BONE PATHOLOGY LECTURES—Elisa Furay
BONE, JOINT, & SOFT TISSUE PATHOLOGY

NORMAL BONE FACTS
o Bones are made up of organic matrix (osteoid)– type 1 collagen
 Many other proteins, including osteocalcin, which is measurable in serum as a sensitive marker for
osteoblast activity
 Osteoid is important for diagnosing osteosarcoma—you need to see new bone formation
o Inorganic – calcium hydroxyapatite
o New bone formation – osteocytes
o Bone resorption – osteoclasts
 RANK activity (receptor activator for nuclear factor) = increased osteoclast activity and these dissolve
bone
 Osteoprotegerin inhibits osteoclasts (so inhibits dissolution of bone)—think
osteoPROTECTerginprotects bone
o There is usually a balance between these. In youth the osteoblasts more active and in old age the
osteoclasts win out
o Woven bone in adults is always pathologic
 Normally cortical bone is nice lamellar bone and should be seen without pathology
 Can see the nice lines
 Woven bone is always pathological
OSTEOCYTES
OSTEOCLASTS
You can see the osteoclasts
(multinucleated) eating the bone
o


(Pic on the Right) Notice RANK/RANK ligand
and osteoprotegerin regulate osteoclasts
 (Pic on the Left) Notice there is a normal
balance between bone formation and
resorption
CONGENITAL AND HEREDITARY DISEASES OF BONE
 Pathogenesis of developmental abnormalities
o DYSOSTOSES - defects in mesenchymal migration and condensation--affects 1 or 2 bones not the whole skeleton
 Usually focal abnormality, e.g. Supernumerary digits or ribs--6 digits or an extra rib in the neck
o DYSPLASIAS - abnormal proliferation or maturation of chondrocytes and osteoblasts or abnormal collagen and
noncollagenous proteins—effects the entire skeletal structure
 All cartilage or bone affected, e.g. Achondroplasia or osteogenesis imperfecta
 ACHONDROPLASIA
o Definition
 Impaired maturation of cartilage in the developing growth plate, due to mutation in FGFR3
 The most common growth plate disease
 Major cause of dwarfism
 Fibroblast growth factor receptor 3 (normally inhibits cartilage) is constantly active due to mutation
 So bones keep shortening and don't grow
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BONE PATHOLOGY LECTURES—Elisa Furay



80% cases new spontaneous mutation, but if inherited it is autosomal dominant
 Trunk is normal but the extremities don't grow - short arms and legs. Bulging head.
o Pathogenesis
 Dominant Mutations In gene coding for Fibroblast growth Factor receptor 3 results in defect in cell
signaling Leading to sustained activation of FGFR3 leading to Inhibition of normal proliferation of cartilage
At the growth plate (so bones don't lengthen)
o Morphology-- Cartilagenous growth plates contain hypoplastic or disorganized chondrocytes
o Appearance
 Shortened proximal extremities
 Trunk of relatively normal length
 Enlarged head with bulging forehead
 Depression at root of nose
 Normal longevity, mental status and reproduction
OSTEOGENESIS IMPERFECTA
o Definition
 “brittle bone disease”
 The most common inherited disorder of connective tissue
 A spectrum (mild to lethal) of hereditary conditions characterized by abnormal development of type 1
collagen, a major component of osteoid.
 Bones aren't as strong as they want to be
 Kids come in to the ED with multiple bone fractures. (MUST R/O CHILD ABUSE-- parents usually
accused)
o Pathogenesis
 Mutations interfere with Synthesis/ Secretion of Procollagen 1 or Procollagen 2  leading to
abnormal Type I Collage (major component of osteoid) fragile bone
 Procollagen alpha 1 and 2 are peptide precursors of Collagen Type I
 Four major forms of this disease
 Range from production of normal collagen producing mild skeletal abnormalities to severe or
lethal phenotypes resulting in abnormal polypeptide chains that cannot form the triple helix.
 Most common inherited as autosomal dominant
o Clinical
 Multiple bone fractures (always rule out child abuse)child abuse is way more common
 Varying degree of this disease:
o Possible death in utero
o May appear later in childhood
 They might just have a few broken bones
 Other organs affected:
 eyes (blue sclerae, due to decreased collagen)
 teeth (misshapen blue-yellow)
 ears (hearing loss, due to abnormal middle ear bones)
Congenital and Hereditary Bone Diseases
o
METABOLIC BONE DISEASE
 OSTEOPETROSIS
o Very Rare, autosomal recessive or dominant types
o Reduced osteoclast activity—so bones become hard and bridle
 Carbonic anhydrase deficiency leads to inability of osteoclasts to acidify and dissolve bone
 Other mechanisms
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BONE PATHOLOGY LECTURES—Elisa Furay
o
o
o
o
AKA “marble bone disease” (clinical fractures)
Dense bone sclerosis, but brittle, easily fractured and misshapen
Medullary cavity filled with spongiosa, no hematopoiesis (anemia, repeated infections)
 Their bone marrow is not normal (its spongiosa) so they don't have normal hematopoiesis
They have neutropenia and anemia
On x-ray their bones have an Erlenmeyer flask appearance
 dense bones, Erlenmeyer flask deformity at ends of radius and ulna



Osteopetrosis in a fetus – abnormal spongiosa in medullary cavity—no hematopoiesis going on in
there
OSTEOPOROSIS
o Categories (***= common)
 Primary
 Postmenopausal *** in females after E production 
 Senile *** in men
 Idiopathic
 Secondary
 Endocrine, e.g. Hyperparathyroidism
 Neoplasia, e.g. Multiple myeloma
 Gastrointestinal
 Systemic rheumatological diseases
 Drugs-exogenous glucocorticoids ***
 Miscellaneous
o Pathogenesis of osteoporosis
 Normal
 Bone mass increases in infancy and childhood and peaks at 30 y/o
o Peaks in 3rd decade
 Peak bone mass determined by
 Genetics
o Vitamin d receptor VDR (Vit D receptors)
 Type of Vitamin D receptor (VDR) accounts for approximately 75% maximal
peak bone mass achieved
 Physical activity
o Stimulus to bone remodeling
 Diet
o Vitamin d and calcium (drinking milk is important)
 Ca++ most important during adolescence;
girls more than boys
 Age
o Bone loss averages 0.7%/year
 Microfractures in the vertebral columns
so you get shorter and shorter and hip
fractures common
 Hormonal status
o Post-menopausal bone loss 2%/year cortical bone, 9%/year cancellous bone
o This is caused by  in E production in post menopausal women so if you go into
menopause early its worse on their bones
o Definition
 Skeletal disorder characterized by low bone mass and microarchitectural deterioration leading to bone
fragility leading to  susceptibility to fractures
 May be localized to certain bones or regions – disuse osteoporosis of a limb
 May involve entire skeleton – Metabolic Bone Disease
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BONE PATHOLOGY LECTURES—Elisa Furay
o
o
Pathogenesis of senile osteoporosis
  age   osteoblastic activity and  osteoclastic activity
 Age
 Ostioblasts – reduced reproductive and biosynthetic potential with increasing age
 Decreased biologic activity of matrix-bound growth factors
 Reduced physical activity – increases rate of bone loss. Exercise acts as stimulus for bone
remodeling. Weight training better than running because load magnitude impacts on bone
density more than the number of lead cycles.
Pathogenesis of postmenopausal osteoporosis
 Post menopausal women have  estrogen   bone mass (due to  osteoblastic acitivity and 
osteoclastic activity)
 Estrogen treatment can lead to  bone loss

o
o
Mechanism of postmenopausal osteoporosis

Incidence

50% of women will have postmenopausal osteoporosis fractures, due to loss of 35-50% of their bone
mass !!!
 Vertebral and hip fractures are common
 2% bone loss per year with postmeopausal osteoporosis due to loss of estrogen
 2% of men have senile osteoporosis—not common in men
Morphology
 Mainly affects cancellous bone (senile osteoporosis leans to cortical bone loss)
 Trabeculae thinner and farther apart
 Increased susceptibility to fracture
 Locations
 Vertebral bodies
 Weight bearing e.g. Femoral neck


the old woman has a Dowager’s hump (caused by microfractures in vertebral columns and
collapse so they also get shorter and shorter)

o
 Normal vertebral body (left) compared to compression fractures of osteoporosis (right)
Clinical--diagnosed radiologically
 Diagnosis by x-ray absorptiometry or CT density
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BONE PATHOLOGY LECTURES—Elisa Furay
o


Prevention and treatment
 Exercise
 Calcium & vitamin d intake
 Estrogen replacement SERMS – selective estrogen receptor modulators; similar to estrogen without some of the
dangerous side effects.
 Bisphosphonates
 Biphosphonates – selectively decrease osteoclast-mediated bone resorption
 Recombinant PTH
 Calcitonin – may reduce the frequency of vertebral fractures and may be of particular benefit to
those patients who are intolerant to estrogen
 **Fractures especially hip fractures have lots of morbidity and mortality involved with this disease
especially in older females
PAGET DISEASE
o Definition
 A disorder characterized by “matrix madness”—this is all going no at the same time
 Bone dissolves and goes from osteolytic stage and then gets to be osteoblastic at certain times
and then at the end you have a burnt out vey sclerotic stage
o Osteolytic stage
o Mixed osteoclastic-osteoblastic stage
o Predominant osteoblastic stage
o Burnt-out sclerotic stage
 End result is increased bone mass, but disorganized and architecturally abnormal—the bones don't work
properly
 Affects 5-10% of white Europeans
 Most patients have very limited symptoms
 This disease predisposes to osteosarcoma in some patients
o Epidemiology
 Uncommon <40 y/o
 M slightly more than F
 Familial Paget disease
 Some linked to the long arm of chromosome 18 and others that are not.
 Predisposes to osteosarcoma in older patients
Morphology
o Osteosclerosis characterized by formation of dense, mineralized bone with few cells.
o Mosaic pattern (jigsaw puzzle) of lamellar bone is pathognomonic
o
o
o

this is woven bone
Monostotic (15%)
 Tibia, ilium, femur, skull, vertebra, humerus
Polyostotic (85%)-- most of the times there are multiple bones involved
 Pelvis, spine, skull
Phases-- bones get involved and the vessels in there hyperdilate (you can feel the
warmth above the area with this disease due to this hypervascularity and
metabolism)
 Osteoclastic activity, hypervascularity, bone loss
 OSTEOLYTIC PHASE bone dissolved and cortex thinner
 Mixed osteoclastic and osteoblastic activity
 mixed phase in between them
 Osteosclerosis
 Bone getting thicker: osteosclerotic phase
 Osteosclerosis characterized by formation of dense, mineralized bone with few
cells.
 The abnormal bone is being formed
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BONE PATHOLOGY LECTURES—Elisa Furay
o

Dx by radiology;
 On the x-ray to the right: 1 – lytic; 2 – mixed; 3 - sclerotic
o Tx: most patients have mild symptoms easily treated with calcitonin and bisphosphonates
o Clinical
 PAIN most common complaint (caused by microfractures)
 dissolving bones and you don't need a cast but they're painful
 LEONTIASIS OSSEA – massive heavy/ skull (lion's skull), hearing loss (abnormal bones of the ear)
 Platybasia of skull
 Bowing of legs, distortion of femoral head and severe osteoarthritis
 Chalkstick fractures of legs—b/c bone being dissolved in osteolytic areas
 Spinal compression fractures
 Hypervascularity leads to warm skin overlying paget bones, and high-output cardiac failure
 Malignancy risk, esp. Osteosarcoma, MFH, chondrosarcoma (1% with monostotic disease,
10% with polyostotic disease)
 > the more bones that are involved
 Increased Alk. Phosphatase; Ca and PO4 normal
VIT. D DEFICIENCY
o Low vit. D → hypocalcemia → excess unmineralized bone matrix
 Inadequate sunlight or diet deficiency
 Most milk is now supplemented with vitamin D
 Decreased absorption
 Inadequate or abnormal synthetic pathway—not common
 End-organ resistance--not common
 Phosphate depletion
o RICKETS (KIDS)
 Growth plates distorted and poorly mineralized leads to weak bone and skeletal deformity
 Lumbar lordosis—curvature of the spine
 Bowing of the legs--not mineralized and can't support the weight of the child



 Normal cartilage to bone maturation ( can see elongated pieces of new
^ Rickets
bone formation
--distorted maturation
o OSTEOMALACIA (ADULTS)
 Loss of bone mass (osteopenia)
HYPERPARATHYROIDISM
o OSTEITIS FIBROSA CYSTICA
 Cortical bone preferentially affected
 X-ray loss of cortex particularly in fingers
 Histology – dissecting mass of osteoclasts (osteoclasts dissecting into the bone spicules)


Dissecting mass of osteoclasts
Loss of bone with microfractures leads to hemorrhage into the bone, with giant cells and fibrosis: “brown
tumor”
 Microfractures-- a common thing seen in a lot of these
 Brown tumor—hemorrage into areas of the dissecting mass— altered Hb in there causes the
brown tumors
o

“brown tumor”
 Looks like a tumor lots of blood in the microfractures
Not a ton of biopsies for this b/c the Dr. usually knows what's going on
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BONE PATHOLOGY LECTURES—Elisa Furay
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

Usually associated with primary hyperparathyroidism (secondary hyperparathyroidism is not as severe)
 Osteitis fibrosa cystica is not seen frequently because of early diagnosis of Hyperparathyroidism
and treatment
 Skeletal abnormalities of secondary hyperparathyroidism are milder than the primary form
because secondary is generally not as severe and prolonged
Entire skeleton is affected

RENAL OSTEODYSTROPHY
o Seen in secondary hyperparathyroidism
 kidney failure so  Phosphate excretion-> hyperphosphatemia so Ca goes down and so parathyroid
glands  PTH production so you start dissolving bones to get Ca up)
o Definition
 Describes all skeletal changes associated with chronic renal failure
 Increased osteoclastic bone resorption
 Delayed matrix mineralization (osteomalacia)
 Osteosclerosis
 Growth retardation
 Osteoporosis
o Types of bone disorders with chronic renal disease
 High-turnover osteodystrophy – increased bone resorption and formation
 Low-turnover or aplastic disease – marked reduction in rate of mineralization, formation and resorption
 Mixed pattern
o Renal osteodystrophy pathogenesis

o
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

Phosphate regulates parathormone secretion
D1,25-[OH]2D3 drops because of decreased conversion of 25-(OH) D3
When you have renal failure a lot of times you are acidotic (acidosis dissolves bone also-osteoclasts make carbonic acid to chew up bones)- secondary PTH as well as acidotic bone loss
Renal osteodystrophy pathogenesis – summary

ISCHEMIC BONE LESIONS
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BONE PATHOLOGY LECTURES—Elisa Furay

OSTEONECROSIS – AVASCULAR NECROSIS
o Ischemia of bone
o 10% of joint replacement done for this—fairly common; usually femoral head
o Pain most frequent presentation for subchondral infarct
o Medullary infarct usually clinically silent
o Commonly see Wedge-shaped infarct with fat necrosis (immediate beneath bony cortex (subchondral))
 Increase in osteoarthritis
o Most cases idiopathic or secondary to steroids
o Causes
 Mechanical vascular interruption
 Corticosteroids
 Thrombosis, sickle cell disease (by clotting off those little capillaries)
 Thrombosis and embolism e.g. sickle cell, nitrogen bubbles,
 Vessel injury
 Vasculitis and radiation therapy
 Increased intraosseous pressure with vascular compression
 Venous hypertension
 Fracture
 Tumors Gaucher disease
 Chronic pancreatitis probably due to release of mediators giving rise to inflammation and thromboses
o Morphology
 Medullary infarcts involve cancellous bone and marrow
 Subchondral infarcts are wedge-shaped
o Clinical
 Subchondral
 Chronic pain, common femoral head lesion is the most common site
 When you dissolve bone (necrosis of bone)  bone Collapse and joint deformity leading to
osteoarthritis
o Patients get hip replacements with this
 Medullary – remain stable; rarely, site of malignancy
o
Subchondral wedge-shaped area of avascular necrosis of femoral head
wedge shaped infarcts pulling away from the bone and you'll get osteoarthritis and you'll need a joint
replacement
 10% of joint problems caused by this
INFLAMMATORY BONE LESIONS
 OSTEOMYELITIS
o Definition
 Inflammation of the bone and marrow
 Most commonly associated with infection
 Pyogens
 Tb
o PYOGENIC OSTEOMYELITIS
 Cause – bacteria
 Routes of entry
 Hematogenous—bloodstream
 Extension from a contiguous site
 Direct implantation—bullet going into bone that has bacteria on it
 Causative agents
 Staphylococcus aureus – 80-90% of cases
o If you get both answers in sickle cell patients on boards put this
 E. Coli, pseudomonas and klebsiella

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BONE PATHOLOGY LECTURES—Elisa Furay
o
o Things that cause Genitourinary infections
o Immunosuppressed patients
 Haemophilus influenzae and group B strep. - neonates
 Salmonella –in sickle cell anemia patients
 Sites of infection—because of variations of circulation
 Dependent on circulation
o Neonate – epiphysis and metaphysis
 In the neonate metaphyseal vessels penetrate the growth plate leading to
epiphyseal and metaphyseal infections.
o Children – metaphysis
o Adult – epiphysis and subchondral region
 After growth plate closes, metaphyseal vessels are reunited with the
epiphyseal vessels leading to seeding of epiphysis and subchondral regions.
 Morphology
 Acute
 Subacute
 Chronic
Pathogenesis of inflammation

o


Dead bone (aka sequestrum)- you get dead bone the term is sequestrum
New bone that forms around it is called unvolucrum
Clinical
 Acute systemic illness—feel like crap, fever, septic
 Sometimes FUO
 FUO= fever of unknown origin
o sometimes they just do a random bone biopsy looking for infection just to see if that's
the cause and if you see granulomas etc then you'd know they had TB or a fungal
infection
 Chronic form—less incident of fever
 Delayed diagnosis
 Extensive necrosis
 Abbreviated antibiotic treatment
 Diagnosis
 X-ray, blood cultures #1 thing, sometimes direct culture of lesion
o X-Ray – lytic zone surrounded by sclerotic bone
o Antibiotics and surgical drainage are treatment with 5-25% not
responding.
 Complications
 Fractures, endocarditis (bacteria seeded to heart valve especially if you have a messed up heart
valve already), squamous cell carcinoma, sepsis, secondary osteomyelitis
o Squamous cell carcinoma (patients w/ non healing ulcer and radiology said it was
consistent w/ osteomyelitis and the patient was on antibiotics for 6 months and it never
healed—they finally bx the finger and found she had SCC—they don't know what came
first: the osteomyelitis or SCC)
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BONE PATHOLOGY LECTURES—Elisa Furay
NEOPLASMS OF BONE
 Metastatic lesions to bone > primary bone tumors
 Most common neoplasms metastasizing to bone in descending order
o Prostate (usually osteoblastic)
o Breast
o Lung
o Kidney
o GI
o Thyroid
 Kinds Of Tumors Leaping Promptly To Bone
o Kidney Ovary Testis Lung Prostate Thyroid Breast
 Most metastases are osteolytic—produce radiolucent area on x-ray b/c they dissolve bone as they grow and make room for
themselves (tumor cells secrete PTHRH, prostaglandins or interleukins that stimulate osteoclast bone resorption), maybe
osteoblastic (by stimulation of osteoblasts)—COMMONLY seen in PROSTATE CANCER--much denser on radiology- Primary Tumors
o Hematogenous 40% e.g. myeloma, malignant lymphoma
o Chondrogenic 22% e.g. Osteochondroma, Chondrosarcomas
o Osteogenic 19% e.g. Osteosarcomas
o Unknown origin 10% e.g Ewing and Giant Cell tumors
 Primary lesions: age & location
o OSTEOSARCOMA-teens, metaphysis knee (distal femur and proximal tibia—not the knee cap)
o CHONDROSARCOMA-adults, trunk, limb girdles, proximal long bones
o GIANT CELL TUMORS-epiphysis long bones
o EWING SARCOMA-diaphysis
o Clinical presentation
 Benign (first 3 decades) >>> malignant (elderly)
 Incidental; pain; mass; pathologic fracture (most commonly a mets cuz they are more common than
primary)
 Radiology is very important
 BENIGN TUMORS OF BONE (MOST COMMON)
o OVERVIEW
 OSTEOID OSTEOMA
 OSTEOCHONDROMA
 CHONDROMA
 FIBROUS CORTICAL DEFECT (NON-OSSIFYING FIBROMA)
 FIBROUS DYSPLASIA
 GIANT CELL TUMOR
 ANEURYSMAL BONE CYST
o OSTEOID OSTEOMA
 Teenagers
 Painful due to prostaglandin e2, relieved by aspirin (inhibits PG production)
 Found in the Femur or tibia cortical lesion (not medullary cavity)
 Random woven bone (always pathologic) rimmed by osteoblasts

o
Osteoid osteoma – woven bone—can see bone spicules with rim of
osteoblasts
 Regular bone spicules with osteoblasts all around it. Area between bone spicules you see
hemorrhage and loose matrix with capillaries and blood in there.
 Compared to fibrous dysplasia, which is much more fibrous in between the spicules and they
don't have osteoblastic rimming
OSTEOCHONDROMA (EXOSTOSIS)
 Epidemiology
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BONE PATHOLOGY LECTURES—Elisa Furay
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




o
1/3 of all benign bone tumors—fairly common lesions
These are little lesions that grow out from the bone
Most solitary, multiple in familial hereditary exostosis (rarely become chondrosarcoma)
o Most of the time solitary and not hereditary
M>F; most in children and adolescents
Familial form is autosomal dominant and involves chromsomes 8, 11 and 19.
Involve only endochondral bones



Clinically
 Arise from metaphysis of the bone and grow away from epiphyseal plate
 Asymptomatic
 Benign
 Usually stop growing when growth plate closes
Morphology
 Broad base, bony growth out from metaphysis and grows away from epiphysis
 Hyaline cartilage cap
Pathogenesis
 Lateral displacement of lateral portion of growth plate

CHONDROMA
 Cartilage only, asymptomatic or painful
 ENCHONDROMA - most common (means cartilage in the bone), small tuomor of cartilage
growing in medullary cavity of hands (most common) or feet, age 20-50; these are incidental
findings
o OLLIER DISEASE = multiple enchondromas (rare transformation to osteosarcoma)
o MAFUCCI SYNDROME = multiple enchondromas with soft tissue hemangiomas,
 ↑ risk ovarian Ca/brain gliomas
o
o
 Enchondroma – benign cartilage encased in reactive bone
 cartilage filling up medullary cavity
 JUXTACORTICAL CHONDROMA – on the bone surface
FIBROUS CORTICAL DEFECT (NON-OSSIFYING FIBROMA)
 Very common, 50% of kids over 2 yrs.
 Asymptomatic—most go away spontaneously; incidental finding
 Small lesions, sometimes multiple
 Larger lesions (non-ossifying fibroma) may cause pathologic fracture
 Metaphysis, around knee (distal femur or proximal tibia)
 Benign fibroblasts in storiform pattern (cartwheel) and histiocytes (giant cells or foamy macrophages)
 Spontaneous resolution

o

Fibrous cortical defect – storiform (cartwheel) pattern of fibroblasts with a few osteoclast-like
giant cells. No bone formation in there.
FIBROUS DYSPLASIA
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BONE PATHOLOGY LECTURES—Elisa Furay

3 clinical presentations
 Monostotic: single bone involved; most common, asymptomatic, teenagers,
ribs/femur/tibia/jaw/skull/humerus; incidental findings
o Lots of different bones involved
 Polyostotic: Multiple bones involved; younger patients, craniofacial bones/hip and shoulder
girdles resulting in arthritis
 Polyostotic disease with café au lait skin lesions and endocrine abnormality, esp. Precocious
puberty (McCune-albright syndrome)
o Polyostotic rarely can transform to sarcoma (osteosarcoma or MFH)

o
o
Fibrous tissue with “Chinese letters” of bone (no osteoblastic rimming, as seen in
osteoid osteoma)
o fibrous tissue with little bits of bone in there not a loose matrix
GIANT CELL TUMOR OF BONE (OSTEOCLASTOMA)—also seen in joints and soft tissues (seen in tendon sheath)
 20% of all benign tumors of bone--common
 20-40 years of age
 Mostly around the knee, pain or pathologic fractures are common presentations
 On bx will see 2 cell populations, mononuclear cells and giant cells (same type of cells but they just
aggregate)
 Benign but locally aggressive, 4% metastasize to lungs
 Just chop it out
 Epidemiology
 May be most common benign bone neoplasm of the 20-40 yr. Age group.
 Pathogenesis
 Monocyte-macrophage lineage
 Only accompanying mononuclear cells are neoplasic
 Location
 In adults both metaphysis and epiphysis; adolescents only metaphysis.

Giant cell tumor: nuclei of giant cells and stromal cells look alike

o
 Overlying cortex is often destroyed leaving soft tissue mass and thin layer of reactive bone.
ANEURYSMAL BONE CYST (ABC)
 Multiloculated blood-filled cystic spaces with wall of fibroblasts, giant cells and reactive bone
 Lots of hemorrhage and blood seen (as compared with giant cell tumor which is solid stroma)
 Generally first 2 decades—younger patients
 Metaphysis of long bones
 Pain and swelling
 Rx curettage



You don't see the giant cells here at low power
Filled with blood and fibroblasts surrounding it Blood and hemorrhage and a few giants cells so
theres not a lot of good material to diagnose this—its mostly a radiological dx
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BONE PATHOLOGY LECTURES—Elisa Furay

MALIGNANT TUMORS OF BONE (MOST COMMON)—benign bone tumors are more common than malignant ones!
o OVERVIEW
 OSTEOSARCOMA
 CHONDROSARCOMA
 FIBROSARCOMA AND MFH (MALIGNANT FIBROUS HISTIOCYTOMA)
 EWING SARCOMA AND PNET (PRIMITIVE NEUROECTODERMAL TUMOR)
o OSTEOSARCOMA (OSTEOGENIC SARCOMA)
 THE MOST COMMON PRIMARY BONE TUMORS (not talking about BM tumors like myeloma and
lymphoma which are more common)





Definition
 Malignant mesenchymal neoplasm that produces osteoid—if we don't
see osteoid its not this
Epidemiology
 Most common primary malignant tumor of bone exclusive of
myeloma and lymphoma
 Secondary forms e.g Paget disease and radiation
 Second decade of life; distal femur and proximal tibia.<--classic
presentation
o Bimodal age distribution – 75% in patients < 20 yrs. Old and
smaller peak in elderly associated with Paget Disease
 M>F
 20% primary bone cancers
 Usually arise in metaphysis!!
Pathogenesis
 Genetic
o P53 mutations (DNA repair)
 Overexpression of MDM2( Murine Double Minute oncogene) binds to to p53
and degrades it inactivating its growth suspressing and apoptotic function in
nonhereditary osteosarcoma.
o Retinoblastoma gene (RB) mutation (cell cycle regulator)
 Patients with hereditary RB has several 100 fold greater risk of osteosarcoma
 Mutations in RB rare in sporadic osteosarcoma, but mutations in P53 frequent
 Other predisposing conditions
o Paget disease
o Radiation therapy of benign bone lesion
 Many arise at sites of bone growth
Morphology
 Metaphysis, around knee
 Osteolytic and invades soft tissue
 Codman triangle (raised calcified periosteum of the bone around the metaphysis)
o Tumor often breaks through cortexs and lifts the periostium resulting in reactive
periosteal bone formation. Presents as triangle between cortes and
raised ends of periosteum (b/c it is calcified) (Codman’s triangle)
 Formation of bone (osteoid) is characteristic
o Must see this on bx
 Radiologically – destructive, mixed lytic and blastic.
Clinical
 #3 malignancy in teens, after leukemia and lymphoma
 Enlarge progressively and painful
 May fracture
 Metastasize early by hematogenous route, 20% have obvious lung mets at dx,
and most have micro-mets at the time the dx is made
o 20% have pulmonary mets at initial diagnosis
o In those patients who die, 90% have mets to lungs, bones and brain
13
BONE PATHOLOGY LECTURES—Elisa Furay
o



o
o
o
Long-term survival is 60%; Chemo and surgery; MDR1 gene product
p-glycoprotein mediates multidrug resistance.
Secondary (usually to Paget’s) are more aggressive
60% 5-yr survival without detectable mets at dx, 20% with mets at dx
Osteosarcoma—lace-like neoplastic bone (can see osteoid here—pink
irregular bone)
CHONDROSARCOMA
 Neoplastic cartilage (no bone formation, which would be classified as chondroblastic
osteosarcoma)
 Bluish glistening cartilage
 NO OSTEOID FORMATION
 Age >40
 Occurs in Pelvis, shoulder, ribs
 Not the knee
 Painful enlarging masses—will see lytic lesion of the bone
 Vary from low- to high-grade—ugly cells w/  mitotic activity
 80-90% 5-yr survival vs 40% 5-yr survival
FIBROSARCOMA
 Large destructive masses, usually metaphysis of long bones and pelvis
 Not as common in bone—more common in soft tissues (will talk about them
near the ned of the lecture)
 Middle-age to elderly
 Most sarcomas tend to be in older people
 Collagen production
 This malignant tumor has fibrous tissue (not osteoid or cartilage)
 Will see spindle cells which a lot of sarcomas have but you have this
cartwheel/storiform pattern
 Big atypical nuclei, lots of mitotic figures (common to many sarcomas)
 Some tumors referred to as MFH malignant fibrous histiocytoma
 There are many diff. variants of this (pleomorphic variant is one) so look for them if you're a pathologist
EWING SARCOMA FAMILY—common on boards
 Definition
 A family of neoplasms of which Ewing sarcoma (ews, undifferentiated) and primitive
neuroectodermal tumor (PNET, with neural differentiation)
o Tumors resemble: lymphoma, rhabdomyosarcome, neuroblasoma and small cell
carcinoma of lung
 Account for 6-10% of all primary bone tumors (second most common bone tumors.
 Tumor variants united by common neural origin and genetic translocations
o C-myc oncogene common to all forms.
o PNETs differentiated toward neural tissue and undiff. Tumors call Ewing
 Children and adolescents with peak age in second decade (same as osteosarcoma)
o Approx. 80% of patients younger than 20 yrs.; Most are are 10 to 15 yrs.
o Boys>Girls; Whites>Blacks
 Aggressive
 Morphology
 Soft tissue expansile mass in medullary cavity
 Femur, tibia and pelvis, some are also seen around the eye socket
o Diaphysis of long tubular bones e.g. femur and flat bones e.g. pelvis.
 Some patients have fever, elevated sed. Rate. Anemia and leukocytosis.
 Sheets of primitive basophilic cells that do not produce osteoid
14
BONE PATHOLOGY LECTURES—Elisa Furay


 Neural marker – MIC2 (CD 99) antigen
Clinical
 Pain and local inflammation
 Biopsy, look for morphology and cytogenetic markers
 Prognosis – 75%, five year survival—pretty good
 X-Ray lytic tumor
 Treatment chemotherapy and surgery with or without irradiation.
Morphology & genetics
 Small round blue cells tumors—just sheets of small round blue cells
o Lots of these type of tumors in pathology (Lymphomas, etc)—so
distinguish them check markers and genetics
 Maybe homer-wright rosettes
o Homer-Wright rosettes: Tumor cells around a central fibrillary space
(neural differentiation)
 Arise in medullary cavity, invade cortex
 GENETIC ABNORMALITY THAT YOU HAVE TO MEMORIZE IS: T(11;22)****
 EWS gene on 22 fuses most commonly with transcription factor gene FLI1, stimulates cell
proliferation so tumor grows out of control
PATHOLOGY OF JOINTS
 OSTEOARTHRITIS—very common
o Definition
 Degenerative joint disease characterized by progressive erosion of articular cartilage.
 Cartilage erodes down causing bone on bone rubbing  leading to pain
 Intrinsic disease of cartilage in which biochemical and metabolic alterations lead to breakdown.
 Inflammation is implied by the name. However, inflammatory cells are not a major feature.
o Causes
 Insidious onset related to aging (so older people get this) and mechanical stress (wear and tear)
 Predisposing factors (secondary arthritis) e.g. Trauma (men that play football), congenital deformities
(one leg is shorter so more stress on other leg), systemic diseases or marked obesity ( weight on joints
 stress on them)
 Gender influences distribution (knees/ hands women, hips men)
o Morphology
 Fibrillation/fragmentation of articular surface (cracks in the cartilage) cartilage flaking off  Erosion of
cartilage
 Water increases and protioglycans decrease leading to fibrillation and cracking of surface
 Ineffective cartilage repair with disorganized cartilage
 Not very good at repairing especially in adults
 Eburnation of bone (polished surface)—bone on bone rubbing together and is very painful!
 Eburnation – Once cartilage is sloughed, underlying subchondral bone is exposed and due to war
becomes “polished ivory.”
 “Joint mice”
 Joint mice – dislodged pieces of cartilage and subchondral
bone in the joint.
 Sometime these will get stuck in the joint and cause
ankylosis—locking of the joint. Wiggle it around to get the
joint to move properly again
 Subchondral cysts of the medullary caviry
 Cysts – Form due to collections of synovial fluid in
Fig. Degenerative
subchondral regions.
osteoarthritis:
 Sclerosis of trabecular bone
3 – relatively normal cartilage
 Osteophytes (bone spurs)
1 – eroded cartilage,
2 – subchondral cyst
 Osteophytes – bony outgrowths at margins of articular
surface capped by fibrocartilage and hyaline cartilage.
 Can cause pain and locking of the joint sometimes
o Clinical features
15
BONE PATHOLOGY LECTURES—Elisa Furay
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Large joints involved include hips, knees, lower lumbar, cervical vertebrae
Joint stiffness and deep aching pain in a.m.
 Deep, achy pain that worsens with use, morning stiffness, range limitation
 Osteophytes can cause radicular pain due to nerve root compression
Use aggravates pain
Crepitus (crackling sound) when you move joint around
Swelling—large swollen and red
Heberden nodes (osteophytes @ dip), esp. In women
 Heberden nodes only found in women. They are osteophytes at the distal interphalageal joint
 Osteophytes can cause radicular pain due to nerve root compression
Osteoarthritis second only to cardiovascular disease for causing long term disability.
RHEUMATOID ARTHRITIS—pretty common
o Autoimmune systemic disease (mostly women) that primarily attacks joints, but other organs and tissues may be
affected
 SYNOVIAL PROBLEM NOT CARTILAGE PROBLEM
 Most commonly affects younger females
o Activated CD4 cells produce cytokines
 Lots of inflammatory cells especially lymphocytes
o Inflammaton of the synovium  inflammatory synovitis leading to Cartilage
destruction and ankylosis
o Affects mainly the Small joints, hands most affected (early hot swollen painful joint,
RA – pannus
later swan neck deformity and boutonniere deformity)
(hypertrophied and
o RA PATHOLOGY
destructive
 Thick hyperplastic/ proliferative synovium, lymphocytes, plasma cells,
synovium with
granulation tissue: called PANNUS formation
inflammatory cells)
 This pannus grows into joint space over articular cartilage causing
erosion (destroys the cartilage) and eventually ankylosis
 Skin rheumatoid nodules - palisading granulomas
 Vasculitis
o Lab tests
 Rheumatoid factor = IgM reactive against IgG (not necessarily present, also
Subcutaneous
non-specific)
rheumatoid nodule –
 Cyclic citrullinated peptide antibody = frequently present, more specific
palisading granuloma
o RA CLINICAL DX-- Dx is mostly clinical
(central necrosis
 Requires 4 or more
surrounded by
 Morning stiffness
palisade of histiocytes)
 Arthritis in 3 or more joints
o Arthritis of typical hand joints
o Osteoarthritis is a single joint and NOT symmetrical
 Symmetric arthritis
o Same joints in both hands affected.
 Rheumatoid nodules
 Serum rheumatoid factor and cyclic citrullinated peptide antibody
 Typical radiographic changes
OTHER ARTHROPATHIES
o JUVENILE RA—not common
 <16 yrs, large joints of knees/wrists/elbows/ankles (as opposed to small joints),
systemic onset with fevers/skin rash, rheumatoid nodules and rheumatoid factor
usually absent, ANA commonly positive
o ANKYLOSING SPONDYLITIS
 90% HLA-B27+, joint locking of the sacroiliac joint (most commonly affected), men
20-30’s
 Easy to recognize—patients cant straighten up they are bent over
Infectious
o REACTIVE ARTHRITIS
(septic)
16
arthritis
BONE PATHOLOGY LECTURES—Elisa Furay

Reiter syndrome (arthritis, conjunctivitis, non-gonococcal urethritis), men 20-30’s, HLA-B27+, related to GI
(Salmonella/Shigella, Yersinia, campylobacter) or GU (chlamydia) infection
o PSORIATIC
 develops in 10% of psoriasis population
o INFECTIOUS—more common
 lots of PMNs; gonococcus (gonococcal arthritis) and gram + cocci most common
 Treat this quickly b/c patient can develop sepsis—culture and then treat with
Erythema
antibiotics
chronicum
o LYME ARTHRITIS
migrans—Lyme
 Borrelia burgdorferi, transmitted by ixodes deer ticks (hard body ticks),
dz
characteristic skin lesion erythema chronicum migrans (targetoid skin lesion),
then arthritis weeks later, then organ involvement (heart—cardiac arryhtmias, brain)—do serology to test
for lyme disease
CRYSTAL-INDUCED ARTHRITIS
 GOUT
o Definition
 Disorder caused by accumulation of excess uric acid in tissue.
 Hyperuricemia >6.8 mg/dl is necessary but not sufficient
o Not everyone with this gets gout but you kind of need it to be elevated if the person has
gout
 Recurrent episodes of acute arthritis; sometimes leading to chronic arthritis with tophi formation
 Big toe is the most common site
 Chronic disease may lead to joint deformities
o Purine metabolism & causes of gout
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Purines come by from nucleotides. Purine Nucleotides synthethized de novo from non-purine precursors
or derived from preformed purines in the diet.
Purine nucleotides catabolized to hypoxanthine or incorporated into nucleic acids.
Degradation of dietary purines and nucleic acids produce hypoxanthine
Hypoxanthine converted to uric acid that is excreted in urine
Hyperuricemia/gout results from
 Increased production of precursors (most common), increased cell turnover (from nt breakdown),
decreased salvage (not very common) or decreased uric acid excretion

Purine synthesis and salvage pathways.
17
BONE PATHOLOGY LECTURES—Elisa Furay

o
o
o
HGPRT is involved in the salvage pathway.
o HGPRT - hypoxanthine guanine phosphoribosyltransferase
CLASSIFICATION
 Primary (90% of cases)
 Over production of uric acid
o 90% enzyme defect unknown
o Partial HGPRT deficiency
o Diet
o Most cases of gout are due to primary overproduction of uric acid with or without
excessive excretion of uric acid
 Reduced excretion of uric acid with normal production
o HGPRT - hypoxanthine guanine phosphoribosyltransferase—may be a small part of
primary gouts
o
 Secondary
 Overproduction of uric acid
o Complete HGPRT deficiency – Lesch-nyhan syndrome (males, retardation, selfmutilation)
 Lesch-Nyhan – Males, hyperuricemia, severe neurologic deficits with mental
retardation, self-mutilation and  gouty arthritis
o Increased nucleic acid turnover (MOST COMMON CAUSE OF SECONDARY)
 ex: patients w/ Leukemias and lymphomas b/c all these cells die w/
chemotherapy and there is  cellular/DNA breakdown
 Treatment of lymphomas and leukemias lead to rapid cell lysis.
 These patients get medication for gout to take along with their chemo
 Decreased excretion of uric acid
 Chronic renal disease
Factors contributing to gout
 Age—usually older people
 Age – Duration of hyperuricemia; 20-30 years of hyperuricemia before gout appears
 Genetic predisposition
 Genetics – Familial and found with multifactorial inheritance in addition to X-linkied
abnormalities of HGPRT.
 Heavy alcohol consumption
 Heavy Alcohol – predisposes to attacks of
gouty arthritis. Due to accelerated ATP
catabolism and to a lessor degree
reduced renal excretion of uric acid due
to lactate acting as a competitive
inhibitor of urate secretion by tubules.
 Obesity
 Obesity – increases risk of asymptomatic
gout
 Thiazides
 Thiazides (Diuretics) – Lead to increased
reabsorption of uric acid by kidney
tubules leading to hyperuricemia. This is
true of dehydration in general.
 Lead toxicity (saturnine gout)
 ***It takes more than hyperuricemia to lead to
gouty arthritis
Morphology
 MANIFESTATIONS
 Acute arthritis
o Severe pain, urate crystals and neutrophils
18
BONE PATHOLOGY LECTURES—Elisa Furay
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Monosodium urate crystals in synovial tissues.
 Pale and elongated (needle-like)—aspirate a joint for bacteria or
crystals!
 Its like putting little needles in your joint
 Most common in your big toe because that has the lowest temperature in the
body and uric acid ppt at low body temperatures
Chronic tophaceous arthritis
o Depsoits of uric acid in all the soft tissues around the joint
(commonly in the feet)
 After recurring episodes of acute arthritis
o Tophi (whitish deposits of uric acid) on articular cartilage
and adjacent to joint capsule—it just destroys the joint
Gouty tophus in
o Granulamatous inflammation
soft tissue
o Fibrosis of synovium.
Soft tissue tophi
Gouty nephropathy—kidney disease
o Crystals in tubules and interstitium renal stones, pyelonephritis, fibrosis
o Marked hyperuricemia and hyperuricaciduria lead to uric acid crystals that obstruct
tubules. Important complication of myeloproliferative disorders. Patients secrete large
amounts of uric acid when treatment starts.
o Can also develop uric acid renal stones leading to obstructive nephropath and
pyelonephritis.
o Most of the time you don't get to this point because we treat it before it gets this bad
o


Clinical
 Stages
 Asymptomatic
 Acute gouty arthritis
o Local pain in single or later multiple joints
 “Intercritical” gout
o Asymptomatic intervals
 Chronic tophaceous gout
o Joint and soft tissue deformity
o About 12 years after initial attack
 20% die from renal failure—probably a lot less now!
o Gout doesn't kill you this does!
o Anatomic location - joints
 In order of frequency
 Great toe (50%)—red swollen up big toe (just aspirate fluid to r/o infectious arthritis)
 Instep of the foot
 Ankle
 Heel
 Wrist
 Peripheral joints tend to be affected because lower temps. Help precipitate uric acid
PSEUDOGOUT
o Calcium pyrophosphate crystal deposition disease
o Older patients, most cases idiopathic
o Knee > wrist, elbow, shoulder, ankle
o Frequently asymptomatic, may mimic osteoarthritis or RA
 Also symptoms are kind of similar to gout
 Analyze joint fluid to differentiate
o Tx supportive
GOUT VS. PSEUDOGOUT POLARIZED MICROSCOPY
o Dx: UpayPeb (Urate=parallel yellow, perpendicular blue)
o Pyrophosphate is opposite
o Pyrophosphate is plate like crystals
19
Ganglion cyst
Baker cyst
BONE PATHOLOGY LECTURES—Elisa Furay
o Uric acid—needle like crystals
MASS LESIONS
 GANGLION CYST-fibromyxoid wall—it is squishy, common mass at wrist
 SYNOVIAL CYST-synovial lining, e.g. called baker cyst behind knee—also squishy
 TENOSYNOVIAL GIANT-CELL TUMOR
o Genetic abnormality T(1;2)—not important though
o PIGMENTED VILLONODULAR SYNOVITIS-knee pain/locking/swelling, 80% at knee. Look like bushy growth.
Uncommon.
o

 Gross pic- pigmented villonodular synovitis
GIANT CELL TUMOR OF TENDON SHEATH-Very common painless mass
of the hand (commonly seen in coming out of the joint space in the
fingers—much more solid and not as compressible
Giant cell tumor of tendon sheath
SOFT TISSUE TUMORS AND TUMOR-LIKE LESIONS
 Soft tissue tumors are usually sporadic, but sometimes associated with genetic syndromes
o Neurofibromatosis, Gardner syndrome, Li-Fraumeni syndrome, Osler-Weber-Rendu syndrome
 All can have soft tissue tumors that occur with them
 40% lower extremity, 20% upper extremity, 10% head/neck, 30% trunk/retroperitoneum
o extremities and retroperitoneum are the #1 places for these
 Sarcoma (malignant tumors) prognostic factors
o Tumor type and genetics (review table 26-9)
o Stage and grade are very predictive of survival rate
o Superficial tumors generally better than deep tumors
 Probably because these are discovered sooner
 FATTY LESIONS
o LIPOMA—Benign
 Common, adults, soft mobile painless mass, many variants
 Well-encapsulated mass, subcutis
 Extremities and trunk just beneath skin surface
 Tend to be more superficial in the subcutis than liposarcoma
o LIPOSARCOMA--malignant
 Several variants indolent to aggressive (so remove them!)
 Will see Lipoblasts
 Deep soft tissues and in the retroperitoneum
 FIBROUS LESIONS
o NODULAR FASCIITIS
 The most common, volar forearm
 In deep skin or muscle, rapidly growing mass, Ddx includes sarcoma
 Most of these don't get bx they get taken out completely b/c not sure if they are malignant or
benign
o MYOSITIS OSSIFICANS—in the muscle and you get calcification (may see osteoid in there)
 Teens/young adults, 50% post-trauma to muscle  hemorrhage that doesn't get
totally reabsorbed and it gets calcified and greats a mass
 Proximal muscles of extremities, produces metaplastic bone/osteoid
 Tends to be rapidly growing—bx it to see what it is
 Initial swelling and pain, then becomes painless mass
 DDx extraskeletal osteosarcoma (because it sometimes has osteoid)
 Look at a lot of sections to look for malignant cells!
 Both of these can look similar on radiology
 FIBROMATOSIS – mature but disorganized fibrous growth—can be cured w/ surgery
o Overgrowth of fibrous tissue
o Palmar (DUPUYTREN CONTRACTURE)—very common
 Unilateral or bilateral (50%)
20
BONE PATHOLOGY LECTURES—Elisa Furay

 finger becomes nonfunctional
 commonly affects finger 4 or 5
o Plantar – usually unilateral
o Penile (PEYRONIE DISEASE)
o All of these cause abnormal contractures
 Fingers curl, penis curves and interferes with reproduction
 DEEP FIBROMATOSIS (DESMOID TUMOR)
o Overgrowth of fibrous tissue
o Extra-abdominal: m=w, shoulder, chest, back, thigh
o Abdominal: ant. Abd. Wall during or after pregnancy
o Intra-abdominal: mesentery or pelvic wall in patients w/ Gardner syndrome (familial adenomatous polyposis)
o Surgical removal is curative
o These are commonly bx to see if they are malignant
 FIBROSARCOMA
o malignant, rare but most common are retroperitoneal, thigh, knee
o Fibrosarcoma
 Histology--herringbone pattern
 Nuclei are very very compact—density of nuclei points toward malignancy
o Look for lots of mitotic figures to differentiate between this and fibromatosis
o Low grade are hard to tell if malignant or not; high grade is easy
 FIBROHISTIOCYTIC TUMORS
o DERMATOFIBROMA (BENIGN FIBROUS HISTIOCYTOMA)—common!
 Common, small painless mass, dermis or subcutis
 Usually freely movable
 Several variants
 Removed usually for cosmetic purposes
o MALIGNANT FIBROUS HISTIOCYTOMA (MFH)
 Now classified as a FIBROSARCOMA, usually pleomorphic
 Deep lesions –more likely to be a sarcoma
 Common, malignant, several variants, very aggressive (except for
angiomatoid variant which occurs in young adults—much less aggressive)
 Muscles of proximal extremities or retroperitoneal
 MFH – Has storiform pattern (cartwheel spokes)—dense nuclei !!!!
SKELETAL MUSCLE TUMORS
 RHABDOMYOSARCOMA – malignant, aggressive
o The most common soft tissue sarcoma in kids, <20yrs but overall its not very common
o Look for Rhabdomyoblast
o Most common genetic abnormality t(2;13) (PAX2-FKHR fusion)
o EMBRYONAL TYPE—clinical dx
 Rare, but most common in kids <5yrs
 Polypoid mass protruding from vagina (SARCOMA BOTRYOIDES)—looks
like a cluster of grapes
 Or mass in nose, ear, orbit
o ALVEOLAR TYPE
 Most common teens, deep muscles of extremities (deep= more likely to be malignant)

21
BONE PATHOLOGY LECTURES—Elisa Furay
o
PLEOMORPHIC TYPE
 Adults, deep soft tissues (deep= more likely to be malignant)
SMOOTH MUSCLE TUMORS
 LEIOMYOMA --#1 benign SM tumor of the uterus
o Benign, uterus (25% of all women), also skin, 1-2 cm
o Multiple skin lesions may be associated with renal cell carcinoma
 LEIOMYOSARCOMA of the uterus–not very common
o Adults, W>M
o Skin or deep tissue of extremities and retroperitoneum; (deep= more likely to be malignant)
 SYNOVIAL SARCOMA—MISNOMER—most of these do not occur in joint spaces!!
o Most deep soft tissues near large joints (but most are not in joint space)
o Very Malignant, highly aggressive
o Biphasic – classic (also, monophasic)
 Spindle cells—like we see in most sarcomas
 Epithelial cells—they almost look like glands sometimes (to tell these two apart—
positive keratin (commonly we see keratin + in carcinomas) & EMA: epithelial membrane antigens)
o Characteristic genetic abnormality t(x;18)
22