportedinupto30%ofthesepatients.Mucormycosis(seepage
208) may occur in patients with poorly controlled type I diabetes. Some investigators have identied an increased
prevalenceofbenignmigratoryglossitis(seepage726) in patients with type I diabetes; however, others have not
beenabletoconrmthisnding.Xerostomia,asubjectivefeelingofdrynessoftheoralmucosa,hasbeenreportedas
a complaint in onethird of diabetic patients. Unfortunately, studies that aempt 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,nodierencefromnormal;andsome,anincreasedsalivaryowrate.
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DiabetesMellitus.A,Thisdiffuse,erythematousenlargementofthegingivaltissuesdevelopedinadiabeticpatientwho
discontinuedtakingherinsulin.B,Thegingivaltissueshavegreatlyimprovedafterreinstitutionofregularinsulininjections.
Severalincisorswereextractedbecauseofsevereperiodontalboneloss.
FIG.1735
ForpatientswithtypeIIdiabetes,dietarymodicationcoupledwithexercisemaybetheonlytreatmentnecessary,
with the goal being weight loss. The dietary and lifestyle changes may need to be coupled with one or more oral
hypoglycemic agents. These drugs are designed to aect dierent pathophysiologic aspects of the disease. For
example,secretagoguesincreasetheinsulinsupply.Theseincludethesecondgenerationsulfonylureamedications,
such as glipizide or glyburide. Metformin is a biguanide that increases glucose utilization and decreases insulin
resistance and hepatic glucose production. Thiazolidinediones, such as rosiglitazone and pioglitazone, also reduce
insulinresistance.Acarboseandmiglitolareglucosidaseinhibitorsthatreducetheabsorptionofglucosefromthe
gastrointestinaltractbyinhibitingenzymaticdegradationofmorecomplexsugars.Ifthesemodalitiesdonotcontrol
thebloodglucoselevels,thentreatmentwithinsulinisnecessary.
ForpatientswithtypeIdiabetes,injectionsofinsulinarerequiredtocontrolbloodglucoselevels.Dierenttypes
of insulin are marketed, each type having dierent degrees of duration and times of peak activity. Insulin was
previously extracted primarily from beef and pork pancreata. In some patients, however, antibodies developed to
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this foreign protein and rendered the insulin useless. To overcome this problem, pharmaceutical companies have
developedbrandsofinsulinthathavethemolecularstructureofhumaninsulin.Laboratoriesproducethishuman
insulinwithgeneticallyengineeredbacteriausingrecombinantDNAtechnology.
Thepatientsscheduleofinsulininjectionsmustbecarefullystructuredandmonitoredtoprovideoptimalcontrol
ofbloodglucoselevels.Thisscheduleiscarefullyformulatedbythepatientsphysicianandtakesintoaccountsuch
factorsasthepatientsactivitylevelandtheseverityoftheinsulindeciency.Itisimperativethatadequatedietary
carbohydrates be ingested after the administration of the insulin; otherwise, a condition known as insulin shock
may occur. If carbohydrates are not consumed after an insulin injection, then the blood glucose levels may fall to
dangerouslylowlevels.Thebrainisvirtuallydependentonbloodglucoseasitsenergysource.Ifthebloodglucose
level drops below 40 mg/dL, the patient may go into shock. This condition can be treated by administration of
sublingualdextrosepaste,IVinfusionofadextrosesolution,orinjectionofglucagon.
Insummary,diabetesmellitusisacommon,complexmedicalproblemwithmanycomplications.Theprognosisis
guarded.Studiessuggestthatstrictcontrolofbloodglucoselevelsresultsinaslowingofthedevelopmentofthelate
complicationsoftypeIdiabetes(e.g.,blindness,kidneydamage,andneuropathy)andreducesthefrequencyofthese
complications. Health care practitioners should be aware of the problems these patients may have and should be
prepared to deal with them. Consultation with the patients physician may be necessary, particularly for patients
withtypeIdiabetesthatshowpoorbloodglucosecontrol,haveactiveinfections,orrequireextensiveoralsurgical
procedures.
Hypophosphatasia
Hypophosphatasiaisararemetabolicbonediseasethatischaracterizedbyadeciencyoftissuenonspecicalkaline
phosphatase. Approximately 150 distinct mutations of the gene responsible for alkaline phosphatase production
havebeendescribed.Oneoftherstpresentingsignsofhypophosphatasiamaybetheprematurelossoftheprimary
teeth,presumablycausedbyalackofcementumontherootsurfaces.Inthehomozygousautosomalrecessiveform,
thereareratherseveremanifestations,andmanyofthesepatientsareidentiedininfancy.Themilderformsofthe
diseaseareinheritedinanautosomaldominantorrecessivefashion,appearinginchildhoodorevenadulthood,with
variabledegreesofexpression.Generally,theyoungertheageofonset,themoreseveretheexpressionofthedisease.
Thecommonfactorsinalltypesincludethefollowing:
Reducedlevelsofthebone,liver,andkidneyisozymeofalkalinephosphatase
Increasedlevelsofbloodandurinaryphosphoethanolamine
Boneabnormalitiesthatresemblerickets
Mostauthoritiesbelievethatthedecreasedalkalinephosphataselevelsprobablyareresponsiblefortheclinically
observed abnormalities. Alkaline phosphatase is thought to play a role in the production of bone, but its precise
mechanismofactionisunknown.
Sixtypesofhypophosphatasiaarenowrecognized,dependingontheseverityandtheageofonsetofthesymptoms:
1.Perinatallethal
2.Perinatalbenign
3.Infantile
4.Childhood
5.Adult
6.Odontohypophosphatasia
PerinatalLethalHypophosphatasia
Theperinatallethalformhasthemostseveremanifestations.Itisusuallydiagnosedatbirth,andtheinfantrarely
survives for more than a few hours. Death is due to respiratory failure. Marked hypocalcication of the skeletal
structuresisobserved.
PerinatalBenignHypophosphatasia
Theperinatalbenignformofhypophosphatasiaappearssimilartothelethalform,buttheseinfantshaveaclinical
course similar to infantile hypophosphatasia. Some investigators have noted that skeletal calcication may be
detectedinsomeofthesefetusesduringthethirdtrimesterofpregnancy,incontrasttothelethalform.
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InfantileHypophosphatasia
Babiesaectedbyinfantilehypophosphatasiamayappearnormalupto6monthsofage;afterthistime,theybegin
toshowafailuretogrow.Vomitingandhypotoniamaydevelopaswell.Skeletalmalformationsthatsuggestrickets
aretypicallyobserved;thesemalformationsincludeshortened,bowedlimbs.Deformitiesoftheribspredisposethese
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
deciduousteethisoftenseen.
ChildhoodHypophosphatasia
Thechildhoodformisusuallydetectedatalaterageandhasawiderangeofclinicalexpression.Oneofthemore
consistent features is the premature loss of the primary teeth without evidence of a signicant inammatory
response(Figs.1736 and 1737). The deciduous incisor teeth are usually aected 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 aected
patientsmayhaveopenfontanelleswithprematurefusionofcranialsutures.Thisearlyfusionoccasionallyleadsto
increasedintracranialpressureandsubsequentbraindamage.Aectedpatientstypicallyhaveashortstature,bowed
legs,andawaddlinggait.Thedevelopmentofmotorskillsisoftendelayed.
FIG.1736
Hypophosphatasia.Prematurelossofthemandibularanteriorteeth.(CourtesyofDr.JackieBanahan.)
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FIG.1737
Hypophosphatasia.Thispanoramicradiographshowsthelossofthemandibularanteriorteeth.(CourtesyofDr.Jackie
Banahan.)
Radiographically, the skull of more severely aected individuals may show uniformly spaced, poorly dened,
smallradiolucencies,apaernthathasbeendescribedasresemblingbeatencopper.Thisappearancemaybethe
resultofareasofthinningoftheinnercorticalplateproducedbythecerebralgyri.
AdultHypophosphatasia
The adult form is typically mild. Patients often have a history of premature loss of their primary or permanent
dentition, and many of these patients are edentulous. Stress fractures that involve the metatarsal bones of the feet
may be a presenting sign of the condition, or an increased number of fractures associated with relatively minor
traumamayalertthecliniciantothisdisorder.
Odontohypophosphatasia
Thisformofhypophosphatasiaisperhapsthemostcontroversial.Aectedpatientspresentwithprematurelossof
the incisor teeth as the only clinical sign of disease, although serologic studies will be consistent with
hypophosphatasia. Some investigators have suggested that this may simply represent a mild expression of the
disorder.
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,assomepatientsgrowolder,serumalkalinephosphataselevelsmayapproachnormal.
Thehistopathologicevaluationofbonesampledfromapatientaectedwiththeinfantileformofhypophosphatasia
shows abundant production of poorly mineralized osteoid. In the childhood or adult form, the bone may appear
relativelynormaloritmayshowanincreasedamountofwovenbone,whichisalessmatureformofosseoustissue.
Thehistopathologicexaminationofeitheraprimaryorpermanenttooththathasbeenexfoliatedfromanaected
patientoftenshowsanabsenceoramarkedreductionofcementumthatcoverstherootssurface(Fig.1738). This
reducedamountofcementumisthoughttopredisposetotoothlossbecauseoftheinabilityofperiodontalligament
berstoaachtothetoothandtomaintainitinitsnormalposition.
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Hypophosphatasia.Thismediumpowerphotomicrographofanexfoliatedtoothshowsnocementumassociatedwith
therootsurface.
FIG.1738
The treatment of hypophosphatasia is essentially symptomatic because the lack of alkaline phosphatase cannot be
corrected. Aempts to treat this condition by infusing alkaline phosphatase have been unsuccessful, presumably
because the enzyme functions within the cell rather than in the extracellular environment. Basically, fractures are
treated with orthopedic surgery, followed by rehabilitation. Prosthetic appliances are indicated to replace missing
teeth,butsatisfactoryresultsarenotalwayspossiblebecausethealveolarboneishypoplastic.Inpatientswhoare
skeletally mature, dental implants have also been used successfully in managing the edentulous spaces. Because
mutationalanalysisofDNAcanidentifycarriersofthedefectivegene,patientsandtheirparentsshouldbeprovided
with genetic counseling. As stated earlier, the prognosis varies with the onset of symptoms; the perinatal and
infantile types are associated with a rather poor outcome. The childhood and adult forms are usually compatible
withanormallifespan.
VitaminDResistantRickets(HereditaryHypophosphatemia
FamilialHypophosphatemicRickets)
AftertheuseofvitaminDtotreatricketsbecamewidespread,itwasrecognizedthatsomeindividualswithclinical
features characteristic of rickets did not seem to respond to therapeutic doses of the vitamin. For this reason, this
condition in these patients was called vitamin Dresistant rickets. Most cases of this rare condition appear to be
inherited as an Xlinked dominant trait; therefore, males are usually aected more severely than females, who
presumably have aenuated features because of lyonization. In the United States, this condition occurs at a
frequency of 1 in 20,000 births. In addition to the rachitic changes, these patients are also hypophosphatemic and
showadecreasedcapacityforreabsorptionofphosphatefromtherenaltubules.Thedisorderiscausedbymutations
in a zinc metalloproteinase gene known as phosphateregulating gene with endopeptidase activity on the X chromosome
(PHEX).Althoughtheprecisemechanismsofactionofthisgeneareunclear,itappearstoplayaroleinvitaminD
metabolism.
In contrast, patients aected by the rare autosomal recessive condition known as vitamin Ddependent rickets
exhibit hypocalcication of the teeth, unlike those with vitamin Dresistant rickets. Otherwise, the two disorders
have similar clinical features. Vitamin Ddependent rickets is caused by a lack of 1hydroxylase, the enzyme
responsibleforconvertingtherelativelyinactivevitaminDprecursor,25hydroxycholecalciferol(calcifediol)tothe
active metabolite 1,25dihydroxycholecalciferol (calcitriol) in the kidney. Therefore, these patients respond to
replacementtherapywithactivevitaminD(calcitriol).
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ClinicalFeatures
PatientswithvitaminDresistantricketshaveashortstature.Theupperbodysegmentappearsmorenormal,but
thelowerbodysegmentisshortened.Thelowerlimbsaregenerallyshortenedandbowed.
Laboratory investigation reveals hypophosphatemia with diminished renal reabsorption of phosphate and
decreasedintestinalabsorptionofcalcium.Thistypicallyresultsinrachiticchangesthatareunresponsivetovitamin
D(calciferol).Withaging,ankylosisofthespinefrequentlydevelops.
From a dental standpoint, the teeth have large pulp chambers, with pulp horns extending almost to the
dentinoenameljunction(Figs.1739and1740).Insomecasesthecuspalenamelmaybeworndownbyaritionto
thelevelofthepulphorn,causingpulpalexposureandpulpdeath.Theexposuremaybesosmallthattheresulting
periapicalabscessesandgingivalsinustractsseemtoaectwhatappeartobeotherwisenormalteeth(Fig.1741).
Studieshavealsoshownthatmicrocleftsmaydevelopintheenamel,givingtheoralmicrooraaccesstothedentinal
tubulesandsubsequentlytothepulp.Onestudyexaminedaseriesofaectedchildrenandfoundthat25%ofthese
patientshadmultipleabscessesinvolvingtheprimarydentition.Aectedadultsalsohaveanincreasedfrequencyof
endodontic problems, with an average of approximately seven endodontically treated teeth per person in people
over40yearsofage,comparedtotwoendodonticallytreatedteethperpersoninamatchedcontrolgroup.
VitaminDResistantRickets.Thisradiographofanextractedtoothshowsaprominentpulpchamberwithpulphorns
extendingouttowardthedentinoenameljunction.
FIG.1739
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VitaminDResistantRickets.GroundsectionofthesametoothdepictedinFig.1739.Apulphornextendstothe
dentinoenameljunction.(CourtesyofDr.CarlWitkop.)
FIG.1740
VitaminDResistantRickets.Thispatientexhibitsmultiplenonvitalteethwithassociatedparulides.Thisaroseinthe
absenceofcariesortrauma.
FIG.1741
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,whichoftenexhibitsclefting.Thecleftsmayextendfromthepulpchambertothedentinoenameljunction.
Microclefts are also seen within the enamel. The pulp frequently is nonvital, presumably because of the bacterial
contaminationassociatedwithboththeenamelandthedentinalclefts.
Foranormalstaturetodevelop,patientswithvitaminDresistantricketsusuallyneedearlytreatmentwithcalcitriol
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and multiple daily doses of phosphate. Endodontic therapy is necessary for the pulpally involved teeth. Initiating
therapy in early childhood with a synthetic vitamin D compound (1hydroxycholecalciferol) appears to reduce
dentalproblemsinaectedpatientswhencomparedwithuntreatedhistoriccontrols.Interestingly,theradiographic
dentalabnormalitiesdonotseemtobeimproved.Someinvestigatorshavesuggestedthatapplicationofthenewer
dental sealants may reduce the frequency of pulpal necrosis, but longterm followup studies will be necessary to
conrmthis.Althoughserumandurinecalciumlevelsmustbemonitoredcarefullytopreventnephrocalcinosiswith
itspotentialforkidneydamage,patientsgenerallyhaveanormallifespan.
CrohnDisease(RegionalIleitisRegionalEnteritis)
Crohndisease is an inammatory and probably an immunologically mediated condition of unknown cause that
primarily aects the distal portion of the small bowel and the proximal colon. It is now well established that the
manifestationsofCrohndiseasemaybeseenanywhereinthegastrointestinaltract,fromthemouthtotheanus.In
addition, other extraintestinal sites of disease involvement (such as, the skin, eyes, and joints) have also been
identied.Theorallesionsaresignicantbecausetheymayprecedethegastrointestinallesionsinasmanyas30%of
thecasesthathavebothoralandgastrointestinalinvolvement.ItisinterestingthattheprevalenceofCrohndisease
appearstobeincreasing,butthereasonsforthisincreasehavenotbeendetermined.Familialclusteringofcaseshas
suggestedthatgeneticfactorsplayaroleinthepathogenesisofthisdisease.
ClinicalFeatures
MostpatientswithCrohndiseaseareteenagerswhenthediseaserstbecomesevident,althoughanotherdiagnostic
peakofdiseaseactivityoccursinpatientsmorethan60yearsofage.Gastrointestinalsignsandsymptomsusually
include abdominal cramping and pain, nausea, and diarrhea, occasionally accompanied by fever. Weight loss and
malnutritionmaydevelop,whichcanleadtoanemia,decreasedgrowth,andshortstature.
A wide range of oral lesions has been clinically reported in Crohn disease; however, many of the abnormalities
describedarerelativelynonspecicandmaybeassociatedwithotherconditionsthatcauseorofacialgranulomatosis
(seepage312).Themoreprominentndingsincludediuseornodularswellingoftheoralandperioraltissues,a
cobblestoneappearanceofthemucosa,anddeep,granulomatousappearingulcers.Theulcersareoftenlinearand
developinthebuccalvestibule(Fig.1742). Patchy erythematous macules and plaques involving the aached and
unaachedgingivaehavebeentermedmucogingivitisandmayrepresentoneofthemorecommonlesionsrelatedto
Crohn disease. Soft tissue swellings that resemble denturerelated brous hyperplasia may be seen, as well as
smallermucosaltags.Anothermanifestationthathasbeenreportedisaphthouslikeoralulcerations,althoughthe
signicance of this nding is uncertain because aphthous ulcerations are found rather frequently in the general
population,includingthesameagegroupthatisaectedbyCrohndisease.Onelargestudyshowednodierencein
theprevalenceofaphthousulcersinpatientswithCrohndiseasecomparedwithacontrolpopulation.Lessthan1%
ofpatientswithCrohndiseasemaydevelopdiusestomatitis,withsomecasesapparentlycausedbyStaphylococcus
aureus, and others being nonspecic. In at least one instance, recurrent severe buccal space infections resulted in
cutaneoussalivarystulaformation.Infrequently,pyostomatitisvegetans(seenexttopic)hasbeenassociatedwith
Crohndisease.
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CrohnDisease.Thispatienthasalinearulcerationofthemandibularvestibule.Anadhesionbetweenthealveolarand
labialmucosaewascausedbyrepeatedulcerationandhealingofthemucosaatthissite.
FIG.1742
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.1743). The severity of
thegranulomatousinammationmayvarytremendouslyfrompatienttopatientandfromvarioussitesinthesame
patient. Therefore, a negative biopsy result at any one site and time may not necessarily rule out a diagnosis of
Crohndisease.Aswiththeclinicallesions,thehistopathologicpaernisrelativelynonspecic,resemblingorofacial
granulomatosis.Specialstainsshouldbeperformedtoruleoutthepossibilityofdeepfungalinfection,syphilis,or
mycobacterialinfection.
CrohnDisease.Thismediumpowerphotomicrographofanorallesionshowsanonnecrotizinggranulomainthe
submucosalconnectivetissue.
FIG.1743
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Most patients with mild Crohn disease are initially treated medically with mesalamine (5aminosalicylic acid) or
sulfasalazine, a drug that is enzymatically broken down by bacteria in the colon to form sulfapyridine and 5
aminosalicylicacid.Somepatientsrespondwelltothismedication,typicallywhenitiscombinedwithanantibiotic
such as metronidazole. With moderate to severe involvement, systemic prednisone may be used and is often
eective,particularlywhencombinedwithanimmunosuppressivedrug,suchasazathioprine,methotrexate,or6
mercaptopurine.FormoresevereorrefractorycasesofCrohndisease,oneofthetumornecrosisfactorinhibitors
(suchas,iniximab,adalimumab,orcertolizumabpegol)maybeused.Sometimesthediseasecannotbemaintained
inremissionbymedicaltherapy,andcomplicationsdevelopthatrequiresurgicalintervention.Complicationsmay
include bowel obstruction or stula or abscess formation. If a signicant segment of the terminal ileum has been
removed surgically or is involved with the disease, then periodic injections of vitamin B12 may be necessary to
prevent megaloblastic anemia secondary to the lack of ability to absorb the vitamin. Similar supplementation of
magnesium, iron, the fatsoluble vitamins, and folate may also be required because of malabsorption. Cigaree
smokingisknowntoexacerbateCrohndisease,andpatientsshouldbeadvisedtostopthishabit.
Orallesionshavebeenreportedtoclearwithtreatmentofthegastrointestinalprocessinmanycases.Occasionally
persistentoralulcerationswilldevelop,andthesemayhavetobetreatedwithtopicalorintralesionalcorticosteroids.
SystemicthalidomideandiniximabhavebeenusedsuccessfullytomanagerefractoryoralulcersofCrohndisease.
PyostomatitisVegetans
Pyostomatitisvegetans 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
pyostomatitisvegetansisanunusualoralexpressionofinammatoryboweldisease,particularlyulcerativecolitisor
Crohndisease.Thepathogenesisofthecondition,likethatofinammatoryboweldisease,ispoorlyunderstood.A
fewpatientswithpyostomatitisvegetanshavealsobeennotedtohaveoneofseveralconcurrentliverabnormalities.
ClinicalFeatures
Patientswithpyostomatitisvegetansexhibitcharacteristicyellowish,slightlyelevated,linear,serpentinepustulesset
onanerythematousoralmucosa.Thelesionsprimarilyaectthebuccalandlabialmucosa,softpalate,andventral
tongue(Figs.1744and1745).Theselesionshavebeencalledsnailtrackulcerations,althoughinmostinstances
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.Theorallesionsmayappearconcurrentlywiththebowelsymptoms,ortheymayprecedetheintestinal
involvement.
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FIG.1744
PyostomatitisVegetans.Thecharacteristiclesionsareseenonthebuccalmucosa,appearingasyellowwhitepustules.
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PyostomatitisVegetans.A,Characteristicsnailtracklesionsinvolvethesoftpalate.B,Samepatientafter5daysof
prednisonetherapy.(FromNevilleBW,LadenSA,SmithSE,etal:Pyostomatitisvegetans,AmJDermatopathol7:6977,1985.)
FIG.1745
Abiopsyspecimenofanorallesionofpyostomatitisvegetansusuallyshowsmarkededema,causinganacantholytic
appearanceoftheinvolvedepithelium.Thismaybetheresultoftheaccumulationofnumerouseosinophilswithin
thespinouslayer,oftenformingintraepithelialabscesses(Fig.1746).Subepithelialeosinophilicabscesseshavebeen
reported in some instances. The underlying connective tissue usually supports a dense mixed inltrate of
inammatorycellsthatconsistsofeosinophils,neutrophils,andlymphocytes.Perivascularinammationmayalsobe
present.
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FIG.1746
PyostomatitisVegetans.Mediumpowerphotomicrographshowingintraepithelialabscessescomposedofeosinophils.
Usually, the intestinal signs and symptoms of inammatory bowel disease are of most concern for patients with
pyostomatitisvegetans.Medicalmanagementoftheboweldiseasewithsulfasalazineorsystemiccorticosteroidsalso
produces clearing of the oral lesions (see Fig. 1745). Often the oral lesions clear within days after systemic
corticosteroid therapy has begun, and they may recur if the medication is withdrawn. If the bowel symptoms are
relativelymild,thentheorallesionshavebeenreportedtorespondtotopicaltherapywithsomeofthemorepotent
corticosteroidpreparations.
UremicStomatitis
Patients who have either acute or chronic renal failure typically show markedly elevated levels of urea and other
nitrogenouswastesinthebloodstream.Uremicstomatitis represents a relatively uncommon complication of renal
failure.Intwoseriesthatincluded562patientswithrenalfailure,onlyeightexamplesofthisoralmucosalcondition
weredocumented.Nevertheless,forthepatientsinwhomuremicstomatitisdevelops,thiscanbeapainfuldisorder.
Thecauseoftheorallesionsisunclear,butsomeinvestigatorssuggestthaturease,anenzymeproducedbytheoral
microora, may degrade urea secreted in the saliva. This degradation results in the liberation of free ammonia,
whichpresumablydamagestheoralmucosa.
ClinicalFeatures
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.1747).
Patientsmaycomplainofunpleasanttaste,oralpain,oraburningsensationwiththelesions,andtheclinicianmay
detectanodorofammoniaorurineonthepatientsbreath.Theclinicalappearanceoccasionallyhasbeenknownto
mimicoralhairyleukoplakia.
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UremicStomatitis.A,Raggedwhiteplaquesaffecttheventraltongueandfloorofthemouth.B,Samepatientafterrenal
dialysis.(FromRossWF,SalisburyPL:Uremicstomatitisassociatedwithundiagnosedrenalfailure,GenDent42:410412,1994.)
FIG.1747
Insomeinstances,uremicstomatitismayclearwithinafewdaysafterrenaldialysis,althoughsuchresolutionmay
takeplaceover2to3weeks.Inotherinstances,treatmentwithamildlyacidicmouthrinse,suchasdilutedhydrogen
peroxide,seemstocleartheorallesions.Forcontrolofpainwhilethelesionsheal,patientsmaybegivenpalliative
therapywithicechipsoratopicalanesthetic,suchasviscouslidocaineordycloninehydrochloride.Althoughrenal
failureitselfislifethreatening,atleastoneexampleofauremicplaquethatpresumablycausedapatientsdeathhas
been recorded. This event was thought to have been caused by the dislodging of the plaque with subsequent
obstructionofthepatientsairway.
Bibliography
Mucopolysaccharidosis
AlpzAR,okerM,elenE,etal.TheoralmanifestationsofMaroteauxLamysyndrome
(mucopolysaccharidosisVI):acasereport.OralSurgOralMedOralPatholOralRadiolEndod.2006;101:632
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partofthisbookmaybereproducedortransmiedwithoutpublisherspriorpermission.
19
ForensicDentistry
EdwardE.Herschaft
Forensicdentistry,whichisalsoreferredtoasforensicodontology,istheareaofdentistryconcernedwiththecorrect
management,examination,evaluation,andpresentationofdentalevidenceincriminalorcivillegalproceedingsin
theinterestofjustice.Thustheforensicdentistmustbeknowledgeableinbothdentistryandlaw.
Classically, forensic dentistry can be considered a subspecialty of oral and maxillofacial pathology. This is
analogoustotherelationshipinmedicinebetweenforensicpathologyandpathology.Therequirementsofforensic
dental eld work, however, often demand an interdisciplinary knowledge of dental science. This has resulted in
otherdentalspecialistsandgeneraldentistsjoiningoralandmaxillofacialpathologistsinprovidinglegalauthorities
withdentalexpertise.
Regardlessofbackground,forensicdentistsassistlegalauthoritiesbypreparingdentalevidenceinthefollowing
situations:
Managementandmaintenanceofdentalrecordsthatcomplywithlegalrequirementstodocumentallunique
dentalinformationthesedataarethefoundationonwhichdentalidenticationofthepatientisaccomplishedand
potentialmalpracticelitigationisreduced.
Identicationofhumanremains,throughthecomparisonofantemortemandpostmortemdentalinformation,in
casesthatinvolvethedeathofanindividualormultipledeathsinmultiplefatalityincident(MFI)situations.
Collectionandanalysisofpaernedmarks(bitemarks)ininanimatematerialorinjuredtissuethatcanbeanalyzed
andpotentiallycomparedwithaspecichumanoranimaldentition.
Recognitionofthesignsandsymptomsofhumanabuse(includingintimatepartnerviolence[IPV],elderabuse,
andchildabuse)andtherightsandresponsibilitiesofthedentalhealthcarepractitionerwhenreportingsuch
abuse.
Presentationofdentalevidenceasanexpertwitnessinidentication,bitemark,humanabuse,malpractice,fraud,
andpersonalinjurycases.
RecordManagement
Thedentalrecordisalegaldocument,ownedbythedentistoranincorporateddentalpractice,whichcontainsall
subjective and objective information about the patient. In the United States, the Privacy Rule governing the use of
protected health information (PHI) is regulated under the federal Health Insurance Portability andAccountability
Act(HIPAA)of1996.Underthislegislationthepatienthastherighttovieworiginaldocumentsandobtaincopies.
Despite the establishment of the Privacy Rule, the ability and necessity of forensic dentists, law enforcement
personnel, medical examiners (MEs), and coroners to obtain released antemortem dental and medical records for
forensic purposes without requiring consent of nextofkin or a guardian was recognized and provided for in the
HIPAAlegislation45CodeofFederalRegulations164.512(g)(1).
Initially, demographic information is secured when the medical and dental history of the patient is obtained.
Resultsofthephysicalexaminationofthedentitionandsupportingoralandparaoralstructuresarerecorded.
Inaddition,theresultsofclinicallaboratorytests,studycasts,photographs,andradiographsbecomecomponents
oftherecord.Withthisdatabase,thedentistcandevelopathoroughassessmentofallofthepatientsmedicaland
dentalproblems.Subsequentdocumentationofthisproblemlistfacilitatesthedevelopmentofaplanoftreatment
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andprognosisforthepatient.
The treatment plan addresses the management of both systemic and oral problems. It can then be periodically
revisedandupdatedasproblemsresolveorasnewonesdevelop.Supplementalmaterial,suchasdentallaboratory
authorizations, referral leers from other practitioners, statements of informed consent, wrien prescriptions, and
insuranceandnancialstatements,alsoisincludedandstoredintherecord.
Theprogressnotes(i.e.,dailylogofactualtreatmentrendered)shouldcontaininformationaboutrestorativeand
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
containsinorganicmaterials,traceelements,andllersthatareuniquetothatproductandcanbedetectedbyxray
uorescence(XRF)technologyevenafterincineration.TheXRFtraceelementandmajorelementanalysisofdental
remains may be useful as an adjunct to traditional evaluation of dental information in some forensic seings,
includingcremationanddismembermentcases(Fig.191).
FIG.191 Thexrayfluorescence(XRF)spectrumfromaparticlerecoveredfromacremationretort.
ThespectrummakesthisamatchfortherestorativeresinFourSeasonsorTetricCeram(Ivoclar
Vivadent,Amherst,NY).(CourtesyofDr.MaryA.BushandPeterJ.Bush.)
Unusual physiologic and psychological reactions and the patients comments concerning therapy are entered in
therecord.Summariesoftelephoneconversationswithpatients,consultants,insurancecompanyrepresentatives,or
legalauthoritiesshouldbenoted.Allentriesshouldbesignedorinitialedbyrecordingpersonnel.Changesinthe
recordshouldnotbeerasedbutcorrectedbyasinglelinedrawnthroughtheincorrectmaterial.Thismethodpermits
the original entry to remain readable and removes any questions concerning fraudulent intent to alter recorded
information.
By2015medicalanddentalrecordsintheUnitedStatesmustbemaintainedinanelectronicformatandnumerous
commercial and individually designed computer software programs have been marketed to assist physicians,
dentists, health care facilities, hospitals, and insurance companies in collecting and preserving the medical and
dental information of patients. The obvious advantage of electronic medical, health, or dental record (EMR, EHR,
and EDR) systems is facilitation of networking and exchange of records among the dierent formats
(interoperability)forroutineprofessionalconsultationoruseinforensicidenticationcasesrequiringmedicaland
dentalrecordsforcomparison.
However, the increased use of EHRs and EDRs has also created legal, nancial, and ethical issues concerning
patient privacy. Additionally, there may be a potential for insurance fraud associated with the computer
enhancementofdentallesionsorrestorationsonelectronicallygenerateddentalradiographs.
The potential charge of insurance fraud associated with the enhancement of dental lesions or restorations on
computergenerated or scanned digital radiography (DR) can be avoided if a clinician stores and maintains
unaltered images. This is accomplished using programs with unchangeable, secure tagged block le extensions in
theirnativeleformats.Whenduplicatesorcopiesarerequired,workingimagesshouldbegenerated.
Computerassistedmanagementtechnology(e.g.,WinID3dentalcomparisonsoftwarebridgedwiththeDexisDR
program)hasbeenanassetinexpeditingthecomparisonofantemortemandpostmortemdentalrecordinformation
inrecentMFIevents,includingtheWorldTradeCenterterroristaack,theIndianOceantsunamidisaster,andthe
Hurricane Katrina recovery eort. Additionally, software such as Adobe Photoshop and Mideo Systems
CASEWORKSeisfacilitatesthesuperimpositionofdigitallyscannedradiographsandphotographsforcomparison.
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Whether preserved in wrien form or by using a computer database, the principles of record management
describeamechanismthatensuresthatdentalinformation,whichmayberequiredtoresolveaforensicproblem,is
properlymaintainedandretrievable.Additionally,recordspreservedinthismannerarereliableevidentiarymaterial
ifsubpoenaedinpeerreviewormalpracticelitigationproceedings.
Timelimitsconcerninghowlongrecordsmustberetainedvaryamongthestates.Asarule,statesmandatethat
recordsbekeptfor7to10years.FederallegislationrelatedtotheproblemofmissingpersonsintheUnitedStates
requiresthatrecordsofpediatricdentalpatientsberetaineduntilthepatientreachestheageofmajority(adulthood).
Dependingonthejurisdictionthiscanvaryfrom18to21yearsofage.
ThemaintenanceperiodforEHRandEDRpatientdataexceedsthedurationofpaperrecordsandmayvaryfrom
20to100years.ProvisionsforsecurityandintegrityofstoredarchivalinformationinEHRsandEDRsmustsupport
ethicalandlegalprinciplesregardingprivacybecausethetechnologyusedtoinputinformationwillbeunavailable
tothosewhomayneedtoexaminethisdatainthefuture.
Identification
Legalsituationsoftenrevolvearoundtheestablishmentofapersonsproperidentity.Anydeathnotcertiedbyan
individuals own physician must be referred to the medical examiner (ME) or coroner for review. However, cases
requiringanautopsytodeterminethetime,cause,andmannerofdeathrepresentasmallpercentageofcases.When
required, these tasks are the responsibility of a coroner or ME. These ocials 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
denedaccordingtothefollowing:
Causeofdeath.Thedisease,injury,orchemicalorphysicalagentresponsibleforinitiatingthelethalsequenceof
events(e.g.,myocardialinfarction,cancer,bullet,knife,poison,ligature,lightning,andinfectiousagents)
Mechanismofdeath.Thepathologicprocessthatresultsindeath(e.g.,congestiveheartfailure,cardiac
arrhythmias,asphyxia,sepsis,exsanguination,renalfailure,andhepaticfailure)
Modeormannerofdeath.AccordingtotheNASHclassication,themodeormannerofdeathisconsideredtobe
Natural,Accidental,Suicide,orHomicide.Naturaldeathsarecausedexclusivelybydisease.Accidentaldeaths
resultfromanenvironmentalorhumantragedy(e.g.,lightningstrikeorvehicularincident).
Undetermineddeath.Althoughthecauseandmechanismofdeathmayberesolved,themannerormodemaynot
beestablishedbecauseofdecomposition,dismemberment,orpostmortemdestructionoftheremainsbyinsectsor
feralanimals.
The coroner is an elected ocial and, depending on the laws of each state, does not necessarily have to be a
physician or have advanced training in death investigation. An ME is an appointed ocial who is a pathologist
specicallytrainedinforensicmedicine.Manyjurisdictionsuseforensicpathologists,andthistrendhascontributed
totheprofessionalizingofapositionincreasinglyinvolvedwiththeinterpretationofadvancedscientictechniques
requiringknowledgeoftoxicology,ballistics,pharmacology,andcriminalistics,aswellaspathology.
Adeathcerticate,identifyingthedecedent,isrequiredbeforeprobationofawill,releaseoflifeinsuranceclaims,
orresolutionofotheraairsassociatedwiththeselementofanestate.Criminalcasesinvolvinghomicide,suicide,
and fraudulent misidentication may also require the expertise of forensic dentists and other forensic scientists
trained in identication techniques. These professionals act as consultants to the coroner or ME and assist in this
aspectofadeathinvestigation.
Besides analysis of the dentition, the most common methods of identication include personal recognition,
ngerprinting (friction ridge analysis), physical anthropologic examination of bones, and serologic and genetic
(DNA)comparisontechniques.
Additionally, the use of facial superimposition techniques (when the teeth are visible) and facial reconstruction
techniquesmayalsopermitscienticallysupportedcomparisonsforidentication.Eachmethodhasitsadvantages
and disadvantages. However, all rely on the principle that identication is the positive correlation obtained by
comparingknowninformationaboutasuspectorvictimwithuniquefactsretrievedbyphysicalexaminationofthe
suspectorvictim.
Regardless of the method used to identify a decedent, the results of the antemortem and postmortem data
comparisonleadtooneofthefollowingfoursituations:
1.Positiveidentication.Thereissucientuniquenessamongthecomparableitemsintheantemortemand
postmortemdatabases,andnomajordierencesareobserved.
2.Presumptive(possible)identication.Therearecommonalitiesamongthecomparableitemsintheantemortem
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andpostmortemdatabases;however,enoughinformationmaybemissingfromeithersourcetopreventthe
establishmentofapositiveidentication.
3.Insucientidenticationevidence.Thereisinsucientsupportiveevidenceavailabletocompareandarriveata
conclusionbasedonscienticprinciples.
4.Exclusionofidenticationevidence.Eitherexplainableorunexplainablediscrepanciesexistamongcomparable
itemsintheantemortemandpostmortemdatabases.Thisresultsininconsistenciesthatpreventtheestablishment
ofanyidentication.Exclusionmaybejustasimportantasadeterminationofpositiveidentication.
PersonalRecognition
Personal recognition is the least reliable method used to identify an individual. It is often based on the visual
identicationofadecedentbyafamilymember,friend,oracquaintance.Thisprocessassessesartifactualmaterial,
such as clothing, jewelry, keys, wallet contents, luggage, other personal eects, scars, and taoos to determine
identication. Evidence in this type of identication can be accidentally or purposely exchanged between bodies.
ThiscanoccurinMFIsituationsorwhenthereiscriminalintenttocreateamisidenticationincasesofidentitytheft
oraliasassociatedwithcriminalactivity.
Evenwhenabodyisviewedshortlyafterdeath,distraughtrelativescaninadvertentlymisidentifythedecedent.
Aftertheoccurrenceofpostmortemchangesassociatedwithsofttissuedecomposition,insectandburnartifact,or
dismemberment,thismethodofidenticationmaybeprecluded(Figs.192and193).
FIG.192 Unrecognizablepartiallydecomposedhumanremainswithamaxillaryremovablepartial
dentureinplace.Noticethattheskintissueoftheneckthathasbeenprotectedbythewindbreaker
jackethasnotreachedthestageofdecompositionofthetissuesoftheexposedface.(CourtesyofDr.
RaymondD.Rawson.)
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FIG.193 Aburnvictimrequiringidentificationbydental,DNA,orfingerprintmethodologyratherthan
personalrecognition.(CourtesyofDr.RaymondD.Rawson.)
Fingerprinting
Anthropometry was the rst scientic system police used to identify criminals. The French law enforcement
ocer, Alphonse Bertillon, developed this system in the laer 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 taoos, and other personal characteristics. Bertillons anthropometry identication
processwaseventuallyreplacedbyanalysisoftheepidermalfrictionridgesofthengers,palms,andfeetcommonly
referredtoasngerprinting.
By the beginning of the twentieth century, forensic science had recognized that the ridgelike paerns on the
ngertips and palms are unique for each person. These friction ridges are genetically determined, and not even
homozygoustwinshavethesamepaernsofloops,arches,andwhorls.Aprincipalvariationinthengerprintsof
twinsisthattheyappearasmirrorimagesofeachother.Themorphometricvariationincombinationsoftheloops,
arches,andwhorlspermitsascienticcomparisonofngerprintrecordswiththefrictionridgesofanunidentied
decedent.
Becausethengerprintpaernisinherited,itisastaticcharacteristicandremainsunchangedthroughoutlife.This
is an important advantage when one compares ngerprint identication with dental identication. The teeth and
supporting structures have uid characteristics. Dental paerns change as teeth erupt, exfoliate, decay, become
restored,and,perhaps,areeventuallyextractedandreplacedwithimplantsorotherprostheticdevices.
Unlikedentalrecords,whichareprincipallyretainedinprivatedentalocesintheAmericasandWesternEurope,
ngerprintinformationismaintainedbygovernmentalagencies.Severalstatesretainrecordsofnoncriminalswho
work in sensitive occupations. In this regard, Nevada has a ngerprint database for employees in the gaming
industry. The Criminal Justice Information Services (CJIS) Division of the Federal Bureau of Investigation (FBI)
containsthelargestbiometricdatabaseintheworldwithapproximately130millionngerprintrecordsincludedin
criminal,civil,andknownandsuspectedterroristformats.
Currently,theserecordsareretainedwithintheIntegratedAutomatedFingerprintIdenticationSystem(IAFIS).
IAFISpermitsinput,matching,andretrievalofevenasinglengerprintimageforidentication.NextGeneration
Identication(NGI)technologyisbeingdevelopedfortheFBItoexpandthemorphometricinformationcontainedin
IAFIStoincludepalmprint,iris,andfacialidenticationdata.
TheestablishmentoftheCJISDivisionsIAFISlespermitsautomatedcomputerdataentryandsearchcapabilities
for matching and retrieval of ngerprint images. This information is available for electronic exchange among law
enforcement agencies for identication purposes. Included in the IAFIS database are criminal and civil tenprint
ngerprintrecords,latentngerprintservices,andsubjectandcriminalhistorysearchcapabilities.Informationfrom
this ngerprint repository is shared with international legal agencies, such as Interpol and the Royal Canadian
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MountedPolice.
Fingerprint nomenclature is standardized in IAFIS, and all ngerprint experts use the same terminology
worldwide. This advantage is not observed in dental identication, in which numerous charting and tooth
numberingsystemsareused.Becausesofttissuesdecomposeshortlyafterdeath,thefrictionridgepaernswithin
the epidermis may not be retrievable for ngerprint comparison. This is the principal disadvantage of ngerprint
identication.
PhysicalAnthropologicExaminationofBonesandTeeth
Forensicanthropologistsandforensicdentistsoftenworktogethertoresolveproblemsassociatedwithidentication.
Bothdisciplinesareconcernedwithanalysisofcalciedstructuresofthebodybonesandteeth.Historically,this
anatomicmaterialhasassistedforensicanthropologistsanddentistsindeterminingtherace,age,andsexofaperson
(Table 191). These characteristics have become less distinct in some populations as individuals from dierent
culturesandraceshaveintermarriedandblendedthesegeneticallydeterminedfeaturesintheirospring.
TABLE191
SkeletalAnthropologicVariationsAssociatedwithRacialandSexualCharacteristicsoftheSkull
RacialCharacteristics
White
Black
Asian/NativeAmerican
Width
Narrow
Narrow
Broad
Height
High
Low
Intermediate
Prole
Straight
Prognathic Intermediate
Orbit
Triangular/teardrop Square
Circular
Nasalopening Tapered
Wide
Rounded
Palate
Wide
Intermediate
Narrow
SexualCharacteristics
Male
Size
Large
Female
Small
Glabellar(supraorbital)ridges Pronounced
Notdeveloped
Mastoidprocess
Large
Small
Occipitalarea
Pronouncedmusclelines
Minimalmusclelines
Mandible
Larger,broaderramus
Smaller
Forehead
Steeper,slopesposteriorly Rounded,morevertical
In addition to the study of osseous material and despite variations in crown and root development within the
dentition,theteethcanbestudiedclinically,radiographically,histologically,andbiochemicallytodeterminetheage
ofalivingindividualordecedent.
Forensically, this information is essential in casework involving the need to establish legal age of majority
(adulthood), medicolegal age at death, clarication of the age of undocumented immigrants, age estimation of
unidentiedremains,andseparationofcomingledremainsinamultiplefatalityincidentamongothers.
From fetal development to adolescence tooth maturation intervals are the principal method of dental age
assessment. Lewis and Senn emphasize that dental age estimation of children becomes more accurate when teeth
having less variance are used in these analyses and data derived from multiple teeth is considered.Additionally,
studies have been performed to assess dierences in crown and root formation and eruption sequences among
childrenofbothgendersandvariousracialandethnicpopulations.
As one approaches adulthood, age estimation acquired by analysis of the dentition can be supplemented with
radiographic data obtained from the calcication centers of the hand and wrist, ribs, clavicles, and other bones to
determinethepreciseageofapersonyoungerthan20yearsofage.
Biochemicallaboratoryproceduresorassessmentofdentalpostformationchangesareusedtodeterminetheage
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of adult individuals. Historically, dental postformation changes of adult teeth included the study of their ground
sectionsforvariationsinpaernsof:
Arition
Periodontalaachment
Secondarydentin
Cementumapposition
Rootresorption
Transparencyofrootdentin
Thisapproach,developedbyGustafsonin1947,hasbeenmodiedtodeterminewhichofthesefactorsaremost
signicantsecondarydentinandtransparencyofrootdentin.Additionally,thesecontemporarymethodsofdental
postformationanalysishavebeensupplementedbythoserelyingonthefollowingtechniques:
Evaluationoftherateofracemizationoflevelsofmetabolicallystableasparticacidenantiomersinenameland
dentintodetermineanexactage.
Occlusaltoothwearwhichcanprovidereliableestimatesofagetowithin3to5years.Often,anthropologic
analysisishelpfulinarrivingatapresumptiveidenticationbasedonthesecriteria.
There are variations in the calcication and eruption paerns among various ethnic and cultural groups, and
studieshavebeenundertakentodelineatethesedierencesfurther.Afterthethirdmolars,longbones,andbonesof
thewristandhandarecompletelydeveloped,evaluationofbiochemicalcomponentsofthecalciedstructuresand
collagenisthemostaccuratemethodfordeterminingchronologicage.
Methods that rely on an analysis of the rate of racemization of the stereoisomers of aspartic acid in enamel and
dentincanbeusedtodetermineanaccuratechronologicage.ThisisrelatedtothefactthatthechangefromtheL
formofthisaminoacidtoitsmirrorimageDformoccursovertime.ThustheratiooftheLtoDformsofaspartic
acidinthedentitionisdirectlyrelatedtotheageoftheindividual.Often,anthropologicanddentalageanalysisis
helpfulinarrivingatapresumptiveidenticationbasedonthecriterianotedpreviously.
Positiveidenticationmaybeachievablewhentheskullandfacialbonesareusedasafoundationtoreconstruct
the facial soft tissues (Figs. 194 to 196). Threedimensional (3D) computer images, computed tomography (CT)
images,andradiographshaveevenbeenusedinthereplicationofthefaceofEuropesoldestmummiedhuman,a
maledubbedi,whose5300yearoldremainswereremovedfromglacialiceinthetalAlpsontheAustrian
Italianborder.
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FIG.194 Reconstructionofthefacialsofttissueusespredetermined,standardanthropologic
thicknessmeasurementsforspecificpointsaroundtheface.Thesemeasurementsarebasedon
variablesthatarerelatedtoracialandsexualcharacteristics.(CourtesyofDr.CleveSmith.)
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FIG.195 Thesofttissuethicknesspointscanbeconnectedwithsculptingclayordigitizedona
computerscreen.Theultimateresultofthesetechniquesisarecreationofthecontourofthesoft
tissuefeaturesthatpermitsavisualidentification.(CourtesyofDr.CleveSmith.)
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FIG.196 Thewidthofthemouthisrelatedtotheinterpupillarydistance.Thelengthandshapeofthe
nosearedeterminedbytherelationshipbetweentheinferiorandsuperiornasalspines.Ifknown,then
theadditionofaspecifichairstyle,eyeglasses,andeyecolorcanfurtherindividualizeafacial
reconstruction.(CourtesyofDr.CleveSmith.)
With knowledge of the anatomic relationships between the skull and face, antemortem facial photographs or
radiographscanbesuperimposedforcomparisonwiththeskullofanunknown.Videosuperimpositionwithtwo
televisioncamerasandanelectronicmixingdevicehasbeenusedsuccessfullytooverlayaphotographofahuman
face on an image of a skull for identication. The development of computer software programs capable of
superimpositionhasfurtherfacilitatedtheprocess.
The anterior dentition of the skull can be overlaid and compared with a smiling antemortem photograph. The
shapesandpositionsoftheindividualteethandtheirrelationshipstoeachotherhavebeenconsidereddistinctive
enoughfeaturesonwhichtobaseidentication,ashavecertainsignicantcranialandfaciallandmarks,including
the orbits, nasal openings, malar eminence, and chin. Prosthetic joint replacements, intraosseous and dental
implants,andradiographicsignsofpriorbonefractureareotheranthropologicndingsthatcanbeusedtofacilitate
identication.
Additionally, prosthetic devices, implanted debrillators and pacemakers, and osseous implants are designated
withindividualidenticationcodenumbersprovidedbytheirmanufacturers.Thesecodescanbevisualizedinthe
variousdevicesandareusefulinidentifyingindividualsincremationanddismembermentscenarioswhentheteeth
andngerprintsarenotavailableforevaluation.
SerologicandGenetic(DNA)Comparison
EveryindividualisuniquebyvirtueofhisorherchromosomalDNAapolymerstructuredasadoublehelixand
composedoffourdierentnucleotides.Thepolymorphicsequencingofthesenucleotidesalongthetwostrandsof
theDNAmoleculeaccountsforthegeneticdiversityofalllivingthings.Thisultimateidenticationmaterialwas
rstusedforensicallytoobtainaconvictioninacriminalcasein1986,andDNAcomparisonhassincebecomean
acceptedforensicmethodtoresolveproblemsofidentication.
Before1986,comparisonofantigenicmarkersfoundonredbloodcells(RBCs)andinbodyuidsofsecretorsof
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
comparisonswerejustiedonlytoplacethesuspectorvictiminapopulationofindividualshavingsimilarserologic
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antigens.
Although DNA has become the principal biologic substance used to eect a positive identication, antigenic
surfacemarkersA,B,andHoftheABObloodgroupsystem,aswellasvariouscomponentsoftherhesus(Rh)and
Lewissystems,continuetobeacceptedformedicolegalcomparison.TheabilitytosecretetheABHantigensinsaliva
andotherbodyuidsisgeneticallydetermined,andmorethan80%ofindividualsaresecretors.Withappropriate
laboratorytests,evendriedsamplesofuidandbloodcanbeanalyzedforthesemarkers.
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,hundredsofcopiesofmtDNAarecontainedinthecytoplasmofthesecells.ThisDNAisonlymaternally
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 eect identication when other
referencesourcesareunavailable.
Restrictionfragmentlengthpolymorphism(RFLP)andpolymerasechainreaction(PCR)analysesaretheprincipal
laboratorytechniquesusedtocompareandevaluatefragmentsofDNAmaterialfromasuspectorvictimsbiologic
forensic specimens (e.g., semen, vaginal uid, teeth, soft tissues, and saliva). Both are extremely accurate, precise,
and reproducible; these methods are used when the conditions of the sample DNA presented dictate the need for
theirrespectiveadvantages.
RFLP methods result in spliing source DNA into thousands of fragments using biologic scissors known as
restrictionenzymes.Fragmentsizevariesamongindividualsrelatedtothevariablenumberoftandemrepeats(VNTR)
ofbasepairs.TheseshortsegmentsofDNAcontainanumberofrepeatunitsthatdieramongindividuals.Aftergel
separation of the fragments and transfer to a nylon mesh, specic DNA fragments are identied using
oligonucleotides labeled with radioisotopes. Analysis of a series of dierent VNTR loci permits generation of an
individualDNAprole.
A match of four or more VNTR loci is consistent with a positive match between DNA evidence gathered from
suspect,victim,orcrimesceneevidence.TheRFLPmethodrequireslargeamountsofhighmolecularweightDNA,a
majordisadvantage.SmallDNAsamples(
TheevaluationofminutequantitiesofDNAorDNAthathasundergonedegradationcanbeaccomplishedwith
thehighlysensitivePCRtest.Usingthislaboratorytechnique,smallerVNTRlociofaspecicDNAsequencecanbe
ampliedintoenoughcopiesforsucientanalysis.Becauseofitshighdegreeofsensitivity,PCRanalysishasbeen
usedtoevaluatesmallamountsofDNAfromasuspectsclothingleftatthesceneofacrime,aswellasfrombone
fragmentsfromtheVietnamWar.DNAamplicationofmicrosatelliteloci(referredtoasSTRs)andminisatelliteloci
(orLTRs)usingPCR,isreferredtoasAmpFLPanalysis.
ThehardandsofttissuesoftheoralcavityandsalivaareoftengoodsourcesforDNAmaterial.However,ifthe
teethorotherhardstructuresofthemoutharetobeusedforthecollectionofDNAevidence,thentheidentication
valueofthesestructuresshouldbeconsidered(beyondtheirabilitytoyieldaharvestDNA).Atoothorjawfragment
capriciously destroyed can result in the loss of valuable radiographic and anatomic sources for eventual dental
identication. Besides the obvious source of DNA from human tissues, the forensic dentist often considers the
evaluation of chewed gum, cigaree remains, licked envelopes, stamps, or similar inanimate objects as potential
sourcesforDNAevidenceusingPCRanalysisdescribedpreviously.
RegardlessofthesurfacefromwhichDNAevidencemaybeharvested,thetwoswabprotocoldevelopedbyDr.
DavidSweetandothersattheBureauofLegalDentistry,UniversityofBritishColumbiaistherecoverymethodof
choice:
Asterilecoonswabismoistenedwithdistilledwaterandrolledoverthesurfaceoftheskinorobjectusing
moderatepressureandcircularmotion.
Thisswabisairdried.
Aseconddrycoonswabisrolledoverthesamesurfaceoftheskinorobjectusingmoderatepressureandcircular
motiontoabsorballmoistureleftbytherstswab.
Thisswabisalsoairdried.
Bothswabsareplacedinproperlylabeledstoragecontainersandsubmiedtothelaboratoryforfrozenstorageat
20C(4F).
Control samples may be collected from whole blood, autopsy tissue samples or oral buccal swabs from a living
individual.
Passage of the DNA Identication Act of 1994 and the establishment of the FBIs National DNA Index System
(NDIS)in1998havefacilitatedtheexchangeandcomparisonofDNAprolesamongfederal,state,andlocalcrime
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laboratoriesintheUnitedStates.ThisisaccomplishedelectronicallythroughtheFBILaboratorysCombinedDNA
Index System (CODIS). Through the CODIS computer programs forensic and oender indexes, biologic evidence
fromcrimescenescanbelinkedtoDNAprolesofindividualsconvictedofsexoensesandotherfelonies.Asof
March2007,thetotalnumberofDNAprolescontainedintheCODISdatabaseswasmorethan4.5million.More
than47,000successfulcomparisons(hits)weremadeamongcasesinwhichtheCODISsystemwasactivated.This
represents a 98% success rate linking DNA from a crime scene with similar material from the convicted oender
proles.
The US Department of Defense has initiated a policy of obtaining DNA samples on all military personnel. This
DNA ngerprint has signicantly reduced the possibility of another unknown soldier among future military
casualties. Despite the positive eects of DNA evidence in resolving questions of identity, the technique is not
withoutcontroversy.Challengeshavebeenmadebypopulationgeneticists,concernedaboutrandommatchingand
variationsamongracialsubgroups.
DentalEvaluation
BasicPrinciples
In an identication case, the principal advantage of dental evidence is that, like other hard tissue, it is often
preservedindenitelyafterdeath.Althoughthestatusofapersonsteethchangesthroughoutlife,thecombination
of decayed, missing, and lled teeth is measurable, reproducible, and comparable at any xed point in time.
Therefore,likethecomparisonofuniquepaernsinangerprint,ascientic,objectiveanalysisofantemortemand
postmortemdentalvariablesisachievable.
Thepresenceandpositionofindividualteethandtherespectiveanatomic,restorative,andpathologiccomponents
providethedatabasefortheantemortemandpostmortemcomparison(Fig.197).Thepaernofthepalatalrugae,
ridgesonthelipsurface,andradiographicoutlineofthemaxillaryandfrontalsinusesarealsoconsideredunique
(Fig.198).Inaddition,thelegalcommunityacceptsthefactthatdentistscanrecognizeproceduresthattheyhave
performed.
FIG.197 Thecombinationofdecayed,missing,andfilledteeth,alongwithuniqueanatomicand
pathologicfindings,providesthedatabaseforcomparisoninadentalidentification.Notethemicrodont
inthemaxillaryleftquadrant.
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FIG.198 Theoutlineshapeofthefrontalsinusisauniquemorphometricfactorthatmaybeusedin
humanidentificationwhencomparingconebeamcomputedtomography(CBCT)andanterior
posteriorradiographsofaknownindividualwiththoseofanunknownpersonordecedent.(CourtesyofDr.
RobertDanforth.)
Problems associated with dental identication information are often related to acquiring and interpreting
antemortemrecords.Mostantemortemdentalrecordsareretrievedfromprivatesectordentalproviders.However,
dentalrecordsmayberecoveredfrominsurancecarriers,dentalschools,hospitals,clinics,stateandfederalprisons,
militaryles,andtheFBINationalCrimeInformationCenter(NCIC)databases.
Toinitiatearequestforantemortemrecords,aputative(suspected)identicationisrequired.Reportsofmissing
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
identicationhasnotbeenestablished.
TheFBINCICcomputerregistryofmissingandunidentiedpersonswasestablishedtohelprectifythisproblem.
Thiscomputersystemmaintainsdemographic,dental,andmedicalinformationonmissingpersons.Itaemptsto
matchthesedatawithsimilarfactsobtainedfromunidentiedbodies.Thelaerinformationissubmiedbyvarious
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.AdisadvantageoftheNCICcomputeridenticationsystemisthatitdoesnothavethecapabilityto
identifypossibledecedentsbasedsolelyondentalinformation.
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
websiteislocatedatLawEnforcementOnline(LEO)athp://cgate.leo.gov.Thisrepositorypermitslawenforcement,
criminal justice, and public safety authorities to maintain a national and international method of electronic
communication,education,andsharingofdentalinformation.
TheArmedForces,DepartmentofVeteransAairs,andmanystatesrequirethatidentifyingmarkingsbeplaced
on removable dental prostheses (Fig. 199). The American Dental Association also supports this policy. It is an
aempttoprovideabasisforidenticationamongthesubstantialpopulationofcompletelyorpartiallyedentulous
individualsintheUnitedStates.
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FIG.199 Dentureidentificationisaccomplishedbyinsertingatypednameorcodenumber(i.e.,
SocialSecuritynumberorhospitalpatientnumber)inanareaofthedenturethatwillnotinterferewith
theaestheticsoftheprosthesis.Thisprocedureisperformedinthelaboratoryduringthefinalacrylic
pack.Informationalsocanbeengravedintheframeworkofanallmetalappliance.
Identifyingmarkingsindentalprosthesesareimportantbecauseevenifdentalrecordsofanedentulousperson
canbeobtained,theymaynotreectthecurrentstatusoftheridgesandalveolarbone.Commonlyusedinformation
foridentifyingmarkinginremovabledentalprosthesesincludesthepersonsname,driverslicensenumber,and/or
otheridenticationnumber.
Evenwhenasuspectedidenticationisachieved,itmaystillbediculttosecureantemortemdentalrecords.The
family or acquaintances of the victim may not know where dental treatment was sought. Reviewing the victims
canceledbankchecksormedicaldeductionsontaxrecordsmaybehelpfulinlocatingantemortemdentalrecordsin
suchcases.
Althoughrecordsobtainedfrominstitutionalorgovernmentaldentalfacilitiesroutinelyindicateallrestoredteeth,
thisisnottrueofchartsforwardedfromprivatedentists.Intheseinstances,previouslyrestoredteethoftenarenot
chartedunlessthecurrentdentistintendstoretreatthem.Therefore,intheserecords,theantemortemradiographs
andprogressnotesbecometheprincipalsourcesfordentalinformation.
Unfortunately,thenomenclatureassociatedwithdentalchartingsystemsisnotstandardized(Table192).In1984,
the American Dental Association adopted the Universal Tooth Numbering System. All insurance companies, the
ArmedForces,dentalschools,andmostdentistsintheUnitedStatesnowusethissystem.Itshouldbeusedinall
forensicdentalcases.
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TABLE192
DentalNumberingSystems
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IntheUniversalNumberingSystem,aconsecutivenumberfrom1to32isassignedtotheadultdentition.Itbegins
with the maxillary right third molar and ends with the mandibular right third molar. The deciduous dentition is
identiedbyleersfromAtoT,beginningwiththemaxillaryrightdeciduoussecondmolarandendingwiththe
mandibular right deciduous second molar. Thus the quadrants are identied in a clockwise direction, beginning
withthemaxillaryright.
Other tooth numbering methods include the Zsigmondy/Palmer System and the Federation Dentaire
Internationale (FDI) TwoDigit System. Each uses a dierent coding technique to identify dental quadrants and
specicteeth.
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
teethareassignedleersAthroughE.
TheFDITwoDigitSystemisendorsedbytheWorldHealthOrganization(WHO)andisusedinmostdeveloped
countries, except the United States. The rst digit represents the quadrant. Quadrants 1 to 4 are assigned for
permanentteeth;5to8representquadrantsfortheprimarydentition.AsintheUniversalNumberingSystem,the
quadrantsareidentiedinaclockwisedirection,beginningwiththemaxillaryright.Theseconddigitdesignatesthe
permanenttoothtypefrom1to8,ordeciduoustoothtypefrom1to5.
ThusintheUniversalNumberingSystem,tooth12isthemaxillaryleftrstbicuspid.IntheFDITwoDigitSystem,
tooth 12 (onetwo) 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.
Unlesstheforensicdentistknowswhichsystemhasbeenusedtoencodetheteethintheantemortemrecord,all
teethshouldbereferredtobytheiractualnames.Thismethodwillpreventerrorsbecausealldentistsusethesame
anatomicnomenclaturewhenreferringtoindividualteeth.
Dental identication problems may be further compounded because dental radiographs can be mounted and
viewedfromrighttoleftorviceversa.Intraoralradiographicduplicatinglmdoesnotcontainaraiseddottoassist
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. Besides the lack of a raised dot,
panoramicradiographicduplicatinglmcanbedetectedbecauseofitssinglesidedemulsionandseriesofnotches
ononeedgetoindicatethattheimageisnotanoriginal(Fig.1910,A).
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FIG.1910 A,Panoramicduplicatingfilmhasaseriesofnotches(arrow)ononeedgetoindicatethat
theimageisnotanoriginal.B,Whenphosphordigitalplatesareinadvertentlyexposedfromthewrong
side,theerrormaynotbedetectedbecausetheapositionmarkeralwaysappearsinthesame
locationafterprocessingregardlessofwhichsideofthesensorhasbeenexposed.Thisproblemcan
bepreventedbyplacingametalindicatoronthesideofthedevicethatshouldnotbeexposed.(Courtesy
ofDr.RichardA.Weems.)
Additionally, when using intraoral digital sensors the operator must be careful not to inadvertently expose the
device from the wrong side. This orientation error can remain undetected because the a placed on the sensor
(which serves the same function as the raised dot on radiographic lm) always appears in the same position after
processingregardlessofwhichsideofthesensorhasbeenexposed(seeFig.1910,B).
With the advent of aesthetic materials for posterior restorations and the reduction in the prevalence of caries, it
maybedicultfortheforensicdentisttodeterminewhetherrestorationsarepresentbysimplevisualassessmentof
theteeth.Inaddition,thepostmortemdentalevaluationisoftenperformedinanautopsyroom,temporarymorgue,
orfuneralhome.Intheselocations,properlightingandaccesstodentalinstruments,whichcanfacilitateanalysisof
theoralstructures,arenotreadilyavailablefordetailedexamination.
Often, there are additional demands for immediacy in providing a coroner, ME, or other legal agent with the
resultsofadentalidentication.Thesedemandsfurthercompoundtheforensicdentiststechnicalandstressrelated
problemswhileperformingthetasksrelatedtothisdiscipline.Becauseofthepreviouscaveats,theforensicdentist
should prepare an equipment kit (Box 191). The kit should be portable, containing instruments and supplies
specicallyrequiredfortheperformanceofdentalproceduresinanautopsyroomenvironment.
Box191
SuggestedInstrumentKitforForensicIdentication
Dentalexplorers
Dentalmirrors
Periodontalprobes
Biteblocks
Tissuescissors
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Osteotome
Rubberair/watersyringe
Coonswabs
Gauze
Flashlightorheadlamp
Specimencontainers
Scalpelsandblades
Cheekretractors
ABFONo.2ruler
Bonemallet
Photographicmirrors
SLRlmbasedcamera
Digitalcamera
Photographiclm,digitalmemorycard
Radiographiclmanddigitalsensors
Rubber,latex,andnitrilegloves
Tissueforceps
Tissueclamp
Tongueclamp
Disclosingsolution
Strykersaw
Writinginstruments
Caselabels
Appropriatecharts
MasksandHEPAlters
ABFO,AmericanBoardofForensicOdontology;HEPA,higheciencyparticulateair;SLR,singlelensreex.
GuidelinesforDentalIdentification
Althoughdentalinformationcansupporttheidenticationofavisuallyrecognizablebody,identicationofdental
remainsisespeciallyhelpfulwhenadecedentisskeletonized,decomposed,burned,ordismembered.Becauseeach
oftheseforensicsituationspresentsdierenttechnicalproblemstothedentist,BodyIdenticationGuidelineshave
beenestablishedbytheAmericanBoardofForensicOdontology(ABFO).Thepurposeofdelineatingthesecriteriais
to assist dentists in comparing antemortem and postmortem dental information. Furthermore, the possibility of
misidenticationisreducedinbothroutineandmassdisastercases.
UndertheBodyIdenticationGuidelines,provisionsaremadeforthefollowing:
ExaminationofthepostmortemdentalremainsincompliancewithinfectioncontrolandOccupationalSafetyand
HealthAdministration(OSHA)requirements
Examinationofantemortemdentalrecords
Comparisonofalldentalandparadentalinformationfromthetwodatabases
Developmentofawrienreportlistingconclusionsandanopinionregardingthestrengthoftheidentication,for
examplepositive,presumptive,insucient,orexculpatory(Exculpatoryevidenceisfavorabletothedefendantina
criminaltrial,clearingthedefendantofguilt.)
PostmortemExamination
The postmortem dental evidence is gathered by photographic, radiographic, and charting techniques.All records
shouldincludethecasenumber,date,demographicandanthropologicinformation,thenameoftheauthoritythatis
requestingthedentalexamination,thelocationoftheexamination,andthenameoftheexaminingdentist.
Photographsshouldbetakenoffullheadandfaceviews.Imagesoftheocclusalplanesofbothdentalarchesand
individualviewsofunusualpathologicorrestorativendingsarealsoobtained.Adigital35mmsinglelensreex
(DSLR) camera and appropriate electronic ash and lens systems for closeup photography should be used. Basic
digitalimagesshouldincludecolorexposureswhichcanalsobeconvertedtoblackandwhiteimagesforanalysis.
Jawresectionisnolongeracommonlyacceptedmethodemployedtofacilitateaccesstothepostmortemdentition.
This change in practice has resulted from ethical and medicolegal challenges and concerns regarding its use.
However, postmortem examination, dental impressions, and radiographs can be obtained by relieving the
mandibularmuscleaachmentsandthoseofthetemporomandibularjoint(TMJ).Thisprocedurepermitsaccessto
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the oral structures by 180 degree reection of the lower jaw. If requested by the coroner or ME, then the dental
specimensfromtheautopsymayhavetoberetainedandpreservedina10%formalinsolution.
The guidelines for body identication recognize that the dentist and dental auxiliary personnel involved in
performingforensicdentalproceduresdosoattherequestanddirectionofalegalauthority,suchasacoroneror
ME. Therefore, it is only with the permission of these individuals that techniques involving postmortem facial
dissectionorjawresectionareperformedbytheforensicdentisttoachievecompleteaccesstodentaltissues.
These measures are used most often in decomposed, dismembered, or incinerated bodies to make postmortem
dental charting and radiographic examination easier. Mandibular reection or soft tissue dissection may be
necessaryinvisuallyrecognizable(viewable)bodieswhentheoralcavityisinaccessiblebecauseofrigormortis.In
thissituationtheprocedureisperformedfromaninframandibularapproach.
Inthoserareinstanceswhentheforensicdentistisauthorizedtoremovethejawsthistaskisaccomplishedwitha
reciprocating (Stryker) saw or osteotome and mallet, causing a Le Fort I fracture of the maxilla. The dissection
instrumentsareplacedabovetheinferiornasalspineandmalarprocessestoensurethattheapicesofthemaxillary
teetharenottransected.Similarly,ifthemandibleisnotremovedbydisarticulation,thencutsintothemandibular
ramishouldbehighenoughtopreventdamagetoimpactedthirdmolars.
While obtaining postmortem radiographic evidence, the forensic dentist may encounter technical obstacles that
needtobeaddressed.Itoftenisdiculttoplaceintraoralradiographiclmordigitalradiographicsensorssecurely
againstthemandibleormaxillaofadeceasedindividual.AmodiedRinnXCPselfsupportinglmholder,which
doesnotrequireactiveparticipationfromtheexaminee,hasbeendevelopedforpostmortemidentication.Because
all dental evidence may eventually be required to be relinquished in court, the use of doublepack intraoral
radiographspermitstheforensicdentisttoretainasetoflms.Digitalradiographicexposureandstorageofimages
precludesthisproblem.
When the jaws cannot be resected postmortem changes in rigor mortis cases and in bodies that are partially
decomposedmaypreventthepositioningofintraoralperiapicalradiographiclmsordigitalsensors.Occlusallms,
5X7 lateral plates, and panoramic radiographs are often used in these situations. Additionally, charting of dental
evidence in fourthdegree burn cases, in which charring of soft tissues results in contraction of the muscles of
mastication,mayprecludetheplacementofthesedevices.WiththecoronerorMEspermission,theentireskullcan
beremovedfromtherestoftheremainsandplacedinapanoramicradiographicmachine.
Fifthdegree burn cases result in cremation (sometimes referred to as cremains).Dentalevidencemaybelostor
compromisedinthesecasesastemperaturesrangebetween870Cand980C(1600Fand1800F).Mostcremated
skeletal and dental remains are structurally recognizable, and it is only the processing of these structures in
commercialcrematoriathatcreatestheashmostassociatedwiththisprocess.Crematedbonesandteetharefragile,
crumbleeasily,andrequireextremecarewhenhandled.
Fragmentationofdentalstructuresindismembermentcasesandtotallossofsofttissuesinskeletonizedremains
necessitate alterations in routine radiation exposure seings. Generally, when radiographs of this type of material
aretaken,10mAand65kVpexposureseingsareused.Becausethereislileornosofttissue,standardexposure
timesorimpulseseingsarehalvedtopreventoverexposureoftheradiograph.
Themaxillacanbesplitalongthemidsagialsuture,andeachhalfcanbeplacedhorizontallyonanocclusallm.
Thisprojectioncanbeusedtosimulateantemortempanoramicradiographsorbitewingviews.Similarexposures
can be obtained from the mandible by mounting the jaw on the edge of a table or bracket tray and placing an
occlusallmunderthesupportinghalf.Exposuresoftheoppositesideofthearcharemadebysimplyippingthe
mandibleandrepeatingtheprocedure.
Databaseshavebeencreatedfromelementalanalysisorchemicalcharacterizationofvariousdentalrestorativeand
endodonticmaterialsusingscanningelectronmicroscopic/energydispersiveXrayspectroscopy(SEM/EDS)andX
rayuorescence(XRF)techniques.Referraltotheseresourcesmayassisttheforensicodontologistinthepostmortem
analysisofdentalrestorationswhenseveredestructionofthedentitionorcremationprecludestheecacyofusing
moretraditionalanalyticalmethods.
Thecharting(odontogram)ofthepostmortemdentitionshouldprovideforsituationsinwhichteetharemissing
afterdeath.Ifsuchadiscrepancyremainsunexplained,thenitmayprecludethepositiveidenticationofthebody.
Scavenging animals or poor investigation of a crime or disaster scene can cause postmortem loss of teeth.
Environmental conditions at or around the time of death, such as tidal action in a saltwater drowning, can also
contribute to perimortem loss of teeth. When teeth are lost in this manner, the crest of the alveolar bone remains
intact. In addition, there is no reossication of the socket (Fig. 1911). This paern is inconsistent with what is
observedafterextractionofatooth.
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FIG.1911 Postmortemtoothlossresultsinanalveolarsocketwithunfracturedmarginsandno
reossification.Inthisexample,teethNos.7,9,10,and11representpostmortemtoothloss.ToothNo.
2isaresultofantemortemloss.TeethNos.4,8,and13werefoundnearthebodyandreinsertedinto
theirrespectivesockets.
Postmortemtoothlossisassociatedwithdecompositionoftheperiodontalligament.Thusthetoothsimplyfalls
outwhenthebodyismovedbyanimalsorduringcrimescenerecoveryeorts.
AntemortemRecordExamination
Antemortemrecordsareusuallyobtaineddirectlyfromthepolice,coroner,orME.Beforeacceptingthisevidence,
theforensicdentistshoulddeterminethattherecordsindicatethenameofthepersontobeidentiedandthename
and address of the submiing dentist. In addition, most jurisdictions require an evidence transfer document to be
signed. This form indicates that the continuity of evidence has been maintained and species who is currently in
possessionofthematerial.
Severalantemortemrecordsofthesamepersonmaybesubmiedfromdierentdentalpracticesforcomparison
with postmortem dental evidence. It is not uncommon for the general dental records of a decedent and those
obtainedfromtheoralandmaxillofacialsurgeon,endodontist,orthodontist,andotherdentalspecialtypracticesto
beforwardedforforensicanalysis.Evenifonlyoneantemortemrecordissent,theforensicdentistshouldrechartall
informationobtainedfromtheradiographs,progressnotes,andodontogramsonastandardizedformorcomputer
generated dental chart. This record should be identical to the one on which the postmortem information was
documented.Allofthismaterialshouldbeappropriatelylabeledastheantemortemrecord.
Theuseofcomputersoftware,suchastheWinID3program,inMFIsituationsaccomplishesthissameprincipleby
entering all antemortem and postmortem dental information into the respective identication program. Besides
making the comparison of records easier to manage, the creation of similar antemortem and postmortem analytic
materialiseasiertopresentincourt.
ComparisonofAntemortemandPostmortemRecordsandWrittenConclusions
Afteralldentalinformationhasbeencollectedfromtheantemortemandpostmortemdatabasesitiscomparedfor
similarities and discrepancies. Comparison of dental evidence is unique among the techniques used to identify a
decedent.Apositiveidenticationmaystillbeestablished,evenwhensomereconcilablediscrepanciesareobserved.
Variouscodesandsymbolshavebeenusedtocharttheantemortemandpostmortemstatusofthejaws.Currently
in the United States, the WinID3 and Unied Victim Identication System/UVIS Dental Identication Module
(UVIS/UDIM) dental identication software programs are most commonly used to compare dental records of
missing individuals to those of unknown human remains and have been used similarly in MFI situations. The
odontogramchartingcodesemployedinWinID3arepresentedinTable193.
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TABLE193
WinID3ChartingCodes
PrimaryCodes
SecondaryCodes
MMesial
AAnnotation
OOcclusal
BDeciduous
DDistal
CCrown
FFacial
EResin
LLingual
GGold
IIncisal
HPorcelain
UUnerupted
NNonprecious
VVirgin
PPontic
XMissing
RRootcanal
JMissingcrown SSilveramalgam
INodata
TDenturetooth
ZTemporary
The UVIS/UDIM software and Plass Data DVI System International software have been employed by forensic
odontologists in the oce of the New York medical examiner and the International Organization (INTERPOL)
National Central Bureau respectively.Although these computer programs can facilitate the process of comparison
amongthenumerousantemortemandpostmortemdentalrecordspresentedinMFIorindividualunknown/missing
identication cases, the ultimate decision regarding the concordance of information between the antemortem and
postmortemrecordsrestswiththeforensicodontologistnotthecomputerprogram.
Furthermore,theforensicdentistmustroutinelyrelyonthebeliefthatantemortemrecordsaretrulythoseofthe
persontheyarepurportedtorepresent.Thelaerproblemisbestexempliedbythecontroversyassociatedwiththe
antemortem dental records used to identify the bodies ofAdolph Hitler and Eva Braun. Until recently, there was
uncertaintyconcerningthereliabilityofthoserecords.Thisuncertaintywasbasedonthepossibilitythattherecords
hadbeenfalsiedtoencouragethemisidenticationofHitlerandhiswife.
ThecasedemonstratedinFig.1912showsthatallteeth,restorations,andanatomicstructuresareidentical,except
that deciduous tooth K is still present in the antemortem radiograph. Tooth No. 20 is erupted in the postmortem
lm. This dierence could not support a positive identication if it were a component of ngerprint or DNA
evidence. The facts that the deciduous tooth has exfoliated and the permanent tooth erupted before death are
acceptablediscrepanciesincomparabledentalevidence.
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FIG.1912 Antemortemandpostmortemradiographsdemonstratingthefluid,changingnatureof
dentalinformation.
Comparisonofdentalevidenceisoftencomplicatedbythequalityoftheevidencesubmied.Thephysicalstatus
of the postmortem dental material can be compromised when teeth have fractured or are avulsed secondary to
trauma.Often,onlyfragmentsofthejawsmaybepresentedforcomparison,andtheremayhavebeenpostmortem
lossofteeth.
Dental restorations can be separated from the teeth or melted in a re. Acrylic restorative material melts in
temperatures less than 540 C (1000 F), gold and amalgam melt at 870 C (1600 F), and porcelain can withstand
temperaturesgreaterthan1100C(2010F).Inaddition,extremetemperatureinarecancausetheteethtoexplode
orappearshrunken.Althoughtheprincipalroleofthedentitionofarevictimistoprovidedataforidentication,
studiesindicatethatmorphologicandmicroscopictissuealterationsoftheteethmayassistforensicscientists,such
asarsoninvestigators,indeterminingtemperatureanddurationofexposuretore.
The problems associated with incomplete antemortem records are compounded when radiographs are of poor
qualityasaresultofexposureanddevelopingerrors.Mischartedinformationintheantemortemrecordcanalsobe
consideredareconcilablediscrepancy.Thiserroroftenoccurswhenteethhavebeenextractedandadjoiningteeth
havemovedintothepositionoftheextractionsite.Restorationsmaybeinadvertentlyindicatedonthewrongtooth
whentheclinicianischartingorenteringinformationintotheprogressrecord.
Regardlessofthedicultiesencounteredwhendentalevidenceiscompared,thenalconclusionsmustbebased
onanobjectiveanalysisofthedatapresented.Theconclusionsmustbesupportableanddefensiblewhentheyare
presentedunderoathinacourtoflaw.
Dentistry'sRoleinMultiple(Mass)FatalityIncidentIdentification
Thetermmultiple(mass)fatalityincident(MFI)evokesimagesofachaoticevent,initiatedbyadestructiveforce,which
resultsinnumerousdeathsnecessitatingidentication.ThesemassdisastereventsresultinginMFIscanbeclassied
inoneofthreeways:
1.Natural
2.Accidental
3.Criminal(e.g.,serialhomicide,masssuicide,andactsofterrorism)
Each type of MFI event results in the death of numerous victims. However, the problems faced by the forensic
dentalteamresponsibleforidentifyingthedecedentsmayvary,dependingonthetypeofMFIencountered.
NaturalDisasters
Natural MFIs include earthquakes, tornadoes, hurricanes, volcanic eruptions, re storms, tsunamis, and oods.
Thesemayoccuroverrelativelyshortperiodsormaybeprotractedoverdaysorweeks.Victimsmaybescaered
throughoutbroadareas,extendingformiles.Inaddition,manyvictimsinnaturalMFIsituationsmaybeunknowns
who cannot be presumptively identied. Transients, homeless individuals, and tourists who are visiting an area
involved in a natural MFI are often dicult to identify. Several countries or states can be aected, as in the 2004
IndianOceantsunamievent.
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Inanaturaldisasterinvolvingmultiplefatalities,theprincipalproblemforthedentalidenticationteamisthat
the environmental infrastructure is often compromised. For example, after Hurricane Katrina, medical and dental
ocesandhospitalfacilitiescontainingantemortemrecordshadbeendestroyedbytornadicactivityandooding.In
addition, communication lines and roads were damaged, preventing the retrieval of most available antemortem
records.Allofthesefactorsdelayedorprecludedthepromptidenticationofmanyvictims.
Accidents
AccidentalMFIeventsaremostoftenassociatedwithtransportationaccidents,res,industrialandminingaccidents,
and military accidents. These situations usually occur over short time periods and are associated with dened
populations(e.g.,airplane,bus,ortrainpassengers;mineorfactoryworkers).
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.ThisoccurredamongthepassengersofMalaysiaAirlinesFlightMH370whenitwasdeterminedthat
twoofthevictimsofthisaccidentweretravelingwithstolenpassports.
Theminingcompany,mill,orindustrialplantcandocumentthosewhohavereportedforwork.Intheseexamples,
the victims of accidents should logically come from the dened population of employees on that shift. Therefore,
antemortem records are rst solicited from the families and health care providers of these individuals. Another
sourceofmedicalanddentalrecordsinthesecasesistheoccupationalhealthlesofworkers,whicharemaintained
bytheemployer.
Problems can be associated with the identication of victims of industrial and military accidents because these
populations may be of similar age, sex, and ethnicity. Commonly, individuals working in industrial or military
seingswearsimilarclothing.Thusmilitaryuniformsandprotectiveindustrialclothingdecreasethepotentialuseof
personalrecognitionasanidenticationaidinthesecases.
CriminalDisasters
UnlikenaturalandaccidentalMFIs,criminalsituationsresultinginmultipledeathsmayoccuroverextremelylong
timeperiods(years)andwiderangesofterritory(e.g.,dierentcitiesorstates).Thiswasthepaernoftherapesand
murders commied by Ted Bundy, whose victims included young women residing in states from Washington to
Floridafrom1974to1978.Theremainsofthevictimsofserialkillerscanbehidden,asintheGreenRiverhomicides
in the Pacic Northwest and the murders of young men commied by John Wayne Gacy in Chicago.
Dismemberment and mutilation of victims is exemplied by the Jerey Dahmer case. Dental structures in these
situationsmaynotalwaysbeavailableforpostmortemreview.
Lawenforcementagenciesareoftenunawareofthevictimsofserialkillersfromotherjurisdictions.Eachagency
maybeinvestigatinganindividualhomicidewithoutrecognizingapaernofbroadercriminalinvolvement.Until
thedevelopmentoftheFBINCICcomputerregistry,coordinatedeortsatidenticationwerehampered.
Theriseinnationalandinternationalterrorisminthetwentyrstcenturyhaschangedtheparadigmassociated
withthetraditionalparticipationofthedentalprofessioninanMFIseing.Untilrecently,forensicodontologistsand
otherdentalprofessionalsweresimplytaskedasexpertsintheidenticationofthedecedents.Currently,thereare
ongoing eorts within organized dentistry to develop eective responses to acts of bioterrorism. These eorts are
exempliedbytheprofessionsencouragementoflegislationauthorizingdentalprofessionals,infederallydeclared
emergencies,toperformvariousproceduresthatareroutinelynotwithinthepracticeoftheprofession.Underthese
provisions,dentistsregisteredandtrainedinemergingmedicaldiseases,bioterrorism,andemergencymedicalcare
wouldbeindemniedforactionstakenintheperformanceoftheseservices.
Actsofterrorismmayincludeexposuretobiologicagents,chemicaltoxins,andthedischargeofnucleardevices.
ThusthedentistinvolvedinMFIrecoveryandidenticationafteranactofterrorismmayadditionallyberequiredto
assist medical workers in providing care for the injured. In these scenarios, dentists must consider their personal
safety and that of their families. Civil defense and emergency preparedness organizational plans are beginning to
includedentistsamongthosechargedwithtriagingtheinjured.Additionalrolesforthedentalprofessionalinfuture
actsofbioterrorismandnuclearorchemicalaackincludeprovidingrstaidcareandimmunizationstoinjuredand
exposedsurvivors.
Responsibilities
In the United States, the National Response Plan (NRP) provides a comprehensive, riskbased, emergency
managementplantorespondtoanyhazardousevent.TheNRPestablishesguidelinestomanagedomesticresponse
to radiological, technical, natural, or terrorist incidents by developing twelve emergency services functions and
delineatingtheagencieschargedwithperformingspecictasksinaresponse.
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AspartofthepresidentialdirectivethatcreatedtheUSDepartmentofHomelandSecurityaftertheSeptember11,
2001,terroristaacks,theNationalIncidentManagementSystem(NIMS)wasalsodeveloped.Theoverallobjective
of this system is coordination of governmental agencies, nongovernmental organizations, and the private sector in
theresolutionofnationallysignicantincidents.
RegardlessofthetypeofMFI,thelocalcoronerorMEisultimatelyresponsibleforperformingtheautopsiesand
identifyingthevictims.Inaccidentsthatinvolvemodesofpublictransportation,theNationalTransportationSafety
Board(NTSB)isempoweredtoinvestigateanddeterminethecauseofthecrash.Otheragencieswithjurisdictionata
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,
representativesoftheUnitedStatesDepartmentofHealthandHumanServices(DHHS)NationalDisasterMedical
System (NDMS) division personnel mobilized with a federal Disaster Mortuary Operational Response Team
(DMORT)orDisasterMedicalAssistanceTeam(DMAT),theclergy,andcommunityvolunteerorganizations.
AlthoughDMORTandDMATunitsincludedentalpersonnel,theseteamsmaynotbemobilizedinallMFIs.In
thesesituations,forensicdentistsandsupportstaresponsibleforidenticationorcareoftheinjuredshouldalsobe
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
dentalteammembersfordealingwiththetechnicalproblemsofcasesinvolvingmultiplefatalities.
Inaddition,trainingsessionscanbeusedtocounselthedentalteamandtoinformmembersoftheposraumatic
stressoftenassociatedwiththistypeofforensicwork.Thisdelayedstressisaresultofthesensoryandpsychological
insultsencounteredbythedentist,hygienist,ordentalassistantwhoisdealingwithhumandeathonalargescale.
DuringanMFItheNDMS,underitsemergencysupportfunctions,isauthorizedandhasresponsibilitytoassist
local authorities by establishing temporary morgue facilities; identifying victims using scientic techniques; and
processing,preparing,anddisposingofvictimsremainstofamilies,funeralhomes,orproperlegalrepresentatives.
ThismissionhasbeenaccomplishedthroughthedevelopmentoftenregionalDMORTsadministeredbytheDHHS.
Each DMORT is composed of funeral directors, MEs, coroners, pathologists, forensic anthropologists, medical
records technicians and transcribers, ngerprint specialists, forensic dentists, dental hygienists, dental assistants,
radiology technicians, mental health specialists, computer professionals, administrative support sta, and security
andinvestigativepersonnel.
Theseindividualsareprivatecitizens,eachwithaspeciceldofexpertise,whoaremobilizedduringadisaster.
The licensure and certication of the DMORT members is recognized by all states because they are considered
temporaryfederalemployeesduringtheemergencyresponse.
Working with the authorization of the coroner or ME, a local dental disaster team or dental component of a
DMORT is responsible for antemortem record assembly and interpretation, postmortem physical and dental
radiographic examination, and nal comparison of dental information. These are the same principles used to
establishanindividualidentication.Yet,whennumerousvictimsneedtobeidentiedinashorttime,problemsof
identicationarecompoundedexponentially.
Noremainshavebeenfoundforonethirdofthe3000victimswhodiedintheWorldTradeCenterterroristaack
in 2001. Less than 300 victims were found intact although tens of thousands of fragmentary human remains and
personal eects have been recovered and processed through the Staten Island landll that has been used as a
temporarysortingfacility.Manyoftheseremainshaveyettobelinkedtoavictim.
Dividing the team into subsections responsible for each of the three identication domains (antemortem,
postmortem, and record comparison) permits a division of labor among the team members. This division reduces
errorsinidentication,inthatspecictasksintheidenticationprocessareassignedtoseparatesubsections.Achain
ofcommandshouldbeestablished,andtheteamleaderofeachshiftshouldbedirectlyresponsibletothecoroneror
ME.Thispersonistheonlymemberoftheteamauthorizedtoreleasetheresultsofthedentalidenticationprocess
toappropriateinvestigativeagencies.
TechnologicAidsinMultipleFatalityIncidentAnalysis
Advances in photographic, radiographic, and computer technology have provided the forensic dental team with
additional resources to enable recovery, documentation, storage, and comparison of forensic dental evidence in
MFIs,aswellasinothersituationsrequiringforensicdentalexpertise(e.g.,bitemarkanalysisanddocumentationof
humanabuse).Amongtheseadvancesaredevelopmentsinthefollowing:
Digitalphotography.Thebasicdigitalcamerausedforforensicevidencedocumentationshouldincludea
throughthelens(TTL),lightmetering,SLR,35mmdigitalcamerabodywithinterchangeablelensesoran
adjustablelenscapableofnormalrange(30to50mm)tomacrorange(90to100mm)focallength.Aremovable
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ashmemorycardwithadequatestoragecapacityisalsorequired.TheScienticWorkingGrouponImaging
Technology(SWGIT)imagingguidelinesprovidetheforensicodontologistwithinformationregardingthe
limitationsandparametersimposedbythejudicialsystemregardingthemanipulationandpresentationofdigital
photographicevidence.
Digitalradiography(DR)equipment.Electronicallygeneratedandstoredradiographicimagingcanbe
accomplishedbythefollowing:
Scanningnormallyprocessedradiographiclmintoacomputer
Usingaphosphorsubstrateshapedandusedlikeradiographiclmtoexposeandscanradiographic
informationintothecomputerbyaspecialproprietarydevice
Usingasensorsizedandshapedlikearadiographiclmthatismadeofascintillationscreenandacharge
coupleddevice(CCD)orcomplementarymetaloxidesemiconductor(CMOS)
Directdigitalradiography(DDR).Whenenergizedbyradiation,thisdevicecreatesadirectimageonthepixelsof
itsCCDorCMOS.Thisradiographicimageisthensenttoacomputerthroughwireorwirelesstechnology.Thus
becauseofitsabilitytosavetime,DDRtechnologyisrecommendedforclinicalandforensiccasework.
Additionally,DDRproceduresreduceexposuretimesbyrequiring90%lessradiationthanthatrequiredtoexposea
standardtypeDlmradiographand50%lessradiationthanthatrequiredinexposureoftypeElmradiographs.
Theparametersbywhichthequalityofaradiographisevaluatedincluderesolutionandcontrastsensitivity.Image
resolutiondescribesthedetailanimageholds.Inlmbasedradiographs,thisisexpressedasafunctionofhow
closelinescanbetoeachotherandstillbevisiblydistinguished.Digitalimagingmeasuresresolutionaspixel
counts.Thecontrastsensitivityisameasureofthesmallestpercentagechangeinanobjectsbasethickness(density)
thatcanbedetectedinaradiograph.ThehighresolutionoftheimageproducedbytheDDRsensorisoneofits
mostadvantageousproperties.
Conebeamcomputedtomography(CBCT).CBCTprovidesa3Dimagingmodalitytocollectacompletemaxillo
mandibularfacialanatomicvolumeofdata.Computersoftwarecanbeusedtoanalyzetheobtainedimage,andthe
diagnosticinterpretationprovidedcanbeusedfortreatmentplanning,assessmentofpathologicconditions,and
evaluationofdentalimplants.ApplicationofCBCTinforensicdentalsituationscanovercomeintraoralaccess
problemswithsomespecimens(e.g.,fourthdegreeburncases).
Portablehandheldxraygenerationdevices(e.g.,NomadmanufacturedbyAribex,andMinXrayHF70DUL
TypeA).Theforensicdentistisabletoexposelmordigitalradiographsquicklyandeortlesslywithabaery
poweredunitthatcanbecarriedtothebodyonthegurneyinthemorgue.Additionalapplicationsfortheuseof
thesedevicesinthedentaloceincludeexposureofradiographsonpediatricorsedatedpatientsorthosehaving
endodontictherapy.
Xrayuorescence(XRF)methodology.Asdiscussedpreviously,analysisofdentalmaterialsincremationand
otherdicultforensicidenticationcasesmaybefacilitatedbyanalysisofspecimenswiththistechnology.
Computersoftwaretechnology.TheadventofcomputersoftwarehasassistedMFIdentalidenticationteamsin
ling,storing,sorting,andmatchingbitsofantemortemandpostmorteminformation.Computerassistancehas
provedbenecialindisastersinvolvinghundredsofvictims.Commonlyusedprogramsincludethefollowing:
TheFBINCICprogram,basedontheCaliforniaDentalIdenticationSystem,developedbyDr.Norman
SperberandDr.RobertSiegel(SanDiego,CA)
CAPMI4(ComputerAssistedPostmortemidenticationversion4.0),developedbyDr.LewisLortonofthe
USArmyInstituteofDentalResearch(Itwasrstusedin1985insupportoftheArrowAirUSmilitarycharter
aviationrunwayaccidentinGander,Newfoundland.)
WinID3dentalcomparisonsoftware,developedbyDr.JamesMcGivney(StLouis,MO)(Bridgedwiththe
DexisDRprogram,WinID3facilitatedcomparisonofantemortemandpostmortemdentalrecordsinHurricane
KatrinarecoveryeortsandvarioustransportationandindustrialMFIevents.)
UDIM(UVISDentalIdenticationModule),thedentalrecording/searchcomponentoftheUVISsystem,
developedbyDr.KennethAschheim(NewYork,NY)
Eachofthesecomputersoftwaresystemsisuserfriendly,canberunonreadilyavailableandaccessiblehardware,
is automated and capable of networking, and relies on objective data entry and storage of antemortem and
postmortemdentalrecords,digitalradiographs,anddigitalimages.Theuseofthesecomputersoftwareprogramsin
MFIsituationsreducesthetimeandeortthathadtobeexpendedinpastevents.Beforetheiruse,anexaminerin
the dental identication team walked along tables with a postmortem record comparing the dental data and
radiographsateachstationcontaininganantemortemrecord.
Despite the fact that these technologic advances have facilitated forensic casework, the caveat for the forensic
dentistremainsthatidenticationistheresultofhumanthoughtprocessesandnotthehighlytechnicalsupportive
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procedures that provide the material being evaluated. To arrive at correct comparative conclusions based on the
evidence, individual dental team members must evaluate the computergenerated matches for denitive
identication.
BitePatternEvidence
BasicPrinciples
Abitemarkisapaernedinjuryorsurfacedisturbanceproducedbyteethontheskinofanindividualorinanimate
object. Historically, analysis of this type of evidence presumes that the dentition of the biter (animal or human) is
uniqueandcanbecomparedscienticallyandrelatedtotheresultantpaernedmarkonthesurfaceofavictimor
object. Although initial studies indicate the uniqueness of the human dentition, the debate among forensic
odontologistsandthoseinthelegalprofessionrelatestotheabilityoftheseuniquefeaturestobetransferredinto
skin,whichisacknowledgedasapoorimpressionmaterial.
Because it is reasonable to consider the teeth as cuing or mashing tools, the basis for accepting bite paern
evidencecanbesupportedonthesamescienticprinciplesusedtoevaluatetoolmarks.However,itisnowbelieved
thatalthoughindividualhumandentitionsmayhavedistinctivefeatures,thepaernedmarksleftbytheteethmay
notbeuniqueforeachpersonasoncethought.Variationsintoothsize,wear,fractures,andpositioninthedental
arch,diastemata,andrestoredsurfacescontributetotheprincipleofdistinctivenesswithinanindividualdentition,
butnotuniquenessamonghumandentitions.
Thus, issues related to the validity, reliability, and admissibility of bite mark evidence continue to rest with the
judicial system and its various rules pertaining to the introduction of scientic evidence in court. Signicant legal
appealshaveresultedinbitemarkevidencebeingoverturnedinseveraljurisdictionsandbecauseofthisevidence
thoseincarceratedhavebeenreleased.Basedontheselegaldecisionsanda2009reportfromtheNationalAcademy
ofSciencescriticalofthisuseofbitemarkevidence,ithasbecomethemostcontroversialcomponentoftheforensic
dentaldiscipline.Thishasresultedinthecurrentphilosophyregardingthesignicanceofbitemarkevidenceresting
initsexclusionaryratherthaninclusionarypowerwhencomparingthedentitionofaputativesuspecttoabitemark
onaninanimateobjectorbitemarkpaernedinjury(BMPI)inmostcases.
Victimsofmammaliananimalbitesaccountformostbiteinjuriesreportedannually.Biterelatedinjuriesrepresent
approximately 1% of all hospital emergency visits that require medical aention. Of these, nearly 370,000 were
associated with dog bites in 2001. The second and third most likely mammalian biters are cats and humans,
respectively.Eachrepresentsfrom5%to20%ofcasesreportingtourbanemergencyrooms.
AsthehabitatsofwildanimalsinNorthAmericacontinuetorecede,humansaremorelikelytocomeincontact
withthesedangerouscarnivores.Thisisreectedintheincreaseinaacksonhumansbymountainlionsandbrown,
black,andgrizzlybears,resultinginbitinginjuriesordeathfrombitingandclawing.
Animalbitesmaybeobservedpostmortemwhenabodyhasnotbeenburiedordiscoveredquickly.Commonly,
insect bites are made by ants and roaches, which leave paerned injuries that can be mistakenly interpreted as
antemortemhumanBMPIsortrauma(Fig.1913).Postmortembitesfromratsandscavengingferaldogsandcatsare
oftenavulsiveandofnarrowerorsmallerdiameterthanhumanbites.
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FIG.1913 Insectbitesontheskinthatmimicthepatterninjuryassociatedwithbitemarktrauma.Ina
decedent,thispatternmayadditionallybemistakenlyinterpretedasantemortemtrauma.(CourtesyofDr.
DavidK.Ord.)
Injuries caused by human bites are routinely related to either aggressive or sexual behavior. Ironically, it is not
uncommonfortheperpetratorofanaggressiveacttobebienbythevictim(asameansofselfdefense).Inchildren,
bitingisaformofexpressionthatoccurswhenverbalcommunicationfails.Bitinginjuriesinchildrencanresultfrom
playgroundaltercationsorsportscompetition.Theyarecommonamongchildrenwhoaenddaycarecenters.
SelfinictedbitesareobservedinLeschNyhansyndrome.ThissyndromeisanXlinked,recessivelytransmied
disease manifesting insensitivity to pain and selfmutilation (among other signs) by chewing away the lips. This
diseaseisrare,andselfinictedbitesaremorecommonlyseeninadultsandchildrenwhoarevictimsofphysical
abuseorsexualassault.Theseindividualsmaybitetheirownforearmsorhandsinanguishortopreventthemselves
fromcryingoutwhiletheyarebeingtraumatized.
Injuries resulting from animal or human bites may become septic or may progress to systemic infections.
Secondary bacterial infections are more commonly associated with human bites than with animal bites, although
80%ofdomesticcatbitesbecomeinfectedbecausebacteriaareinjectedintothedeeppuncturewoundsinictedby
theirneedlelike,carnassialteeth.Infectiouscomplicationsincludetetanus,tuberculosis,syphilis,actinomycosis,cat
scratch disease (caused by Bartonella henselae), and those infectious complications related to streptococcal and
staphylococcalorganisms.Anaerobicorganismsassociatedwithbiteinjuriesmayeventuallyresultincomplications,
suchasosteomyelitis,septicarthritis,tenosynovitis,meningitis,andinfectionsofthelymphaticsystem.
Viral complications, including hepatitis B virus, herpes simplex, and cytomegalovirus, have resulted from
transmission through human bites. The human immunodeciency virus (HIV) can also potentially be transmied
through the exchange of blood and saliva in a bite injury. The risk of seroconversion from this mode of HIV
transmission,however,isbelievedtobeextremelylow.Animmunocompromisedindividualwhoisalreadyinfected
withtheHIVvirusisatincreasedriskofsecondaryinfectionwhenbienbyacat.
Rabiesisthemostseriousinfectiouscomplicationthatresultsfrommammaliananimalbites.Itisoftennecessary
toidentifythespecicoendinganimalforrabiescontrolorpotentiallitigation.Thisidenticationisnotroutinely
done by matching the animals teeth to the paern injury. When humans bite, however, the marks left in injured
tissueorinanimateobjectsareoftenanalyzedandcomparedwiththeallegedperpetratorsdentition.
HistoricalandLegalIssues
ReferencestobitingduringactsofpassionoraggressioncanbefoundintheBible,KamaSutra,andOldEnglishlaw.
In colonial America, the Reverend George Burroughs was charged with the crime of biting one of the women
accusedofwitchcraftduringtheSalem,Massachuses,witchhuntincidentsin1692.Hewashangedforthisoense.
Bitemarkevidencewasprovidedinexpertdentaltestimonyinthe1870OhiotrialofAnsilL.Robinson,whowas
accusedofmurderinghismistress.Althoughthedefendantwaseventuallyacquied,theexpertdentalpresentation
byDr.JonathanTaftbecameabenchmarkforfutureexpertsinthediscipline.
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Theconceptofacceptingevidencerelatedtotheanalysisofpaernscreatedbythedentitionwasrstacceptedby
theappellatelevelcourtsoftheUnitedStatesjusticesystemin1954.Atthattime,Doylevs.StateofTexasbecamethe
rst modern case in which a criminal conviction was based on evidence relating a suspects dentition to paern
marksinaninanimateobject(apieceofcheese).BecauseoftheDoylecase,morethan260decisionsinvolvingbite
markevidencehavebeenenteredintothecaselawrecordsoftheappellatecourtsoftheUnitedStates.
Thelegalcommunityhasrecognizedtoolmarkandngerprintpaernanalysisasscienticallyacceptableforensic
disciplinesforsometime.Theevidencepresentedbyexpertsintheseareashasbeenacceptedin20%ofstatecourts
undertheFryestandard(Fryevs.UnitedStates),andtheremaining80%ofstatecourtsandallfederalcourtsunderthe
FederalRulesofEvidence702705.Thesearespecialrulesdealingwiththeadmissibilityofscienticevidenceinthe
Americanjudicialsystem.Thustheyarealsoapplicabletobitemarkinformation.
TheFrye test had been the standard for scientic admissibility in most state and federal courts since 1923. The
threecomponentsofscienticevidenceadmissibilitythatareconsideredundertheFryetestincludethefollowing:
1.Thescienticprinciplemustberecognizable.
2.Thescienticprinciplemustbesucientlyestablished.
3.Thescienticprinciplemusthavegainedgeneralacceptancewithinthescienticdisciplinetowhichitbelongs.
Among the three requirements, only the concept of general acceptance must be met to satisfy the Frye test of
admissibility.
In 1993, the US Supreme Court ruled on the admissibility of scientic evidence in Daubert vs. Merrell Dow
Pharmaceuticals.ItwastheCourtsdecisioninthiscasethatthegeneralacceptanceaspectoftheFryetestshouldno
longerbethesole,determiningfactorusedinconsideringadmissibilityofscienticevidence.Essentially,theCourt
replaced this principle with one that stresses scientic validity. This decision removes the responsibility of
determiningsoundscienticevidencefromthescienticcommunityinwhichithasgainedgeneralacceptance.
Instead, the Daubert ruling gives great latitude to the trial judge in considering the admissibility of scientic
evidence. Trial judges often have limited knowledge of scientic methodology; however, under Daubert they are
required to determine if the weight and admissibility of expert testimony is not only scientically valid but also
relevantandgermanetotheissuesinindividualcases.ThustheresultsoftheSupremeCourtsdecisioninDaubert
aretomakethejudgeagatekeeperandtheexpertwitnessaproviderofscienticallyvalidevidence.
The general acceptance concept is no longer the sole determinant of admissibility in Daubert. It becomes one of
severalfactorsthatmustbemetforscienticevidencetobeadmissible.Thesefactorsincludethefollowing:
Techniquesusedmustbetestableandtested.
Peerreviewandpublicationofresultsarenotrequiredbutmaypersuadethejudgeinadmiingevidence.
Standardsshouldbeestablishedforevaluationofthescienticmethodsanderrorratesassociatedwiththe
techniquesused.
Considerationisgiventoacceptanceofscienticprinciplesthathavegainedgeneralacceptancewithinthe
scienticdisciplinetowhichtheybelong.
BitemarkevidenceiscurrentlyadmissibleundertheFryestandardandFederalRulesofEvidenceasdetermined
bytheDaubertdecision.AlthoughsomelegalexpertsbelievetheFederalRulesofEvidenceprovidebeerguidelines
foradmissibilitydecisions,challengestothescienticbasisofbitemarkevidencemaybeavertedundereithersetof
standardsasthisevidenceisusedmoreroutinelytoexcluderatherthanincludeasuspect.
CharacteristicsofBiteMarks
To evaluate a paerned mark, its characteristics must be recognizable and distinguishable. Reasonably, the mark
should be consistent with the face of the instrument from which it was generated. Specic teeth can create
representativepaernsthatarerecognizable.Thesearedescribedasindividualcharacteristicsoftheentirebitemark.
Human incisors make rectangular marks. Depending on the amount of arition observed on the incisal edges of
cuspids,thesesurfacesmaybeassociatedwithpointortriangularpaerns.Unlikemandibularbicuspidteeth,which
haveadiminutivelingualcusp,maxillarybicuspidsoftenmarkinapaernthatresemblesagureeight.
Class characteristics of a human bite mark are related to the shapes that are created when groups of teeth from
bothdentalarchesareimpressedintoabiensurface.Semicircular,ovoid,orellipticalpaernsareusuallyobserved,
butvariationsmaybeassociatedwithtapered,square,andUshapedarches.Typically,bitemarksarecomposedof
twoarcshapedareascorrespondingtothemaxillaryandmandibulararchesandtheirrespectiveteeth.Whenonly
onearchcontactsasurface,acrescentpaernmaybeformed.Thegreatestdimensionsofanadulthumanbitemark
donotusuallyexceed4cm(Fig.1914).
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FIG.1914 Abitemarkpatterndemonstratingtheindividualandclasscharacteristicsassociatedwith
impressionsmadebythehumandentition.Anecchymoticareainthecenteroftheovoidpatternis
observed,whichisnotalwaysrelatedtothesuckingactionofasexualbite.Therefore,thisfinding
shouldnotbeoverinterpretedtoimplysexualintentonthepartofthebiter.Theimpressionsmadeby
theteethofthemandibulararcharemoredelicate.
Individual and class characteristics of bite paerns are generated by groups of specic teeth. The dynamics of
occlusionandmusclefunctionmustalsobeaccountedforwhenvariationsinindividualandclasscharacteristicsofa
bitemarkareconsidered.Suchvariationscanbecausedbymalocclusion,individualtoothmobilityassociatedwith
periodontal disease, and movement of facial muscles during biting. Class II malocclusion can cause the palatal
surfacesofthemaxillaryanteriorteeth,ratherthantheirincisaledges,tocontactthematerialbeingbien.Shieldlike
imprints of the palatal surfaces are generated in the bite mark rather than the rectangular paerns routinely
associatedwiththeseteeth.
Aberrant muscle forces associated with tongue thrusting can alter the way the teeth contact a bien surface.
Temporomandibular joint dysfunction can also contribute to variations in bite paerns. It can be associated with
midline shifts or inability to achieve maximum opening while biting. Periodontal disease may result in individual
toothmobility,whichcouldaectthebitemarkpaern.
Whenbien,manyinanimateobjectstendtoactlikedentalimpressionmaterial,retainingthemarksoftheteeth.
Such cases have involved bite marks in foods, chewing gum, paper toweling, and a roll of masking tape. Unlike
inanimate material, the skin is a dynamic tissue that can change after it is injured. Swelling, caused by the acute
inammatoryresponseofthetissue,candistortandaecttheinterpretationofthepaern.Bleedingintotheareaof
abitemarkcanmaskthepaern.
The age of an injury is the time elapsed from its iniction to the analysis of the damaged tissue. Reliable
determination of the age of antemortem skin injuries requires histopathologic and histochemical analysis to relate
the injury to the time of the alleged incident (Table 194). Color changes in the bien tissue, associated with the
degradation of hemoglobin from lysed RBCs, can be used only to broadly estimate the time of occurrence and
qualify the age of a bruise as recent or old. Environmental factors, including seasonal temperature, location of the
body,andpresenceorabsenceofclothing,mayadditionallyactasimportantvariablesrequiringconsiderationwhen
aemptingtodeterminetheageofinjurypaerns.
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TABLE194
HistopathologicandClinicalChangesUsedtoMonitortheTimeElapsed(Aging)inSkinInjuriesAssociatedwith
BiteMarks
Time
PredominantCellularInltrateandDeposits
Healing
VariableClinicalColor
Hours
48
Polymorphonuclearleukocyteswithaperipheralfront
12
Polymorphonuclearleukocytes
1624
Macrophagespeak
2436
Polymorphonuclearleukocytespeak
Redbluepurple
Blueblack
Peripheralbroblasts
Days
13
Centralnecrosis
3+
Hemosiderin
Greenblue
Collagenbers
45
Capillarygrowth
Lymphocytespeakatperiphery
1014
Granulationtissue
Brownyellowgreen
Tanyellow
Contusionsandareasofecchymosisarenotunusualinbitemarksmadeinlivingtissue.Theabsenceofbleeding
intotheinjurymayimplythatitwasinictedafterdeath.Additionalpostmortemsofttissuechangesthatcanaect
thequalityofabitepaerninjuryanditseventualweightasevidenceincludeartifactscreatedbylividity(causedby
theselingofbloodpigmentsindependentbodyareas),decomposition,andembalming.
Bite marks from sexual aacks are commonly found on the neck, breasts, arms, buocks, genitalia, and thighs.
Axillary bites and bite paerns on the back, shoulder, penis, and scrotum are often associated with homosexual
activity.Abusedchildrenmaybebieninareasoftheface,particularlythecheek,ear,andnose.Assailantsalsocan
bebien.Theanalysisofthesebitepaerninjuriesisjustasincriminatingasthosefoundonthevictimofaviolent
act.
A review of 778 bite mark injuries concerning the anatomic locations most often bien, victim and biter
demographics, the type of crimes in which biting occurred, and legal disposition of cases revealed the following
information:
Femaleswerebienmoreoftenthanmales.
Perpetratorsweremalemoreoftenthanfemale.
Themostcommonsitesbienwerethearms.Bitesintheselocationsoccurredmorecommonlyamongmales.
Femaleswerebienonthebreastmoreoftenthanmales.Thislocationaccountedforthesecondmostcommonly
bienareaofthebody.
Thetypeofcrimeandtheageofthevictimwererelatedtopaernsinlocation,distribution,andnumberofbites.
GuidelinesforBiteMarkAnalysis
In 1984, the American Board of Forensic Odontology (ABFO) established Guidelines for Bite Mark Analysis.
Additional workshops of the Board have provided further insight into the techniques available to recover, store,
analyzeandevaluatebitemarkevidencebasedontheGuidelines.ThedevelopmentoftheGuidelinesalsocreateda
scientic approach to the description of the bite mark, collection of evidence from suspect and victim, and
subsequentanalysisoftheevidence.
TheGuidelinesdonotmandatespecicanalyticmethodsforcomparison.Throughtheircarefuluse,however,the
qualityoftheinvestigationandconclusionsbasedonbitemarkevidencefollowcustomaryprocedures.Thuswith
these guidelines, it should be possible to determine the weight of bite mark evidence required to establish the
validityofbitemarkcomparison.AccordingtothecurrentGuidelines,bitemark,suggestiveofabitemark,andnotabite
markarethetermsusedtoindicatethecondenceleveloftheodontologistthatapaernedmarkrepresentsabite
mark.
DescriptionoftheBiteMark
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Demographic information (i.e., age, race, sex, and name of the victim; examination date; referring agency; case
number)isobtainedincasesinvolvingbothlivinganddeceasedvictims.Thenamesoftheforensicdentalexaminer
andreferringagencycontactpersonshouldalsobeincluded.
Thelocationofthebiteisthendescribed.Aentionisdirectedtotheanatomiclocation,surfacecontour,andtissue
characteristicsofthebienarea.Underlyingstructures,suchasboneorfat,mayinuencetheanalyticqualityofthe
paerninjury.Relativeskinmobilityisalsoevaluated.
The shape, color, size, and type of injury are recorded. Metric measurements of the horizontal and vertical
dimensionsofthebitemarkaredetermined.Irregularitiesandvariationsfromthestandardsemicircular,ovoid,and
crescentshapesassociatedwithhumanbitemarksarenoted.Injurytypesincludeabrasion,laceration,ecchymotic
and petechial hemorrhage, incision, and avulsion.Artifactual injuries, such as proximate stab and bullet wounds,
shouldberecordedbecausethesemaydistortthepaernbyseparatinganatomiccleavagelinesoftheskin(Langer
lines).
EvidenceCollection
ExaminationoftheVictimandtheSuspect
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. Therefore, to ensure
objectiveanalysis,itisrecommendedthatdentalimpressions,photographs,anddemographicinformationobtained
fromtheputativesuspectedbiterbecollectedbyadentistotherthantheodontologistmakingthecomparison.
Astandardhealthhistoryandinformedconsentareobtainedbeforeanyevidencerecoveryprocedureregarding
thesuspectisperformed.Anintraoralandextraoralexaminationofthesuspectiscompleted,whichincludesdental
charting,softtissueandtongueevaluation,andprobingoftheperiodontium.Therefore,knowledgeofthemedical
historyofthesuspectrelativetosystemicproblemsassociatedwithcardiovasculardisease,allergy,seizuredisorder,
diabetes,andrespiratorydiseaseorrequirementsforantibioticprophylaxishasmedicolegalimportanceinforensic
casework,aswellasintraditionalpatientevaluation.
A search warrant, court order, or legal consent may be required before evidence is collected from a suspect.A
specic list of the dentalrelated evidence desired should be recorded in the legal document. This list usually
includesfacialandoralphotographs,impressionsoftheteeth,occlusalregistrationsandbiteexemplars,andsaliva
samples.Thesedocumentsprotecttherightsofthesuspectagainstunreasonablesearchandseizureandprovidefor
dueprocess,asguaranteedbytheFourthandFourteenthAmendments,respectively,totheUSConstitution.
Bite marks are considered similar to such physical evidence as ngerprints, hair, blood, and semen samples, as
wellastosobrietytests.Therefore,thismaterialisnotprotectedunderprovisionsoftheFifthAmendment,which
dealswithselfincrimination.
Evidence collection from the victim entails noninvasive and invasive techniques. The former include
photography,salivatraceevidencecollection,fabricationofstudycastsofthebitemark,andstereolithography(SLA)
tocreate3DmodelsoftheBMPI.Thelaermayinvolvetissueincision,excision,andpreservationofaBMPIina
decedent.Preservationofthistissuepermitsanalysisoftheinjurybytransilluminationandobservationofthearea
fromthesideoppositethelightsource.
Photography
Becauseevidenceassociatedwithbitemarks,humanabuse,andsexualandphysicalassaultistransitory,thereisan
immediacyassociatedwiththecollectionofphysicalevidenceinthesecases.Initialphotographsofthepaernmark
shouldbetakenbeforeanyinvestigativeproceduresthatmayalterthepristinebitemarkevidence(e.g.,touching,
removing,impressing,swabbing,andcleansing).
Ideally,standardvisiblelightphotographictechniquesincludetheuseofa35mmDSLRcamerawithaateld
macrolensanddedicatedelectronicash.Numerousimagesusingdierentcameraandlightingpositions,exposure
seings,andcolorandblackandwhiteexposuresshouldbeobtained.Additionallegalconsiderationsandprotocols
related to the documentation of image enhancement, restoration, compression, and analysis have been established
fordigitalbitemarkimages.
Orientation positions and closeup views with a reference scale are required.A reference scale permits the bite
mark images to be measured and prepared as lifesize (i.e., 1:1) representations of the paern injury. Ultimately,
theseimagescanthenbecomparedwithcastsandotherexemplarsobtainedfromthesuspect.Thescaleshouldbe
stabilizedandpositionednextto,andinthesameplaneas,thebitemarktoeliminatepotentialdistortionartifactsin
theresultantimages.Itshouldneverbehandheld.Thescaleshouldbeomiedfromatleastoneimagetodocument
thatnomarksorotherinjurieshavebeenintentionallyhiddenbyit.
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TheABFONo.2photomacrographicreferencescale(LightningPowderCompany,Inc.;Salem,OR)wasdeveloped
bytheABFOforuseinbitemarkphotography(Fig.1915).Thisstandardized,Lshaped,accuratescalehasbecome
thegoldstandardinbitemarkphotographicanalysis.Variationsofithaveeventuallycometobeusedinallvarieties
offorensiccaseworkrequiringaccuratemeasurementofevidenceatcrimescenesorinthelaboratory.
FIG.1915 TheAmericanBoardofForensicOdontology(ABFO)No.2ReferenceScale.
This nonexible instrument contains two metric scales, an 18% color gray scale, three circular symbols, and
rectifying grids. Each of these components is used to account for photographic distortions, which can negate the
value of the photographic evidence. Techniques using Adobe Photoshop and Mideo Systems CASEWORKSeis
computersoftwarehavebeenusedtorectifydistortionsobservedintheABFONo.2referencescaleandultimately
toeliminatethesefromabitemarkimagebeinganalyzed.
Withlivingvictims,serialpicturesoftheBMPIaretakenoverseveraldays.Thisseriesprovidesdocumentationof
the color changes associated with healing of the wound. In addition, special advanced photographic techniques,
using nonvisible energy sources at the extremes of the electromagnetic spectrum and uorescent alternative light
sources, can be used to identify latent images of the teeth that may remain after the bite mark has clinically
disappeared. These techniques require special lms and illumination sources, bracketing of aperture (fstop)
openings, variations in shuer speeds, and/or lens lters to work within the desired wavelengths and include the
following(Table195):
Reectiveultraviolet(UV)photography.Thistechniqueenhancesthebitemarkimagebyselectivelyidentifying
photoactivechromophores,suchasmelaninandhemoglobinpigmentinthesuperciallayersoftheinjuredtissue.
Variationsintheamountofthesenaturallightabsorbingorganicpigmentsinthetraumatizedtissueareobservable
inimagesexposedwiththisenergysource.Thisisbasedontheuorescencecreatedwhentheskinisexposedto
UVlightinthe200to400nmwavelengthrange.AlthoughtheremaybefocusingproblemsassociatedwithUV
photographyandexposuresmustbemadewithatripodmountedcamera,thefactthatthistechniquemaypermit
recoveryoflatentevidence,evenmonthsafterallclinicalsignsofabitemarkinjuryhavedisappeared,makesthe
eortworthwhile.
Infrared(IR)photography.TungstenlampsandquarhalogenlampsaregoodsourcesofIRradiationwhen
aemptingtoexposeIRimagesfromunlteredlightsources.ToexposeimagesspecicallywithintheIR
wavelengthsof750to1000nm,altermustbeplacedinfrontofthelenstoabsorbvisiblelight.TheKodak87gel
lteraccomplishesthistaskbylimitingalltransmianceoflightexceptatthedesignatedwavelengths.
Additionally,IRphotographyrequiresthatthecameralensberefocused(focusshift)afterinitialfocusingunder
visiblelightandbeforeexposureoftheimage.Likealternatelightsourcephotography,thefocalplaneforIR
photographyliesbelowtheskinsurface.Thedeeperfocaldepthpermitsvisualizationoffadedtaoosandwound
damagewithinabloodstain.Thistechniqueisnotthebestforidentifyingindividualcharacteristicsinbitemark
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injuries.
Alternatelightsource(alternatelightimaging[ALI])photography.Thistechniqueisalsoreferredtoasuorescent
photography.Itisadvantageousinassistinginvestigatorstolocateanddocumentevidenceinvolvingthepresenceof
inkresidues,ngerprintpaerns,andthechromophorespreviouslyindicated.ALIenhancesvisualizationof
pigmentsderivedfromchromophoresthatmaybefoundwithinevidenceinvolvinglatentserologicuidsand
subdermalbruisesorpaerninjuriesofvictimsofviolentorsexualcrimes.ALItechniquesilluminatedeepertissue
targetsbyusingapredominantlymonochromaticbandoflightbetweenthewavelengthsof430and460nm.To
accomplishthevisualizationoftheweakuorescentglowfromthedesiredpigments,ALIphotographymustbe
performedbyeliminatingallothersourcesoflightfromstrikingtheimagingsurface(lmordigitalsensor).This
requiresthatALItechniquesbeperformedintotaldarknesswithyellowlters,suchastheKodakgelatinNo.15.
Becauselongerexposuretimesarealsorequired,imagesexposedusingALImustbemadewithatripodmounted
camera.
TABLE195
ComparisonofPhotographicElectromagneticEnergySpectrumSourcesandTheirForensicImagingCapabilities
Visible
Light
UltravioletLight
Infrared
Light
AlternateLightImaging
Fluorescence
Lightwavelength
400
200400nm
700nm
700
450nm
1000nm
Filter
None
Kodak
Kodak
Kodak
WraenFilterNo.18Agel(visibly
opaqueglasslter)
Gel87
Gel15
TargetPigmentorMaterial
Hemoglobininpaerninjuries
andvessels
Melanin
Taoos
+
+
Inkvariationsindocument
forgeries
Gunshotresidues
Latentngerprints
Serologicuids(saliva,semen,
andblood)
Residualbers
As previously stated, photographs of the suspect should involve the same aention to technical quality control.
Extraoral, intraoral, and occlusal photographs are taken. Additional images of wax or acrylic test bites and
measurementsofmaximuminterincisalopeningarealsorecorded.
SalivaEvidence
Althoughtheforensicdentistisconcernedprincipallywiththeanalysisofthephysicalevidenceassociatedwitha
bitemark,biologicevidenceintheformofserologicandDNAmaterialisalsoofprobativeimportance.Collectionof
salivatraceevidencefromthesurfaceofthebiteinjuryofthevictimisperformedbeforeotherevidencegathering
manipulationoftheinjury.ThereisanincreaseintheyieldofrecoveredDNAforanalysiswhenthisprocedureis
carriedoutaccordingtothetwoswabprotocoldescribedpreviously.
Usingthistechnique,asalivasampleiscollectedbyrstrubbingthebienareawithacoonswabthathasbeen
moistenedinsterile,distilledwater.Theswabshouldcontainnopreservatives.Thebitemarkissubsequentlyrolled
withasecond,dry,coonswab.Bothsamplescanbeconsideredasingleexhibitbecausetheyhavebeencollected
fromthecenterofthepaerninjury.Theyareplacedinanevidenceboxandpermiedtoairdrybeforesubmission
tothelaboratory.Nocontrolswabsarerequiredfromadjacentareasofthevictimsskin.
DNA from the victim of a BMPI should be obtained from whole blood samples or buccal swabs.Additionally,
autopsytissuesamplescanbeobtainedfromdecedentvictims.AllsamplescanbeusedforDNAcomparisonwith
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bodilyuidortissuesamplesobtainedfromthesuspect.
Becauseavictimmaybebienthroughtheclothing,areasofgarmentsthatapproximateaBMPIshouldalsobe
retained and evaluated for saliva. Many victims of sexual abuse wash the area of a bite mark before reporting for
treatment.ThisisunfortunatebecausebiologicevidenceassociatedwithDNArecoverycanbelost.Inthisregard,
emergencyroompersonnelshouldbetrainedtorecognizepotentialBMPIsandbeinstructednottowashordisinfect
theseareasuntilsalivaevidencecanbeobtained.
ImpressionsandStudyCasts
Whenabiteinjuryexhibitsindentationsthatcanberelatedtothedentitionofanallegedbiter,accurate,3D,lifesize
exemplars(casts)canbeobtainedfrommoldsofthearea.Dentalimpressionmaterialsareusedtocreatethemolds
thatarethenreinforcedtopreventdimensionalchangesanddistortions.
TheGuidelinesforBiteMarkAnalysisdeliberatelydonotdictatewhichimpressionmaterialsshouldbeusedto
create exemplars of a bite mark. Low and mediumviscosity vinyl polysiloxane (VPS) impression materials are
dimensionally stable, meet American Dental Association specications, and are all acceptable. Hydrocolloid,
polysulde,polyether,andalginatematerialsarenotrecommendedbecauseofproblemsassociatedwithlongterm
stability.
Orthopedic cast materials, heavybody VPS materials, and nonexothermic resins have been used to create the
rigid,stabletraysforbitemarkimpressions.Allimpressiontraysandstudycastsshouldbeappropriatelylabeled
withdemographicinformationforthespeciccase.Additionally,anatomicdirectionmarkersshouldbeaddedtothe
impressiontraybeforeitsremovalfromtheskinsurface.Thiswillensurethattheimpressioniscorrectlyoriented
relativetotheactualpaerninjury.
Original impression trays and study casts are retained for eventual presentation in court. Working casts and
modelsshouldbeduplicatedfromtheoriginalimpressionormastercasts.Itisrecommendedthatmastercastsbe
pouredintypeIVstone,accordingtothemanufacturersspecications,andthatthesecastsremainpristine.
TissueSamples
Tissue samples of a bite mark can be retained from decedents. With the permission of the ME or coroner, the
epidermis,dermis,andunderlyingmuscleandadiposetissuecanberemovedfortransilluminationanalysis.Before
excision,anacrylicringorstentmustbesecuredwithin1inchofthebordersoftheinjuredtissuesample.Theringor
stentpreventsshrinkageanddistortionofthespecimenwhenitisplacedintoa4%formalinsolutionforxation.
Theacrylicmaterialisboundtotheskinsurfacewithcyanoacrylateandsutures(Fig.1916).Thesetissuessamples
canbetransilluminatedbybacklighting.Thisprocesspermitsobservationofthepaerninjuryinthebruisedskinby
amannerthatisnotpossiblewhenthetissueisinsitu.
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FIG.1916 Anexperimentalbitepatterninjuryonacadaver.Thisbitemarkhashadanacrylicstent
gluedandsuturedarounditscircumferencebeforedissectionandfixationin4%formalin.(CourtesyofDr.E.
StevenSmith.)
EvidenceAnalysisandComparison
The responsibility of comparing the photographs of the bite paern injury with the dentition of the suspect rests
withtheforensicdentist.Asanexpertintheanalysisofthesepaerns,thispersonobjectivelyevaluatestheevidence.
Theforensicdentistrstdetermineswhetherthepaernistrulyaresultofbitingorwhetheritisanartifact.Paerns
ofbloodsplaeraroundawound,othertoolmarks,orinsectartifactsunrelatedtotheteethmaybemistakenforbite
marksinphotographsprovidedforevaluationbycrimesceneinvestigators,police,andemergencyroomorautopsy
personnel.
Onceitisestablishedthatthepaernisrelatedtotheteeth,itcanbecomparedtothedentitionofthesuspectfor
inclusionaryorexclusionarypurposes.Anexpertopinionisthenmadeaccordingtotheresultsoftherelationshipof
thebitepaernandsuspectsteeth.AccordingtotheABFOGuidelinesforInvestigativeandFinalBiteMarkReports,
thebiter,theprobablebiter,notexcludedasthebiter,excludedasthebiter,andinconclusivearethetermsusedtoindicate
thecondenceleveloftheodontologistthatthedentitionoftheputativesuspectisconcordantwithabitepaerned
markobservedonaninanimateobjectorvictim.
Toaccomplishthesegoals,thedentistusesnumerousmethodsthathavebeenacceptedinthecourts.Imagesofthe
bite mark and the teeth can be digitized in a computer. This information can then be enhanced and subsequently
overlaidformatchingpurposes.
Historically,aclearoverlayofthechewingsurfacesoftheteethwasmadebysimplytracingthesesurfacesona
sheet of transparent acetate. Placing the incisal edges of the study casts on the glass of an oce photocopier and
duplicating on special paper achieved the same end.A similar eect was obtained by placing an opaque powder,
suchasbariumsulfate,intowaxoracrylictestbitesandbyobtainingradiographsoftheseexemplars.Allofthese
overlayswerethensuperimposedoverthebitemarkforcomparison.
Studiesindicatethattherearelimitationstotheaccuracyofthesepotentiallysubjective,biasedoverlaytechniques
andithasbeensuggestedthathandtracedoverlaymethodsbediscontinued.Additionally,astonecastexemplarof
thedentitionofasuspecthasbeenplacedovera1:1imageofaBMPIforcomparison(Figs.1917and1918).This
methodofcomparisonmayalsohavelimitationsconsideringthatcomputerbasedtechnologythatcurrentlyexiststo
moreobjectivelyassisttheodontologistinbitemarkcasework.
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FIG.1917 Anoverlayofthemaxillarycastofasuspect'sdentitiononaphotographofabitepattern
injury.Notethediastemabetweenthecentralincisorteeth.Thedistalincisalsurfacesofthelateral
incisorteetharenotintheplaneofocclusion.
FIG.1918 Arepositionedoverlayofthemaxillarycastofasuspect'sdentitiononaphotographofa
bitepatterninjury(samecaseasdepictedinFig.1917).Thedragmarks,diastemaspace,andmesial
contactpointsofthelateralincisorteethbecomeapparentinthepattern.(FromNucklesDB,HerschaftEE,
WhatmoughLN:Forensicodontologyinsolvingcrimes:dentaltechniquesandbitemarkevidence,GenDent42:210214,1994.Publishedwith
permissionbytheAcademyofGeneralDentistry.1994bytheAcademyofGeneralDentistry.Allrightsreserved.)
Presently, images of the bite mark and the incisal edges of the teeth of the suspect are routinely digitized and
computergenerated hollow volume overlays are fabricated, enhanced, and subsequently compared using Adobe
Photoshoporothergraphicseditingprograms(Fig.1919).
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FIG.1919 Ontheleftside,dentalcastsofanallegedsuspectarebeingscannedandscaledto1:1
beforedigitizingtheirimage.Therighthalfoftheillustrationshowsthreephotographsofbitemarkson
thevictim.Transparentoverlaysoftheteethoftheallegedsuspecthavebeendigitallysuperimposed
over1:1digitalimagesofthevictim'sbitemarkusingasoftwareprogramdevelopedbyMideo
Systems,Inc.(HuntingtonBeach,CA)(CourtesyofDr.DavidK.Ord.)
In court, bite mark evidence must be able to withstand legal challenges based on its scientic validity and the
credibilityoftheexpertwitnesswhopresentstheevidence.Thisistrueregardlessofthetechniquesusedtoretrieve,
compare,anddetermineaconclusionbasedontheevidence.WhentheGuidelinesforBiteMarkAnalysisareused,
suchchallengescanbeminimized.
HumanAbuse
EpidemiologyandClassification
Dentalprofessionalsarelikelytoencountermorevictimsofphysical,neglective,sexual,andpsychologicalabuseas
thescopeoftheproblemsassociatedwithviolenthumanbehaviorbecomemorerecognizedandopenlydiscussed.
Currently in the United States, statistics reveal more than 3 million cases of child abuse, 2 million cases of elder
abuse,and4millionvictimsofintimatepartnerviolence(IPV)annually.
Childabuseisthenonaccidental,physical,mental,emotional,orsexualtrauma;exploitation;orneglectendured
by a child younger than 18 years of age while under the care of a responsible person, such as a parent, sibling,
babysier, teacher, or other person acting in loco parentis. Elder abuse and abuse of the disabled are similar in all
regards,exceptthattheydealwithgeriatricvictimsorindividualswhoarephysicallyand/ormentallyimpairedor
disabled.Thesepopulationsoftenrequirespecialcareorhavebeeninstitutionalized.
Victims of IPV are unique and dier from those of child, elder, or disabled abuse because they often have
autonomytochoosetheircircumstances.Unliketheabusedchild,orgeriatricordisabledresidentinanursinghome,
theabusedintimatepartnercanmakechoicestoleavethetraumatic,violentenvironment.
Of the 3 million cases of alleged child abuse or neglect investigated by state and local child protective services
(CPS)intheUnitedStatesin2004,872,000childrenweredeterminedtobevictimsofchildmaltreatmentand1490
cases resulted in death. The National ChildAbuse and Neglect Data System (NCANDS) is a federally sponsored
program directed by the Department of Health and Human Services to collect and analyze annual data on child
abuseandneglect.
Recognizing the global problem, in 2006 the United Nations released the rst UN SecretaryGenerals Study on
Violence against Children. This document addresses violence against children in the home, school, workplace,
community, and other seings. The project is the rst comprehensive, global study conducted by the United
Nationsonallformsofviolenceagainstchildren(Box192).
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Box192
Epidemiological,StatisticalOverviewoftheUnitedNations
S e c r e t a r y G e n e r a l s S t u d y o n V i o l e n c e A g a i n s t C h i l d r e n
Almost53,000childrendiedworldwidein2002asaresultofhomicide.
Upto80%to98%ofchildrensuerphysicalpunishmentintheirhomes,withonethirdormoreexperiencing
severephysicalpunishmentresultingfromtheuseofimplements.
150milliongirlsand73millionboysyoungerthan18yearsexperiencedforcedsexualintercourseorother
formsofsexualviolenceduring2002.
Between100and140milliongirlsandwomenintheworldhaveundergonesomeformoffemalegenital
mutilation/cuing.InsubSaharanAfrica,Egypt,andtheSudan,3milliongirlsandwomenaresubjectedto
genitalmutilation/cuingeveryyear.
In2004,218millionchildrenwereinvolvedinchildlabor.Amongthese,126milliondidhazardouswork.
Estimatesfrom2000suggestthat1.8millionchildrenwereforcedintoprostitutionandpornography,and1.2
millionwerevictimsoftracking.
Victims and their abusers come from all racial, ethnic, religious, socioeconomic, and educational backgrounds.
Reports concerning the distribution of cases among the dierent types of abuse vary widely. Up to 70% of child
abusecasesmaybetheresultofphysicaltrauma.Somestudiesrelate15%to25%ofthecasestosexualabuseand
50%toneglect.Neglectiveabuseissubclassiedbythecaretakersneglectofthechildsmedical,dental,andsafety
needs;physicalwellbeing;oreducation.
Intentionaldruggingorpoisoningandfailuretothriveareadditionaltypesofmaltreatmentclassiedasabusive.
Munchausen syndrome by proxy (MSBP) is a form of child abuse in which the caregiver intentionally overstates,
contrives,and/orcreatesaphysical,emotional,orbehavioralprobleminthechild.Thevictimismadetoappearsick
or is harmed in some other way to deceive health care professionals and others in order to gain aention and
sympathyforthecaregiver.
Many abusive individuals were themselves abused as children. Criminal charges are often lodged against an
abusingcaretaker.Itisrecognized,however,thatcounselingandpsychologicalandemotionalsupportcanalsohelp
tostabilizeaviolent,dysfunctionalfamilyunit.
SignsandSymptoms
Regardlessoftheoverallstatisticalvariationsinsubclassicationoftheproblemofabuse,thedentistismostlikelyto
encounter physical and sexual abuse, as well as health care and safety neglect among pediatric, older adult, and
disabled dental patients. Of the children and older adults who are physically abused, 50% manifest orofacial and
scalpinjuries(Figs.1920and1921).Theseunexplainedinjuriesareinappropriatelyreportedbythecaretakerorare
inconsistentwiththehistoryprovided.Abusivetraumatotheface,mouthandskullincludesthefollowing:
Lacerationofthelabialorlingualfrenum,whichresultsfromablowtotheliporforcefulfeeding
Repeatedfractureortheavulsionofteeth
Zygomaticarchandnasalfractures
Bilateralcontusionsofthelipcommissuresfromtheplacementofagag
Bilateralperiorbitalecchymoses(raccoonmask)
Mastoidecchymosis(Balesign)indicatingfractureofthemiddlecranialfossaandrelatedtraumaticbraininjury
Traumaticalopeciasecondarytograbbingtheheadhairofthevictimwhilethrowingthem
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FIG.1920 Anavulsedtooth,afracturedtooth,andatornlabialfrenumassociatedwithoralfacial
injuriesinphysicalchildabuse.
FIG.1921 Bilateralperiorbitalecchymoses(raccoonmask)andfracturednasalboneina77yearold
whitefemalevictimofphysicalelderabuse.(CourtesyofDr.JohnD.McDowell.)
Paern injuries can be associated with the semicircular or crescent shape of bite marks. Other instruments that
contact the skin may leave parallel linear paerns; these include injuries made by a hanger, strap, belt, or ruler.
Multipleparallellinesareassociatedwithngermarksafteranopenhandedslap.Multiplecircular,punchedout,or
ulcerated areas are caused by intentional burning with a cigaree or cigar. Loop paerns are created by electrical
cord,rope,andwire(Figs.1922and1923).
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FIG.1922 Multiplecircularulceratedinjuriesareassociatedwithintentionalburnsfromacigarette.
Whenachildisaccidentallyburnedbyacigarette,onlyoneellipticulcerisobserved.
FIG.1923 Parallellinear(railroadtrack)patternsareassociatedwithblowstotheskinwithsuch
straightedgedobjectsasabelt,ahanger,anelectricalcord,andaruler.
Othercharacteristicsofchildandelderabuseinjuriesarerelatedtotheirmultiplicityandrepetitivenature.They
oftenappearinvariousstagesofresolution.Someinjuriesareacute;othersarehealingorevenscarred.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
aempttomaskorhidethephysicalsignsofabuse.
By adulthood, 10% of men and 25% of women are the victims of sexual abuse. Oral infections associated with
sexually transmied 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
ndingscanresultfromthephysicaltraumaassociatedwithperformingfellatioorcunnilingus(seepage280).
Among siblings, nursing or baby bole caries is a sign of neglective abuse and indicates the caretakers
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inaention to the dental needs of the children. When infants and toddlers are placed to bed with a nursing bole
lled with cariogenic solutions (e.g., milk, soft drinks, and sweet juices), the maxillary incisors are bathed in the
sugarysolutionandcanmanifestseverecaries.Themandibularteeth,protectedfromthecariogenicmaterialbythe
position of the tongue and nipple during sucking, are spared the destructive eects, and the child takes on the
appearanceofapseudoprognathismorpseudoClassIIImalocclusion(Fig.1924).
FIG.1924 PseudoprognathismorpseudoClassIIImalocclusionobservedinaneglectedchildwith
nursingbottle(babybottle)decay.(CourtesyofDr.CynthiaHipp.)
The dentist may become aware of other abusive behavior directed to a child or older patient by a responsible
caretaker.Abusivebehaviorcaninvolverefusalordelayinseekingtreatmentforseriousmedicalordentalproblems,
abandonment,refusaltocooperatewithplannedtreatment,andfailuretoreturntothesamephysicianordentistfor
treatment.
RoleofDentistryinRecognizingandReportingHumanAbuse
Awarenessofthesignsandsymptomsofabuseamongindividualsofallagesshouldbeagoalforeverydentist.Asa
componentofthedentalrelicensureprocess,thestateofNewYorkrequiresdocumentationofcontinuingeducation
creditsintheareaofchildabuserecognitionandthedentalprofessionalsresponsibilitytoreportsuchcases.
By statute, all states require that dental personnel, other health care professionals, teachers, and day care and
nursing home employees report suspected cases of child and elder abuse. Unfortunately, the reporting of IPV is
limited in most jurisdictions to cases involving the use of a weapon while commiing a violent act.Although the
dentisthasnolegalrequirementtoreportIPVintheseareas,theAmericanDentalAssociationsPrinciplesofEthics
and Code of Professional Conduct indicate a responsibility on behalf of dental professionals to intercede in cases
involvingfamilyviolence.
The agency to which the report is made varies among the dierent jurisdictions. Commonly, the police, social
service, child welfare, senior services agencies, or family services departments are the governmental oces
designated to accept reports. When a report is made in good faith, the dentist is immune from any counter
prosecution or civil liability that might stem from a false report. Failure to report is considered a misdemeanor in
moststates.Inaddition,thedentistmaybesubjecttolicenserevocationormalpracticelitigationbyfailingtomakea
report.
Whenadentistdeterminesthatareportofchildorelderabuseshouldbemade,documentationofthephysical
evidence to support the charge is mandatory. All evidence is collected according to the principles described for
identication and bite mark cases. Descriptions of the injuries and their locations, supporting photographs and
radiographs, and information stating the basis for suspicion of abuse are included in the report. When abuse is
considered, the dentist should examine the patient and assess the problem separately from the abusive caregiver.
Parental consent is not required to obtain appropriate physical evidence from victims younger than the age of
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majority.
DentistsasExpertWitnesses
Observational,orlay,witnessestestifyonlytothefactsknowntothem.Theyarereferredtoaswitnessesoffact.Such
witnessesarepermiedtomakeinferencesaboutphysicalfactsbasedonordinaryexperience.Thewitnessoffactis
notentitledtopresenthearsayevidencerelatedbyanotherperson.
The judicial system recognizes that people with a scientic background or specialized eld of study that is
admissible under the Frye rule or Federal Rules of Evidence can provide the courts with analyses or explanations
relativetothatdiscipline.Thefactsandopinionsoeredbysuchawitnessarebeyondthescopeofinformationthat
couldbeexpectedtobeprovidedbyalaypersonorwitnessoffact.Awitnesswhoisqualiedtotestifyunderthis
standardisacknowledgedasanexpert.
Members of the dental profession are experts. They are qualied to testify by the judge, who bases his or her
opinion on educational background, dental and forensic expertise, publications, and other professional
qualications. Dentists who have additional training in one of the dental specialties may be called on to present
specicinformationfromthatdiscipline.
Dentalexpertsassistaorneysand,ultimately,thetriersoffact(judgesandjuries)inunderstandingthescopeand
complexities of dental science and practice in relation to questions of law. The dentist should not become an
advocateforeithersideinacasebutshouldstrivetobeaneducatorandfriendofthecourt.
Asexperts,dentistsmayberequiredtotestifyincivillitigationcasesthatinvolvethefollowingsituations:
Malpracticebasedonnegligence.Thiscategoryincludesbaery(e.g.,extractionofthewrongtooth);
misdiagnosis;andfailuretodiagnose,refer,orinform.Alloftheseactionsfalloutsidethestandardofcareforthe
profession.
Personalinjury.TMJdamageordentaltraumasueredinvehicular,home,sports,recreational,andworkrelated
accidentsfallunderthiscategory.
Dentalfraud.Chargingformaterialsorproceduresthatwerenotusedorperformedareexamplesoffraud.
Identicationofmultiplefatalityincidentvictims.Incriminalcourt,dentalexpertiseisrequestedinidentication
ofhomicidevictimsandinbitemarkandhumanabusecases.
Dentistsareoftenunfamiliarwith,andmaybeintimidatedby,theadversarialnatureofcourtroomprocedureand
protocol.Whenpresentingevidence,thedentalexpertshouldrememberthathisorherroleinthelegalprocessisto
helpthetrieroffactunderstandthedentalissuesinthecase.Tothisend,andasascientist,thedentalexpertwitness
shouldpresenttheevidencecondently,accurately,andobjectively,relatinginformationinnontechnicalterms.
Whencrossexaminedbytheopposingaorney,thedentalexpertwitnessshouldremaincomposedandcondent.
Asanexpert,thedentisthastherighttorefertorecordsandexemplarspreparedforthecase.Thedentistisentitled
to read and review any books or articles proered by the opposing aorney with the intent of discrediting the
testimony.
Pretrial preparation is required if the dental expert and the aorney who has retained his or her services are to
developtheevidencetobepresentedincourt.Bothmustbeawareofthestrengthsandweaknessesofthematerial
anddecidehowbesttoprovidethejurywiththisinformation.Adequatetimemustbealloedtoprepareexhibits
forcourt.Itisalsoadvantageoustoaempttodeterminethepositionthatwillbetakenbydentalexpertscalledby
theopposingside.
Summary
Eachpractitionerhasaresponsibilitytounderstandtheforensicimplicationsassociatedwiththepracticeofhisor
herprofession.Thisunderstandingshouldincludemorethanethicsandjurisprudence,whichweretraditionallythe
only aspects of knowledge of the law acquired by dental professionals. Appreciation of forensic dental problems
involvingbodyidenticationpermitsclinicianstomaintainlegallyacceptablerecordsandassistlegalauthoritiesin
theidenticationofvictimsofmultiplefatalityincidentsandcrimes.
Thepursuitofjusticeincasesofrape,homicide,andhumanabuseoftenreliesondentaltestimonytointerpretbite
marks or BMPIs. The development of UV and IR wavelength photographic techniques and equipment has given
forensicdentiststheopportunitytoprovideobjectivescienticevidenceinthesetypesofcases.Evidencegathered
usingtheseresourcescanbeanalyzedandassessedwithcomputersoftware,laboratory,andclinicalproceduresthat
alsoenhancetheabilityoftheforensicodontologisttointerpretresults.
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Therelianceofthelegalcommunityonthedentalprofessiontocontinuetoprovideexpertiseincivilandcriminal
proceedingsensuresthatforensicdentistrywillremainaviablecomponentoftheforensicsciencesandthepractice
ofdentistry.
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AlAmadSH,ClementJG,McCulloughMJ,etal.Evaluationoftwodentalidenticationcomputersystems:
DAVIDandWinID3.JForensicOdontostomatol.2007;25(1):2329.
AmericanBoardofForensicOdontology.Bitemarkmethodologyguidelines.ABFODiplomatesReferenceManual
(revised01/22/13).[SectionIII:Policies,Procedures,Guidelines&Standards,pp109121(PDFavailable
online)]hp://www.abfo.org/resources/abfomanual/[AccessedAugust8,2013].
AmericanBoardofForensicOdontology.Bodyidenticationguidelines.ABFODiplomatesReferenceManual
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BarsleyRE.Forensicandlegalissuesinoraldiagnosis.DentClinNorthAm.1993;37:143144.
BergerMA.Evidentiaryframework.CecilJS,etal.Shepardsreferencemanualonscienticevidence.McGrawHill:
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BlankenshipJA,MincerHH,AndersonKM,etal.Thirdmolardevelopmentintheestimationofchronologic
ageinAmericanblacksascomparedwithwhites.JForensicSci.2007;52:428433.
BowersCM,JohansenRJ.Photographicevidenceprotocol:theuseofdigitalimagingmethodstorectify
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then management with hydroxychloroquine, an antimalarial drug, should be considered. Hydroxychloroquine

NumberofCases Parotid Submandibular Sublingual

NumberofCases Parotid Submandibular Sublingual

NumberofCases Palate Lips Buccal Retromolar FloorofMouth Tongue Other

NumberofCases UpperLip LowerLip

Palate UpperLip LowerLip Buccal Retromolar FloorofMouth Tongue

Immunohistochemical staining can be helpful in distinguishing polymorphous lowgrade adenocarcinoma from

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