The Normal Skeleton

- Essential for
mechanical
support and
mineral
homeostasis
- Houses
hemopoetic
tissue
- Determines
body size &
shape

Inorganic
65%

Organic
35%

206 bones
of varying
size and
shape

The Normal Skeleton

Inorganic Matrix

Calcium hydroxyapatite
[Ca10(PO4)6(OH)2]

- Mineral homeostasis
99% of calcium stores
85% of phosphate stores
65% of sodium and magnesium stores
- Bone strength

Organic Components of Bone

Bone Cells
- Osteoprogenitor cells Osteoblasts
Osteocytes
- Hematopoietic progenitor cells Osteoclastic
precursors Osteoclasts

Bone Matrix

- Type 1 Collagen (29%)

- Non-collagenous proteins (3%)
- Serum

Organic Matrix
Osteoblasts
Synthesize proteins
Initiate mineralization
Bind hormones
Make bone
Regulate osteoclasts
Osteoid (matrix)
12-15 days

Bone (mineralized matrix)

Organic Matrix
Osteoclasts
Large multinucleated cells
responsible for bone resorption.
Derived from monocytes/macrophage
hematopoietic progenitor cells that
are recruited to the bone
microenvironment where locally
produced cytokines and growth
factors induce their differentiation into
actively resorbing osteoclasts.
Bind to the bone surface via integrins,
where they form resorption pit
(Howships lacunae).

Regulation of Osteoclasts
Intercellular Signals - RANK and RANKL
Receptor Activator of NF-KappaB (RANK) (member of TNF family
of receptors) expressed on the surface of osteoclast precursors.
RANK ligand (RANKL) is expressed on the surface of osteoblasts
and marrow stromal cells.
Binding of RANK ligand to RANK receptor results in osteoclast
maturation and activation, and thus bone resorption.
RANK ligand is upregulated by PTHRP, vitamin D3, some
malignancies.
Osteoprotegrin (OPG), also secreted by osteoblasts/marrow
stromal cells (Wnt/-catenin signaling pathway), blocks RANK
ligand- RANK interaction, thereby inhibits osteoclast maturation and
activation.
Osteoblasts can enhance or inhibit osteoclast development and
function by expressing OPG and RANK ligand in various
proportions.

Organic Components of Bone

Bone Cells
Bone Matrix
- Type 1 Collagen (29%) - 90% by weight of
organic component
- Non-collagenous proteins (3%)
- Minerals 60%
- Water 10%

Non-Collagenous Organic Matrix

Cell adhesion proteins
- Osteopontin, fibronectin,
thrombospondin

Calcium binding proteins

- Osteonectin, bone sialoprotein

Proteins involved in
mineralization
- Osteocalcin

Enzymes
- Collagenase, alkaline
phosphatase

Growth factors
- TGF- , IGF-1, PDGF

Cytokines
- IL-1, IL-6, RANKL

Proteins concentrated from

serum
- Albumin
- 2-microglobulin

The Normal Skeleton

Modeling and Remodeling
Bone is in a dynamic state of formation and resorption in
response to constantly changing mechanical stresses and the
demands of mineral homeostasis.
Remodeling occurs continuously throughout life and is
carried out in microanatomical units, bone multicellular
units .
In these units, a closely coupled sequence of bone resorption
and formation takes place.
Sequence is initiated by a phase of osteoclastic bone
resorption, followed by a phase of reversal ( marked by a
deposition of cement line indicating the extent of bone resorption which has
taken place).

This is then followed by a phase of bone formation by

osteoblasts.

Regulation of Bone Modeling

The coordinated balance of bone formation and
resorption is regulated by systemic hormones, bloodderived factors and local mediators.
Remodeling also occurs in response to physical forces,
bone being deposited in sites subjected to stress and
resorbed from sites where there is little stress.
The key cell is Osteoblast
- Responds to stimulation from osteocytes
- Responds to stimulation from blood borne factors
- Stimulates development of osteoclasts
- Activates osteoclasts

Types of Bone
Osteoid (unmineralized bone matrix)
Woven bone (first laid down in fetal
skeleton and disease states)
Lamellar bone (slowly deposited, mature
bone)
- Cortical
- Cancellous

Woven (Immature) Bone

Characterized by the presence of bundles of randomly
arranged, short, thick collagen fibers, best appreciated
by examination under polarized light.
Osteocytes in woven bone lie in large round lacunae and
more closely packed than in lamellar bone.
First formed in the developing skeleton (fetal bone).
In adults, it is seen in pathological conditions: Bone
tumors, fracture callus, diseases with high bone turnover
(Pagets, hyperparathyroidism).
Formed quickly.
Woven bone is less strong than lamellar bone.

Types of Bone
Lamellar (mature) bone
The matrix is composed of
bundles of thin collagen fibers.
Each bundle is laid down at
approximately right angles to
adjacent bundles, creating the
characteristic parallel
arrangement of alternating light
and dark bands seen on
polarized light.
This structural organization
provides the highest level of
density of collagen per unit
volume of tissue.
Deposited slowly.
Resists unidirectional force.

Cortical Lamellar Bone

Most of the lamellae are
concentrically arranged around
a central Haversian canal,
which is lined by osteoblasts
and contains vessels.
These concentric lamellae are
oriented in the long axis of the
bone, forming long cylindrical
columns (Haversian systems
or osteons).
Small segments of interstitial
lamellar bone fills the space
between osteons.

Skeletal Development and

Developmental and Metabolic
Disease States

Skeletal Morphogenesis
Determined by Homeobox genes encoding for
transcription factors required for the normal
development of the skeleton.
Most of the embryonic skeleton are first formed as a
cartilage model or anlage (Exception: cranial vault
bones).
Cartilage proliferation plays an important role in
continuing skeletal growth and modeling.

Fetal Bone Formation

Femur and hip joint in a 5-week
fetus.
Bone is modeled in cartilage and
is covered by a condensation of
mesenchymal cells (future
periosteum), (arrow mark).
Note that cells in the diaphysis of
the cartilage model are larger and
paler than those in the upper end.
Before any bone formation occurs
within the embryonic cartilage
skeleton, the cartilage cells
toward the middle of the
individual skeletal parts become
larger and more separated by
interstitial matrix.

Fetal Bone Formation

As the
chondrocytes in the
center of the shaft
of a long bone
continue to enlarge,
the cartilage matrix
lying between the
cells becomes
calcified and the
chondrocytes die.

Fetal Bone Formation

Osteoblasts (perhaps derived
from periosteum) are seen to
line up on the surface of the
remaining calcified cartilage
matrix and start making bony
matrix (osteoid).
This process of cartilage
calcification, vascular invasion
and then deposition of bony
matrix on the remaining
calcified cartilage matrix is
called enchondral
ossification.
Enchondral ossification begins
about 8 th
wk of gestation

Fetal Bone Formation

First laid down bone (core of calcified
cartilage and primitive bone on the
surface) during endochondral ossification
is called primary spongiosa.
As the primary spongiosa is remodeled
and the calcified cartilage is removed by
osteoclasts, the bone trabeculae come to
be formed entirely of lamellar bone by
osteoblasts (secondary spongiosa).
Before birth, conversion of a considerable
portion of the shaft of a long bone into
osseous tissue is completed and at birth
only the ends are still formed of cartilage.

Fetal Bone Formation

During infancy and
childhood, a secondary
center of ossification is
formed within the
cartilagenous ends of the
long bones.
As the secondary center of
ossification grows, only
remaining cartilages are
those covering the articular
surface and a thin layer
(plate) of cartilage
between the secondary
center of ossification and
shaft of the bone.

Fetal Bone Formation

In intramembranous ossification, bone
is directly formed within primitive
mesenchymal tissue.
Mesenchymal cells proliferate and
differentiate into osteoblasts that form
osteoid, which is then rapidly
mineralized to form woven bone.
This bone formation occurs at several
points within the membrane, each focus
of ossification enlarging and then fusing
with its neighbors
Resulting continuous mass of woven
bone is subsequently remodeled to
lamellar bone.

Regulation of Bone Modeling

The key cell is the Osteoblast
- Responds to stimulation from osteocytes
- Responds to stimulation from blood borne
factors
- Stimulates development of osteoclasts
- Activates osteoclasts

Intercellular Signals
RANK and RANKL
Receptor Activator of NF-KappaB Ligand
(RANKL)
- Expressed on Osteoblasts
- Upregulated by PTHRP, vitamin D3, some
malignancies
- Binds to RANK (TNF family) on Osteoclasts and
precursors to activate them
- Function inhibited by Osteoprotegrin (TNF
family): binds to RANKL acting as a decoy
preventing RANK-RANKL interaction

Regulation of Osteoclast
PTH, IL-11, vitamin D3

Osteoblasts
paracrine

(& marrow stromal cell

molecular mechanisms

Osteoclasts

(activation, proliferatio
fusion, differentiation, survival)

M-CSF Osteoclasts
OPG (decoy) blocks RANKL and
checks stimulation of osteoclasts

Skeletal Development
Any failed step in skeletal morphogenesis
or modeling may cause disease
- Mesenchyme condensations
- Chondrocyte proliferation
- Defective matrix production
- Defective modeling/remodeling

Skeletal Morphogenesis
Defects in Mesenchmyal Condensation
Examples include synpolydactyly
and cleidocranial dysplasia.
Mutation in homeobox HoxD13
gene results in a mesenchymal
condensation abnormality leading
to an extra digit between the third
and fourth fingers with some
degree of fusion.
Loss of function mutations in the
RUNX2 (CBFA1) causes
cleidocranial dysplasia (open
fontanelles, delayed closure of
cranial sutures, primitive clavicles,
delayed eruption of secondary
teeth).

Skeletal Morphogenesis
Achondroplasia
Caused by an activating mutation in
fibroblast growth factor receptor 3
(FGFR3) gene.
Constitutively active FGFR3 inhibits
cartilage proliferation in cartilage
anlages and growth plates, thus
suppress growth.
Autosomal dominant inheritance,
however, 80% of cases are due to new
mutations.
Shortened limbs and ribs, bulging
forehead.
Normal longevity, intelligence and
reproductive status.

Verne Troyer: 28

Abnormalities in Structure and

Function of Bone
Collagen synthesis
- Osteogenesis imperfecta
- Marfans syndrome
- Ehler Danlos syndrome
- Scurvy

Abnormality of Matrix Turnover

- Osteopetrosis

Metabolic disorders
- Vitamin D deficiency (Rickets, osteomalacia)
- Osteoporosis
- Pagets disease of bone
- Defects in types 2, 10, 11 collagen result in fragile cartilage
Fractures
Severe osteoarthritis

Defective degradation of cartilage

- Mucopolysaccharidoses

Osteogenesis Imperfecta
Group of phenotypically related disorders caused by
deficiencies in type I collagen synthesis
Most commonly recognized congenital disease
affecting collagen production
Mutations in the gene encoding 1 and 2 chains of
type I collagen.
- Mutations resulting in decreased synthesis of
qualitatively normal collagen are associated with
skeletal abnormalities.
- Mutations resulting in abnormal polypeptides that
can not be arranged in triple helix causes more
severe phenotypes.

Osteogenesis Imperfecta
Four types (type I, II,III, IV) based on the clinical
expression and mode of inheritance.
Principally affects bone but also impacts other tissues
rich in type I collagen (joints, eyes, ears, teeth, skin).
Patients make too little bone: Cortex of bones is thin
and medulla have thin (attenuated) bony trabeculae;
which makes patients vulnerable to fractures with minor
trauma (brittle bone disease).

Osteogenesis Imperfecta

Defective Osteoblasts and Matrix

Production
Type

Clinical
Features

Inheritance

Biochemical Defect

Type I

Mild
Blue sclerae
Fractures

AD

Type 1 procollagen
Glycine replaced

Type II

Severe/Lethal
Blue Sclerae
Fractures

AR

Deletion in
COL1A1, COL 1A2

Type III

Moderate/ severe
Blue sclerae
Fractures

Type IV

Moderate
Normal sclerae
Fractures

AD/AR

AD

Frameshift prevents
integration of
COL1A2 in molecule
Point mutation in
COL1A2

Ehler-Danlos Syndrome
Heterogeneous group of
connective-tissue
disorders, recently
classified in diff types
Hyperextensibility of skin,
easy bruising,
hypermobile joints, Aortic
dissection; blue sclera
may be present
Bone is osteopenic,
kyphoscoliosis,
spondolisthesis

Marfans Syndrome
Heterogeneous group of inherited (AD) connective tissue
disorder affecting bones, heart, aorta and eyes
Mutation in locus of fibrillin gene on chromosome 15
Usually tall with exceptionally long extremities, and long
tapering fingers and toes
Hyperflexible joints, kyphosis, scoliosis, pectus
excavatum
Eyes: subluxation of lens - ectopia lentis
CVS: Mitral valve prolapse, Aortic dilatation due to cystic
medionecrosis - AR; Aortic dissection

Abnormality of Collagen Synthesis:

Metabolic Bone Disease

Scurvy

Vitamin C deficiency
Failed cross-linking of collagen
Fragile capillaries and venules
- Subperiosteal hemorrhages

Defective osteoid synthesis

- Microfractures

Bony deformities

Abnormalities in Matrix Turnover

(Modelling/Remodelling)
Osteopetrosis (too much bone): Marble bone disease

- Group of rare genetic diseases resulting from impaired

formation and function of osteoclasts and characterized
by diffuse symmetrical skeletal sclerosis (thickening of
cortical bone and narrowing of the medullary cavity).
- Progressive deposition of bone on pre-existing matrix
Mutations in carbonic anhydrase II gene interfering with the
acidification of resorption pits.
Mutations in chloride channel gene interfering with the function
of proton pump.
Mutations in RANK ligand gene resulting in fewer osteoclasts
o normal.

Osteopetrosis
Bones lack medullary canal and ends of bones are bulbous and
misshapen (Erlenmeyer Flask deformity).
Primary spongiosa , which is normally removed during growth
by osteoclasts, persists and fills the medullary cavity.
- No mature bone trabeculae in the medullary cavity and no room for
hematopoietic cells (anemia, granulocytopenia, thrombocytopenia,
extramedullary hematopoiesis (hepatosplenomegaly)).

Deposited bone is not remodeled and tends to be woven in

architecture and prone to fracture with little trauma.
Obstruction (narrowing) of cranial neural foramina leads to
nerve compression & paresis in the cranial nerves.

Osteopetrosis
Radiologic Findings
Marked symmetrical increase
in the density of bone
Normal demarcation of
cancellous (medullary) bone
and cortical bone is lost.
Metaphyseal flaring
(Erlenmeyer flask deformity),
more prominent around the
knee and hips

Abnormal Skeletal Development

Summary

Any failed step in skeletal morphogenesis may

cause disease.
Abnormal Mesenchymal Condensations
- Syndactyly

Abnormal Chondrocyte Proliferation/ Cartilage

Development
- Dwarfism

Abnormal Matrix Production

- Osteogenesis imperfecta, Marfans, Ehler Danlos, Scury

Abnormal Modelling/Remodelling
- Osteopetrosis

Metabolic Bone Diseases: Vitamin D

Deficiency
Delayed or inadequate mineralization of osteoid formed
by osteoblasts.
This under mineralized bone is weaker and more prone
to fracture and deformity.
Causes Rickets in children and osteomalacia in adults.
Labs:
- low serum calcium, phosphate, vitamin D levels
- raised serum alkaline phosphatase.

Causes of vitamin D deficiency:

- poor dietary intake
- malabsorption from GI tract
- renal disorders causing decreased synthesis of 1,25 dihydroxyvitamin D
- rare inherited disorders.

Osteoporosis

Metabolic Bone Disease

Osteoporosis
Diminished bone mass
Localized or diffuse
Primary or secondary
Risk of fracture
Severe disease of elderly
Expensive to health care - > $ 14
BILLION/YR

Secondary Osteoporosis
Endocrine
- Hyperparathyroidism
- Hyperthyroidism, Diabetes, Addisons
disease, Pituitary tumors
Neoplasia: Carcinomatosis, multiple myeloma,
paraneoplastic disease
Gastrointestinal: Malnutrition, hepatic
insufficiency, vitamin D or C deficiency,
malabsorption
Drugs: Chemotherapy, corticosteroids, alcohol
Immobilization

Regulation of Osteoclast
PTH, IL-11, vitamin D3

Pathogenesis
PTH Stimulation of
osteoblasts ( RANKL)
to activate osteoclasts
Osteoclastic Activity
Massive bony resorption

Metabolic Bone Disease

Hyperparathyroidism: Pathology
Unabated Osteoclastic
Activity

Giant cell tumor-like mass

Neo-vascularization, Hemorrhage
(Brown tumor)

Renal Osteodystrophy
Chronic renal failure hyperphosphatemia
Hypocalcemia Secondary PTH
Reason for Hypocalcemia
Decreased vitamin D metabolism in kidney (inhibition of
conversion of vitamin D to active metabolites by phosphate)
Diminished intestinal absorption of vitamin D

Iron and aluminum accumulation in bone (from

dialysate) prevents further bone deposition

Renal Osteodystrophy
PTH Osteoclastic activity Bone
resorption
Matrix mineralization (osteomalacia)
Osteoporosis
Growth retardation

Pagets Disease
Disease of Osteoclasts
Etiology
- Virally induced [Paramyxovirus (measles, RSV) - nucleocapsid
antigens identified in osteoclasts)
(Paramyxovirus- slow virus disease)
- Genetic predisposition - mutation - p62

Pathogenesis
- Virus stimulates IL-6
- IL-6 & M-CSF Activate osteoclasts
- Osteoclasts hyper-responsive to RANKL & vit. D
- p62 - RANK/RANKL SIGNALLING - Osteoclasts
(till date, no virus has been isolated from affected bone)

Pagets Disease
Disease of stages
Osteolytic Stage:

Osteoclastic activitypatchy, florid

Mixed Lytic and

Blastic Stage:
Predominantly
Osteoblastic

Osteosclerotic
(burnt-out) Stage:
End stage: bone
mass

Pagets Disease

More common in whites in England, France

Austria, US, Germany, New Zealand,
Australia
Less in Japan, China, Scandinavia, Africa
5-11% of whites, Adults, M = F
Diagnosis:
- X-ray
- Serum Alkaline Phosphatase
- Urinary Hydroxyproline

May be monostotic or polyostotic

Pagets Disease
Complications
Deformities - Pain (compressed nerves)
Fracture/Microfractures (chalk-stick #)
Pain
Degenerative Joint Disease Pain
Rarely:
High-Output cardiac failure (osteoblastic phase)
Tumors
- Sarcoma- 5-10%, High grade, Lethal
- Giant cell tumor
- Extra-osseous hematopoiesis

SGU Medical School Bone Pathology Course, November, 2011

Lecture #2

Fracture, Osteomyelitis and Arthritis

Ashraf Khan, MD, FRCPath
University of Massachusetts
Medical School
Worcester, MA

Fractures
Etiology:
- Traumatic
Significant Trauma
Stress #: slowly develops with repetitive
physical activity (aerobics, marching)

- Pathologic
Metabolic Bone disease
Tumors and other bone pathology (cysts etc.)

Fractures
Stages of Healing

Inflammatory Phase (1 wk)

Reparative Phase (2-3 wk)
Remodeling Phase

Inflammatory Phase
Immediately following a fracture, there is a disruption of
blood vessels at the medulla, cortex, periosteum of the
bone and surrounding soft tissues.
This results in hematoma formation, which lies between
the fractured ends of a bone and extends beneath the
periosteum and into the surrounding soft tissues.
Fracture hematoma favors bone repair and its removal
retards healing.
Fibrin mesh seals the fracture site and provides
scaffolding for other cells.
The bone marrow near the fractured ends of a bone
shows hemorrhage and fat necrosis.
Vascular injury leads to ischemia, which in turn leads to
necrosis of the ends of bone.

Inflammatory Phase

There is granulation tissue formation with in-growth

from the surrounding viable bone of fibroblasts and
capillaries into the fibrin mesh (clot) between the
fractured bone ends.
This is accompanied by an inflammatory infiltrates,
initially containing neutrophils, but later containing more
chronic inflammatory cells including macrophages.
Macrophages remove red cells, necrotic fat and tissue
debris.
Migrating inflammatory cells and degranulated platelets
release cytokines (FGF, PDGF, IL, TGF- family
including bone morphogenic proteins ), which activa
the osteoprogenitor cells in the periosteum, medullary
cavity and surrounding soft tissues and activate
Thus a and
soft osteoclastic
tissue callusactivity.
(Procallus) is formed toward
osteoblastic
the end of inflammatory phase: Organizing fibrin +

Bone Morphogenetic Proteins

They are normally present within the bone and
marrow and may be elevated in fracture.
Polypeptides responsible for post-fetal differentiation
of mesenchymal cells into chondrocytes and
osteoblasts.
More than 16 human Bone Morphogenetic Proteins
(BMPs) have been identified.
Osteoinductive BMP (BMP 2 and BMP 9) provide a
signal for the differentiation of mesenchymal cells into
osteoblasts.
They are also critical for chondrogenesis cartilaginous callous formation - and bone formation
by enchondral ossification

Reparative Stage
During this stage, primary callus (skeletal repair
tissue that unites the fractured bone ends) is formed
and consists of newly formed bone and cartilage.
Activated osteoprogenitor cells deposit trabeculae of
woven bone within medullary cavity and beneath the
periosteum.
Subperiosteal trabeculae of woven bone are oriented
perpendicular to the cortical axis.
Activated mesenchymal cells in the bone and soft
tissue surrounding the fracture site also differentiate
into chondroblasts that make fibrocartilage and
hyaline cartilage.
Cartilage formed in fracture callus undergoes
endochondral ossification and is usually surrounded
by organized woven bone.

Reparative Stage
Callus which lies within the reparative tissue in the
medulla is called internal callus.
External callus develops around the fractured bone
ends and is in contact with the surrounding soft
tissues, including the muscle.
Normal callus contains variable amount of bone,
cartilage and fibrous tissue depending on stability,
vascularity and extent of injury.
When the fracture site is unstable and poorly
vascularized, an abundance of cartilage is seen.
Internal callus, which is relatively well vascularized
and mechanically more stable contains less cartilage
and more woven bone compared to external callus.
In an uncomplicated fracture, primary callus reaches
its maximal girth at the end of second or third week,
which helps stabilizes the fracture site.

Remodeling Phase
Secondary callus is the term used to describe the
mature lamellar bone which gradually replaces the
woven bone of primary callus. In this way, the normal
cortical and cancellous bone architecture is restored
following injury.
In this stage, osteoblasts lay down new bone in
apposition on the surface of the woven bone in
primary callus.
At the same time, there is resorption of primary callus
by osteoclasts.
As the callus matures and is subjected to weightbearing forces, the portions that are not physically
stressed are resorbed. Thus, the callus is reduced in
size until the shape and outline of the fractured bone
have been re-established.
Similarly, the medullary cavity is also restored.
This process of gradual remodelling occurs over a

Fractures
Remodeling Phase
- Callus slowly resorbed and
remodeled to the shape &
contour of normal bone.
- Woven bone replaced by
lamellar bone.
- Complete resolution:
Fracture site may not be
apparent.

Fracture Healing by Internal

Fixation
Absence of cartilage from the healing process at the
fracture site.
Absence of subperiosteal reaction or peripheral
(external) callus formation.
Apposition of new bone on trabecular surfaces at an
early period after fracture
Rapid healing
Absence of significant osteoporosis due to early
mobilization

Fractures
Complications
Delayed union
- Displaced or comminuted fractures
- Devitalized bone resorbed slowly
- Interposition of soft tissue impedes callus
formation - resection of soft tissue necessary

Inadequate immobilization
Permanent deformity
Infection: in Open or Comminuted #

Fractures

Complications - Pseudoarthrosis
Poor immobilization
Callus composed of
fibrous tissue- Bony
callus does not form
Non-union
Cystic degeneration
- cyst lined by
synovium-like cells
(pseudoarthrosis)
False joint impedes
callus formation
Resection required
for complete healing

Complications of Fractures

Fractures can lead to

systemic complications,
including shock
syndrome and
myoglobunuria, the latter
occurring when there is
significant muscle injury.
Fractures can cause fat
embolization through the
damaged venous system
by disrupting the bone
marrow
whichtissue.
contains
adipose
Fat
embolization becomes a
clinical problem in severe
multiple
fractures
and
extensive
orthopedic
Lung tissue with fat globules
surgery.
stained with oil red O stain.

Fractures
Determinants of Healing
- Age
- Fracture type
- Fracture site
- Extent of soft tissue
injury
- Local factors
vascular supply
mechanical forces

- Overall Health &

Nutritional status
Diabetes,
Calcium &
phosphorous levels
(osteoporosis,
osteomalacia)
Vitamin deficiency
Infection

Fracture
Summary
Repair occurs in phases
Ongoing bony remodeling complete
resolution
Impeded repair due to infection or instability
severe complications

Osteomyelitis
Inflammation of Bone or Marrow
Implies infection
Stages
Acute Chronic
Etiology
- Hematogeneous
(seeding from
systemic disease)
- Direct inoculation

Organisms
- Bacterial
- Fungal
- Viral
- Protozoal

Pyogenic Osteomyelitis
Usually Bacterial
No organism isolated in 50%.
S. aureus (80-90%) - receptors for bone
matrix components e.g. collagen
Gram - rods (E. coli, Klebsiella,
Pseudomonas) - GU infection, IV drug
abuse
Mixed bacterial (direct inoculation)
H. influenza (neonates)
Group B Streptococcus (neonates)
Salmonella (sickle cell disease)

Acute Hematogenous Osteomyelit

Epidemiology
- Young, growing children
- Adults (> 50 years)
- Gender M:F = 2:1
- Location
Long tubular bones (femur, tibia, humerus)
Vertebral bodies

- Predisposing factors: catheter, trauma,

infection, underlying disease, IV drug
abuse

Acute Hematogenous Osteomyelitis

Hematogenous
osteomyletis usually begins
in the metaphysis of a bone.
Thought to be initial site of
infection for anatomic
reasons:
- Nutrient arteries terminate in
venous sinusoids (ideal lakes
for bacterial seeding) rather
than forming anastomosis
with veins through capillaries.
- These vascular loops and
terminal branches have low
oxygen tension and inhibited
phagocytosis, conducive to
bacterial growth.

Acute Hematogenous
Osteomyelitis
Once infection takes
hold, it spreads to
adjacent trabecular and
cancellous bone.
Continuing infection
results in the formation
of abscesses within the
medulla and beneath
the periosteum.

Acute Hematogenous
Osteomyelitis

Inflammatory swelling leads to

the loss of both endosteal and
periosteal blood supply resulting
in necrosis of nearby bony
trabeculae including a segment
of cortex.
This necrotic bone is called
sequestrum.
After infection reaches
periosteum, it is elevated,
becomes reactive and starts
forming new bone.
A sleeve of new bone
(involucrum) develops around
the necrotic cortex and medulla.
Subperiosteal abscess
eventually ruptures into soft
tissue, forming soft tissue

Vertebral Pyogenic Osteomyelitis

Most commonly arises in
lumbar spine, less
frequently thoracic and
cervical spine.
Predisposing factors
include urinary tract
infection, diabetes and IV
drug abuse.
Begins in vertebral body
then spreads through the
vertebral end plate to
involve the disc (discitis).
Disc destruction is more
common in pyogenic than
non-pyogenic infections of

Vertebral Pyogenic Osteomyelitis

More than one vertebral
segment may be
involved.
May breach the anterior
cortex and ligamentous
structures to form
paravertebral soft tissue
abscesses
(retrophryngeal abscess,
psoas abscess extending
to groin and politeal
fossa).
May spread posteriorly to
involve the posterior arch

Pyogenic Osteomyelitis
Pathology
The initial response to infection with
pyogenic organisms is acute
inflammation, resulting in fluid exudate
containing neutrophils and fibrin.
Continuing exudation raises the tissue
pressure, which comprises the vascular
space, leading to
bone death (bone
unable to expand to relieve the pressure
on vascular space, no swelling as in soft
tissue).
Major problem in treating patients with OM
is the extent of osteonecrosis, which
interferes with the access of antibiotics.

Pyogenic Osteomyelitis
Pathology
After infection reaches
periosteum, it is elevated,
becomes reactive and starts
forming new bone.
A sleeve of new bone
(involucrum) develops around
the necrotic cortex.
This involucrum is initially
composed of reactive woven
bone trabeculae, but later,
may become organized into a
neocortex of compact bone.

Pyogenic Osteomyelitis
Summary of Pathology
Acute inflammation
Bone necrosis
Subperiosteal abscess
Progressive ischemia leads to segmental
bone necrosis (sequestrum) surrounded by
viable new bone (involucrum) formation
Draining sinus tracts
Extension into joint space (acute septic
arthritis)

Acute Osteomyelitis
Treatment

Treat early
IV antibiotics 4-6 weeks
- Exception: Children with hematogenous
spread
Oral therapy if organism is susceptible
Good compliance
Rapid response

Consider surgical debridement

Evolution to Chronic Osteomyelitis

5-25% of Acute Osteomyelitis do not
resolve Chronic Osteomyelitis
- Delay in diagnosis
- Inappropriate treatment:
Inappropriate antibiotics
Therapy is too short

- Inadequate surgical debridement - extensive

necrosis
- Underlying medical condition

Chronic Osteomyelitis
Pathology
- Chronic Inflammation
- Resorption of Dead bone
- Deposition of Woven bone

Brodie abscess: Intracortical abscess

Sclerosing OM of Garr: Jaw - extensive
new bone obscuring the underlying bone

Chronic Osteomyelitis
Sequelae
Recurrent acute exacerbations
Pathologic fracture
Secondary amyloidosis
Endocarditis
Sepsis
Septic Arthritis
Rarely, malignant complications
- Squamous cell carcinoma of fistula tract
- Sarcoma of infected bone

Tuberculous Osteomyelitis
1-3% of patients with pulmonary TB
Immunocompetent or compromised
Location
- Spine (Potts spine) > knees > hips

Burrowing abscesses with

calcification

Skeletal Tuberculosis
Very Destructive
Spreads through
medullary cavity
causing extensive
necrosis
Extends thru IV discs
involving multiple
bones
Difficult to control

Pathology of Joint Diseases

The Normal Joint

Components - Synovium & Cartilage
Synovial cells: Mesenchymal cuboid or fibroblast like cells - 1-4
cell thick
Produce:
- Hyaluronic acid
- Proteins
- Secrete fluid into joint space
Articular cartilage: Shock absorber
Chondrocytes regulate matrix turn over:
Synthesis:
-Type II collagen
-Proteoglycans
Breakdown: Matrix degrading enzymes

Devoid of vessels, nerves

1-4 mm thick
Nourished by synovial fluid

Arthritis
Osteoarthritis
Rheumatoid arthritis
Other: gout, pseudogout (covered earlier)
Seronegative arthritis
Infectious

Arthritis
Multiple Etiologies
Infection

Immune-mediated
Injury

Inflammation of the Joint

Crystal deposition

Degenerative

Osteoarthritis
Degenerative Joint Disease
Most common form of arthritis
Progressive destruction of articular
cartilage
Not true inflammatory arthritis
Billions of health care dollars/lost work
days

Osteoarthritis
Degenerative Joint Disease
Primary
- Aging
phenomenon
- Oligoarticular
- 80-95% of people
over 65 years

Secondary
- Younger patients
- Predisposition
Diabetes
Hemachromatosis
Ochronosis
Obesity
Congenital deformity

- Polyarticular
- Severe

Primary OA
Most common form of arthritis
Primary OA typically involves
variable number of joints in
characteristic locations, as shown*
Age: 75% of persons over age 70
have OA
Female sex
Obesity
Hereditary
Secondary:
- Trauma
- Neuromuscular dysfunction
- Metabolic disorders

*Exceptions to these locations should trigger consideration of secondary causes of OA.

Osteoarthritis
Pathogenesis
Cartilage is made up of chondrocytes and matrix.
The matrix is composed of water, proteoglycans, type
II collagen and glycoproteins (fibronectin,
chondronectin).
The mechanisms leading to OA are complex and not
entirely clear.
It is thought to start with chondrocyte injury by
genetic, biochemical factors and aging.
Chondrocytes respond to injury by proliferating
(cloning) and secreting proteases and inflammatory
mediators in addition to collagen and proteoglycans.
Eventually, there is remodeling of the cartilagenous
matrix. In early OA, water content of the matrix
increases and concentration of proteoglycans
decreases.

Osteoarthritis (OA)
Subsequently, superficial layers of cartilage is
degraded. This manifests itself as vertical and
horizontal cracks (splits).
Later, deeper fissures and cracks develops on the
articular cartilage which becomes reduced in
thickness as chondrocytes in the superficial layer die
and portions of the superficial cartilage are sloughed
off.
Often chondrocytes in the deeper portion of the
cartilage proliferate adjacent to the fissures.
The underlying subchondral bone plate shows
thickening and there is reduplication of the tidemark.
Eventually, cartilage may be lost in the weightbearing regions of the affected joint.

Osteoarthritis (OA)
The exposed subchondral bone plate becomes the new
articular surface, and friction with the opposing
degenerated articular surface polishes the exposed bone
(eburnation).
Small fractures in the articulating bone allows the joint
fluid to be forced into subchondral regions, leading to the
formation of subchondral cysts. Hypermetobolic state of
the subchondral bone also contributes to subchondral
cyst formation.
Subchondral cysts have a fibrous wall and are usually
filled with myxoid or fibromyxoid material.

Osteoarthritis (OA)
In non-weight-bearing areas of the joint and around the
margins of the joints, ostoecartilagenous outgrowths
develop (osteophytes) by endochondral ossification.

Osteoarthritis (OA)
Part of the eroded cartilage may break off and form
loose bodies (joint mice). Loose bodies, which lie
freely within the joint cavity, have a central core of
necrotic bone. The covering cartilage remains viable as it
is nourished from the joint fluid.

Osteoarthritis
Pathology- Joint Mice
Microfractures

chunks of
dislodged bone
and cartilage

loose bodies
(joint mice)

Inflammatory Arthritis
Pathogenesis
Inflammation of synovium
Cytokine release
Edema, granulation tissue
Synovial overgrowth
Diminished nutrition to cartilage
Cartilage breakdown

Rheumatoid Arthritis

Rheumatoid arthritis

Systemic disease manifested by polyarthritis:

pain, inflammation, swelling, destruction
Prevalence estimated at ~0.5 - 1%
Female:male ratio = 2.5:1
Genetic predisposition
Symmetrical arthritis, typically of the hands and
feet, also often involving ankles, knees, wrists,
elbows and shoulders
Joint destruction occurs early and is a marker fo
disease progression
Hochberg MC, Spector TD. Epidemiol Rev. 1990;12:247-52; Doran MF, et al.. Arthritis Rheum.
2002:46:625-31.

Rheumatoid Arthritis
Erosion of cartilage with
ingrowth of synovium
Osteoclastic activity (due to
elevated levels of RANKL
produced by activated T cells
and synovial fibroblasts)
Subchondral cysts,
Subchondral Osteoporosis
(localized and systemic) as
opposed to osteoarthritis.

Rheumatoid Arthritis

Eventually, after the cartilage has been

destroyed, the pannus bridges the opposing
bones in a joint, leading to fixation (stiffness)
in the fused joint (fibrous ankylosis, fibrous
obliteration of the joint).

Rheumatoid Arthritis
Unlike OA, there is little reparative activity,
osteophyte formation, new bone
formation,
or bone sclerosis.

Rheumatoid Arthritis: Summary

Papillary synovial hyperplasia
Chronic inflammation
Organizing fibrin
Pannus
Erosion of underlying cartilage
Narrow (fused) joint space

Systemic Pathology in RA
Soft tissue- Rheumatoid nodules
Lung involvement
Vasculitis
Uveitis
- Usually in juvenile RA

Rheumatoid Nodule

Found in 25% of RA patients.

Non-tender firm nodule most commonly found in
regions of skin (subcutaneous fibroadipose tissue)
subject to pressure (over bony prominences):
ulnar aspect of forearm, elbow, occiput,
lumbosacral area.
Also develop in joints, tendons, soft tissue, lung,
heart (peri-, myo-, endocardium), aorta, spleen,
viscera.
Histologically, it is characterized by its
irregular shape and a central zone of necrotic
fibrinoid material surrounded by histiocytes
and chronic inflammatory cells.
May be the result of vascular damage.

Pulmonary Involvement in RA
30% - 40% of patients

Pleura:
- Chronic pleuritis
- Pleural effusion
- Pleural rheumatoid
nodules

Intrapulmonary
rheumatoid nodules

Parenchyma
- Diffuse interstitial
pneumonitis & fibrosis
- End-stage lung disease

Pulmonary
hypertension

Vasculitis in RA
Acute necrotizing vasculitis - Can affect any
organ
- Heart - Myocardial Infarction
- Brain - Cerebrovascular Occlusion
- Kidneys - Renal Failure
- Mesentery - mesenteric and intestinal infarction
- Gangrene of digits

Complications in RA
Life Expectancy by 3-7 yrs
End-stage lung disease
Vasculitis & its complications
Systemic amyloidosis
Iatrogenic effects of Tx- Immunosuppression

Differences: OA vs. RA
AM stiffness:
- OA< 30 minutes,
- RA>1 hour

Sxs:
- OA worse with activity
- RA better with activity

Joint distribution:
- OA: weight bearing joints
and PIP & DIP
- RA: wrist /MCP/PIP

RA is systemic disease fever, weight loss

OA is non-inflammatory,
RA is inflammatory
OA has reparative activity
and new bone formation
- osteophytes,
subchondral sclerosis
RA - No reparative bone
formation - periarticular
osteopenia

Crystal Deposition Disease

Gout
Acute gouty arthritis
- Red, painful, swollen

Chronic tophaceous gout

- Fibrosis, crystal deposits, joint destruction

Gouty tophus
- Large crystalline masses with associated
tissue reaction

Crystal Deposition Disease

Gout
Epidemiology
- Hyperuricemia
Primary (genetic predisposition)
Secondary (increased nucleic acid turnover:
leukemia, alcohol, obesity, drugs, renal disease,
purine rich diet)

- Peak in 5th decade

- Linked to duration of hyperuricemia (20-30
years)

Crystal Deposition Disease

Tophaceous Gout
Deposition in areas
of low temperature
Incite inflammatory
response
Bone and joint
destruction
May ulcerate skin

Crystalline Diseases
Calcium Pyrophosphate
Epidemiologyseudogout)
- >50 years of age
- 30-60% of people over 85 years
- M=F
- Equal race distribution

Crystalline Diseases
Calcium Pyrophosphate
Hereditary
(Pseudogout)
- Linked to chr 8 (ANKH gene, encodes transmembrane
pyrophosphate transport channel)

Secondary:
- trauma, diabetes, amyloidosis, hyperparathyroidism,
hemochromatosis

Idiopathic (sporadic)

Crystalline Diseases
Calcium Pyrophosphate
(Pseudogout)
Pathogenesis
- Unknown
- Altered matrix enzymes that
modulate phosphate metabolism
- Deposits ingested by PMNs
- Cytokine release

Crystalline Diseases
Calcium Pyrophosphate
Clinical courseeudogout)
- Acute, subacute, or chronic arthritis
- Mimic gout, osteoarthritis, rheumatoid
arthritis
- Mono-articular or poly-articular
- 50% of patients suffer severe joint
damage

Crystalline Diseases
Hydroxyapatite
Tumoral Calcinosis
Mechanism unknown
- May be seen in children

Massive accumulations of
hydroxyapatite crystals
Form nodules in soft tissues near
joints

Crystal Deposition Disease

Summary
Crystal deposits due to hereditary
and environmental factors
Cause arthritis, bone and soft
tissue destruction
Elicit an inflammatory response that
results in injury
Distinguishable by histologic
characteristics of crystals

Infectious Arthritis
Organisms
- Bacteria: Rapid joint destruction
Gonococcal: Late adolescents, adults, women
Non-Gonococcal:

- S. Aureus (older children, adults)

- H. influenza, Streptococcus: Children <2 yr
- Gram-: E. Coli, Salmonella (sickle cell anemia), Pseudom
- Mycobacteria (Tuberculous arthritis)
- Borrelia (Lyme disease)

- Virus:
Parvovirus B19, Rubella, Hepatitis C

Septic Arthritis
Etiologic microorganisms are pyogenic bacteria such
as staphylococcus, Streptoccoccus, Neisseria.
Usually a monarticular infection most commonly
involving the hip in infants and young children and
the knee in older children and adults.
Contributing predisposing factors:
- Chronic diseases (diabetes, alcoholism, renal disease)
- Chronic joint diseases (rheumatoid arthritis, SLE)
- Immunosuppressed states (AIDS)

Clinical Presentation
Symptoms include fever, malaise, pain (arthralgia).
Physical examination reveals that the joint is warm, painful,
erytematous and distended, with a decreased range of motion.
The most common sites: Knee > hip > shoulder, ankle, elbow
> wrist.
Workup of a patient with septic arthritis include repeated joint
aspiration for culture and fluid analysis including gram stain,
white cell count (elevated), protein level (elevated) and
glucose level (decreased).
Because infection of synovium precedes joint fluid infection,
etiologic diagnosis by joint fluid aspiration may be delayed
and repeated joint aspiration
several days may be required
to confirmover
the diagnosis.
A biopsy is indicated if clinical suspicion continues in the
setting of nonconfirmatory lab tests.

Septic Arthritis-Pathology
Microscopic examination
shows that the synovial lining
is usually ulcerated and
covered by an acute
inflammatory fibrinous
exudate containing numerous
neutrophils.
The underlying subintima is
composed of granulation tissue
containing heavy inflammatory
infiltrates. Organisms may be
identified by gram stain in the
inflamed synovium in the
acute stage.

Septic Arthritis-Pathology

The articular cartilage shows

loss of matrix staining and
necrosis of cartilage cells in
the superficial zone. Cartilage
is particularly susceptible to
enzymes released by bacteria
and disintegrating neutrophils
and is rapidly destroyed.

Septic Arthritis-Pathology
If left untreated, a pannus of
inflamed fibrous tissue extends
over the articular cartilage
from the inflamed synovium.
This tissue may become
organized and lead to fibrous
ankylosis of the joint.

Complications of Septic Arthritis

Soft tissue inflammation
Osteomyelitis
Sepsis
Degenerative Joint Disease
Fibrous and bony ankylosis

Tuberculous Arthritis
Is a chronic progressive monoarticular disease involving the
knee or hip and most commonly affecting middle-aged or
older persons.
Usually develops as a complication of adjoining osteomyelitis
or after hematogenous spread from a visceral (lung) site of
infection.
Synovial tissue reveals yellow cheese-like areas of necrosis.
Microcopic examination shows granulomas with caseous
necrosis. Inflamed synovial tissue extends pannus-like over
synovial tissue, causing cartilage and bone destruction.
Chronic disease results in severe destruction with fibrous
ankylosis and obliteration of the joint space.

Lyme Arthritis
Caused by infection with spirochete Borrelia
Burgdorferi.
Approximately, 60-80% of untreated patients with
Lyme disease develop joint symptoms within a few
weeks to two years after onset of the disease.

Serologic or molecular tests are usually required for

confirmation of diagnosis.

Lyme Arthritis
There is thickening of the
synovial lining characterized
by chronic papillary synovitis
with synoviocyte hyperplasia,
fibrin deposition, onion-skin
thickening of the arterial walls
and mononuclear cell
infiltrates (lymphocytes and
plasma cells).
Silver stains may sometimes
reveal small numbers of
microorganisms (Spirochetes)
in the vicinity of blood vessels.

Viral Arthritis
Arthritis can occur in a setting of a variety of viral infections:
Hepatitis C, Hepatitis B, Rubella, Mumps, Epstein-Barr virus,
Parvovirus B19.
The biopsy findings reveal only nonspecific chronic
inflammation.
The pathogenesis is unclear. Changes could be due to
- Direct infection of the joint by the virus. (Rubella, some alpha viruses)
- Autoimmune reaction induced by the virus (HIV-associated chronic
arthritis).

Seronegative
Spondyloarthropathies
Heterogeneous group of diseases
Arthritis one of several manifestations
Associated with identified infectious
agents
In part, immune mediated
Similar, but milder disease than
rheumatoid arthritis
HLA-B27 associated

Seronegative
Spondyloarthropathy
Sex
Ankylosing
Spondylitis

Relapse Extraskeletal
Disease

HLAB27

M>F Yes

Uveitis, Aortitis

Reiters Syndrome

M>F Rarely

Conjunctivitis,
80%
Aortitis,
Urethritis/Cervicitis

Psoriatic Arthritis

M>F Yes

Uveitis,
Conjunctivi

Enteropathy
Associated Arthritis

tis
M>F Rarely Uveitis, IBD Yes

90%

Yes

Seronegative Spondyloarthropathy
Pathology
Chronic synovitis
Destruction of articular cartilage
Fibrosis and narrowing of joint space
(fibrosing ankylosis)*
Ossification of fibrous tissue (bony
ankylosis)*
Joint immobility*
*Most common is ankylosing spondylitis

Immune-mediated Arthritis
Summary
Heterogeneous group of systemic disorders that
share common features
Most associated with a genetic predisposition
- HLA-DR in rheumatoid arthritis
- HLA-B27 in seronegative diseases

Probable link to environmental trigger

- Likely infectious in nature

Histopathologically similar, though RA tends to

be more severe
All are progressive diseases

BONE TUMORS

Bone Tumors
General Principles
Incidence
- Most common malignant tumor is a
METASTASIS
- 2,500 new primary bone tumors/year U.S.
- True incidence unknown, most asymptomatic,
not biopsied
- Sarcomas result in 1,300 deaths/year in U.S.

Normal Tissue

Benign Tumor

Bone

Osteoma
Osteoid Osteoma
Osteoblastoma

Cartilage

Enchondroma
Osteochondroma
Chondromyxoid fibroma
Chondroblastoma

Fibro-osseous

Fibrous dysplasia
Osteofibrous dysplasia

No Normal
Counterpart

Giant cell tumor

Aneurysmal bone cyst

Malignant Tumor
Osteosarcoma
Osteoblastic
Chondroblastic
Telangiectatic
Dedifferentiated
Chondrosarcoma
Conventional
Clear cell
Mesenchymal
Dedifferentiated
Adamantinoma

Malignant giant cell tumor

Ewings sarcoma

Bone Tumors
Predisposing Factors-Usually None
Rarely arises as a complication of:
- Osteomyelitis (sarcoma, SCC)
- Gauchers disease (sarcoma)
- Bone grafts/prostheses (sarcoma)
- Radiation (sarcoma)
- Bone infarcts (sarcoma)
- Pagets disease (sarcoma)

Bone Tumors
Clinical Symptoms
Benign tumors usually asymptomatic
Malignant tumors are aggressive
Symptoms
- Pain
- Pathologic fracture
- Metastases

Radiology
- Site and appearance clues to diagnosis

Bone Tumors
Benign
- Well-circumscribed
- Scalloped border
- No destructive growth
- No invasion of other tissues
or joint
- Usually small
- Typical in younger patients

Malignant Bone Tumors

Pathologic Features
Histologic grade: Usually high grade, poor
prognosis
- Important predictor of behavior
- Determines likelihood of adjuvant therapy

Tumor stage
- Predicts clinical outcome

Benign Bone Forming Tumors

Osteoid Osteoma
Tumor of young adults
Male predilection
Predilection for
appendicular skeleton
Classic clinical
presentation:
Nocturnal pain alleviated
by aspirin

Benign Bone Forming Tumors

Osteoma (Bone Island)
- Benign
- Mature bone
- Predilection for
craniofacial bones
- Gardners
Syndrome

Osteosarcoma
Epidemiology
- Most common bone
sarcoma (20%)
- Bimodal age distribution
Elderly (Pagets,
radiation)
Children, young adults

- Location
Metaphyseal (long bones)
in youth
Flat bones in elderly

Osteosarcoma
Genetic Alterations
Hereditary tumors
- p53 mutations (LiFraumeni)
- Retinoblastoma gene (hereditary Rb)

Sporadic
- P53 mutations
- MDM2 (inactivates apoptotic capacity of p53)
- Rb mutations are rare

Osteosarcoma
Pathology
Anatomic location
- Intramedullary (usually low grade)
- Intracortical (high grade)
- Juxtacortical (low or high grade)

Grade
- Grade 1: mild cytologic atypia
- Grade 2: intermediate
- Grade 3: high grade, pleomorphic

Cartilage Tumors
General Features
Most are benign
Types of cartilage:
- Hyaline (found in tumors and normal)
- Myxoid (found only in tumors)
- Fibrocartilage (rare in tumors)
- Elastic (extremely rare in tumors)

Osteochondroma
- Benign cartilage
tumor of metaphysis
- Young adults
- Occur only in bones
with enchondral
ossification

Enchondroma
Benign
- Hyaline and myxoid cartilage

Metaphyseal and diaphyseal

Medullary cavity
May erode (but not invade) cortex
Present with pathologic fracture
Solitary or syndromic (Olliers or
Mafuccis disease)
May give rise to chondrosarcoma

Multiple Enchondromatosis
Olliers Disease
- Disfiguring
- 20% develop chondrosarcoma

Mafuccis Disease
- Enchondromas and soft tissue
vascular tumors
- 20% develop chondrosarcoma
- 100% develop another
extraskeletal malignancy

Chondrosarcoma
Typically occurs in older adults
Pelvis, humerus, proximal femur
May arise in enchondroma (low
grade)
Low grade (1/3) do not
metastasize, but may recur and
dedifferentiate
High grade metastasize

Giant Cell Tumor of Bone

Benign locally aggressive
tumor
4-5% of all primary bone
tumors
Age 20-40 yrs
Epiphysis
End of long bones
X-ray: expanding lytic lesion
soap bubble appearance

Ewings Sarcoma & Primitive

Neuroectodermal Tumor (PNET)
Family of small blue cell tumors
with a characteristic t(11;22) and
t(21;22)
6-10% of all primary malignant
bone tm.
Age: youngest among malignant
bone tm
Diaphysis of long bones
Prognosis: dismal, improves by
chemo

Metastatic Tumors to Bone

Metastatic carcinoma, most
common malignant tumor of
bone
May be blastic or lytic
Multifocal or solitary
Common Primary sites:
- B(breast)
- L(lung)
- T(thyroid)
- And a (adrenal)
- Kosher (kidney)
- Pickle (prostate)

Metastatic Tumors to Bone

Should consider
- Multifocal disease
- Location (vertebrae, diaphysis)
- Older patient
- Pertinent history

Pathology of Bone Tumors

Summary
Primary bone tumors classified according to matrix
production
Tumor site key to differential diagnosis
Benign tumors are well-circumscribed, do not
infiltrate bone
Malignant tumors are radiographically and
histologically infiltrative
Metastatic disease most common, may mimic
primary bone tumors