Bone (nontumor and tumor)

The 206 bones in the body can be classified by shape (long bones-femur; flat bones-pelvis or short tubular bones-hands/feet). They can also be classified as axial (vertebrae and girdles) or appendicular, or based on their embryological origin (endochondral-formed via an intermediate cartilage model, or intramembranous-formed directly from mesenchyme without an intermediate cartilage model)

Parts of a long bones: diaphysis (shaft), physis (growth plate), epiphysis (ends of bone, partially covered by articular cartilage), metaphysis (junction of diaphysis and epiphysis, most common site of primary bone tumors)

Cross section: periosteum, cortex (composed of cortical bone or compact bone), medullary space (composed of cancellous or spongy bone)

Blood supply: diaphysis: a nutrient artery enters medullary canal at center of diaphysis, divides and supplies entire diaphysis; also contributions from vessels within the Volkmann / Haversian system;

epiphyses: supplied by medullary arteries; sometimes from the epiphysis along additional vessels that traverse the joint

metaphysis: supplied by vessels within the medulla that loop back

Vascular channels: 2 types in compact bone, either haversian (longitudinal) canals or transverse/oblique (Volkmann’s canals)

Drawings: haversian canals

Bone composition: 35% organic (cells, proteins), 65% calcium hydroxyapatite (contains 99% of body's calcium, 85% of phosphorus, 65% of sodium, also magnesium)

Hydroxyapatite crystal is formed via phase transition; 12 day lag between matrix deposition and mineralization

Collagen resists tension, hydroxyapatite and proteoglycans in cartilage resist compression

Thicker cortex in middle of long bones resists bending; cancellous bone at ends of long bones resists compression

Drawings of bones:

skeleton with major bones labeled

femur: femoral head; anterior surface; posterior surface; distal femur; upper femur longitudinal midsection

finger: developing finger (image)

humerus: anterior view; posterior view; longitudinal section of humerus head

patella: anterior surface; posterior surface

pelvis: male; female

radius and ulna: anterior surface; posterior surface

tibia: proximal; tibia and fibula-anterior surface; posterior surface

Normal histology

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Bone: mineralized osteoid; either lamellar bone or woven bone (see below)

Micro images: cortical bone #1; #2; #3 (various); cancellous (spongy) bone; cancellous bone-various; bone and cartilage-various

Drawings: cortical bone #1; #2

Virtual slides: normal rib

Cement line: junction between original resorbed surface and new bone; sharp and basophilic with routine staining; also called reversal front activate osteoclastic surface

Lamellar bone: layered bone with concentric parallel lamellae; gradually replaces woven bone; normal type of bone found in adult skeleton; stronger than woven bone

Micro images: cross section #1; #2; polarized light

Osteoblasts: arise from marrow mesenchymal cells; when active, are plump and present on bone surface; eventually are encased within the collagen they produce and get flattened (see osteocytes below); have a perinuclear halo resembling plasma cells in cytologic preparations due to prominent Golgi zone; synthesize and transport collagenous matrix, initiate and regulate mineralization, control removal of bone via osteoclasts, express Vitamin D receptors; activity is promoted by physical activity (Wolf’s law); express parathormone receptors (mediates the activation of osteoclasts)

Osteoblasts control osteoclast activity via parathyroid hormone (parathormone), PHRP (Parathyroid hormone related protein), IL-1, TNF alpha; digestion of bone by osteoclasts releases cytokines and growth factors for osteoblasts

Express parathormone receptors (mediate the activation of osteoclasts)

Micro images: osteoblasts and osteoclasts; osteoblasts

Positive stains: alkaline phosphatase, estrogen receptors, parathyroid hormone

EM: resemble fibroblasts due to well developed rough endoplasmic reticulum and Golgi

Osteoclasts: cause bone resorption due primarily to remodeling and not calcium homeostasis; derived from monocyte fusion; multinucleated (2-12 nuclei) giant cells, associated with bone surface; use their ruffled borders (with villous extensions) to bind to matrix adhesion proteins, produce resorption pits/bays (shallow concavities) called Howship’s lacunae; plasma membrane forms a seal with bone; osteoclast acidifies extracellular area, which solubilizes the mineral and releases enzymes which dissolve the matrix; contains tartrate-resistant acid phosphatase

Micro images: osteoclasts #1; #2; #3

EM: numerous mitochondria, rare lysosomes; ruffled edge in area of cell membrane is associated with bone resorption

Osteocytes: the mature form of osteoblasts after they are surrounded by matrix; most numerous cell in bone; communicate with each other via osteocytic cell processes with gap junctions that travel through canaliculi (bone tunnels); may maintain serum calcium and phosphorus levels; can translate mechanical forces into biologic activity

Drawings: osteocytes

Micro images: osteocyte #1; #2; #3

EM images: cell process extending from an osteocyte through a canaliculus in the bone matrix

Osteoid: non mineralized bone always present at the formative surface of bone, but usually a very thin layer; resembles hyalinized collagen; composed of type I collagen (90%), acid mucopolysaccharides, noncollagen proteins including bone morphogenetic protein (may initiate bone formation), adhesion proteins (fibronectin, osteopontin, thrombospondin), calcium binding proteins (osteonectin, bone sialoprotein), mineralization proteins (osteocalcin), enzymes (collagenase, alkaline phosphatase); increased if increased bone formation (fracture callus, Paget’s disease, hyperparathyroidism), if inadequate mineralization or if toxic / inhibitory structures present in bone (aluminum, iron, fluoride)

Osteon: dense compact cylindrical unit underlying cortical bone; formed in childhood by ingrowth of periosteal vessels that follow a cutting cone of osteoclasts through the cortex; tunnel is haversian canal, is filled in partially with osteoblast created bone matrix

Micro images: haversian systems #1; #2; #3

Osteoprogenitor cells: mesenchymal stem cells near bony surfaces, can produce osteoblasts

Periosteum: outer fibrous layer and inner cellular (cambium) layer of osteoprogenitor cells (fibroblasts and osteoclasts); contains nerve fibers, Sharpey’s fibers/perforating collagenous fibers that penetrate outer layer of bone; may become detached from bone due to benign or malignant processes, causing new bone formation between elevated periosteum and bone and producing radiologic changes

Drawings: perforating fibers

Micro images: perforating fibers

Tetracycline: binds to actively mineralizing surfaces and fluoresces in ultraviolet light

Micro images: double tetracycline labeling of bone; normal iliac crest with tetracycline labeling

Woven bone: immature (streamer) bone due to haphazard (random) arrangement of collagen fibers, found during growth, healing, repair, infections or in some neoplasms; highlighted with polarized light or reticulin stain; abnormal in adults and associated with fibrous dysplasia or other causes of accelerated bone turnover

Micro images: developing bone; under polarized light

Bone Histomorphometry: measuring bone formation (% active osteoblastic surface, % osteoid surface, % mineralizing surface), bone mineralization (osteoid volume, mineral apposition rate), bone resorption (% total eroded surface, % active osteoclastic surface). Bone resorption is identified by numerous osteoclasts in Howship’s lacunae and in bone margins

Basic multicellular unit: to fulfill the biological requirements, bone needs to continuously renew itself, which it does at multiple sites called basic multicellular units (BMUs). Cyclic events involving matrix resorption and formation occur in these BMUs, i.e., activation of osteoprogenitor cells to proliferate and differentiate (A), resorption of bone matrix by osteoclasts (R), quiescent phase for reversing resorption to formation (R) and the formation of bone matrix by osteoblasts (F). The cellular activities are coupled within each BMU’s remodeling cycle, i.e., A-R-FBone is modeled to reach peak bone mass; then 5-10% is remodeled per year in these BMUs

Bone growth

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Growth plate is responsible for interstitial growth of bone (growth within the bone itself)

Bone growth involves resting chondrocytes as they proliferate, mature, orient in a column and degenerate, leaving newly calcified columns for osteoblasts to migrate into

Abnormalities in chondrocyte function disrupt this sequence and produce abnormally short and misshapen bones (example: achondroplasia [short stature], may be due to mutation in fibroblast growth factor)

Chondrocytes of the growth plate behave differently than chondrocytes of articular cartilage; are regulated by Indian hedgehog gene

Limb patterning controls bone development; sonic hedgehog and homeobox genes organize segmentation, anterior-posterior, medial, lateral and longitudional limb patterning during fetal development; gene abnormalities cause extra or missing digits, short or long limbs or congenital amputations

Bone production is identified by well-stained small spicules of bone with lacunar cells present and osteoblasts on bone margins

Bones are classified based on embryologic development as endochondral (formed by ossification of cartilaginous anlage, such as long bones) and membranous (formed from connective tissue, such as skull)

Endochondral bone formation

Primitive mesenchyme differentiates into cartilaginous anlage of future bone, which is degraded, mineralized and removed by osteoclast like cells; allows ingrowth of blood vessels and osteoprogenitor cells; occurs at base of articular cartilage, leading to increase in bone length and diameter

Micro images: various images

Epiphyseal growth plate: site of endochondral bone formation; area between centers of ossification; chondrocytes here have zones of proliferation, hypertrophy, and mineralization, then primary spongiosa; regulated by PHRP; when bone reaches adult length, epiphysis closes by becoming ossified; closed epiphysis is actually more easily invaded by osteosarcoma than open epiphysis with cartilaginous barrier

Micro images: growth plate; epiphyseal plate #1; #2

Periosteum: produces osteoblasts, which deposit beginnings of cortex (primary center of ossification); similar process occurs at epiphysis (secondary center of ossification)

Intramembranous bone formation

Cranium, clavicles

Formed from mesenchyme, which differentiates into fibrous tissue containing osteoblasts without an intervening cartilaginous stage

Micro images: various images #1; #2

Biopsy

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Frozen sections are useful to document adequacy, to allow quicker definitive treatment (if diagnosis can be made), for assessment of margins, to obtain culture for possible infectious lesions, to differentiate between aseptic and infectious loosing of implants

FNA: helpful for metastatic disease, recurrent tumor or unsuspected malignancy; not helpful for cartilaginous lesions, cystic lesions or obviously benign lesions that require surgical management (chondromyxoid fibroma, giant cell tumor)

References: Archives 2001;125:1463

Developmental abnormalities

Achondrogenesis

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Type I: rare, lethal; extreme limb shortening, marked discrepancy between head and trunk size, severely delayed ossification

Type IA: autosomal recessive; rib fractures, no ossification of vertebral pedicles; chondrocytes have inclusion bodies, but cartilage matrix is near normal

Type IB: distinctly abnormal cartilage matrix with rarefaction of ground substance and peculiar ringlike pericellular arrangement of collagen fibers

Achondrogenesis type IB is lethal osteochondrodysplasia due to mutations in transporter gene for diastrophic dysplasia sulfate

Genetic defect causes complex derangement in cartilage matrix assembly; impaired decorin deposition causes lack of development of normal interterritorial matrix, preventing necessary structural substrate for proper endochondral bone formation and severe skeletal phenotype

Xray images: short and abnormal long bones in fetus with type IB

Case report of type IB in child of consanguineous (first cousins) parents (Archives 2001;125:1375)

Gross images: 19 week fetus; 21 week fetus

Micro: abnormal endochondral bone formation with curved cartilage-bone junction at growth plates, periosteal bony spurs; spongelike cartilage matrix due to lack of interterritorial matrix; epiphyseal cartilage composed of multiple discrete units of chondrocytes encased in territorial capsule and separated from each other by clefts containing fibroblast-like cells; mosaic of chondrocyte units (chondrons) due to breakdown of usual matrix continuity of epiphyseal cartilage

Micro images: abnormal cartilage bone junction, abnormal matrix

References: more information

Achondroplastic dwarfism

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Major cause of dwarfism

Reduction in chondrocytes at growth plate is due to defect in fibroblastic growth factor receptor 3 gene (FGFR3)

FGFR3 inhibits cartilage proliferation, and is constitutively active in these patients

Autosomal dominant, but 80% of cases are new mutations

Clinical: short proximal extremities, normal trunk, enlarged head (bulging forehead, depression of root of nose)

Normal intramembranous bone formation, so bone cortices seem thickened compared to short bone length

Normal life, IQ, reproductive status

Micro: narrow/disorganized zones of proliferation and hypertrophy in growth plates; chondrocytes in clusters, not columns; base of growth plate has prematurely deposited struts of bone which seal the plate

Fibrodysplasia ossificans progressiva

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Rare autosomal dominant disorder with congenital malformation of the great toes and progressive heterotopic ossification in defined anatomic patterns

Early preosseous lesions resemble aggressive juvenile fibromatosis

Pathophysiology: spontaneous and post-traumatic flareups heralded by intense connective tissue edema with perivascular lymphocytic infiltration into skeletal muscle, angiogenic fibroproliferative lesions that spread along muscle planes and evolve through endochondral ossification to form mature lamellar bone; leads to immobilization of joints making movement impossible, later death due to starvation (ankylosis of jaw) or from restrictive disease of chest wall

May be mediated by mast cells (Hum Path 2001;32:842)

Treatment: none; surgical trauma induces further bone formation

Case reports: 7 year old girl with 13 cm thoracic tumor (with images)

Gross/clinical images: FOP skeleton

References: Hum Path 1997;28:339; UPOJ (with clinical images)

Malformations

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Failure of development of a bone (phalanx, rib, clavicle), supernumerary ribs or digits, syndactyly (fusion of adjacent digits) or arachnodactylism (long, spider-like digits)

Craniorachischisis: failure of closure of spinal column and skull; produces meningomyelocoele or meningoencephalocoele

Scoliosis

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Abnormal curvature of vertebral column

Kyphoscoliosis: lateral and posterior curvatures

Syndromes

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Maffuci’s syndrome: multiple enchondromas and soft tissue hemangiomas; also ovarian carcinoma, brain gliomas

Reference: AJSP 1995;19:1029 (with spindle cell hemangioendotheliomas)

McCune-Albright syndrome: polyostotic fibrous dysplasia, cafe-au-lait skin pigmentation, endocrine abnormalities; almost exclusively women; also see below

Multiple hereditary exostosis: autosomal dominant disorder of multiple osteochondromas diagnosed during childhood; bowing of underlying bones, wide metaphyses; evolution to chondrosarcoma

Multiple osteomas: associated with Gardner syndrome (autosomal dominant, epidermal cysts, fibromatosis, pigmented ocular fundus lesions, multiple colorectal adenomas with carcinoma at ages 35-40 years)

Ollier’s disease: multiple enchondromas, often ovarian sex-cord tumors

Sapho syndrome: see below

Thanatophoric dwarfism

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Also called thanatophoric dysplasia

“Thanato”: denoting death

Lethal form of dwarfism, occurs in 1 per 20,000 live births

Type I: short, curved femur; II: straighter femur with cloverleaf skull

Mutation in FGFR3 gene, but different from that in achondroplastic dwarfism

Clinical: micromelia (short limbs), frontal bossing with relative macrocephaly (abnormally large and hyperconvoluted temporal lobes), small chest, bell shaped abdomen

Die at birth or shortly thereafter from respiratory insufficiency due to small thoracic cavity

Case reports: variant in 18 week male fetus (Archives 1993;117:322)

Micro: diminished proliferation of chondrocytes and poor columnization of zone of proliferation

References: more information

Osteomyelitis

Osteomyelitis-general

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Infection of bone (osteitis) or bone marrow space (myelitis)

Usually pyogenic, fungal or tubercular

HIV+ patients may be infection by unusual organisms

May resemble neoplasms, particularly after antibiotic treatment

Severe osteomyelitis is not associated with grade IV sacral decubitus ulcers in non-septic patients (Archives 2003;127:1599)

May cause secondary AA amyloidosis

Xrays: permeative, destructive lesion with periosteal new bone formation; chronic osteomyelitis may produce focal destruction or focal abscess

Micro images: various images; mild chronic osteomyelitis-figure 3

References: more information

Amebic osteomyelitis

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Case reports: infection of mandibular bone graft by Acanthamoeba castellanii (Hum Path 1981;12:573)

Bacterial osteomyelitis (acute)

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Rare due to antibiotics

Usually pyogenic

Hematogenous spread: most common cause; usually long tubular bones of children; usually metaphyseal in children and adults, although involvement of flat bones is more common in adults

Direct extension: less common, may be associated with trauma or rarely iatrogenic implantation of infectious material

In elderly, may affect vertebral column; associated with systemic urinary tract infection, diabetes (affects small bones in feet); in younger adults, associated with immunodeficiency or intravenous drug abuse

50% of cases are due to unknown bacteria

80% of cases with known organisms are due to Staphylococcus aureus, which produces receptors to bone matrix components

Sickle cell patients may have infections by Salmonella choleraesuis, S. paratyphi B and S. typhimurium

Neonates are prone to Treponema (periostitis), gram negative rods, Group B Streptococci, Hemophilus influenzae and Listeria species

Other known organisms are E. coli, Pseudomonas and Klebsiella in intravenous drug addicts (affecting clavicle, sternoclavicular joint, spine or pelvis), Pseudomonas and mixed bacteria in post-traumatic cases

Rarely associated with malakoplakia; cases with draining sinus are rarely associated with malignancy (squamous cell carcinoma)

Designated as acute, subacute or chronic, based on clinical duration of disease, not inflammatory cells present; chronic disease related to delayed diagnosis, inadequate antibiotics or debridement of dead bone, extensive bone necrosis, weakened host defenses; may produce tuberculoid granules with variable central necrosis (AJSP 1985;9:531)

Xrays: may be negative early; three phase bone scans (with Gallium or Indium scanning), MRI or other studies may be necessary; late Xrays show prominent periosteal reaction resembling neoplasm

Pathophysiology: bacteria proliferate in bone, kill osteocytes, cause necrosis, spread along haversian system or medullary cavity within shaft and to periosteum; subperiosteal abscesses impair blood supply, which causes more necrosis and often draining sinuses

Sites: in children, at areas of rapid growth or increased risk of trauma (distal and proximal femur, proximal tibia and humerus, distal radius)

Sequestrum: dead piece of bone; gradually separated from living bone by granulation tissue; may pass through sinus tract; is avascular and dense on Xray

Involucrum: sleeve of living tissue created by periosteum which is deposited around sequestrum

Sclerosing osteomyelitis of Garre': in jaw, associated with extensive new bone formation that obscures underlying osseous structure; also called periostitis ossificans

Xray: lytic bone destruction surrounded by sclerosis; chronic disease may resemble malignant bone tumor due to destructive and regenerative bone changes

Treatment: surgery to remove dead bone (sequestrum), antibiotics (levels in bone may be lower than serum - often Cloxacillin, Nafcillin, third generation cephalosporins, guided by culture and sensitivity reports and drug’s minimum inhibitory concentration)

Complications: may develop sinus tract lined by squamous epithelium that forms large epidermal inclusion cyst within bone; rarely transforms to well differentiated squamous cell carcinoma with excellent prognosis

Case reports: 17 month old immunocompetent black girl with disseminated Mycobacterium avium disease (Hum Path 1980;11:476)

Gross: varies with patient age; infants under age 1 year often have permanent joint and epiphyseal damage sparing metaphysis and diaphysis; children 1 year and older have opposite changes (sparing of joint, damage to metaphysis); adults have joint infection and extensive bone involvement; acute disease has pus tracking through bone, periosteal elevation and shell of reactive periosteal bone around necrotic center; neonates may have considerable subperiosteal spread; chronic disease is accompanied by prominent periosteal bone formation

Micro: neutrophils (may persist for weeks), lymphocytes and plasma cells with bone necrosis, reactive new bone formation, capillary proliferation and fibrosis; subtypes include plasma cell osteomyelitis and xanthogranulomatous osteomyelitis (abundant foamy macrophages); bone marrow space replaced by inflammatory tissue

Micro images: lactobacillus sepsis and osteomyelitis; from extension of soft tissue infection

Virtual slides: osteomyelitis

Chronic osteomyelitis

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Develops in 15-30%

Due to lack of treatment, inadequate antibiotic treatment or incomplete surgical debridement of necrotic bone

Brodie abscess: small intraosseous abscess in cortex, walled off by reactive bone with no periosteal reaction; cavity may contain infectious organisms or be sterile; may have late recrudescence

Chronic multifocal osteomyelitis

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Recurrent variant of osteomyelitis in children and young adults of unknown origin

Low grade fever, local swelling and pain; periods of exacerbation and remission over years; negative cultures

Sites: metaphyses of tubular bones, clavicle; multiple asymptomatic sites

Associated skin lesion - pustulosis palmoplantaris

Xrays images: images and text

Treatment: non steroidal anti-inflammatory drugs, not antibiotics (since cultures are negative)

Micro: neutrophilic inflammation early; late fibrosis of marrow with chronic inflammatory infiltrate; often plasma cell predominance, fragments of necrotic bone with multinucleated giant cells

DD: rheumatic disease, bacterial osteomyelitis, malignancy

References: Hum Path 1999;30:59

Echinococcus osteomyelitis

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Rare; due to infection by larva of Echinococcus tapeworms; usually E. granulosus, also E. multilocularis and E. oligarthrus

Life cycle: tapeworm’s gravid segment breaks off from implantation site in small intestine of dogs, coyotes and wolves (in North America), disintegrates in colon releasing eggs which pass in feces; eggs are ingested by sheep, goats, deer, moose, humans; hatch in small intestine, disseminate via blood; at implantation site, larva secrete hyaline membrane that differentiates into outer acellular laminated structure and inner germinal layer which produces protoscolices; cysts may be ingested by dogs

Cysts may rupture and produce fever, urticaria, anaphylactic shock, dissemination of infection, pathologic fractures if in bone

Sites: 60% liver, 20% lungs, 3% brain, 1% bones (50% in lower vertebrae)

Xray: extensive complex cystic changes

Treatment: excision, albendazole or praziquantel

Case reports: 86 year old woman with draining sinus in tibia (Archives 2002;126:1551)

Gross: ragged surface, multiple cavities filled with red-brown necrotic material and yellow-white cystlike structures

Micro: acellular laminated membranes with germinal layer; rare degenerating scolices and hooklets; intense acute and chronic inflammatory infiltrate may erode bone

Gross/micro images: H&E, PAS, GMS

Cytology: hydatid sand (free daughter cysts, free scolices)

Positive stains: PAS and GMS (membranes)

Fungal osteomyelitis

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Case reports: 41 year old man with injury to lumbar/cervical region and Phialemonium obovatum infection (Archives 1993;117:841), Scedosporium apiospermum (Pseudallescheria boydii) osteomyelitis (Hum Path 1998;29:1266)

Syphilitic osteomyelitis

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Caused by Treponema pallidum and T. pertenue (yaws)

Bone involvement more common in congenital syphilis; appears at 5th month of gestation in areas of active endochondral ossification (osteochondritis) and periosteum

Acquired syphilis involves bone in tertiary phase, usually nose, palate, skull, tibia, vertebrae, hands/feet

Xray: reactive periosteal bone deposition (“saber shin” of tibia)

Gross: bone destruction and production; necrotic, well-defined bone defects of cortex and periosteum surrounded by sclerotic bone

Micro: edematous granulation tissue, plasma cells, granulomas, necrotic bone and new bone production

Positive stains: silver stains

Tuberculous osteomyelitis

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Usually young adults or children

Sites: vertebrae, hip, knee, ankle, elbow, wrist; usually involves synovium, epiphysis or metaphysis

In US, due to immigrants and immunosuppression

1-3% with tuberculosis have bone infection; usually from focus of acute visceral disease, direct extension or lymphatics

Rarely causes inguinal mass with fluctuant psoas abscess

In AIDS patients, bone infection usually multifocal

Advanced cases are associated with cutaneous sinuses, which cause secondary bacterial infections

Associated with fusion of joint, denudation of cartilage, sequestra of medullary cavity

Can detect in synovial fluid by culture and examination

Pott’s disease: involvement of spine (thoracic/lumbar); extensive necrosis of intervertebral discs with extension into soft tissue; may produce significant deformities or neurologic deficits; difficult to treat

DD: foreign body granuloma post-surgery (AJSP 1997;21:563)

Xanthogranulomatous osteomyelitis

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Case reports: two cases with prominent foamy macrophages, neutrophils, plasma cells and fibrin (Archives 1984;108:973)

Non-neoplastic or metabolic disease

Aseptic bone necrosis

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Also called avascular bone necrosis, osteonecrosis

Common; affects almost every bone, including tibial tuberosity (Osgood-Schlatter’s disease), proximal femoral epiphysis (Legg-Calve’-Perthes disease)

>50% of cases are multifocal

Causes 10% of joint replacements

Significant cause of arthritis due to fractures through articular surface of hip, knee and other major joints; also due to collapse of necrotic bone segment with resulting reparative granulomas that destroy bone at margin of infarct, may cause detachment of cartilage and secondary degenerative joint disease

Causes: fracture, dislocation, corticosteroids, nitrogen bubbles in dysbarism, vasculitis, radiation, vascular compression, venous hypertension, thrombosis (sickle cell disease), Gaucher’s disease, alcoholism

Pathophysiology: initially necrosis of epiphysis, with variable necrosis of adjacent cartilage; dead bone is resorped by “creeping substitution” over months/years; new bone is soft, may flatten and cause degenerative joint disease

Creeping substitution: dead trabeculae that are not resorbed by osteoclasts serve as scaffolds for deposition of new living bone

Gross: intact articular cartilage except at edge of necrotic area, which exhibits cracking and folding; necrotic area in cross section is yellow, opaque, chalky with hyperemic fibrous tissue at margin; adjacent bone may be thickened; late changes are breaks in smooth contour of femoral head, destruction of articular cartilage, loose bodies and marginal osteophytes (changes of degenerative joint disease)

Gross images: femoral head #1, #2

Micro: dead trabeculae (empty lacunae) stain deeper blue than nonnecrotic bone; have ragged margins with osteoclasts on one side and osteoblasts on the other; lacunae may be enlarged and cystic or normal size with pyknotic nuclei; calcium salts due to necrotic adipocytes; marrow has fat necrosis and calcium deposits (marrow is a more sensitive indicator of necrosis than bone)

Micro images: osteonecrosis due to metastatic melanoma (melanoma cells are eosinophilic ghost cells)

Black bone

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Case reports: 42 year old white woman with black vertebrae after chronic minocycline treatment (Archives 1991;115:939)

Black cartilage

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Due to levodopa or methyldopa

Pigment occurs in rib cartilage, rarely in intervertebral disks

Harmless but irreversible

References: Archives 1994;118:531

Cartilaginous rest

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Case report in 6 year old boy in neck (Archives 2003;127:e438)

Micro images: cartilage with adjacent hair follicles

Fracture

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See also fracture callus (below)

Break in continuity of bone, often with severance of blood vessels, periosteum or muscle

Complete (bone broken completely) vs. incomplete, closed (intact overlying tissue, also called simple) vs. compound (fracture site communicates with skin surface), displaced (ends of bone not aligned), comminuted (many fragments), pathologic (due to diseased bone) or traumatic

Fractures often due to weakened bone (osteoporosis, tumor, infection) or falls in elderly and children

Types of fractures: spiral configuration through cortex is typical; transverse fractures (like breaking chalk) are associated with Paget’s disease, osteopetrosis or other severe bone disturbances; stress or insufficiency fractures-see below; avulsion fractures are associated with trauma at ligamentous and tendinous insertions, often in pelvis or distal thigh

Osgood-Schlatter’s disease: avulsion fractures of tibial tubercle causing fragmentation, in children

Healing process: hematoma forms between two ends of bone, creates fibrin mesh which seals fracture site, young capillaries enter hematoma, dead bone reabsorption begins at 3 days, periosteal inner layer promotes intramembranous bone growth on each side of fracture, which meets at fracture site to form a primary callus, which anchors ends but doesn’t support weight bearing; this is resorbed and replaced by secondary callus, composed of mature lamellar bone; new bone is laid down along lines of stress

In children, marked bone remodeling occurs, even with gross deformities or shortening of a long bone; open reduction and internal fixation of fractures is usually not needed

Movement along fracture line creates lining of synovial cells and pseudoarthritis; soft tissue must be removed and bone stabilized to promote healing

Fractures may not heal due to improper immobilization, devascularization of bone fragments, persistent infection or interposition of soft tissue between ends of bone

Primary callus: exuberant cartilage and disorderly membranous bone may resemble osteosarcoma; increased callus is present in unstable areas

Noncorrosive nails are isolated from bone substance by fibrous tissue; do not elicit a foreign body giant cell reaction

Pseudoarthrosis: false joint developing after chronic nonunion of a fracture

Xray images: fractures in children

Case report: sarcoma with leukemoid reaction developing 35 years after uncomplicated fracture (Archives 2003;127:e186)

Micro: varies with type of injury; a few days - acute tissue damage and hemorrhage, necrotic bone [empty lacunae, poorly staining bone matrix] at fracture, may be more extensive in patella, femoral neck, carpal scaphoid; 1-2 weeks - hypercellular, hypervascular tissue, often with brisk mitotic activity, resembles sarcoma but without atypia or atypical mitotic figures; reduced callus in midshaft of tibia or other poorly vascularized areas; callus reduced if rigid internal or external surgical fixation

Micro images: remodeling in metaphysis

Stress fractures

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Also called fatigue or insufficiency fractures

Due to physical activity (ballet dancing, long distance running, military training) or metabolic bone disease

Usually lower limbs, especially femoral neck in those with metabolic disease, tibial shaft in joggers or dancers, second or third metatarsal bones in military trainees

May require serial parallel cuts to find evidence of stress fractures

Treatment of subchondral insufficiency fracture: immobilization, no NSAIDs

Gross: white-gray with linear notched zone paralleling subchondral bone end plate

Micro: zonal with necrotic, reparative (fracture callus, granulation tissue) and viable tissue

DD: aseptic bone necrosis (younger patients, wedge shaped infarct, total necrosis of bone trabeculae and bone marrow)

References: AJSP 2000;24:464, more information

Subchondral insufficiency fractures of femoral head

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Relatively common in elderly osteoporotic women or renal transplant recipients

Usually resolves after conservative therapy, without surgery

May cause acute onset of hip pain

Xrays: bone marrow edema by MRI

Micro: fracture callus and granulation tissue growing along both edges of fracture line

Giant cystic arachnoid granulations

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Arachnoid granulations are pathway for drainage of cerebrospinal fluid from subarachnoid space into dural venous sinus system

Typically produce small, well-defined indentations of inner table of skull

Giant cystic arachnoid granulations may present as destructive-appearing osteolytic lesions, with CSF-containing cysts

References: Hum Path 1993;24:438

Glomus coccygeum

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Glomus bodies normally are present near coccyx at caudal end of spinal column; may be misidentified during rectal resection for rectal or uterine carcinoma, treatment of pressure sores or trauma

Not a pathologic finding, but an unusual “normal” finding

Gross: small nodule in soft tissue ventral to tip of coccyx

Micro: 1-4 cm, sharply circumscribed glomus bodies composed of glomus cells without atypia or pleomorphism surrounding vascular channels with fibrous stroma containing nerve fibers; cells are small with moderate cytoplasm and finely dispersed chromatin; no infiltration or expansile growth

Micro images: H&E and stains

Positive stains: vimentin, smooth muscle actin, neuron specific enolase

Negative stains (glomus cells): S100, desmin, CD31, Factor VIII related antigen

EM: small cells with bundles of actin filaments

EM images: smooth muscle cells with actin filaments

References: Archives 1999;123:905, AJSP 1990;14:922

Hyperostosis cranii ex vacuo

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Also called thickened calvarium

May be due to intracranial hypotension associated with chronic shunting, as skull lacks the outward pressure needed to expand

Case reports: 23 year old woman with long standing ventriculoperitoneal shunt due to shaken baby syndrome (Archives 2003;127:94)

Gross: circumferentially thickened skull, particularly inner table, involvement calvarium and base

Gross/Xray images: thickened skull

Micro: increased cancellous space with normal trabecular bone

Micro images: figure 2B-increased cancellous space

DD of thickened calvarium: Paget’s disease, fibrous dysplasia, thalassemia, hyperostosis frontalis interna (inner table has varying thickness of lobulated bone)

References: Hum Path 1994;25:545

Hyperparathyroidism

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Only 25% have bone disease, usually bone pain

Presents in young to middle-aged adults with recurring kidney stones, peptic ulcer, nausea, vomiting, weakness, headaches

Affects entire skeleton, cortical bone more than medullary bone

Usually detected early, so osteitis fibrosa cystica (severe changes, also called Recklinghausen’s disease) are rare

Skeletal abnormalities with secondary hyperparathyroidism are typically mild

Causes: parathyroid adenoma of one gland is most common; rarely carcinoma or hyperplasia

Xray: diffuse osteopenia; specific pattern for fingers of cortical cutting cones (erosion of tufts of phalanges, subperiosteal cortical resorption, especially on radial side)

Laboratory: marked hypercalcemia and hypophosphatemia

Gross: thin bone cortices, loss of lamina dura around teeth; rarely associated with brown tumor of hyperparathyroidism

Micro: increased osteoclastic activity with tunneling of osteoclasts into bone matrix (dissecting resorption); also marked increase in bone formation and peritrabecular fibrosis

DD: myelofibrosis (fibrous tissue diffusely throughout marrow, not around trabeculae), acute phase of Paget’s disease (osteoclasts don’t tunnel, have more nuclei, different clinical presentation and laboratory findings)

Hypophosphatasia

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Rare genetic disease due to disturbance in synthesis of alkaline phosphatase

Different disorder than hypophosphatemia

Autosomal recessive form: severe disease in infants, rapidly fatal

Autosomal dominant form: may not be identified until adulthood, may be asymptomatic, although associated with short stature, deformity of extremities, rickets-like disorder

Laboratory: reduced levels of alkaline phosphatase in blood, bone, intestines, liver, kidney; normal serum calcium and phosphorus

Micro: infants - increased osteoid, irregular epiphyseal cartilage with lengthened chondrocyte columns; adults - osteomalacia with increased nonmineralized bone but reduced osteoblasts

Infarct

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Diaphysometaphyseal infarction: due to infection, vasculitis, sickle cell disease, pheochromocytoma, other vascular disease, Gaucher’s disease, pancreatitis, idiopathic, decompression sickness (historically)

Epiphysometaphyseal infarction: same as above, also fractures and dislocations, corticosteroids for collagen vascular diseases, thromboembolic disease, systemic lupus erythematosus, rheumatoid arthritis, Langerhans cell histiocytosis, osteochondrosis

Medullary infarcts: patchy necrosis involving cancellous bone and marrow; cortex has collateral blood flow

Subchondral infarcts: wedge shaped; cartilage remains viable since nutrients are present in synovial fluid

Sites: femoral head or other convex articular surfaces (see aseptic bone necrosis above)

Xray: no changes until third week; then reduced density in areas of dead bone and increased density due to new bone formation; changes appear irregular / mottled; thick, serpentine border

Xray images: ill defined sclerotic lesion within proximal tibial metaphysis #1; #2

Complications: large infarcts are rarely associated with osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma; usually adult males in femur / tibia; poor prognosis (Archives 1996;120:482)

Case reports: vertebral infarcts due to staph endocarditis (Hum Path 1982;13:631)

Gross: early (identifiable at autopsy) - elongated pale area with hyperemic border sharply demarcated from adjacent bones, radiologically normal

Micro: early - ghost marrow cells with pyknotic basophilic nucleated red blood cells; irregular cystic spaces due to fat necrosis, focal calcification, dead trabeculae; late - ingrowth of granulation tissue at periphery of lesion, “creeping substitution” of dead bone by layering of new bone on trabecular surfaces at periphery, rim of collagen forms around periphery, often with calcification

Note: osteocytes may be lost even in normal bone due to decalcification

DD: enchondroma (radiologically resembles infarct but lacks its sharp border, has diffuse calcification)

Metal toxicity

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Causes: aluminum (from antacids), iron, fluoride

Micro: increased osteoid, but well demarcated mineralization front and minimal osteoblasts

Positive stains: aurintricarboxylic acid highlights aluminum

Mucopolysaccharidoses

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Lysosomal storage diseases caused by deficiencies in enzymes degrading heparan sulfate, dermatan sulfate and keratan sulfate

Disorders affect hyaline cartilage since enzymes are produced by chondrocytes

Usually cause short stature, chest wall abnormalities, short bones

Case reports: 19 year old black man with lethal mucopolysaccharidosis VII due to beta-glucuronidase deficiency (Mod Path 1994;7:132)

Necrosis

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See aseptic bone necrosis, radiation necrosis

Micro: dead bone stains deeper blue than normal bone, no lacunar cells, margins of bone are ragged; may have osteoclasts on bone margins

Osteogenesis imperfecta

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Also called brittle bone disease

One of the most common congenital connective tissue matrix diseases

Disease of type I collagen due to mutations in genes coding for alpha 1-2 collagen chains, usually autosomal dominant

A type of osteoporosis with marked cortical thinning and attenuation of trabeculae, plus other collagen related signs/symptoms

Skeletal abnormalities may be mild (reduced amounts of normal collagen) or severe/lethal (abnormal polypeptide chains cannot form collagen triple helix); associated with short stature and increased fractures (hundreds of minor / major fractures during childhood, usually in lower limb, often involving growth plate fragmentation around knees)

Blue sclera: due to translucent sclera and visualization of choroid

Hearing loss: sensorineural defect and impeded conduction due to abnormalities of middle ear bones

Dental imperfections: small, misshapen, blue-yellow teeth, due to dentin deficiency

Type I: usually acquired mutation, autosomal dominant, normal lifespan with increased fractures during childhood but decreasing after puberty

Type II: usually autosomal recessive, uniformly fatal due to extraordinary bone fragility with multiple intrauterine fractures; unstable triple helix

Type III: autosomal dominant or recessive, growth retardation, but otherwise like type I

Type IV: autosomal dominant, short stature, but otherwise like type I

Xray: nodules of cartilage at growth plate resembling a bag of popcorn; marked swelling of distal femur

Gross: cartilaginous nodules due to fragmentation of growth plate

Micro: severe forms lack an organized trabecular pattern; crowded osteocytes within bone (due to reduced collagen synthesis); large areas of woven bone; less severe forms still have crowded osteocytes with thin lamellar bone

Osteopathia striata

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Also called Voorhoeve’s disease

Rare; benign, usually painless

Xray: longitudinal dense striations in affected bones

Osteopetrosis

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Also called marble bone disease, Albers-Schonberg’s disease

Rare, hereditary, diffuse and symmetric skeletal sclerosis (increased bone density) caused by osteoclast dysfunction

Bones have "stone-like" quality, but are abnormality brittle and fracture like chalk

One cause is deficiency of carbonic anhydrase II, required by osteoclasts and renal tubular cells to excrete hydrogen ion; deficiency causes failure to solubilize and resorb matrix and failure to acidify urine

Associated with anemia and hepatosplenomegaly since reduced bone marrow

Types: “malignant” - autosomal recessive; detected in utero due to fractures, anemia, hydrocephaly, cranial nerve problems, infections, hepatosplenomegaly; “benign” - autosomal dominant; repeated fractures, mild cranial nerve deficits, anemia

Xray: shortened long bones, loss of metaphyseal flare (Erlenmeyer flask deformity), uniform opacity of pelvis and peripheral bones alternating with normal bone causing a striped appearance; may cause spinal spondylolisthesis

Treatment: bone marrow transplant (reverses many skeletal abnormalities), human interferon gamma

Gross: bones are solid and heavy with no medullary canal, long ends are bulbous, small neural foramina compress nerves

Gross images: thickened bone

Micro: primarily woven bone since bone is not remodeled; central core of cartilage with dense and irregular bony trabeculae; often abundant osteoclasts; reduced marrow space

Micro images: bony trabeculae within marrow (arrow at osteoclast); giant cells in A: osteopetrosis; B: foreign body reactions; C: sarcoidosis; D: giant cell tumor; E: chondroblastoma

EM: osteoclasts lack ruffled borders, lack features of actively resorbing osteoclasts; surface of bone has massive smooth cartilaginous matrix with scattered rough areas of abnormal ossification, but devoid of orderly lamellar haversian system of normal bone; many irregular fracture lines present (Hum Path 1981;12:376)

DD: osteoblastic metastases, myelosclerosis, Paget’s disease

References: more information

Osteopoikilosis

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Usually autosomal dominant with high penetrance

No symptoms, no abnormal labs

Associated with osteosarcoma in affected bone, scleroderma, other conditions

Xray: multiple sclerotic, round lesions of variable size in cancellous bone near joint surfaces

Micro: resembles bone island

Micro images: image #1; #2; #3

References: more information #1; #2

Osteoporosis

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Reduction in bone mass due to increased bone porosity, which predisposes bones to fracture

Usually refers to postmenopausal or senile loss of bone severe enough to cause fractures

Affects entire skeleton due to metabolic bone disease, but may be localized due to limb disuse

Usually due to increased bone resorption, with normal levels of bone formation

Osteopenia: defined as radiologic decrease in density of skeleton

Primary causes: due to postmenopausal condition, older age (15 million cases in US) or idiopathic

Secondary causes (due to identifiable conditions): endocrine (hyperparathyroidism, thyroid disorders, hypogonadism, pituitary tumors, type I diabetes, Addison’s disease), neoplasms (myeloma, carcinomatosis), gastrointestinal disturbances (malnutrition, deficiency of vitamins C or D), drugs (corticosteroids, chemotherapy), osteogenesis imperfecta, immobilization, homocystinuria, anemia

Menopause: postmenopausal women may lose 2% of cortical bone and 9% of cancellous bone/year; osteoporosis affects women more than men because estrogen deficiency leads to increased osteoclast activity, and osteoblasts cannot keep pace

Age related changes: osteoblasts have reduced reproductive and biosynthetic potential in elderly

Immobilization: important cause because mechanical forces stimulate bone remodeling; zero gravity (astronauts), immobilization cause reduced skeletal mass; athletes have higher bone density; weight training is more effective than jogging in increasing skeletal mass

Genetics: variation in Vitamin D receptor type accounts for 75% of maximal peak bone mass achieved; Vitamin D intake and parathyroid hormone levels are not significant causes, although low calcium intake in women is an important cause

Other risk factors: Whites / Asians, smoking, alcohol abuse

Bone mass: peak bone mass occurs in young adults, based on physical activity, muscle strength, diet, hormones; subsequent remodeling causes small deficit in bone formation with each resorption/formation cycle, which causes bone loss of 0.7% per year

Sites: cancellous compartment of vertebral bone (with high surface area) affected first, causing loss of vertebral height in elderly, leading to dowager’s hump; also thinning of cortex; hip and wrist also affected

Xray: flattening of vertebral bodies, widening and swelling of intervertebral discs, fish-mouth appearance; usually thoracic and upper lumbar spine

Diagnosis: radiographic measurement of bone density, iliac crest biopsy

Prevention/treatment: calcium, Vitamin D and exercise to build up/maintain bone mass; biphosphonates (inhibit post-menopausal bone loss)

Gross: loss of cancellous bone, accentuation of vertical trabeculae in spine

Micro: thin trabeculae disconnected from each other; increase in osteoclastic activity (may be uneven) or increased percentage of surface with resorptive pitting

Micro images: osteoporosis

Transient osteoporosis

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Young patients with bone pain in legs and localized patchy osteopenia by Xray

Usually juxtaarticular

May spontaneously disappear or be migratory (transient migratory osteoporosis)

Micro: disconnected bone trabeculae; variable fat necrosis, increased osteoclastic activity, hypervascularity of marrow

Paget’s disease

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Also called osteitis deformans

“Collage of matrix madness”, with furious osteoclastic bone resorption (osteolytic phase), hectic bone formation (mixed osteoclastic/osteoblastic phase), burnt-out osteosclerotic stage (gain in bone mass, but bone is disordered)

90% are over age 55, rare before age 40

More common in whites in US, England (3% at autopsy), France, Austria, Germany, Australia, New Zealand (5-11%); rare in blacks, Scandinavia, China, Japan, Africa

May be due to slow virus infection of paramyxovirus, similar to subacute sclerosis leukoencephalitis (virus identified in osteoblasts)

Sites: 85% of presenting patients are polyostotic (pelvis, spine, skull), 15% monostotic (tibia, ilium, femur, skull, vertebrae, humerus); rare in hands/feet, ribs, fibula [note: polyostotic patients are more likely to seek medical attention; monostotic patients are often asymptomatic, but actually are more common]

Xray: early-radiolucency; late-increased bone density, increased microfractures, loss of distinction between cortex and medulla; may have sharp demarcation between normal and affected bone; may extend into soft tissue if florid disease

Diagnosis: Xray, elevated serum alkaline phosphatase and urinary hydroxyproline (normal serum calcium and phosphorus)

Symptoms: often mild; localized pain due to microfractures and nerve compression; may have secondary osteoarthritis due to weak femur or tibia, chalk-like fractures of tibia, fibula, femur, spinal cord injuries due to spinal fractures; also associated with high output congestive heart failure due to shunting of blood through warm skin (bone is hypervascular and hot)

Leontiasis ossea: cranium too heavy to lift

Platybasia: invagination of base of skull due to weak bone, compression of posterior fossa structures

Associated neoplasms: sarcoma (5% with severe polyostotic disease), giant cell tumor, giant cell granuloma

Treatment: calcitonin, diphosphonates

Micro: diagnostic features are increased osteoclastic and osteoblastic activity with supportive radiologic findings; acutely is primarily woven bone; focal mosaic pattern of lamellar bone, resembles jigsaw puzzle with prominent irregular cement lines; osteoclasts present at surface of bone but don’t tunnel; in osteolytic phase, osteoclasts may have up to 100 nuclei; chronic cases have thick trabeculae and thicker bones; fine fibrosis of marrow

Micro images: various images; polarized light

Virtual slides: Paget’s disease

Positive stains: reticulin (highlights disorganization of lamellar bone)

DD of cement lines: radiation therapy, chronic osteomyelitis, reactive bone adjacent to carcinoma, polyostotic fibrous dysplasia (cortical bone has eccentric atrophy)

Radiation necrosis

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Major complication of radiation therapy, usually within 3 years of treatment

Micro: necrotic bone, marrow fibrosis, neovascularization, irregular heavily staining cement lines

DD: Paget’s disease

Renal osteodystrophy

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Skeletal changes of chronic renal disease (see also hyperparathyroidism)

Increased osteoclastic bone resorption resembling osteitis fibrosa cystica

Associated with osteomalacia, osteosclerosis, growth retardation, osteoporosis

Rickets / osteomalacia

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Defect in matrix mineralization due to Vitamin D disturbance (deficiency, abnormal metabolism or calcium deficiency)

Causes accumulation of unmineralized bone matrix

Various causes related to decreased serum calcium or phosphorus, including rare inborn errors of metabolism or common chronic renal failure; also phosphaturic mesenchymal tumor

Associated with vague, generalized bone pain or muscle weakness (due to hypocalcemia)

Rickets: children with irregular, broadened, cup shaped epiphyseal growth plates around knee and wrist

Osteomalacia: adults, bone formed during remodeling is undermineralized, causes osteopenia and fractures

Hypophosphatemia: usually due to renal tubular defect, diuretics, hyperparathyroidism; rarely due to a vascular tumor

Xray: generalized osteopenia with multiple bilateral and symmetrical linear fractures (insufficiency or stress fractures)

Diagnosis: biopsy of long bone or iliac crest

Gross/clinical images: rickets

Micro: adults - wide, noncalcified matrix surrounding disorganized bone trabeculae; junction between osteoid and mineralized bone is irregular and granular; may be increased bone volume; children - thickened, poorly defined growth plate, particularly on metaphyseal side; tongues of uncalcified cartilage may extend into metaphysis; wide osteoid seams

Virtual slides: rickets

Oncogenic osteomalacia

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Rare paraneoplastic syndrome of osteomalacia due to phosphate wasting

Bone demineralization is caused by tumor and may be cured by its excision

Most mesenchymal tumors in these patients are phosphaturic mesenchymal tumor (mixed connective tissue variant, see below), AJSP 2004;28:1

Symptoms: bone pain, fractures, renal phosphate wasting, hypophosphatemia, decreased 1,25 Vitamin D3 levels, resistance to Vitamin D supplementation

SAPHO syndrome

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Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis

Variable and nonspecific histologic findings

Often peculiar bone lesions of anterior chest wall and pustular dermatoses

Mean age 35 years, range 5-63 years

Micro: early lesions resemble bacterial osteomyelitis with acute inflammation, edema, prominent periosteal bone formation; late lesions have markedly sclerotic bony trabeculae with prominent marrow fibrosis and mild chronic inflammation

References: AJSP 1996;20:1368

Fibrous and Fibroosseous tumors of bone

Cortical irregularities of femur

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Formerly called periosteal desmoid, but not neoplastic

No clinical significance

Xray: small irregularities in distal cortex of femur

Micro: bland fibrous tissue

Fibrous dysplasia

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Developmental, non-neoplastic disorder of bone-forming mesenchyme, causing bone maturation arrest at the woven bone stage

Usually associated with activating point mutation in some somatic cells (possibly alpha submit of signal transducing G protein) that leads to elevated intracellular cyclic adenosine monophosphates (cAMP)

Usually begins prior to puberty and grows slowly, although mean age at diagnosis is 32 years; 60% males

Medulla of diaphysis or metaphysis of craniofacial bones, femur, ribs are most common

May be accompanied by intramuscular myxoma in same extremity

May be related to cemeto-ossifying fibroma (AJSP 1995;19:775, Archives 1993;117:284)

Types: monostotic, polyostotic, McCune-Albright syndrome, Mazabraud's syndrome

Malignant transformation: rare, monostotic or polyostotic; may represent dedifferentiation of low-grade osteosarcoma; may occur after radiation therapy

Case reports: 42 year old man with iliac lesion displaying marked degenerative atypia (Archives 2004;128:794), 48 year old with chest pain

Gross: well circumscribed, intramedullary; tan-white-yellow, gritty; large lesions distort bone; cortical bone often thin and expanded

Micro: curvilinear trabeculae (Chinese letters) of metaplastic woven bone (never matures) in hypocellular, fibroblastic stroma; no osteoblastic rimming (due to maturation arrest), 20% of cases have cartilaginous nodules (particularly in femoral neck region); also myxoid areas, rapidly growing secondary aneurysmal bone cysts, hemorrhage, foamy macrophages, calcified spherules (similar to cementifying fibromas), cellular areas, focal hyaline cartilage or cystic areas; usually abrupt transition of normal to abnormal bone; no/rare mitotic figures, no atypia (rarely is degenerative); overall resembles endochondral ossification in skull

Micro images: (1) figure 1a: Xray shows poorly circumscribed, osteolytic lesion with cortical thinning; 1b: CT shows cortical thinning, well-defined margins, no soft tissue extension; 2a: hypercellular stroma and woven bony trabeculae, but no osteoblastic rimming; b-d: plump hyperchromatic nuclei, dense and smudgy chromatin, no mitotic figures; (2) quiz case

Virtual slides: fibrous dysplasia

Negative stains: keratin

EM: immature woven bone trabeculae lined by abnormal osteoblasts resembling fibroblasts

DD: well differentiated osteosarcoma (has lacy, malignant bone; intramedullary extension, cortical violation, soft tissue extension)

References: AJSP 1993;17:924, more information

Monostotic

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80% of cases, teenagers/young adults, no gender preference; resolves after puberty, doesn't become polyostotic

Asymptomatic unless involves face (causes disfigurement)

Malignant transformation in 0.5%

Sites: ribs, femur (causes crook neck deformity of neck resembling candy cane, also called Shepherd’s crook), tibia, jaw

Xray: incidental lucent or ground glass lesion replacing bony spongiosa with well defined and occasionally sclerotic margins; thin cortex; shepherd’s crook deformity

Xray images: Shepherd’s crook deformity; actual shepherd’s crook (type of staff)

Treatment: conservative surgery if symptoms (limited resection, curettage, partial removal in jaw to cure deformity)

Polyostotic

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20% of cases, slightly younger than monostotic patients, may persist into adulthood

Involvement of shoulder and pelvic girdles causes crippling deformities, fractures

Sites: femur, skull, tibia; craniofacial involvement in 100% with extensive skeletal disease, 50% otherwise; usually unilateral

Associated with progressive disease (recurring fractures, long bone deformities, facial deformities), worse if earlier age of onset; rare malignant transformation into sarcoma, more likely after radiation

50% have abnormal cutaneous pigmentation

McCune-Albright syndrome

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1-3% of cases

Common presentation is precocious puberty in girls

Due to somatic mutation of c-fos oncogene (alpha subunit of signal-transducing G proteins - Gsalpha) that causes activation of cAMP pathway

Polyostotic fibrous dysplasia, cafe-au-lait skin pigmentation (large, dark lesions with serpiginous [“coast of Maine”] borders in chest, neck, back), almost exclusively in women

Also endocrine abnormalities (precocious puberty in girls, hyperthyroidism, pituitary adenomas that secrete growth hormone, primary adrenal hyperplasia)

Malignant transformation in 4%

Gross/clinical images: 4 year old girl with mosaic pattern of darkened skin and body cast due to fractures

References: slide show with images; more information

Mazabraud's syndrome

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Rare; fibrous dysplasia (usually polyostotic) that precedes soft tissue myxomas (multiple, intramuscular, right side of body)

May be associated with McCune-Albright syndrome also

Fibrous dysplasia protuberans

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Exophytic variant in which lesions protrude far beyond normal bone contour, mimicking surface bone lesions

References: Hum Path 1994;25:1234

Fracture callus

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Xray: stress fractures may resemble tumors with extensive periosteal new bone formation; postmenopausal women may have insufficiency fractures in pelvis resembling metastatic carcinoma

Xray images: healing fracture

Micro: spindle cell proliferation with cartilage and bone; may be hypercellular but orderly maturation present

Micro images: fracture callus with sarcoma

Virtual slides: fracture callus

DD: chondrosarcoma, pathologic fracture

Liposclerosing myxofibrous tumor

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Also called polymorphic fibroosseous tumor of bone

Mixture of lipoma, fibroxanthoma, myxoma, myxofibroma, cyst formation, fat necrosis, ischemic ossification and fibrous dysplasia-like features

Mean age 40 years but also teens to 60’s

Usually incidental findings, but may gradually enlarge causing fracture, or occasionally undergo malignant transformation

Sites: 80% involve proximal femur; also ileum, humerus, rib

Some of these cases may be a variant of fibrous dysplasia with similar mutations (Hum Path 2003;34:1204)

10% have malignant transformation

Xray: well-defined, lytic lesion with sclerotic margin, resembling bone infarct

Xray images: liposclerosing myxofibrous tumor of bone

Micro: fat, xanthoma cells, cementum-like ossicles, Paget-type bone, myxofibrous tissue with cystic change; also curvilinear trabeculae in fibrous tissue in some cases

References: Hum Path 1993;24:505, more information

Metaphyseal fibrous defect

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Also called fibrous cortical defect

Called nonossifying fibroma if loose, > 5 cm and associated with intramedullary component

Distinctive lesions in teenagers, no gender preference

Benign; asymptomatic except for possibly pain

Probably a developmental defect (not neoplastic), usually resolves in a few years and is replaced by cortical bone

Sites: usually metaphysis of distal femur, tibia; 50% are multiple; often < 1 cm

Xray: sharply demarcated radiolucencies surrounded by thin zone of sclerosis without a periosteal reaction

Xray images: tibia

Treatment: usually none; curettage and bone grafts if large and at risk for pathologic fracture

Case reports: 14 year old boy with tibial lesion and leg pain (Archives 2000;124:917)

Gross: red-brown, granular, well circumscribed

Micro: storiform pattern of fibroblasts with scattered benign giant cells, foamy histiocytes, cholesterol crystals, hemosiderin; mitotic figures common; rarely has bizarre (degenerative) nuclear features; resembles fibrous histiocytoma

Micro images: spindle cells with storiform pattern and giant cells; quiz case; dense fibroblasts without giant cells #1; #2; #3

DD: giant cell tumor (older patients, usually epiphyseal, lytic, no sclerosis, diffuse giant cells with 40+ nuclei), benign fibrous histiocytoma (painful, in pelvic and long bones, similar histology)

References: more information #1, #2, #3, #4

Myositis ossificans

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Also called benign fibroosseous lesion (better term since may not involve muscle or inflammation), myositis ossificans circumscripta, heterotopic ossification

Benign, solitary, reactive fibroblastic proliferation with reactive bone formation

50% have history of trauma, although often trivial

Rapid growth

May occur in hand (called florid reactive periostitis, fibroosseous tumor of digits, parosteal fasciitis)

Rarely associated with malignancy, but may be confused with malignancy (Hum Path 1975;6:653)

Rarely is generalized, associated with skeletal anomalies of hands and feet causing immobilization and death (see fibrodysplasia ossificans progressiva)

Rarely occurs within the abdomen (intraabdominal heterotopic ossification); usually men, mean age 61 years, with small bowel obstruction associated with heterotopic bone formation in small bowel mesentery after abdominal surgery (AJSP 1999;23:1464)

Sites: upper extremity flexors, quadriceps, thigh adductors, gluteal muscles, soft tissues of hand; usually near a bone

Xray: periosteal reaction and soft tissue calcification 3-6 weeks after injury, with replacement by heterotopic bone at 10-12 weeks

Treatment: excision or conservative

Case report: post gastric reduction surgery for obesity (Archives 2004;128:321), 11 year old with florid reactive periostitis in hand after minor trauma (Hum Path 1997;28:745)

Gross: 2-5 cm, well circumscribed, soft red-brown center, gritty periphery; lesion often encased in shell of bone

Micro: cellular stroma, new bone, rarely cartilage; early - highly cellular with immature fibroblasts centrally, brisk mitotic activity, focal hemorrhage, resembles nodular fasciitis or osteosarcoma; later - woven bone with large, plump, crowded osteocytes and myofibroblasts; process is zonal; lamellar pattern may develop over time; more mature peripherally with osteoblastic rimming

At 3 weeks, inner zone resembles nodular fasciitis, intermediate zone contains osteoblasts which deposit woven bone, outer zone contains mineralized trabeculae and eggshell type calcification; bone marrow eventually fills intertrabecular spaces

Micro images: image #1; #2; #3

EM: prominent myofibroblasts

DD: extraosseous osteosarcoma (elderly patients, malignant cytology, either no zonation or more mature centrally), juxtacortical osteosarcoma (either no zonation or more mature centrally), progressive osseous heteroplasia (due to mutations of GNAS1 gene)

References: more information, florid reactive periostitis

Ossifying fibroma

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Benign neoplasm, affects ages 3 months to 70 years

Some are indolent; some growth rapidly

Sites: craniofacial skeleton (maxilla, mandible, paranasal sinuses); psammomatoid tumors usually don’t affect the jaw

Incidental or symptoms of facial enlargement, nasal obstruction, pain, proptosis

Treatment: excision of small lesions, wide excision of large or rapidly growing lesions; 30-60% recur; no malignant transformation

Case reports: psammomatoid, sino-orbital tumor in 13 year old girl (Archives 2003;127:e301)

Gross: discrete mass that is well delineated from surrounding bone, no encapsulation, tan-white, rubbery cut surface, firm to gritty

Micro: central lesion of bone with variable fibrous proliferation of round, polyhedral or spindly cells and calcifications; trabecular and psammomatoid patterns, myxomatous matrix; occasional osteoclast-like giant cells

Psammomatoid: numerous small, round ossicles or psammomatoid bodies embedded in cellular fibrous stroma; ossicles present within bony trabeculae and cellular stroma

Images: (1) MRI, gross, H&E; (2) psammomatoid: Xray, H&E

DD: central cementifying fibroma (women, typically involves jaw, cementicles related to dental cementum)

Osteofibrous dysplasia

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Non-neoplastic, self-limited intracortical fibroosseous lesion commonly affecting tibia and fibula of children

Also called fibroosseous dysplasia, ossifying fibroma of long bones, Campanacci’s lesion

Mean 13 years, range 0-39 years, no gender preference

Closely related to fibrous dysplasia but is a cortical (not medullary) lesion with osteoblastic rimming of bone and lamellar bone that does mature

May present with pathologic fracture

Associated with adamantinoma of long bones; may be a precursor lesion (Hum Path 2004;35:69, AJSP 1992;16:282)

Xray: no medullary involvement

Sites: diaphysis of tibia or fibula of neonates

Prognosis: excellent, but may recur; regresses as patients mature

Micro: spindle cell proliferation with production of woven bone trabeculae with prominent osteoblastic rimming; loose, slightly myxoid stroma

Micro images: spindle cell proliferation with woven bone and osteoblastic rimming; 10 year old with tibial mass

Positive stains: keratin in spindle cells (not seen in fibrous dysplasia), S100, Leu7/CD57

DD: well differentiated osteosarcoma

References: Hum Path 1993;24:1339, more information #1, #2

Post-traumatic lesions

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Adult lesions of ribs show bland fibrous stroma containing bone trabeculae with zonal maturation pattern (Hum Path 1999;30:770)

Bone forming tumors other than osteosarcoma

Bone forming tumors - general

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Most are benign, although they often are not biopsied

Tumors in childhood are usually benign; tumors in elderly are usually malignant

Some tumors (giant cell tumor, well differentiated cartilaginous tumors) have borderline features

Important to be aware of patient age, bone involved, area of bone involved (epiphysis, metaphysis, diaphysis; cortex, medulla or periosteum) and radiologic appearance before making microscopic diagnosis

Diagram of common tumor locations

Xrays are important to define the tumor’s location and aggressiveness, and are necessary to diagnose low grade cartilaginous tumors

Clinical symptoms are usually not helpful in making a diagnosis

Adamantinoma of long bones

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Rare malignant primary bone tumor with epithelial and mesenchymal elements

Common in tibia, usually shaft, usually young adults

25% have symptoms for 5 or more years

Epithelial component derives directly from mesenchymal tissue and gradually increases in amount, may undergo sarcomatoid transformation (AJSP 2003;27:1530)

Osteofibrous dysplasia-like form: children and adolescents, relatively benign behavior, although may progress to classic adamantinoma; often recurs after curettage; no conspicuous nests of epithelial cells (Hum Path 1998;29:809)

Classic form: usually adults, more aggressive

Xray: single or multiple lytic lesions of shaft (cortex or medulla) with marked surrounding sclerosis

Treatment: excellent prognosis with complete excision; may have nodal or pulmonary metastases

Gross: poorly defined, firm and fibrous; may extend into adjacent soft tissue

Micro: three forms: (a) osteofibrous dysplasia-like form with scattered epithelial elements, (b) classic form with large groups of bland epithelial cells in clusters with peripheral palisading in fibrous stroma with haphazard osteoid deposition, (c) sarcomatoid transformation with highly pleomorphic cells, high mitotic count, deposition of osteoid and chondroid matrix, no epithelial features

Squamous differentiation and keratin production is uncommon

Micro images: image #1; #2; #3; quiz case; various images and text

Positive stains: keratin (epithelial and spindle cells)

EM: spindle shaped epithelial tumor cells joined by desmosomes

DD: metastatic carcinoma (unusual below knee, older patients, more malignant cytology, no osteofibrous dysplasia-like areas)

References: AJSP 1982;6:427 (immunostains); more information

Metastatic calcification

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Also called calcium hydroxyapatite deposition in soft tissue, tumoral calcinosis

Associated with trauma, renal failure, hyperparathyroidism, metastatic carcinoma, myeloma, scleroderma, hypermetabolic states, sarcoidosis

In blacks, associated with elevated serum phosphate, occurs in teens with painless masses in hips, elbows, shoulders, gluteal area

Sites: kidney, alveoli of lungs, cornea, conjunctiva, gastric mucosa, blood vessel walls

Case report: seven siblings with bleeding, then aggregation of foamy histiocytes, then cystic cavities lined by osteoclast-like giant cells (AJSP 1993;17:788)

Micro: calcium deposits are associated with inflammatory cells and giant cells

DD: dystrophic calcification (dead tissue that is not rapidly absorbed; associated with coagulation necrosis, caseous necrosis, fat necrosis)

Ossifying fibromyxoid tumor

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Uncommon (120 cases reported) soft tissue tumor of uncertain lineage, usually with bone present

May be a type of translocation-associated sarcoma

Adults (median age 49 years, range 14-83 years), more often males, with small, painless mass in trunk or proximal extremities

Usually histologically benign with benign clinical course; local recurrences in 17%, malignant behavior in 5%

Poor prognostic factors: high cellularity, high nuclear grade, > 2 mitotic figures/50 HPF

Gross: well circumscribed, involves subcutaneous tissue or muscle

Micro: nests/cords of round/oval cells with indistinct cytoplasm in myxoid matrix with fibrosis and osteoid formation; lobulated at low power; surrounded by partial capsule of mature bone; usually minimal atypia and minimal mitotic figures, but may have necrosis, vascular invasion, high nuclear grade

Positive stains: S100 (60%), vimentin, Leu7/CD57 (focal), GFAP (focal), desmin (13%), pan-keratin (10%)

Negative stains: smooth muscle actin

EM: complex cell processes, basement membrane deposition

References: AJSP 2003;27:421, AJSP 1989;13:817 (initial report)

Osteoblastoma

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Also called giant osteoid osteoma

25% as common as osteoid osteoma

Mean age 20 years, often 10-30 years, but any age, 2/3 male

Related to osteoid osteoma but larger nidus (greater than 1.5-2.0 cm), no reactive bone, lack of intense pain (dull, achy), no response to aspirin

Rarely has systemic manifestations of weight loss, fever, generalized periostitis (“toxic” osteoblastoma)

Sites: usually spine, sacrum or major bones of lower extremity; medulla of metaphysis

Xray: may appear malignant due to cortical expansion and destruction, nidus may be identifiable

Prognostic factors: presence of bizarre tumor cells is not significant; 20% recur; poorer prognosis within central neuraxis

Gross: red, granular, well circumscribed, variable surrounding sclerosis

Micro: resembles osteoid osteoma; nidus composed of anastomosing bony trabeculae rimmed by osteoblasts; loose and vascular intratrabecular spaces; may have scattered bizarre tumor cells (degenerative); rarely produces cartilaginous matrix (AJSP 1993;17:69); no spindle cells, no infiltration of adjacent soft tissue

Micro images: image #1; #2; quiz case

DD: well differentiated osteosarcoma (infiltrative)

References: Hum Path 1994;25:117, more information

Aggressive osteoblastoma

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Resembles osteoblastoma by Xray but with atypical cytology

Short tubular or flat bone lesions are most likely to be aggressive in one study (AJSP 1996;20:841)

Micro: wide and irregular trabeculae, bordered by epithelioid osteoblasts; focal lack of trabecular pattern of osteoid proliferation; low mitotic rate, no lace like osteoid, no atypical mitotic figures, no necrosis, in infiltration of adjacent intertrabecular space

Malignant if permeates surrounding tissues and no peripheral maturation

DD: osteosarcoma

Osteoid osteoma

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Rare; benign tumor similar to osteoblastoma but nidus measures 1.5-2.0 cm or less

75% under age 25; 2/3 male; 50% in femur/tibia; also humerus, hands and feet, vertebrae, fibula

Cortex of metaphysis is most common site in long bones

Intense localized pain, particularly at night, due to production of prostaglandin E2 or nerve fibers in reactive zone (Mod Path 1998;11:175); pain relieved dramatically by aspirin, NSAIDs or surgery

Vertebral lesions associated with scoliosis

Intraarticular / juxta-articular tumors are rare, cause joint dysfunction (Mod Path 2000;13:1086, AJSP 1991;15:381)

Xray: small, round lucency with variable mineralization surrounded by extensive sclerosis

Xray images: nidus in femoral neck

Treatment: CT localization of nidus (tetracycline labeling may help) and excision or radiofrequency ablation; recurrence is unusual

Gross: nidus (actual tumor) is 1.5 cm or less, red, granular, softer than sclerotic tissue and distinct; surrounded by sclerotic bone for several centimeters

Gross images: osteoid osteoma #1, #2

Note: must examine gross specimen for a nidus and not submit the entire mass for decalcification

Micro: extremely well circumscribed lesion; central nidus is sharply delimited, composed of anastomosing bony trabeculae with variable mineralization, lined by plump osteoblasts, within vascularized connective tissue; surrounded by sclerotic bone; benign giant cells present; no inflammation

Micro images: intraarticular tumor; adjacent lymphoid synovitis; quiz case

Virtual slides: osteoid osteoma nidus

EM: osteoblasts have irregular indented nuclei, glycogen, abundant fine intracytoplasmic fibrils, rare lysosomes with iron; variable atypical mitochondria (Hum Path 1976;7:309)

DD: osteomyelitis (Brodie abscess is similar clinically and by Xray, not histologically)

References: more information and images

Osteoma

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Rare; slow growing tumor of skull, mandible, maxilla, sinus; nonfacial tumors are usually parosteal (outside the periosteum)

Ages 40-50 years, 2/3 male

May obstruct sinus cavity, impinge on brain/eye, interfere with oral cavity function, cause cosmetic problems

Benign; may represent end stage of fibrous dysplasia or other fibroosseous lesions; may not actually be neoplastic

Gardner’s syndrome: autosomal dominant with Y and 5q abnormalities; multiple osteomas, epidermal cysts, fibromatosis, pigmented ocular fundus lesions, multiple colorectal adenomas with carcinoma at ages 35-40 (may be variant of familial adenomatous polyposis)

Treatment: excision; recurs if incompletely excised

Gross: well circumscribed, round/oval sessile tumor which projects from subperiosteal or endosteal surfaces of cortex; hemorrhagic, gritty tan tissue

Micro: dense, mature, predominantly lamellar bone rimmed by osteoblasts, surrounded by vascular, loose connective tissue

Micro images: image

DD: reactive bone associated with infection, trauma, hemangiomas; parosteal osteosarcoma (for parosteal tumors)

References: Hum Path 1982;13:449 (inner table of skull), more information

Osteosarcoma

Osteosarcoma-general

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Most common primary bone tumor after myeloma

Definition: malignant bone tumor that produces osteoid directly from tumor cells and unconnected with cartilage, regardless of the amount of neoplastic cartilage or fibrous tissue present elsewhere

60% male; usually ages 10-25 years or ages 40+ with other diseases (see below); rare before age 5

Associated with Paget’s disease after age 40 years (see below), post-radiation exposure (see below), Thorotrast administration, chemotherapy in children, fibrous dysplasia, osteochondromatosis, chondromatosis, rarely with hip implants

Not associated with trauma, although trauma may lead to discovery of tumor

Sites: metaphysis of long bones (distal femur, proximal tibia, proximal humerus; sites of peak mitotic activity for bone cells); occasionally diaphysis, rarely epiphysis; less common in flat bones or short bones; usually arises within medullary cavity and extends to cortex

Multicentric: usually children, densely sclerotic by Xray, extremely aggressive, associated with p53 mutations

Post-radiation: 10-15 years after 40-60 Gy exposure for various conditions; may cause fibrosarcoma, osteosarcoma or MFH; usually high grade, poor prognosis unless can excise with wide surgical margin

Xray: large, destructive, lytic or blastic mass with permeative margins; may break through cortex and elevate periosteum; sunburst pattern due to new bone formation in soft tissue

Xray images: large destructive lesion #1; #2; metastatic osteosarcoma

Codman's triangle: shadow between cortex and raised ends of periosteum (due to reactive bone formation), non-specific

Biopsy: incision should be placed so it will be entirely removed by subsequent excision

Sites of metastasis: lung (98%, 20-80% at diagnosis, rarely within pulmonary arteries), other bones (37%), pleura (33%), heart (20%), rarely to lymph nodes, GI tract, liver, brain

Note: excision of metastatic lung nodules may prolong survival

Poor prognostic factors: associated Paget's disease, telangiectatic histology, elevated serum alkaline phosphatase, minimal postchemotherapy tumor necrosis, involvement of craniofacial bones (not jaw) or vertebrae, multifocal tumor, loss of heterozygosity of RB gene

Good prognostic factors: jaw or distal extremities; solitary; parosteal, periosteal or well differentiated intramedullary histology; extensive necrosis (>95%) after preoperative chemotherapy

5 year survival: 70%

Treatment: preoperative chemotherapy is helpful to spare limbs; MDR1 gene expression determines chemosensitivity

Case reports: arising in phylloides tumor (Archives 2003;127:e227), metastases presenting as jejunal polyp (Archives 2000;124:1682), with fatal pulmonary embolism (Archives 1999;123:437), in toe phalanx (AJSP 1988;12:300), intracortical tumor of tibia (AJSP 1984;8:65), with Cowden’s disease (Archives 1993;117:1252)

Gross: big, bulky, gritty, hemorrhagic with cystic degeneration; spreads within medullary cavity, destroys cortical bone, elevates periosteum and invades soft tissue; rarely penetrates joint along tendons/ligaments; may form satellite nodules (“skip metastases”); usually has well defined proximal and distal margins; 25% have large amounts of cartilage

Gross images: metaphyseal tumor; large and bulky lesion; distal femur and Xray; soft tissue extension #1; #2; jejunal metastasis; pulmonary embolus

Micro: high grade spindle cell tumor that produces osteoid matrix unconnected by cartilage (by definition); tumor cells produce neoplastic bone - basophilic thin trabeculae of neoplastic bone resembling fungal hyphae or neoplastic osteoid - eosinophilic, homogenous, glassy with irregular contours and osteoblastic rimming; destroys or grows around trabeculae; vascular invasion and necrosis common; may have osteoblastic, fibroblastic (pure spindle cell growth with minimal matrix) or chondroblastic predominance (malignant appearing cartilage with peripheral spindling and osteoid production)

Osteoid may be variable in amount; with bizarre giant cells in stroma or acellular stroma; vessels may have hemangiopericytoma-like features; tumor cells may be spindly, oval or round of variable size; 25% have osteoblast-like multinucleated giant cells; cartilage may be mineralized, immature, myxoid

Micro images: osteoblastic; with fascicular growth pattern; chondroblastic #1; #2; #3 as pulmonary emboli; quiz case; case history #1-fibroblastic variant; case history #2; implant related tumor; in phylloides tumor: mammogram (current-1a, prior-1b); jejunal metastasis; vascular invasion in jejunal metastasis

Virtual slides: osteosarcoma #1, #2

Positive stains: alkaline phosphatase, vimentin, variable smooth muscle actin and desmin, S100 (if chondroid differentiation), vWF (Mod Path 2005;18:388), rarely hCG (Archives 1989;113:416)

Negative stains: keratin, EMA

Molecular: usually aneuploid or hyperploid except periosteal and well differentiated (usually diploid), 20% have p53 mutations

EM: differentiated tumor cells resemble normal osteoblasts with abundant dilated endoplasmic reticulum, rare mitochondria; matrix composed of nonperiodic fibrils, scattered collagen fibers, focal calcium deposits of hydroxyapatite crystals

DD: exuberant fracture callus, myositis ossificans, giant cell tumor (unlikely in metaphysis of young patient)

References: Mod Path 2002;15:878 (p53), more information

Chemotherapy effect

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Report extent of necrosis in resected osteosarcomas (recommended to take one slide of entire tumor, decalcify and embed)

Consider cells viable if in doubt

Micro: fibrosis, granulation tissue, frank necrosis, dense bone formation within marrow cavity

Osteosarcoma variants

Anaplastic osteosarcoma

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Micro: bizarre and undifferentiated tumor cells with malignant osteoid

DD: metastatic carcinoma, pleomorphic sarcoma

Epithelioid osteosarcoma

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Rare pattern with rosette-like configuration simulating glands

Usually male patients under age 30

Sites: metaphysis of long tubular bones

Xray: highly destructive with variable mineralization

Survival: poor, with 75% dead of multiple lung metastases despite surgery with wide margins and systemic chemotherapy; estimated 5 year survival of 15%

Case reports: 49 year old man with vertebral tumor (Archives 1993;117:295)

Micro: osteoblastic osteosarcoma with small multinodular growth pattern, lacelike osteoid deposits, hemangiopericytoma-like vessels, rosette-like formation, epithelioid tumor cells

Positive stains: EMA

References: Hum Path 2001;32:726

Fibrohistiocytic osteosarcoma

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Micro: resembles malignant fibrous histiocytoma but with malignant osteoid

High grade surface osteosarcoma

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Very rare

Occurs on surface of bone

Same prognosis as conventional osteosarcoma, but poorer prognosis than parosteal (juxtacortical) osteosarcoma

Xray: surface tumor with variable mineralization

Gross: fish-flesh appearance of sarcoma

Micro: resembles conventional osteosarcoma

References: AJSP 1984;8:181

Low grade intraosseous (central) osteosarcoma

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Rare (1% of osteosarcomas), good prognosis

Usually age 20’s, no gender preference

Sites: usually long bones (femur, tibia)

Xray: poor margination with cortical disruption and soft tissue extension, variable matrix mineralization, no sclerotic margin

Treatment: wide local excision or amputation; 15% develop high grade osteosarcoma with recurrence

Case reports: tibial tumor with lymphoid infiltrate (Archives 2000;124:868), local recurrence with dedifferentiation (Hum Path 2000;31:615), with pagetoid bone features (Mod Path 2004;17:288)

Gross: mean 9 cm, range 2-25 cm, white, fibrous to gritty depending on mineralization

Micro: paucicellular, infiltrates between bone trabeculae composed of interlacing fascicles of spindle cells with mild atypia and rare mitotic figures in heavy collagenous background; variable bone or osteoid production may resemble fibrous dysplasia

Micro images: case report above with pagetoid features - heavy irregular bony trabeculae; coalescing plates of tumor bone; mosaic pattern of cement lines resembling Paget’s disease; figure 6a: low grade features with cement lines in adjacent bone; 6b: high grade features of dedifferentiated tumor

Positive stains: Ki-67/MIB-1

DD: fibrous dysplasia (no cortical disruption, no atypia, usually no trabecular bone), paraosteal osteosarcoma (surface location but same histology)

References: Hum Path 2000;31:633 (MIB-1), Mod Path 1998;11:421 (CGH)

Osteoblastoma-like

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Rare, 1% of all osteosarcomas

Mean age 29 years, range 19-47 years, more common in males

Treatment: resection with wide surgical margins; may recur if inadequate margins, may metastasize

Micro: resembles osteoblastoma, but permeation of surrounding host tissue

References: Mod Path 1993;6:707

Paget’s disease associated osteosarcoma

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Usually associated with polyostotic Paget’s disease

Multicentric tumors associated with increasing localized pain

Much older age than conventional osteosarcoma

Very poor prognosis, with death due to pulmonary metastasis or local extension

Sites: pelvis, humerus, femur, tibia, skull

Xray: Paget’s disease and destruction

Micro: high grade sarcoma (osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma) with osteoclasts and atypical osteoblasts

Micro images: high grade sarcoma

References: AJSP 1981;5:47; more information

Parosteal osteosarcoma

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Also called juxtacortical osteosarcoma (outside of the periosteum)

Ages 30-60 years, either no gender preference or female predominant

Arises in metaphyses of long bones

70% occur at posterior aspect of distal femoral shaft, also tibia, humerus; rarely in hands, mandible

Slow growing; may not be detected for 15 years; symptoms of inability to flex the knee / painless swelling

Xray: prominent extracortical calcified mass that encircles bone; no continuity with bone or marrow

Xray images: bone surface mass

Very good prognosis (80% 5 year survival); rarely recurs with dedifferentiation leading to worsening prognosis

Case reports: with high grade intramedullary component (Hum Path 1989;20:488)

Gross: large lobulated mass encircling bone, firm to hard; may contain cartilage; may have satellite nodules

Gross images: fleshy fibrous area with hemorrhagic dedifferentiated component; tumor arising from periosteum

Micro: low grade neoplasm of well formed bony trabeculae, osteoid, variable cartilage and highly fibrous spindle cell stroma in chaotic pattern; stroma is hypocellular but malignant with mild atypia; 25% have medullary involvement; 15% have coexisting areas of dedifferentiation; rarely has abundant osteoclast-like giant cells; no/rare mitotic figures; no fatty or hematopoietic marrow

Micro images: fibrous stroma and well formed trabeculae; bland tumor cells producing trabeculae

Molecular: supernumerary ring chromosomes

EM: numerous myofibroblasts, mixed with osteoblasts and fibroblasts; normal cartilaginous areas; undifferentiated cells have desmosomes between them (Hum Path 1980;11:373)

DD: myositis ossificans (orderly maturation, not attached to underlying bone; more active histologically), high grade surface osteosarcomas (may be juxtacortical but different histology), conventional osteosarcoma with periosteal spread, osteochondroma (tumor continuous with bone, fatty or hematopoietic marrow present)

References: more information

Periosteal osteosarcoma

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<2% of all osteosarcomas

Same age as conventional osteosarcoma, slight female predominance

Related to periosteal chondrosarcoma

Sites: usually diaphysis of proximal tibia or femur

Xray: small lucent lesions on bone surface with bone spicules perpendicular to shaft and penetrating soft tissues; no medullary involvement (by definition)

Good prognosis (better than high grade osteosarcoma, poorer than parosteal osteosarcoma or juxtacortical chondrosarcoma), with

high local recurrence rate and 15% metastatic rate

Case report: 15 year old with tibial tumor (Archives 2003;127:e229)

Gross: grows on surface of long bones; limited to cortex with only rare medullary invasion

Micro: intermediate to high grade osteosarcoma with prominent cartilaginous component; cartilage in lobules with peripheral spindling and central bone formation; malignant osteoid / bone is present, but may be focal

Micro images: image #1; #2; Xray, gross, H&E

Molecular: usually diploid

DD: juxtacortical chondrosarcoma (lobules of malignant cartilage with calcification and surface endochondral ossification, no malignant osteoid)

References: more information

Small cell osteosarcoma

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Very rare

Poor prognosis

Micro: diffuse growth of small, uniform, round/spindle tumor cells, focally produces malignant osteoid, occasionally mixed with cartilage

Positive stains: vimentin, variable S100

Negative stains: CD99, keratin, EMA, factor VIII related antigen, desmin, synaptophysin, LeuM1, CD45/LCA

EM: high N/C ratio, poorly differentiated cytoplasm, numerous free ribosomes and mitochondria, small junctions, envelopment of individual and groups of cells by matrix (Hum Path 1991;22:267)

DD: Ewing’s sarcoma/PNET, lymphoma

References: Hum Path 1993;24:1211 (immunostains), more information

Telangiectatic osteosarcoma

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Very uncommon if limit diagnosis to typical Xray, gross and microscopic findings

Associated with pathologic fractures

Xray: purely lytic destructive lesion simulating aneursymal bone cyst

Probably similar prognosis as conventional osteosarcoma

Gross: resembles aneurysmal bone cyst with large cavity containing blood filled cystic spaces separated by septa

Gross images: tumor with blood filled cavity #1; #2

Micro: prominent blood-filled cysts, malignant stroma in septa separating cysts; minimal osteoid

Micro images: blood-filled cystic spaces with malignant stroma #1; #2; large cystic spaces

DD: aneurysmal bone cyst (no malignant cells present within septa)

References: more information

Well differentiated intramedullary osteosarcoma

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Very rare; also called low grade osteosarcoma, intraosseous osteosarcoma

Usually adults, femur and tibia

Excellent prognosis, but 15% eventually develop conventional (high grade) osteosarcoma

Xray: large lesions with cortical destruction and extraosseous extension; much of tumor is well circumscribed, with a focally aggressive growth pattern

Gross: firm, fibrous, no fish-flesh appearance

Micro: so bland that appears benign but invades bone and soft tissue; hypocellular spindle cells with mild atypia, marked collagen production; variable osteoid production; no/rare mitotic figures

Molecular: usually diploid

DD: fibrous dysplasia (no cortical destruction on Xray), parosteal osteosarcoma

Cartilaginous tumors other than chondrosarcoma

Bizarre parosteal osteochondromatous proliferation

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Also called Nora’s lesion

Rare form of myositis ossificans, resembles subungual (Dupuytren’s) exostosis, except for t(X;6) in the latter (AJSP 2004;28:1033)

75% affect small tubular bones of hands and less commonly the feet; do not involve the nailbeds

25% affect large bones

Usually ages 20-39 years

Xray: hands - heavily calcified mass attached to underlying cortex / periosteum, but not continuous with it (so not an osteochondroma); long bones - lesions may be destructive or in soft tissue

Benign, but may recur locally (35-54%)

Treatment: surgical excision with wide margins

Case reports: with associated fibrosarcoma (Skeletal Radiol 2001;30:44)

Gross: resembles small osteochondroma

Micro: irregular maturation of cartilage in bone produces chondro-osteoid with characteristic blue quality (“blue bone”); contains enlarged, bizarre, binucleated chondrocytes with maturation into bone; also spindle cell proliferation between bony trabeculae without atypia

Micro images: image #1; #2; #3; #4

Molecular: t(1;17)(q32;q21) or variant translocations involving 1q32 in one study (Hum Path 2004;35:1063)

DD: osteochondroma, florid reactive periostitis, periosteal chondroma, juxtacortical chondrosarcoma, parosteal osteosarcoma, periosteal osteosarcoma

References: Hum Path 2002;33:1205, AJSP 1993;17:691, AJSP 1983;7:245 (initial description), more information

Chondroblastoma

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Rare (<1% of primary bone neoplasms), usually teenage males with open growth plate

Painful, often causes joint effusions and restricts joint mobility

Sites: distal femur, proximal humerus, proximal tibia, pelvis, ribs, feet, scapula; usually epiphysis (open) or apophysis such as iliac crest; may extend into metaphysis; also skull in older patients

Xray: extremely well circumscribed tumor of epiphysis with spotty calcifications in patient with open epiphysis

Treatment: excision or curettage with bone grafting

Course: usually benign, but commonly recurs (often with atypia), rarely invades locally; rarely pulmonary metastases occur after surgical manipulation of primary tumor; patients survive after removal of localized metastases but not if multiple

Case reports: 29 year old man with knee chondroblastoma with aneurysmal bone cyst formation (Archives 2005;129:e16), 18 year old man with metacarpal tumor (Archives 2004;128:e120), multiple benign tumors (Hum Path 1980;11:296)

Gross: well-circumscribed, white-blue-gray, firm; usually 3-6 cm; variable calcification, necrosis, cystic areas

Micro: varies with time - early hypercellularity, followed by necrosis, followed by fibrous or chondroid areas with occasional spindle cells; compact polyhedral chondroblasts with abundant pink cytoplasm and variable pigment, well defined cell borders and hyperlobulated nuclei with grooves in mineralized, chicken-wire matrix that surrounds chondroblasts; chondroid differentiation almost always present (pink vs. blue matrix); may have marked cellularity, intracytoplasmic glycogen granules, mitotic figures, necrosis, osteoclast-type giant cells; 25%-50% have secondary aneurysmal bone cyst; hyaline cartilage is rarely seen; no significant nuclear atypia

Micro images: figures 1/2: expansile and lytic lesion of proximal digit and articular surface; 3: giant cells; 4: chondroid-type matrix with chicken-wire, pericellular calcifications; quiz case #1; #2; micro images and text #1; #2; giant cells in A: osteopetrosis; B: foreign body reactions; C: sarcoidosis; D: giant cell tumor; E: chondroblastoma

Positive stains: S100, vimentin, low molecular weight keratin, PAS with diastase (glycogen), reticulin (surrounds each cell), neuron specific enolase, occasionally muscle specific actin (Hum Path 1997;28:316)

EM: resembles tissue culture epiphyseal cartilage cells with prominent fibrous lamina that causes microscopic well defined cell borders

DD: giant cell tumor (metaphyseal or epiphyseal in patients with closed epiphysis, clustered giant cells that are larger and more numerous than chondroblastoma, no chondroid differentiation, no chicken wire matrix), chondromyxoid fibroma (metaphyseal, myxoid with pseudolobular pattern with pleomorphic stellate cells)

References: Hum Path 1993;24:944, more information

Chondroma

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Benign cartilaginous tumor

Either enchondroma (arise from diaphyseal medullary cavity), subperiosteal/juxtacortical chondroma or soft tissue chondroma

One study claims cytofluorometric DNA ploidy analysis is more reliable than clinical and histologic features in distinguishing these tumors from chondrosarcomas (Mod Path 1999;12:863)

Molecular: 12q13-15 (HMGA2 / HMGI-C) is involved in structural rearrangements (also in other benign mesenchymal tumors, Mod Path 2003;16:1132)

Molecular images: FISH with HMGA2 rearrangement

Enchondroma of hands and feet

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Usually asymptomatic or pain due to pathologic fracture

Age 20-49 years, no gender preference

May be due to displaced growth plate

Sites: small bones of hands and feet (rare in thumb or ribs)

70% solitary; 30% multiple

Multiple enchondromas: may produce severe deformities; associated with chondrosarcomatous transformation

Maffuci’s syndrome: multiple enchondromas and soft tissue hemangiomas; also ovarian carcinoma, brain gliomas

Ollier’s disease: nonhereditary disease of multiple enchondromas of long bones and flat bones (up to 50% of skeleton) with associated skeletal deformities, histologic features of low grade chondrosarcoma should be ignored if radiographically benign; most lesions regress when skeleton matures; often ovarian sex-cord tumors

Xray: thinning but preservation of cortex, O ring sign, no penetration into soft tissue, pathologic fractures common

Xray images: enchondroma with fracture; enchondromas of digits

Treatment: excision, may recur if incompletely excised; often leave alone

Case reports: Ollier’s disease in 34 year old man with molecular study (Hum Path 2000;31:1299), Ollier’s disease in 53 year old man with multiple foci of chondrosarcomatous transformation (Hum Path 1984;15:91), tenosynovial chondroma of hand (Hum Path 1978;9:476)

Gross: well circumscribed, pale-blue, solid, resembles cartilage but without myxoid change

Micro: lobules of hyaline cartilage encased by bone and covered by perichondrium (fibrous tissue); resembles low grade chondrosarcoma due to hypercellularity, binucleation, myxoid change but radiographically is benign; also calcification, endochondral ossification

Necrosis common in benign lesions due to avascular cartilage; tongues of bone extend into cartilage (vs. sharp interface at growth plate)

More atypia present with Ollier’s disease and Maffuci’s syndrome

Micro images: enchondroma #1; #2; #3

Virtual slides: enchondroma

DD: low grade chondrosarcoma (breaks through or erodes cortex, marked myxoid change, large tumors occupy marrow space and entrap bony trabeculae), epiphyseal dysplasia (in babies, affects multiple joints)

References: more information

Enchondromas of long bones

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Rare

Xray: well circumscribed tumor of metaphysis or diaphysis with flecks of calcification; doesn’t invade the cortex

Enchondroma protuberans: rare, exaggeratedly eccentric enchondroma resembling radiographically an osteochondroma (Hum Path 1982;13:734)

Gross: well circumscribed, pale blue, solid, no myxoid change

Gross images: fibula

Micro: hypocellular, few binucleated cells, may be multifocal but does not infiltrate marrow; no myxoid change

Micro images: quiz case

Calcifying enchondroma

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Metaphysis of long bones with massive tumoral calcification

Juxtacortical (periosteal) chondroma

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Rare; usually 3 cm or less; surface of long bone or small bones of hand/feet

Usually teens to twenties, more common in males

Sites: metaphysis or shaft of tubular bones; may arise in zones lacking periosteum such as the femoral neck

Xray: well defined, 2-4 cm, sharply scallops outer cortex of underlying bone

Treatment: excision; may recur if incompletely excised

Case reports: 40 year old woman with femoral tumor (Archives 2003;127:e257)

Gross: single periosteal mass, often with internal calcifications

Micro: benign hyaline cartilage tumor covered by periosteum or reactive bone; hypercellular with variable myxoid features and binucleation; does not invade surrounding tissue, no mitotic figures

Micro images: Xray, H&E; image #1; #2

DD: periosteal chondrosarcoma (patients in 30’s, larger size, infiltrates soft tissues, aggressive appearance on Xray, similar histology), periosteal osteosarcoma (osteoid and spindle shaped malignant cells)

References: AJSP 1985;9:666, more information

Soft tissue (extraskeletal) chondromas

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Adults, hands and feet

Benign, but recur locally

Gross: lobulated, hyaline and calcified

Micro: lobulated on low power; clusters of plump tumor cells with fine punctate calcification; nuclear hyperchromasia and binucleation common; may have focal fibrosis; may have osteoclast-like giant cells, histiocyte-like cells, vacuoles resembling lipoblasts

DD: chondrosarcoma (rare in hands and feet), calcifying aponeurotic fibroma

Chondromyxoid fibroma

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Extremely rare benign bone tumor arising young adults

Age 15-25 years, no gender preference

Presents with dull, achy pain

Site: metaphysis of long tubular bones, small bones of feet or any bone, skull base (clivus)

Xray: extremely well circumscribed, lytic defect with scalloped, sclerotic margin similar to metaphyseal fibrous defect

Treatment: benign, 25% recur after curettage; fewer recurrences after en bloc excision; may erode through cortex but no distant metastases (AJSP 1979;3:363)

Case reports: 35 year old woman with tumor of frontal-sphenoid junction and orbital infiltration (Archives 1997;121:626)

Gross: 3-8 cm, well circumscribed, solid, glistening, yellow-white-tan, lobulated, zonation, "old" tumor more hyalinized; resembles hyaline cartilage; no myxoid change

Micro: well circumscribed, hypocellular lobules of poorly formed hyaline cartilage composed of chondroblasts with abundant pink cytoplasm and myxoid tissue with fibrous septae containing spindle cells and osteoclasts; more cellular at periphery of nodules; tumor cells present in lacunae in myxoid areas, stellate in myxoid areas with long delicate cell processes that approach other cells; atypia is common, including large, hyperchromatic nuclei; scattered calcification and osteoclast-like giant cells, although fewer giant cells in old tumors; extensive vascularity is present in peripheral areas; no/rare mitotic activity

Micro images: quiz case; images and text #1; #2

Positive stains: S100 (variable)

Negative stains (chondroid areas): muscle specific actin, smooth muscle actin, desmin, CD34 (but vessels stain)

Molecular: anomalies at 6q25 (Hum Path 2000;31:306) or 6q13 (Mod Path 1998;11:1071)

EM: myofibroblasts, chondrocytes and cells with features of both

DD: fibromyxoma (similar to chondromyxoid fibroma but no cartilaginous areas, usually older adults), chondroblastoma (cells are similar but not lobulated), chondrosarcoma (similar histology but malignant radiologically, no hypocellular center, infiltrates surrounding tissue), fibrous dysplasia with myxoid change (not lobulated)

References: Mod Path 1999;12:514, AJSP 1997;21:577 (skull base), Hum Path 1998;29:438, Hum Path 1989;20:952; more information

Mesenchymoma

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Also called cartilaginous and vascular hamartoma

Chest wall lesion of infancy; usually present at birth

Benign

Micro: primarily cartilaginous with chondroid areas exhibiting endochondral ossification mixed with spindle areas resembling aneurysmal bone cyst

Fibrocartilaginous mesenchymoma

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Rare, benign tumor of metaphysis of tibia or other long bones

Ages 9-25 years old

Treatment: excision, with high rate of recurrence but no metastases or death

Micro: spindle cells, bone trabeculae, islands of cartilage, some resembling epiphyseal plates

References: AJSP 1993;17:830

Malignant mesenchymoma of bone

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Rare, <50 cases reported

Two or more unrelated malignant mesenchymal elements other than fibrosarcoma or MFH

Case reports: rhabdomyosarcoma, chondrosarcoma and osteosarcoma within acetabulum (Archives 1990;114:614), 21 year old woman with tibial osteosarcoma and rhabdomyosarcoma (Mod Path 1997;10:1047)

Osteochondroma

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Also called exostosis

Most common benign bone tumor

50-75% males, mean age 10 years, usually age 20 years or less

Common; solitary or multiple

Slow growing, painful if impinges on nerve or stalk is broken; usually stops growing and ossifies at puberty

Benign, but 1-2% of solitary tumors and 5-25% of multiple tumors undergo malignant transformation to chondrosarcoma

May be neoplastic, due to mutations in EXT1 and EXT2 polymerases that add heparan sulfate to proteoglycans and appear to be tumor suppressor genes

Secondary chondrosarcoma: if grows during adolescence, > 8 cm, irregular cartilaginous cap > 3 cm or lucent zones within lesion, invasion of surrounding tissue

Multiple hereditary exostosis: also called osteochondromatosis; autosomal dominant disorder, abnormalities of 8q24.1, 11p11-12, 19; diagnosed during childhood; may see bowing of underlying bones, retarded growth; may have wide metaphyses; 0.5 to 5% of patients have evolution to chondrosarcoma

Sites: metaphysis, not medullary cavity; usually distal femur, proximal tibia, proximal humerus; occasionally pelvis, scapula, ribs; rarely digits; not in intramembranous bones

Xray: metaphyseal lesions grow in direction opposite to adjacent joint; cortex and medulla are continuous with underlying bone

Xray images: osteosarcoma arising in osteochondroma

Case reports: iliac tumor in 25 year old woman (Archives 2003;127:e355), osteosarcoma arising in radiologically benign solitary osteochondroma (Archives 1999;123:832), bursa formation in secondary chondrosarcoma (AJSP 1985;9:309); 19 year old woman with knee pain

Gross: cartilage-capped bony outgrowth up to 10 cm (mean 4 cm), attached to skeleton by bony stalk, not in medullary cavity; may have bursa around its head; cartilage cap usually regular and thin

Gross images: various images; with cartilage cap; quiz case

Micro: periosteum appears as pink fibrous capsule; cartilage resembles disorganized growth plate with ossification towards base; medullary cavity merges with that of underlying bone; bony trabeculae appear normal; normal appearing marrow; no spindle cells

Micro images: iliac crest Xray; CT; gross; H&E; various images; osteosarcoma arising in osteochondroma

DD: secondary chondrosarcoma (see above, usually well differentiated but with invasion into surrounding tissue), parosteal osteosarcoma (spindle cells between bony trabeculae), bizarre parosteal osteochondromatous proliferation

References: more information

Chondrosarcoma

Chondrosarcoma-general

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Malignant cartilage forming tumor that does not produce osteoid

May arise from osteochondroma

Third most common bone malignancy after myeloma and osteosarcoma

Divided into conventional (central, peripheral, juxtacortical/periosteal) and variants (clear cell, dedifferentiation, mesenchymal, myxoid)

Higher levels of platelet derived growth factor isoform AA and PDGF-alpha receptor are present in chondrosarcomas vs. enchondromas / mature joint cartilage; higher levels also in high grade vs. low grade chondrosarcoma (AJSP 2001; 25: 1520)

Chondrosarcoma-conventional

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Most common subtype of chondrosarcoma

Usually ages 30-60 years, 75% males

16% occur in patients age 20 years or less, may be higher grade and at different sites (AJSP 1987;11:930)

Often large painful tumors of long bones or ribs that grow rapidly during adolescence and reach 8 cm or larger

Associated with preexisting enchondroma, but not with chondroblastoma, osteochondroma, fibrous dysplasia or Paget’s disease

Childhood tumors usually involve extremities and are often chondroblastic osteosarcomas

Conventional tumors are divided by location into central, peripheral and juxtacortical/periosteal forms

Prognostic features: grading important for 5 year survival: well differentiated-78%, moderate-53%, poorly differentiated-22%; distant metastasis occur in 4% of well differentiated vs. 30% of higher grade tumors

Tumors often recur at a higher histologic grade

Poorly differentiated tumors are uncommon, recur locally due to satellite nodules; metastasize early to lungs, only rarely to lymph nodes

Sites: large bones - pelvis, ribs, femur, humerus, vertebrae; unusual in hands, feet, jaw, skull

Xray correlation: presume malignant if large tumor of long bones or grows rapidly during adolescence to 8 cm or more; have fluffy calcification, poorly defined margins, erosion or thickening of cortex; usually no periosteal new bone formation

Treatment: since often implants in soft tissue after biopsy, wide en bloc excision advocated except for well differentiated tumors, which are amenable to conservative therapy; patients may have local recurrence or metastases up to 20 years later

Case reports: with squamous cell carcinoma (Hum Path 1986;17:317)

Gross: pearly white or light blue, often with focal calcification; may have small cysts or myxoid change

Gross images: with Xray; anterior mediastinum; drawing

Micro: tumor cells produce cartilaginous matrix; either well, moderate or poorly differentiated; may have only minor or focal atypia, but consider malignant if malignant radiologic features (see above); no direct osteoid or bone formation by tumor cells (if present, classify as osteosarcoma, although may be non-neoplastic bone); intracytoplasmic hyaline globules common in low grade tumors (Hum Path 1994;25:1283)

Grading: based on cellularity and nuclear changes in chondrocytes; well, moderate or poorly differentiated correspond to grades 1-3; grade 4 is spindled tumor representing either chondroblastic osteosarcoma or dedifferentiated chondrosarcoma

Well differentiated: less cellular with only a few double nucleated cells and mild/moderate atypia; not well circumscribed, lobulated architecture with abundant cartilaginous matrix separated by narrow fibrovascular bands; tumor cells resemble chondroma; permeate existing trabecular bone and fill marrow space; lie in lacunar space surrounding hyaline cartilaginous matrix; malignant features more obvious at growing edge of tumor; may have reactive thickening of cortex

Poorly differentiated: marked hypercellularity, extreme pleomorphism with markedly hyperchromatic nuclei; bizarre tumor giant cells and small cells, frequent mitotic figures; usually mixed with other grades; tumor cells destroy cortex and form soft tissue mass

Micro images: grade 1 chondrosarcoma #1; #2; grade 2 chondrosarcoma #1; #2 (quiz case); #3 (quiz case); grade 3

Positive stains: S100 (nuclear and cytoplasmic); staining resembles adult cartilage in well differentiated tumors or fetal cartilage in poorly differentiated tumors; high grade tumors may be p53+

Negative stains: neural-type cadherin (Archives 2002;126:425)

Molecular: often 20q+, 8q+

EM: glycogen, lipid droplets, dilated cisternae of granular endoplasmic reticulum

DD: chondroma vs. well differentiated chondrosarcoma (Xray is determinative, for chondrosarcoma must see permeation of tumor through cortex into soft tissue), osteosarcoma (tumor cells make bone)

References: more information and images

Conventional - Central chondrosarcoma

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Located in medullary cavity, usually of flat or long bone

Sites: pelvic bones, ribs (at costochondral junction), shoulder girdle; rarely small bones of hands/feet, temporal bone of skull

Xray: osteolytic lesion with splotchy calcification, ill-defined margins, fusiform thickening of shaft, cortical perforation by tumor

Gross: rarely grow beyond periosteum

Conventional - Periosteal (juxtacortical) chondrosarcoma

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Much less common than periosteal chondroma

May arise secondary to osteochondromatosis

Involves shaft of long bone (usually femur)

Related to periosteal osteosarcoma

Rarely metastasizes; better prognosis than central chondrosarcoma

Xray: poor circumscription

Case reports: 13 year old girl with thigh mass (Archives 1997;121:70), 73 year old man with dedifferentiation in primary tibial tumor (Mod Path 1996;9:279)

Gross: usually 5 cm or larger

Micro: infiltrates soft tissue; cartilaginous lobular pattern, spotty calcification, endochondral ossification

DD: periosteal osteosarcoma

Conventional - Peripheral chondrosarcoma

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Arise from cartilaginous cap of pre-existing osteochondroma (10%) or de novo

Xray: large tumors with heavily calcified center, surrounded by less dense periphery with splotchy calcification

Chondrosarcoma-clear cell

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Rare; usually age 15-25 years, more common in males

Epiphyses of long tubular bones

May represent malignant counterpart of chondroblastoma

Have relatively low grade behavior, with 15% mortality at Mayo Clinic; may undergo dedifferentiation

Sites: proximal femur or humerus

Xray: lytic lesion, slightly expansile, sharply marginated, may appear benign, may be heavily mineralized

Treatment: en bloc resection with a margin of normal bone and soft tissue

Micro: lobules of tumor cells with sharply defined borders, clear or ground-glass cytoplasm with vacuoles, central nuclei with occasional prominent nucleoli, numerous osteoclast-type giant cells, often mixed with small trabeculae of reactive bone; 50% also contain conventional low-grade chondrosarcoma; may have secondary aneurysmal bone cyst changes

Micro images: image #1; #2

Positive stains: S100

EM: chondroid cells in various stages of differentiation

DD: chondroblastoma

References: AJSP 1984;8:223, Hum Path 1996;27:1301 (has chondrocytic differentiation)

Chondrosarcoma-dedifferentiated

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Coexistence of well differentiated (low grade) cartilaginous component and high grade anaplastic component

More common in recurrent versus primary tumors

Older patients than other spindle cell sarcomas of bone

Often in pelvic and shoulder girdles

Xray: resembles chondrosarcoma with areas of highly aggressive tumor

Poor prognosis, even if arise in osteochondroma; 5 year survival of 10% to 35% (pelvis)

Case reports: with rhabdomyosarcomatous component (Hum Path 1985;16:318)

Gross: cartilage tumor adjacent to fish-flesh appearance of sarcoma

Micro: high grade spindle cell sarcoma at periphery of typical low grade chondrosarcoma with abrupt change, usually central; has features of malignant fibrous histiocytoma, rhabdomyosarcoma, fibrosarcoma, osteosarcoma, undifferentiated sarcoma (different from pre-existing chondrosarcoma)

Micro images: dedifferentiated chondrosarcoma #1; #2; #3 (quiz case); #4 (quiz case); case report (FNA); various images

Positive stains: alpha-1-antichymotrypsin, actin, desmin, myoglobin, p53, variable S100

Negative stains: keratin (usually)

DD: chondroblastic osteosarcoma (gradual transition from high grade cartilaginous tumor to spindle cell sarcoma, young patients)

References: Hum Path 1982;13:36, AJSP 1996;20:293 (rhabdomyosarcomatous differentiation)

Chondrosarcoma-mesenchymal

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Cartilaginous tumor with primitive component composed of mesenchymal cells at condensation stage

Rare; usually teenagers or young adults; no significant gender preference

Unpredictable prognosis; may have short or prolonged survival after metastases

Initial study suggests Sox9 is specific for this tumor versus other small blue cell tumors (Hum Path 2003;34:263)

Sites: diaphysis of jaw, pelvis, femur, ribs, spine; often involves extraosseous structures such as orbit, paraspinal region, meninges, extremity soft tissue

Xray: resembles conventional chondrosarcoma

Gross: pink, fleshy, with calcification; resembles other sarcomas

Micro: dimorphic pattern of well differentiated cartilage with abrupt boundary from undifferentiated stroma composed of small round/oval cells resembling lymphoma, hemangiopericytoma or Ewing’s sarcoma/PNET; occasional spindle cells; minimal pleomorphism, no/rare mitotic figures

Micro images: mesenchymal chondrosarcoma (may be extra-skeletal)

Positive stains: vimentin, CD57/Leu7, neuron specific enolase, CD99/MIC2 in small round blue cells (Hum Path 1996;27:1273)

Negative stains: S100 (positive only in chondroid areas), desmin, actin, cytokeratin, EMA, synaptophysin

Molecular: translocation der(13;21)(q10:q10) identified in 2 patients with skeletal and extraskeletal tumors (Mod Path 2002;15:572)

DD: small blue cell tumors (Ewing’s/PNET, lymphoma, small cell osteosarcoma; all usually lack chondroid lobules)

References: Archives 1990;114:943 (staining pattern resembles embryonic cartilage)

Chondrosarcoma-myxoid (chordoid)

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Occurs in bone or soft tissue

Micro: rows of cuboidal cells in myxoid background, resembling chordoma

Positive stains: S100, vimentin

Negative stains: keratin

EM: resembles conventional chondrosarcoma

DD: chordoma (different site, keratin+)

Chondrosarcoma-secondary

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Approximately 10-15% of chondrosarcomas arise secondary to a preexisting condition, including exostosis (solitary or multiple), chondrodysplasia, multiple chondromas

Usually low grade with excellent prognosis

Patients usually younger than conventional chondrosarcoma

Usually presents as change in size or symptoms of preexisting lesion

DD: chondroblastic osteosarcomas (more common in children)

Hematologic neoplasms

General

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40% of bone tumors, usually myeloma or lymphoma

Lymphoma-general

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7-12% of bone malignancies

Diagnosis of primary lymphoma of bone (which has excellent prognosis) requires no evidence of lymphoma found elsewhere within 6 months after diagnosis

Variable ages, often in bones with marrow

Often presents with bone pain and systemic symptoms

Xray: destructive permeative process involves extensive areas of bone with lytic and sclerotic lesions

Bone scans usually positive

Per Dr. Unni, stage is more important than histologic subtype

Prognosis: excellent if confined to bone, no evidence of other disease after staging and no evidence of lymphoma after 6 months; also excellent if involvement only of skeletal sites; poor prognosis if involvement of lymph nodes or if known primary is elsewhere

Gross: fish-flesh; rarely minimal tumor associated with markedly sclerotic bone that requires extensive decalcification

Micro: diffusely infiltrates marrow, sparing trabeculae; often significant crush artifact; usually diffuse large B cell type

DD: chronic osteomyelitis (has granulation tissue, no atypia), granulocytic sarcoma (CD45+, CD43+, myeloperoxidase+, lysozyme+, CD20-), carcinoma (keratin+, clinical history)

References: more information

Acute leukemia

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70-90% of cases have bone lesions, usually diffuse

References: more information

Anaplastic large cell lymphoma

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Rare involvement in bone

T cell or null cell origin

Mean age 33 years, range 4-63 years, 2/3 male

Poor prognosis, even if ALK positive

Xray: osteolytic lesions, often multiple; may involve axial bones

Case reports: 71 year old man with rib tumor (Archives 2000;124:1339)

Micro: anaplastic, pleomorphic large cells; monomorphic variant has large cells that are not bizarre or lobulated

Micro images: large pleomorphic tumor cells; CD30+, EMA+, granzyme B+, Alk1+; H&E, CD30+, Alk+; C: anaplastic cells surrounded by neutrophils, D: CD30+

Positive stains: CD30, ALK, EMA, granzyme B

Negative stains: EBV

Molecular: t(2;5)(p23;q35)

Molecular images: FISH

References: Mod Path 2000;13:1143

Burkitt’s lymphoma

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Massive jaw involvement in cases from Africa

Also involves long bones and pelvis

Diffuse large B cell lymphoma

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Primary disease defined as lymphoma presenting in bone with no evidence of disease elsewhere for at least 6 months after diagnosis

Usually adults, median age 44 years, 80% male in one study

Sites: usually long bones of extremities, but can involve any site

Xray: large area of bone destruction and production, resembling osteomyelitis

5 year survival: 50-75%, stage most important predictive factor; 50% have germinal center like phenotype (bcl6+, CD10+), which is associated with improved survival (AJSP 2003;27:1269)

Treatment: radiation therapy, chemotherapy

Case reports: 70 year old man with iliac involvement (Archives 2003;127:e323)

Gross: pink-gray tumor in diaphysis or metaphysis of long bone, with patchy cortical and medullary destruction; often soft tissue extension; variable periosteal reaction

Micro: typical pattern of pleomorphic large centroblastic cells with well defined cell borders, abundant cytoplasm, multilobated nuclei and prominent nucleoli; frequent mitotic figures, may have prominent fibrosis

Micro images: (1) technetium bone scan, H&E, CD20; (2) A: multilobulated nuclei, B: immunoblastic features; (3) H&E, bcl6+, bcl2+, p53+

Positive stains: CD20, CD19, CD22, CD79a, CD45/LCA, reticulin surrounds individual cells and groups of cells, bcl2 (70%); p53 (55%), bcl6 (30%), variable CD30

Negative stains: CD138

DD: Ewing’s sarcoma/PNET (syncytium of smaller cells with minimal cytoplasm, uniform nuclei, no indented nuclei, no prominent nucleoli)

References: Mod Path 2001;14:1000

Hodgkin’s lymphoma

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Bone lesions in 15% of patients, 60% are multifocal; often asymptomatic and late manifestation

Sites: vertebrae, pelvis, ribs, sternum, femur; also nodal involvement (often paraaortic)

Xray: osteolytic, osteoblastic, mixed; vertebral lesions often osteoblastic

Micro: mixed cell infiltrate with rare pleomorphic cells

Positive stains: CD15, CD30

Negative stains: CD45 / LCA

References: more information

Lymphoblastic lymphoma

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Pre-B lymphoblastic lymphoma may present as solitary bone tumor

Positive stains: TdT, CD43, CD99, CD79a; CD20 (variable), keratin (focal, granular)

Negative stains: CD3, CD45 (often)

DD: Ewing’s sarcoma

References: AJSP 1998;22:795

Mastocytosis

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Uncommon, disorders with abnormal growth or accumulation of mast cells

Often appears as skin lesions (urticaria pigmentosa) in children, who have favorable prognosis

WHO classification: cutaneous mastocytosis, indolent systemic mastocytosis, systemic mastocytosis with clonal hematologic non-mast cell lineage disease, aggressive systemic mastocytosis, mast cell leukemia, mast cell sarcoma, extracutaneous mastocytoma

Systemic mastocytosis

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Due to transformed myelomastocytic bone marrow progenitor cells

Variable symptoms of diarrhea, weight loss, weakness, fractures or osteoporosis in 25%, arthralgia, flushing, bronchospasm

Bone marrow is site most commonly affected other than skin

Xray: 60% show diffuse osteoporosis or focal osteolysis and osteosclerosis

Prognosis: variable, poor if mast cell leukemia

May have associated malignancies

Diagnosis: one major and one minor criteria; or three minor criteria

Major diagnostic criteria: multifocal dense infiltrates of mast cells (15 or more mast cells in aggregates detected in sections of bone marrow or other extracutaneous organs and confirmed by tryptase immunohistochemistry)

Minor diagnostic criteria: (1) in biopsy of bone marrow or other extracutaneous organs, more than 25% of mast cells are spindle shaped or have atypical morphology, or, of all the mast cells in bone marrow smears, more than 25% are immature or atypical mast cells; (2) detection of KIT point mutations at codon 816 in extracutaneous organs, blood or bone marrow; (3) mast cells in bone marrow, blood or other extracutaneous organs that co-express CD117 with CD2 or CD25; (4) serum total tryptase of 20 ng/ml or more, unless there is an associated clonal myeloid disorder (then this parameter is invalid)

Case reports: 82 year old woman presenting with bone marrow eosinophilia (Hum Path 1994;25:727), 24 year old man following mediastinal germ cell tumor (Hum Path 1993;24:111), 14 year old girl with multiple upper extremity nodules (with images), with flow cytometry data, IgD myeloma

Micro: paratrabecular aggregates resembling microgranulomas of oval / spindled cells with clear cytoplasm and distinct cell outlines resembling hairy cell leukemia; associated with eosinophils and thickened bone; focal lesions may be perivascular and associated with medial or adventitial hypertrophy and collagen fibrosis

Micro images: mast cells in bone marrow #1; #2

Positive stains: mast cells - tryptase, chymase, CD25 (AJSP 2004;28:1319), CD68 and lysozyme (nonspecific)

Negative stains: myeloperoxidase, CD20

Molecular: c-kit mutations

References: AJSP 1998;22:1132 (tryptase immunostains), more information

Myeloid sarcoma of bone

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Also called extramedullary myeloid tumor, granulocytic sarcoma

Extramedullary tumor mass of neoplastic immature myeloid (granulocytic or monocytic) cells

Often misdiagnosed, particularly without immunostains

Present in 2-8% of AML patients; prognosis is that of underlying leukemia

Equivalent to blast transformation in setting of myelodysplastic syndrome or myeloproliferative disease (Korean J Lab Med 2006;26:143)

Rarely no leukemia/myelodysplasia is identified in blood or bone marrow (J Neurosurg 2006;105:916)

Case reports: Case of the Week #130 (bone)

Treatment: aggressive treatment recommended (Leukemia 2007;21:340, Cancer 2002;94:1739), usually evolves to AML or has additional tumor masses at other sites

Gross images: bone tumor

Micro: myeloid tumors - blastic type has myeloblasts with mild/moderate rim of basophilic cytoplasm, fine nuclear chromatin, 2-4 nucleoli; immature type has myeloblasts, promyelocytes and eosinophilic myelocytes; differentiated type has promyelocytes, eosinophilic myelocytes and more mature forms; rarely crystalline inclusions similar to Charcot-Leyden crystals (Archives 2002;126:85)

Cytology: usually background lymphoglandular bodies; Auer rods and eosinophilic myelocytes are rare; resembles large cell lymphoma (Cancer 2000;90:364)

Micro images: differentiated (left) versus blastic types (center and right)-site unknown; various images #1; #2

Myeloid sarcoma - bone chapter - continued

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case of the week (bone) - #1; #2; #3; #4; CD45/LCA; CD45RO; CD3; CD34; CD20

other - orbital mass with t(8;21) has blasts with immature eosinophils

stains: chloroacetate esterase-lymph node #1; #2; lysozyme-orbit; myeloperoxidase #1-lymph node; #2-lymph node; #3-mediastinum; #4-breast (left), CD43 (right); CD68 #1-spine; #2-uterus

Positive stains: almost all tumors - lysozyme and CD43; myeloid tumors - myeloperoxidase and CD117; myeloblasts - CD13, CD33 (Archives 2001;125:1448); monocytic tumors - CD68 and variable CD163 (AJCP 2004;122:794); monoblasts - CD14, CD11c (Diagn Pathol 2007;2:42), CD56 (AJCP 2000;114:807) HLA-DR, CD99 (55%, Mod Path 2000;13:452), chloroacetate esterase (Ann Saudi Med 2001;21:287)

Negative stains: CD3, CD20, CD79a, CD34

Cytogenetics: most common are monosomy 7 (11%), trisomy 8 (10%) and MLL rearrangements (9%)

DD: poorly differentiated lymphoma, Burkitt’s lymphoma, small round cell tumors

Myeloma of bone

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Also called multiple myeloma, plasma cell myeloma

Neoplastic proliferation of plasma cells with multifocal skeletal involvement

Most common bone neoplasm (40% of total, 50% of malignancies), usually diagnosed by marrow aspiration and biopsy

Clinical: Usually older patients (rare before 40 years), 2/3 male, with widespread skeletal lytic lesions, pathologic fractures and back pain; also weakness, normochromic normocytic anemia with rouleux formation, pallor, hepatosplenomegaly, hypercalcemia, primary amyloidosis (AL type) and renal insufficiency due to toxicity of light chains (Bence Jones proteins) to renal epithelium

Causes 1% of cancer deaths in Western countries, African Americans > Whites

Infections common (due to impaired humoral immunity) with Streptococcus pneumoniae, Staphylococcus aureus, E coli; cellular immunity is normal

Hyperviscosity syndrome present in 7%, usually due to IgA or IgG3

Most patients have elevated serum levels of IL-6; many are also infected with HHV8

Sites: multifocal involving vertebral column, ribs, skull, pelvis, sternum; begins in medulla, then erodes cortical bone

Can spread to skin, lymph nodes

Xray: multiple, punched out defects, associated with generalized osteoporosis, not associated with sclerosis

Xray images: prominent skull defect #1; #2; #3; vertebral lesion

Prognosis: poor; < 1 year if multiple lesions and no treatment; many years if indolent

Median survival is 3 years with chemotherapy; 10% survive 10 years

Poorer prognosis if plasmablastic morphology, CD10+

Cell of origin is less differentiated than plasma cells; expresses antigens associated with myelomonocytes (CD33), megakaryocytes (GpIIb/IIIa), erythroid cells (glycophorin)

Laboratory: Monoclonal secretion of immunoglobulins > 3g/dl in serum or 6 mg/dl in urine of Bence Jones proteins, usually IgG (55%) or IgA (25%), appearing as a monoclonal spike in serum or urine electrophoresis; may create falsely positive elevated hemoglobin (Archives 2000;124:616)

Serum protein electrophoresis images: monoclonal gammopathy #1; #2; #3

Serum protein immunofixation images: IgD lambda myeloma in 68 year old woman

In 20% of cases, only monoclonal light chains (Kappa or Lambda) are present, usually in urine

Rouleux formation in peripheral smear (erythrocytes resemble stacked coins) is due to protein present, parallels erythrocyte sedimentation rate

Flow cytometry images: prominent monotypic pattern (in this case lambda, with minimal kappa)

M component: monoclonal immunoglobulin, up to 160kd, restricted to plasma and extracellular fluid

Prognostic factors: Cyclin D1 expression is associated with advanced stage and grade (AJCP 2001;116:535); IgD form is aggressive (and rare); high IL-6 levels associated with poor prognosis

Treatment: alkylating agent chemotherapy, bone marrow transplantation, anti-topoisomerase II alpha agents

Note: highly proliferative tumors usually are topo II alpha positive and sensitive to anti-topo II alpha agents

Case reports: plasmablastic transformation at terminal phase (Hum Path 2003;34:710), association with sarcoidosis (Archives 2002;126:365)

Myeloma of bone (continued)

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Gross: multiple masses of soft, red, currant jelly like material throughout the skeletal system; may resemble lymphoma; generalized osteoporosis

Gross images: vertebrae with myeloma lesions #1; #2; skull lesions #1; #2; bony lesions

Micro: plasma cells to plasmablasts; all cells have large nuclei, may be multinucleated; often with prominent nucleoli, perinuclear hof (due to prominent Golgi apparatus), Mott Cells (blue grapelike inclusions), Russell bodies (cytoplasmic crystalline rods), Dutcher bodies (intranuclear crystalline rods), hyaline inclusions, vacuoles or granules; also sinusoidal vascular pattern; 10% have amyloid in vessel walls or as masses

“Flaming” plasma cells: fiery fringes formed by pseudopodic cytoplasmic projections that are carmine red after Wright-Giemsa staining; peripheral cytoplasm has numerous dilated endoplasmic reticulum cisterns distended with immunoglobulin that may fragment and appear around the cell; associated with IgA myelomas (Archives 2001;125:1394)

Bone marrow biopsies should have >10% plasma cells to diagnose myeloma

Micro images: low power bone marrow; high power bone marrow #1; #2; #3; bone marrow smear #1; #2; #3; flame cell; hemangioma-like; prominent lambda staining #1; #2; prominent kappa staining; plasma cells forming rosettes; sarcoidosis and myeloma

Virtual slides: myeloma #1; #2

Peripheral blood images: plasma cell; plasma cells with blastic features

Positive staining: kappa or lambda light chains (usually one markedly more than the other), CD38 (plasma cells), CD79a, CD138, variable EMA, variable CD10

Negative stains: keratin, CD45 / LCA, CD19, CD20

Molecular: 13q-, 14q, rearrangements common

t(4;14)(p16.3;q32) in 25% of cases, causing increased expression of FGFR3 (fibroblast growth factor receptor 3) and IgH

t(11;14)(q13;q32) [cyclin D1]: usually part of complex karyotype; may be missed by routine cytogenetics, particularly if the proliferative rate is low (AJCP 2000;113:831)

DD: reactive synovitis with Dutcher bodies (Archives 2002;126:199, image), osteomyelitis with plasma cell predominance (other inflammatory cells, capillary proliferation, plasma cells not monoclonal), metastatic carcinoma, lymphoma

References: more information

Variants:

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Indolent multiple myeloma: similar to smoldering but with a few bone lesions and mild anemia; most develop overt multiple myeloma within 3 years

Multilobated nuclei: <20 cases reported through 1998; associated with light-chain disease

Aggressive with shorter survival, more renal failure, lytic bone disease, hypercalcemia, amyloidosis

Micro: either mature plasma cells, multinucleated plasma cells or cells with multilobated, cleaved, or monocytoid nuclei; markedly irregular nuclear contours or nuclear lobulation similar to neutrophils

Micro images: multilobated nuclei; kappa light chain staining

DD: metastatic carcinoma, T-cell lymphoma, myelomonocytic leukemia, megakaryocytes, neutrophils, histiocytes

References: Archives 2001;125:1249 (multilobated nuclei)