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Bone chapter (nontumor and tumor)
See also Bone marrow-nonneoplastic, Joints, Mandible/maxilla
Reviewers: Dariusz Borys, M.D., David Lucas, M.D. (see Reviewers page)
Revised: 8 June 2013, last major update IN PROGRESS
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.
Table of contents
Primary references normal anatomy normal histology bone formation & growth biopsy
Developmental
abnormalities: achondrogenesis achondroplastic dwarfism fibrodysplasia ossificans progressiva malformations scoliosis syndromes thanatophoric dwarfism
Osteomyelitis: general amebic bacterial chronic multifocal echinococcus fungal syphilitic tuberculous xanthogranulomatous
Non-neoplastic
or metabolic disease: aseptic bone necrosis black bone black cartilage cartilaginous rest fracture giant cystic arachnoid granulations glomus coccygeum hyperostosis cranii ex vacuo hyperparathyroidism hypophosphatasia infarct metal toxicity mucopolysaccharidoses necrosis osteogenesis imperfecta osteopathia striata osteopetrosis osteopoikilosis osteoporosis Paget’s disease radiation necrosis renal osteodystrophy rickets / osteomalacia SAPHO syndrome
Fibrous/fibroosseous
tumors of bone: cortical irregularities of femur fibrous dysplasia fracture callus liposclerosing myxofibrous tumor metaphyseal fibrous defect myositis ossificans ossifying fibroma osteofibrous dysplasia post-traumatic
Bone
forming tumors (not osteosarcoma): general adamantinoma metastatic calcification ossifying fibromyxoid tumor osteoblastoma osteoid osteoma osteoma
Osteosarcoma: osteosarcoma-general chemotherapy effect anaplastic epithelioid fibrohistiocytic high grade surface low grade central osteoblastoma-like Paget’s disease associated parosteal periosteal small cell telangiectatic well differentiated intramedullary
Cartilage forming tumors (not chondrosarcoma): bizarre parosteal osteochondromatous proliferations chondroblastoma chondroma chondromyxoid fibroma mesenchymoma osteochondroma
Chondrosarcoma: chondrosarcoma-general conventional clear cell dedifferentiated mesenchymal myxoid secondary
Hematologic neoplasms: general lymphoma-general acute leukemia anaplastic large cell lymphoma Burkitt’s lymphoma diffuse large B cell lymphoma Hodgkin’s lymphoma lymphoblastic lymphoma mastocytosis myeloid sarcoma myeloma plasmacytoma
Vascular tumors: angiosarcoma epithelioid hemangioendothelioma glomus tumor hemangioma hemangioendothelioma hemangiopericytoma lymphangioma
Other
tumors of bone: amyloid aneurysmal bone cyst benign fibrous histiocytoma benign notochordal cell tumors brown tumor of hyperparathyroidism chest wall hamartoma chordoma cyst of degenerative joint disease desmoplastic fibroma desmoplastic small cell tumor ecchordosis physaliphora epidermoid inclusion cyst Erdheim-Chester Ewing’s/PNET fibrosarcoma ganglion cyst of bone giant cell granuloma giant cell tumor implant related sarcoma infantile myofibromatosis inflammatory myofibroblastic tumor Langerhans cell histiocytosis leiomyosarcoma lipoma liposarcoma malignant fibrous histiocytoma malignant peripheral nerve sheath tumor massive osteolysis meloreostosis metastases to bone myofibrosarcoma myxoma neurofibroma osteitis fibrosa cystica osteochondromyxoma phosphaturic mesenchymal tumor post-radiation sarcoma rhabdomyosarcoma schwannoma sinus histiocytosis with massive lymphadenopathy solitary bone cyst solitary fibrous tumor subungual exostosis subungual keratoacanthoma xanthoma
Miscellaneous: staging-not myeloma staging-myeloma features to report grossing
top
AJCC Cancer Staging Manual (7th ed)
American Journal of Clinical Pathology
American Journal of Surgical Pathology
Archives of Pathology and Laboratory Medicine
Human Pathology
Modern Pathology
Websites: PathoPic, www.BoneTumor.org
Please refer to these primary references for more detailed discussions and photographs
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; 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
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
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: 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
Non-neoplastic or metabolic disease
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
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)
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)
Causes: aluminum (from antacids), iron, fluoride
Micro: increased osteoid, but well demarcated mineralization front and minimal osteoblasts
Positive stains: aurintricarboxylic acid highlights aluminum
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)
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
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
Also called Voorhoeve’s disease
Rare; benign, usually painless
Xray: longitudinal dense striations in affected bones
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: 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
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
References: more information
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
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
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)
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
Skeletal changes of chronic renal disease (see also hyperparathyroidism)
Increased osteoclastic bone resorption resembling osteitis fibrosa cystica
Associated with osteomalacia, osteosclerosis, growth retardation, osteoporosis
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
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
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
Formerly called periosteal desmoid, but not neoplastic
No clinical significance
Xray: small irregularities in distal cortex of femur
Micro: bland fibrous tissue
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)
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
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
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
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
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
Exophytic variant in which lesions protrude far beyond normal bone contour, mimicking surface bone lesions
References: Hum Path 1994;25:1234
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
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
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
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: florid reactive periostitis
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)
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
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
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
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
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)
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)
Osteosarcoma
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: large and bulky lesion; 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; 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
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
Micro: bizarre and undifferentiated tumor cells with malignant osteoid
DD: metastatic carcinoma, pleomorphic sarcoma
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
Micro: resembles malignant fibrous histiocytoma but with malignant osteoid
High grade surface osteosarcoma
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
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)
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
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
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
<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)
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
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
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
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
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
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
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
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
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
Metaphysis of long bones with massive tumoral calcification
Juxtacortical (periosteal) chondroma
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
Soft tissue (extraskeletal) chondromas
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
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
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
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
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)
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; 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; 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
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)
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: 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
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
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
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
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
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
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)
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)
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)
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+)
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
40% of bone tumors, usually myeloma or lymphoma
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
70-90% of cases have bone lesions, usually diffuse
References: more information
Anaplastic large cell lymphoma
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
Massive jaw involvement in cases from Africa
Also involves long bones and pelvis
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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
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
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
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
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
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
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
See Staging
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)
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:
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)
Nonsecretory multiple myeloma: rare, no monoclonal protein in serum or urine, but do have typical myeloma osteolytic lesions and bone marrow plasmacytosis; no renal failure or hypercalcemia; diagnose based on monoclonal protein in plasma cells via immunostaining
Osteosclerotic multiple myeloma: component of rare POEMS [Crow-Fukase] syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal IgM gammopathy and skin lesions); single or multiple bone lesions; bone tissue consists of plasmacytoma surrounded by sclerotic bone; patients younger than classic myeloma with protracted clinical course
Plasma cell leukemia (primary)
Primary if initial diagnosis is based on leukemic phase of myeloma, otherwise secondary
2% of myeloma patients; associated with younger age, hepatosplenomegaly, lymphadenopathy
More commonly IgD, IgE or light chain only myeloma than myeloma in general
Lymphadenopathy and organomegaly more common than myeloma in general
Poor prognosis
Diagnosis: plasma cells are >20% of white blood cells in peripheral blood or absolute count is 2 x 109 or more
Micro: hypercellular and diffusely infiltrated marrow
Smoldering multiple myeloma: myeloma patients with stable disease for months/years; no anemia, no bone lesions, no renal insufficiency, no hypercalcemia; have >10% plasma cells in bone marrow and monoclonal serum protein
Vascular tumors of bone
Also called hemangioendotheliomas in bone, although angiosarcomas have more cytologic atypia
Rare; may be multicentric
1/3 affect long tubular bones, but any bone may be affected
1/3 are multifocal, usually in one geographic area, such as an entire leg
After diagnosis, search for multicentricity
Distant metastases common, often to lungs
Graded 1-3 based on atypia of endothelial cells
Grade 1 have excellent prognosis vs. poor prognosis for grade 3
Xray: lytic areas of destruction, with minimal/no reactive new bone formation
Gross: red, hemorrhagic
Micro: obvious atypia of tumor cells, solid areas alternating with irregular, anastomosing vascular channels; necrosis and hemorrhage, brisk mitotic activity; variable differentiation often within same tumor; may be epithelioid or histiocytic; may have benign giant cells, eosinophils, occasionally reactive bone formation
Positive stains: factor VIII related antigen, CD31
EM: endothelial cell features, may have pericytic features
DD: telangiectatic osteosarcoma, metastatic renal cell or other carcinoma, hemangioma (no atypia)
References: Hum Path 2003;34:680, more information
Epithelioid angiosarcoma
80% male, mean age 62 years, range 26-83 years
60% multifocal
Aggressive clinical course
Definition: >90% of tumor cells have epithelioid features
Case reports: 48 year old with humerus tumor (Hum Path 1997;28:985)
Gross: friable, hemorrhagic, destructive tumor, 2-12 cm; poorly defined, infiltrates medullary canal, frequently erodes cortex and invades adjacent soft tissue
Micro: solid and infiltrative sheets replacing the marrow and encasing bony trabeculae; no lobular growth pattern; usually with prominent vascular channels or cystically dilated spaces; tumor cells are large, polygonal with abundant eosinophilic cytoplasm, large nuclei with open chromatin, prominent eosinophilic nuclei; frequent intratumoral hemorrhage, neutrophils, intracytoplasmic lumina; frequent mitotic figures and necrosis; may have rhabdoid or spindled features
Positive stains: CD31, factor VIII related antigen, cytokeratin (often), CD34 (variable)
Negative stains: EMA
EM: long junctions, intracytoplasmic filaments, mitochondria, rough endoplasmic reticulum; may contain rare Weibel-Palade bodies
DD: metastatic carcinoma (no well formed vascular channels, no neutrophils; negative for factor VIII, CD31 and CD34); mucin+ cytoplasmic vacuoles
References: AJSP 2003;27:709
Epithelioid hemangioendothelioma
Inconsistent use by pathologists - some include epithelioid hemangiomas or angiosarcomas
Better use is to define as borderline or low grade malignancy affecting bone, soft tissue, liver, lung
Rare tumor
22-55% are multicentric, may be associated with nearby skin or soft tissue lesions
Associated with pain
Xray: osteolytic appearance without bony expansion, may have peripheral sclerosis; infiltration is associated with higher-grade lesions
Sites: femur, occasionally vertebrae
Poor prognostic factors: visceral involvement
Treatment: surgical excision, may respond to radiation therapy
Case reports: first cervical vertebrae of 17 year old girl (Archives 2001;125:1611)
Micro: cohesive growth pattern of cells with eosinophilic and often cytoplasmic vacuolization, some vacuoles contain erythrocytes; vesicular nuclei, some with prominent grooves, mild atypia; recent and old hemorrhage; variable eosinophils, vasoformative features may be primitive and accompanied by myxohyaline stroma; no/rare mitotic activity, no anastomosing channels
Micro images: epithelioid cells with cytoplasmic vacuoles
Positive stains: CD31, CD34, factor VIII related antigen
Negative stains: mucin (Alcian blue, mucicarmine, PAS), S100, cytokeratin
DD: metastatic carcinoma, chordoma (destructive lobulated pattern and multivacuolated physaliferous cells, keratin+, S100+), epithelioid hemangioma (well formed vascular spaces)
References: AJSP 1996;20:1301, more information
Bone involvement usually secondary to erosion of soft tissue (subungual) tumor
Rarely is a primary bone tumor, usually in terminal phalanx
Case reports: tumor of coccyx (Archives 1991;115:78)
Micro images: image; smooth muscle actin+
References: more information
Most common vascular tumor of bone
Identified in vertebrae in 12% of autopsies, 34% are multiple
Usually incidental finding; ages 20-50 years, no definite gender preference
May actually be vascular malformations, not neoplasms
Multiple bony hemangiomas more common in children, associated with cutaneous, soft tissue or visceral hemangiomas
Sacral hemangiomas in infants associated with congenital anomalies
Xray: sunburst appearance due to trabecular bone, particularly in spine and skull; nonspecific in long bones
Sites for clinically significant hemangiomas: skull, vertebrae (causing spinal cord compression), jaw; occur in marrow
Gross: elevation of periosteum; currant jelly cut surface
Gross images: cavernous hemangioma #1; #2; #3
Micro: thick walled lattice-like pattern of vessels; either capillary or cavernous; often with reactive new bone formation; no endothelial atypia
Micro images: capillary hemangioma #1; #2
DD: osteoblastoma, hemangioendothelioma
References: more information
Epithelioid hemangioma
Rare; usually affects long tubular and flat bones, but may occur in any bone
Also occurs in skin and subcutis
Mean age 34-46 years, range teens to 70’s
25% multifocal
Xray: lytic or blastic, well defined or poorly circumscribed margins
Treatment: curettage, excellent prognosis
Gross: 2-15 cm; well circumscribed, soft, dark red, limited to medullary cavity
Micro: replaces marrow, surrounds bony trabeculae, erodes cortex, may have soft tissue component; lobular growth pattern; epithelioid cells line well formed vessels, but may also grow in sheets and cords; nuclei are grooved, vesicular, may have prominent nucleoli; no severe nuclear atypia; abundant eosinophilic cytoplasm, often with vacuoles; < 5 mitotic figures/10 HPF; stroma is loose connective tissue with lymphocytes, eosinophils, extravasated red blood cells
Positive stains: EMA, factor VIII related antigen, Ulex europeus; variable CD31, CD34, keratin
DD: epithelioid hemangioendothelioma
References: AJSP 1993;17:610
Some lump together with angiosarcoma
See also epithelioid hemangioendothelioma above
<100 cases reported
Borderline or intermediate grade malignancy
Wide age distribution
Often multiple, associated with similar skin and soft tissue lesions located nearby
Prolonged clinical course; only rarely metastases
Tend to develop in long tubular bones, but may occur in any bone; 50% are multifocal
Xray: lytic, expansile, may erode cortex and infiltrate soft tissue; variable margins
Treatment: curettage, en bloc resection and radiotherapy; protracted clinical course with 20% dying of disease
Gross: 2-10 cm, solid, tan-white
Micro: sheets or cords of epithelioid or histiocyte-like epithelial cells with abundant eosinophilic cytoplasm, often vacuolated, with large vesicular nucleus, nuclear atypia less than angiosarcoma; variable nuclear grooves, rare/no mitotic activity, well formed vessels but no/rare anastomosing channels, new/old hemorrhage, no lobular growth pattern; stroma is hyalinized or basophilic, may appear chondroid, variable eosinophilic and lymphocytic infiltrate, may have osteoclast-like giant cells
Positive stains: CD31, CD34, factor VIII related antigen (usually)
Negative stains: keratin (usually)
References: Hum Path 2003;34:680
Most common site is pelvis
Benign or malignant behavior
Case reports: tumor of sternum (Archives 1991;115:242)
Micro: uniform round/oval cells arranged around deformed vascular spaces
Micro images: spindle cells arranged around large, irregularly shaped vessels; reticulin surrounds each tumor cell (reticulin stain)
DD: metastatic hemangiopericytoma from meninges
References: AJSP 2004;28:1; more information
Very rare
Usually multiple, associated with soft tissue lymphangioma
Often infants and children
May lead to death due to lung involvement and chylothorax
References: AJSP 1993;17:329
Other tumors of bone
Rare; due to massive destructive deposition of AL amyloid in bone
Micro: large, rounded deposits of amorphous eosinophilic material surrounded by giant cells
References: AJSP 1997;21:179
Aneurysmal bone cyst (ABC)
Uncommon; expanding osteolytic lesion of blood-filled spaces of variable size separated by connective tissue septa with osteoclast giant cells and variable reactive bone
Usually ages 1-20 years, no gender preference
Benign but grows rapidly; simple curettage is followed by recurrence in 20%; rarely transforms to osteosarcoma
Sites: metaphysis of posterior vertebrae (often multiple), flat bones, shaft of long bones; rarely within wall of major artery or in soft tissue (AJSP 2002;26:64, AJSP 1994;18:632, AJSP 1993;17:1062)
May also be secondary to trauma or arise in preexisting bone lesion (giant cell tumor, chondroblastoma, fibrous dysplasia)
Xray: eccentric expansion of bone, cortical erosion and destruction, small peripheral area of periosteal bone formation; fluid levels detectable by CT; MRI shows honeycomb appearance with fluid levels
Xray images: associated with osteosarcoma
Treatment: 25% recur after curettage so aggressive curettage with bone grafting or en bloc resection recommended
Gross: spongy, hemorrhagic mass covered by thin shell of reactive bone; small amount of tissue compared to large size of lesion on Xray
Gross images: cystic hemorrhagic mass
Micro: large cystic spaces filled with blood and separated by fibrous septa, alternating with solid areas; cysts and septa lined by fibroblasts, myofibroblasts and histiocytes but not endothelium; clusters of osteoclast-like multinucleated giant cells with loose spindly stroma to cellular stroma, reactive woven bone, degenerated calcifying fibromyxoid tissue; variable mitotic figures and hemosiderin; no malignant osteoid, no atypia
Micro images: irregular vascular spaces and septa containing giant cells; multinucleated giant cells and spindle cells; quiz case #1; #2; blood filled spaces; blood filled spaces and stroma with multinucleated giant cells
Molecular: abnormalities of 17p13.2 loci in 63% (Mod Path 2004;17:518)
DD: solitary bone cyst, giant cell tumor (lacks fibroblastic cells), hemangioma, telangiectatic osteosarcoma (more atypia), giant cell reparative granuloma (if in jaw), low grade osteosarcoma (hypocellular)
References: Mod Path 2000;13:1206 (molecular), more information
Very uncommon
Usually older than 20 years
Associated with pain
Benign behavior
Sites: pelvic bones, other unusual sites
Xray: small, lytic lesions with sharply defined margins and a sclerotic rim
Treatment: curettage and bone grafting, may recur locally
Case report: 45 year old man with painful shoulder lesion composed of xanthomatous material (Archives 2002;126:599)
Cytology: scattered foam cells, minimal inflammatory infiltrate, no mitotic activity
Micro: storiform pattern of spindled cells with frequent foam cells and variable benign multinucleated giant cells; resembles cutaneous counterpart
Micro images: foam cells with delicate fibrous stroma and reactive bone
DD: metaphyseal fibrous defect / nonossifying fibroma (similar histology but characteristic radiologic findings, usually younger than age 20 years, metaphysis of long bones), fibrous cortical defect, xanthoma, low grade fibrosarcoma, giant cell tumor of bone
References: AJSP 1985;9:806, more information
Benign notochordal cell tumors
Intraosseous tumors
Not notochordal rests or hamartomas
At autopsy, found in 14% of spinal columns and 11.5% of clivus’s, usually ages 40+ years, often multiple
Treatment: follow-up but no surgery; may undergo malignant transformation to classic chordomas
Gross: usually small within axial bones, rarely involve entire vertebrae
Micro: well demarcated but unencapsulated; sheets of adipocyte-like vacuolated or eosinophilic cells with fewer vacuoles; often cytoplasmic eosinophilic hyaline globules; bland round nuclei with mild pleomorphism; may contain colloid-like material; bone trabeculae often sclerotic but no bony destruction; no intercellular myxoid matrix, no necrosis, no mitotic figures
Positive stains: PAS+ diastase resistant eosinophilic hyaline globules
DD: chordomas (osteolytic, lobules are separate by thin fibrous septa, lobules contain cords, strands or sheets of physaliphorous cells with myxoid matrix, cells have mild to marked nuclear atypia), notochordal vestiges (cords or strands of notochordal cells within myxoid background, cells have eosinophilic cytoplasm with small vacuoles, pyknotic round nuclei, CK18 negative, usually replaced by fibrocartilage by age 1-3 years)
References (click on LWW logo, Fulltext for images): AJSP 2004;28:756
Brown tumor of hyperparathyroidism
Solitary or multiple
Treatment: resect parathyroid tumor causing hyperparathyroidism or control hypophosphatemia medically (tumor rapidly regresses)
Gross: large lytic lesion resembling bone tumor; brown due to hemorrhage
Micro: numerous giant cells with interstitial hemorrhage, hemosiderin, microfractures, ingrowth of vascularized fibrous tissue with fibroblasts
DD: giant cell tumor (more uniformly distributed giant cells, no interstitial hemorrhage, no fibroblastic stromal cells), giant cell granuloma (different clinical history and laboratory findings)
Extremely rare
Benign
Multilobular masses in chest wall of newborns and infants; may interfere with normal delivery
Excellent prognosis, treatment may not be required
Xray: large lesion that deforms one or more ribs
Gross: islands of cartilage and cysts
Micro: cartilaginous nodules with variable hypercellularity, cartilage matures into trabecular bone and resembles growth plate; also spindle cell proliferation with giant cells and aneurysmal bone cysts
DD: chondrosarcoma
References: AJSP 1980;4:247
Rare malignant midline bone tumor arising from fetal notocord, usually within vertebral bodies, but possibly also in intervertebral discs or presacral soft tissue
May arise from intraosseous benign notochordal cell tumors (AJSP 2007;31:1573, Mod Path 2005;18:1005)
Usually males, age 40-60 years
Slow growing with repeated recurrences; late distant metastases to skin, bone, ovary (Archives 1990;114:208)
Invasiveness may be due to expression of cathepsin K (Hum Path 2000;31:834)
Sites: 50% sacrococcygeal (ages 40-59 years), 35% spheno-occipital / clivus (particularly children, image of clivus), 15% thoraco-lumbar spine
Sacrococcygeal: sacrum destroyed by osteolytic tumor; tumor may extend into retroperitoneum, presents as palpable extrarectal mass
Spheno-occipital: presents as nasal, paranasal or nasopharyngeal mass involving cranial nerves
Posterior mediastinum: Xray presentation is well-circumscribed, encapsulated soft tissue mass separate from spine (Hum Path 1995;26:1354)
Xray images: sagittal MRI of sacral tumor
Poor prognostic factors: large tumor size, positive surgical margins, tumor necrosis, high proliferative activity, areas of dedifferentiation; also up regulation of N cadherin and down regulation of E cadherin (AJSP 2005;29:1422)
Chordoma (continued)
Treatment: aggressive surgery, often leading to long survival (Oncologist 2007;12:1344); in children, external radiation is often successful for base of skull tumors (AJSP 2006;30:811); some tumors may dedifferentiate to high grade spindle cell sarcomas
Case reports: Case of the Week #110, chordoma of distal ulna (chordoma periphericum, AJSP 2001;25:263), lumbo-sacral tumor with high grade malignant cartilaginous and spindle cell components (AJSP 1990;14:384), spheno-occipital tumor evolving to an acute pontocerebellar hemorrhage (Archives 1989;113:1075)
Gross: soft, gelatinous, hemorrhagic, gray tumor
Gross images: chordoma at base of skull; drawing of clival chordoma
Micro: cords and lobules of physaliferous (having bubbles or vacuoles) cells separated by fibrous septa with extensive myxoid stroma; cells may be very large, with vacuolated cytoplasm, prominent vesicular nucleus (Archives 2004;128:1457); also small tumor cells with small nucleus; rare mitotic figures
Micro images: physaliferous cells #1; #2; #3; #4; sacral tumor #1; #2; #3; quiz case; incipient chordoma #1; #2; benign notocordal cell tumor #1; #2
stains: pan-keratin; synaptophysin; Alcian blue; neural type cadherin (figure 2D)
Cytology images: Diff Quik
Chordoma
Positive stains: S100, keratin (CK 8/18, CK19, AE1-AE3), EMA, 5' nucleotidase, glycogen, neural-type cadherin (Archives 2002;126:425), variable CK903, vimentin, CEA, lysozyme, synaptophysin (Hum Pathol 1998;29:119)
Negative stains: CK7, CK20, chromogranin (Hum Path 1998;29:119)
Molecular: aneuploid
EM: mitochondria-endoplasmic reticulum complexes, parallel bundles of crisscrossing tubules, desmosomes (Archives 1993;117:1055)
DD: metastatic renal cell carcinoma (prominent vascularity, not lobulated, S100 negative) or other carcinoma, chondrosarcoma (not midline, no fibrous septa, EMA and keratin negative), signet cell adenocarcinoma of rectum, myxopapillary ependymoma (negative for epithelial markers), parachordoma (soft tissue tumor composed of epithelioid cells, smaller “glomoid” cells and spindle cells, negative for CK7, CK19, CK20, CEA)
References: Archives 1988;112:553 (stains), Mod Path 1997;10:545 (keratin stains), more information
Cyst of degenerative joint disease
Xray: cystic lesion in subchondral bone, may be expansile; associated with severe degenerative joint disease
Gross: mucoid material
Micro: no epithelial lining
Rare, benign/borderline behavior; bony counterpart of soft tissue fibromatosis
75% younger than age 30 years, may be more common in males
Sites: metaphysis of long bones (56%), mandible (26%), pelvis (14%)
Xray: lytic and honeycombed (“soap bubble” appearance) metaphyseal lesions, cortical thinning with soft tissue extension
Treatment: wide local excision to prevent otherwise frequent recurrences
Causes local destruction, no metastases
Case reports: 19 year old man with rib lesion (Archives 2002;126:721)
Gross: white-gray, fibrous-rubbery mass with variable bony spicules and cysts
Micro: mature, bland fibroblasts separated by abundant collagen with thin walled, dilated vascular channels; may infiltrate into soft tissue; no necrosis, no pleomorphism or atypia, no mitotic activity
Micro images: bland spindle cells infiltrating into soft tissue #1; #2; various images
Molecular: trisomy 8, trisomy 20
EM: predominantly myofibroblasts, also fibroblasts and primitive mesenchymal cells
DD: fibrous dysplasia, low grade fibrosarcoma
References: AJSP 1979;3:423 (ultrastructure), more information
High grade malignant neoplasm, usually of peritoneum or other serosal surfaces, rarely in bone or soft tissue
Case reports: 34 year old man with hand mass and later lung metastases (AJSP 1999;23:1408)
Positive stains: CAM5.2, AE1-AE3, EMA, desmin, chromogranin, synaptophysin
Molecular: EWS-WT1 gene fusion
Ectopic notochordal rests present in 2% of adult autopsies at clivus (base of skull) or anterior pons
Notocord represents a primitive spine which normally induces development of future vertebrae and eventually forms nucleus pulposus of intervertebral disc
Case reports: 14 year old boy with symptomatic vertebral body lesion diagnosed as giant notocordal rest (AJSP 2003;27:396)
Gross: discrete gelatinous nodule
Micro: cells are uniform without lobularity or variability; no pleomorphism or necrosis or mucinous pools containing syncytial cell cords, no/rare mitotic activity; not infiltrative or destructive
References: AJSP 2003;27:396
Due to squamous epithelium embedded within bone
Benign, resembles cutaneous lesion
Ages 25-50 years
Sites: skull, distal phalanx, less commonly in toes
Xray: well-defined, radiolucent lesion, often associated with soft tissue swelling
Case reports: 55 year old man with work related trauma and cyst in great toe (Archives 2003;127:e298)
Treatment: excision, not amputation
Micro: cyst wall composed of keratinized stratified squamous epithelium with keratin debris; no skin appendages
Micro images: Xray, toe, H&E
DD: chondroma (proximal phalanx, spotty stippled calcifications), osteoid osteoma (reactive sclerosis), glomus tumor (sensitivity to cold, scalloped edges, very rare in bone), osteomyelitis, dermoid cyst (contains skin appendages)
Very rare (<100 cases reported), nonfamilial, neoplastic, xanthogranulomatous, non-Langerhans cell systemic histiocytosis First identified by William Chester in 1930
Etiology not well understood
Mean age 57 years, range 25-76 years, no gender preference
Three year survival is 50-65%; prognosis usually depends on extent of extraosseous disease
Xray: bilateral and symmetric osteosclerosis of long bones (diaphysis and metaphysis), usually lower extremities; occasionally involves axial skeletal
Also involvement of retroperitoneum, lungs, kidney, hypothalamus / posterior pituitary (causing diabetes insipidus), retroorbital space, heart, skin
Case reports: 32 year old man with vertebral osteolytic lesions and liver involvement (Archives 2003;127:e337), 35 year old woman with progressive course over 6 years (Mod Path 2002;15:666), 50 year old woman with retroperitoneal and renal sinus xanthogranuloma (AJSP 1994;18:843), 60 year old man with lung and eye involvement (Archives 2004;128:1428), autopsy findings (Archives 1991;115:619), 47 year old Japanese man (Hum Path 1996;27:91)
Images: CT scans, H&E, CD68, EM
Micro: diffuse infiltration with large, foamy histiocytes, lymphoid aggregates, fibrosis, rare Touton-like giant cells
Positive stains: CD68 and factor XIIIa (strong), S100 (weak or negative)
Negative stains: CD1a
EM: lipid droplets in cytoplasm but no Birbeck granules
References: AJSP 1999;23:17, Hum Path 2000;31:734, Hum Path 1999;30:1093
Hemophagocytosis associated variant
Case report: death within 3 months of presentation due to lung involvement and hemophagocytosis causing severe anemia (Archives 2005;129:e39)
Micro: hemophagocytosis due to foamy histiocytes containing red blood cells, lymphocytes or neutrophils, present in bone marrow aspirate smears, bone marrow biopsy, lung and other organs
Ewing’s sarcoma / primitive or peripheral neuroectodermal tumor (PNET)
Terms usually used interchangeably; some suggest to call PNET if neural morphologically or a soft tissue tumor and Ewing’s if undifferentiated or a bone tumor
#2 bone sarcoma in children (6-10% of childhood primary malignant bone tumors) after osteosarcoma
Usually whites ages 5-20 years, variable gender preference
May present with pain, fever, weight loss, leukocytosis and increased erythrocyte sedimentation rate mimicking osteomyelitis
Sites: marrow of femur, tibia, humerus, fibula, pelvis, ribs, vertebra, mandible, clavicle; may permeate cortex and invade soft tissue
Xray: destructive, lytic tumor with reactive periosteal bone resembling onion skin; widening of medullary canal
Post-treatment Xray: treatment successful if regression of soft tissue mass, reconstitution of cortical pattern
Treatment: preoperative chemotherapy, surgery, radiation therapy
5 year survival: 75%; 50% are cured; metastases to lung, skull, pleura, CNS; 10-25% have multiple lesions at presentation
Poor prognostic factors: high stage, direct extension into soft tissue, aneuploidy, metastases, grossly viable tumor post chemotherapy, possibly filigree pattern (bicellular strands of tissue separated by filmy vascular stroma)
Case reports: definite neuronal differentiation post-treatment but with fusion transcript (AJSP 2003;27:1161), 26 year old with fibula tumor (Archives 2003;127:e311), 8 year old with femur tumor (Archives 2003;127:e171)
Grossing these tumors: first priority is to obtain sufficient formalin-fixed tissue for diagnosis; second priority is to obtain 100 mg of viable snap-frozen tissue for special studies
Gross: white, fleshy, ill-defined tumor with extensive involvement of medulla and cortex with periosteal elevation; may be necrotic or resemble pus
Micro: sheets of small, round, uniform cells 10-15 microns (larger than lymphocytes) with scant clear cytoplasm, divided into irregular lobules by fibrous strands; indistinct cell membranes; round nuclei with indentations, small nucleoli; may have Homer-Wright rosettes (central fibrillary space) or pseudorosettes (cells arrange themselves around vessels), hemorrhage and necrosis, prominent vasculature, variable mitotic figures, may have large pleomorphic cells (AJSP 1980;4:29), organoid pattern, filigree pattern (large areas of perivascular tumor necrosis with “ghost cells”); little stroma, no spindling; may have adamantinoma-like features (AJSP 1999;23:159)
Post-treatment: marked pleomorphism, tumor giant cells
Micro images: small blue cells #1; #2; CD99; quiz case; Xray, MRI, H&E, EM; Xray, CT, H&E, PAS, CD99; case report
Positive stains: CD99 (O13, MIC2), usually PAS+ diastase sensitive (glycogen), NSE, Leu7/CD57, FLI1 protein, vimentin; variable low molecular weight keratin, variable synaptophysin
Negative stains: S100, CD45/LCA, muscle markers, vascular markers
Molecular: t(11,22)(q24;q12) in 85%; 22q12 is EWS, a transcription factor; 11q24 is FL-1; EWS-FL1 is a transactivator of the c-myc promoter; also t(21;22)(q22;q12) in 5-10% - ERG and EWS
EM: primitive appearance with limited cytoplasmic organelles; glycogen, desmosome associated proteins but no true desmosomes; rare dense core granules
DD: metastatic neuroblastoma (patients younger than 5 years, primary should be evident), lymphoma (CD20+, older patients, polymorphic infiltrate), desmoplastic small round cell tumor, embryonal rhabdomyosarcoma
References: AJSP 1992;16:746 (initial study of MIC2), more information
Age 40 years or older, no gender preference
Sites: medulla of metaphysis of long bones, usually distal femur or proximal tibia, jaw
Often secondary to infarct, Paget’s disease, radiation
Occasionally is multicentric, but metastatic sarcomatoid carcinoma (kidney or other sites) is more likely
Xray: osteolytic, soap-bubble appearance; invasive or well-defined margins depending on differentiation of tumor
Treatment: amputation, wide local excision
Poor prognostic factors: high grade cytology (10 year survival 34% versus 83% for low grade)
Gross: fish-flesh appearance of sarcomas; may destroy cortex and extend into soft tissue
Micro: resembles soft tissue fibrosarcoma with herringbone pattern of spindle cells with variable anaplasia; no malignant osteoid; classify as malignant fibrous histiocytoma if prominent pleomorphism; well differentiated tumors are hypo- or hypercellular with mitotic figures and atypia; high grade tumors have more hyperchromasia and mitotic figures; may have small cells simulating Ewing’s/PNET; other variants are sclerosing epithelioid and myofibroblastic
DD: desmoplastic fibroma, fibroblastic osteosarcoma, metastatic sarcomatoid carcinoma
References: more information
Uncommon
Within bone, but close to a joint space at ends of long bones; often in distal tibia or proximal humerus
May be an extension of soft tissue ganglion
Treatment: simple curettage
Gross: cyst surrounded by condensed bone, often multiloculated with gelatinous content and fibrous tissue wall
Micro: cystic space with no epithelial lining; may be filled with mucoid material or foamy macrophages
DD: solitary bone cyst, periarticular cyst associated with degenerative joint disease
References: AJSP 1982;6:207
Formerly called giant cell reparative granuloma
Giant cell lesion primarily of jaw, also other craniofacial bones and short tubular bones of hands and feet
May be response to injury, but some cases behave aggressively
Giant cells have features of macrophages and osteoclasts; mononuclear cells appear to be proliferative, not giant cells
Xray images: CT scan
Case reports: temporal bone in 32 year old man (Archives 2003;127:1217)
Gross: unencapsulated, brittle, brown-purple, granulation tissue mass
Micro: fibrillar connective tissue stroma with small oval and spindly mononuclear cells mixed with uneven clusters of multinuclear (5-40) giant cells; also small capillaries, hemorrhage, hemosiderin, reactive bone with osteoblastic rimming; no pleomorphism, no/rare mitotic figures
Micro images: H&E, CD68, Ki-67
Positive stains: giant cells - CD68, tartrate-resistant acid phosphatase (TRAP), patchy macrophage markers; mononuclear cells - Ki-67, TRAP
References: AJSP 1980;4:551, AJSP 1986;10:491
Also called osteoclastoma
Benign but locally aggressive neoplasm with large numbers of osteoclast-like giant cells in background of epithelioid to spindle shaped mononuclear cells
Ages 20-40 years; 55% women, more common in Oriental countries
Associated with Paget’s disease of bone
Giant cells appear to be due to fusion of circulating monocytes; stromal cells appear to be neoplastic and may originate from mesenchymal stem cells that reside in bone marrow (Hum Path 2003;34:983)
Question diagnosis if tumor is in a child, lesion is in metaphysis or diaphysis of long bone, multiple lesions (unless patient has Goltz’s syndrome), lesion in non-sacral vertebrae, jaw of non-Paget’s patient or hands/feet
Sites: knee is common site (distal femur, proximal tibia), distal radius, sacrum but can affect any bone, usually at epiphysis, may spread into metaphysis; uncommon in hand/feet, jaw, vertebrae other than sacrum
Xray: lytic, expansile lesion of epiphysis extending to articular cartilage, usually without peripheral bone sclerosis, periosteal reaction or mineralization within the lesion; within soft tissues usually produces eggshell ossification at periphery
Xray images: destructive sacral lesion with rim of reactive bone
Treatment: surgical curettage (34% recur) or en bloc excision (7% recur); may implant into adjacent soft tissue; radiation therapy only if surgical excision impossible since it may promote malignant transformation
Course: low grade malignancy; metastasis to lung or lymph nodes (1-2%) associated with cortex interruption; have similar benign microscopic appearance; good prognosis if remove metastasis; may die of tumor if diffuse metastases
Case report: anaplastic-like changes in sacral tumor after preoperative embolization (Archives 1999;123:163), 36 year old man with rib tumor (Archives 2004;128:452)
Gross: large, peripheral expansile lesion, well-circumscribed, hemorrhagic / red brown, cystic with necrosis; thinned cortex; may appear fleshy white or pink or yellow in areas of foam cells
Micro: regular and uniform distribution of stromal cells and giant cells; stromal cells are mononuclear, resemble macrophages; giant cells are large, multinucleated (10-50 nuclei) with similar nuclei as stromal cells, resemble osteoclasts; also necrosis, hemorrhage, hemosiderin, reactive bone; mitotic figures (not atypical); 1/3 have focal deposition of osteoid or bone; may have aneurysmal bone cyst component, foam cells with spindling of mononuclear cells; no chondroid differentiation, no atypia
Micro images: giant cells in background of spindled mononuclear cells #1; #2; #3; #4; anaplastic-like changes; A: H&E with multinucleated giant cells and mononuclear cells; B: HAM-56+; C: Microphthalmia transcription factor+; D: TRAP+; A: multinucleated giant cells and hemorrhage; B: spindle cells and epithelioid cells; post-chemotherapy smears show multinucleated giant cells, epithelioid cells and spindle cells; classic features; quiz case; images and text; various images; multinucleated giant cells and mononuclear cells; Ki-67 staining in mononuclear cells; cyclin D1 nuclear staining of giant cells; giant cells in A: osteopetrosis; B: foreign body reactions; C: sarcoidosis; D: giant cell tumor; E: chondroblastoma
Positive stains: giant cells - acid phosphatase, lysozyme, alpha-1-antitrypsin, alpha-1-antichymotrypsin, cyclin D1, estrogen receptor (50%, Hum Path 2002;33:165); mononuclear cells - Ki-67
EM: giant cells have ruffled border and abundant mitochondria (resemble osteoclasts); viral-like and other intranuclear inclusions, some similar to Paget’s disease of bone
DD: other giant cell tumors (giant cells usually only focal): brown tumor of hyperthyroidism, giant cell granuloma, pigmented villonodular synovitis, chondroblastoma, aneurysmal bone cyst; osteosarcoma, metaphyseal fibrous defect / nonossifying fibroma, chondromyxoid fibroma, Langerhans’ cell histiocytosis, solitary bone cyst, osteoid osteoma, osteoblastoma
References: Mod Path 2003;16:210 (cyclin D1), Mod Path 2000;13:1206 (cytogenetics), Archives 2005;129:360 (HAM56, MITF, TRAP, c-Kit), Archives 1986;110:713 (histiocytic stains), more information
Benign metastasizing giant cell tumor
Cannot predict which benign appearing tumors will metastasize (rate is 1-10%)
Good prognosis after resection of metastasis, although may undergo sarcomatoid transformation
Case reports: 41 year old man with pulmonary metastases after excision of fibula tumor (Archives 2002;126:1133), 23 year old man with tibial tumor and subsequent lung metastases (Archives 2005;129:119), with intratumor vascular invasion (Hum Path 1981;12:762)
Gross: circumscribed nodule
Micro: evenly distributed multinucleated giant cells in hemorrhagic background of mononuclear cells, spindle cells and inflammatory cells; also reactive bone formation, 2-3 mitotic figures/HPF
Micro images: (1) chest Xray, H&E of lung metastasis; (2) figure 1: original tumor with large multinucleated giant cells; multiple lung nodules on Xray; 3/4: lung nodules show reactive bone with variable fibrosis but no giant cells
Malignant giant cell tumor
Very uncommon
To diagnose, must document either prior or coexisting benign giant cell tumor at same location as spindle cell sarcoma
Usually due to prior giant cell tumor and radiation therapy
Older age than for benign giant cell tumors, same sites
Case reports: 44 year old man with ischium giant cell tumor of bone and juxtaposed MFH; no prior history of radiation therapy (Mod Path 1989;2:541)
Micro: resembles high grade sarcoma (osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma)
Implant related sarcoma
Uncommon but well recognized complication; sarcomas arise in bone or soft tissue at site of orthopedic hardware or a prosthetic joint
Mean 55 years old, usually male
Associated with hip arthroplasty for degenerative joint disease, intramedullary nail for fracture, staples for fixation or hardware for fracture fixation
Mean 11 years from hardware placement to sarcoma diagnosis
Usually osteosarcoma or malignant fibrous histiocytoma
Aggressive behavior with frequent metastases
Xray images: osteosarcoma surrounding implant; MFH surrounding intramedullary nail
Gross images: osteosarcoma adjacent to implant; osteosarcoma with pathologic fracture
DD: infection, reaction to prosthetic wear debris
References: Mod Path 2001;14:969
Also called congenital fibromatosis, solitary infantile myofibromatosis
Rare; median age 16 months, range 6 months to 16 years
Solitary lesion in craniofacial bone, single nodule in soft tissue, multiple nodules in bone and soft tissue or diffuse involvement of viscera
Xray: well circumscribed bone lucency
Spontaneous resolution with good prognosis unless visceral involvement
Case reports: 11 month old boy with solitary lesion of parietal bone (AJSP 1993;17:308)
Micro: same as soft tissue counterpart - proliferation of spindle cells with pink cytoplasm, myxoid background; cells arranged in nodules with slitlike vascular spaces or hemangiopericytomatous pattern
Micro images: various images #1; #2
Positive stains: vimentin, alpha smooth muscle actin
DD: sarcoma
References: AJSP 1991;15:935 (solitary lesions)
Inflammatory myofibroblastic tumor
Also called inflammatory fibrosarcoma or inflammatory pseudotumor
Very rare in bone
Xray: destructive bone tissue that expands into soft tissue
Xray images: osteolytic lesion with irregular margin and sclerotic rim, extending into soft tissue
Case reports: iliac bone of 70 year old woman (Archives 2000;124:1514), two cases in young adults (AJSP 1997;21:1166)
Gross: solitary, well-demarcated, gray-yellow tumor, may expand into adjacent soft tissue
Micro: cellular area with fascicles composed of thin spindle cells with eosinophilic cytoplasm, mild pleomorphism, frequent normal mitotic figures and inflammatory infiltrate of lymphocytes and plasma cells; also hypocellular fibrous area with minimal inflammatory cells
Micro images: cellular and hypocellular areas; alpha smooth muscle actin
Positive stains: vimentin, alpha smooth muscle actin
Negative stains: desmin, h-caldesmon, AE1/AE3, CAM5.2
Molecular: may be neoplastic
DD: malignant fibrous histiocytoma (marked pleomorphism, inflammatory cells usually neutrophils and macrophages), leiomyosarcoma (more pleomorphism, atypical mitotic figures, fewer inflammatory cells, caldesmon+)
Formerly called Histiocytosis X
Either solitary bone involvement, multiple bone involvement (variable skin involvement) or multiple organ involvement (bone, liver, spleen, other sites)
Ages 5-15 years, 60% male
Neoplastic, although cause unknown
Xray: lytic masses that may extend into soft tissue
Xray images: involvement of both parietal bones with soft tissue extension #1 (plain film); #2 (CT scan)
Sites: skull, jaw, humerus, rib, femur; metaphysis or diaphysis
Case reports: Case of the Week #72
Treatment: often recurs after excision (Pediatr Blood Cancer 2007 Jan 24; [Epub ahead of print])
Gross: sharply circumscribed
Micro: infiltration by Langerhans cells (polygonal cells with eosinophilic cytoplasm, oval nuclei with longitudinal grooves resembling coffee beans); also eosinophils, giant cells, neutrophils, foam cells, lymphocytes, plasma cells, fibrosis, necrosis; may have typical and atypical mitotic figures
Micro images: H&E; CD1a; quiz case
Cytology: highly cellular with large, polygonal cells with ample cytoplasm, nuclei are round, oval or bean shaped with fine and even chromatin and prominent longitudinal grooves; inconspicuous nucleoli, mild pleomorphism; no/minimal mitotic figures; scattered eosinophils and neutrophils and multinucleated osteoclast-like giant cells; necrosis common
Cytology images: Pap stain of parietal bone #1; #2; temporal bone; B: Diff Quik; C: Pap (arrow at eosinophil); D: CD1a; E: H&E
Positive stains: CD1a, S100; also vimentin, Langerin, variable CD68
Negative stains: HAM56, CD21, CD35
EM: Birbeck granules (electron dense cross striations)
EM images: image
Molecular: often loss of DNA sequences involving several chromosomes and 1p (Hum Path 2002;33:555)
DD: osteomyelitis, sinus histiocytosis with massive lymphadenopathy, lymphoma (lacks nuclear features), macrophages, mastocytosis, monocytic leukemia
References: eMedicine, more information #1, #2
Solitary bone involvement
Also called eosinophilic granuloma
Accounts for most cases
Usually young adults with localized pain
Lesions may spontaneously regress
Sites: any bones but hands and feet; most common is cranial vault, jaw, humerus, rib, femur
Xray: osteolytic lesion of metaphysis of long bones, with variable periosteal proliferation; may resemble metastatic carcinoma or Ewing’s/PNET; may extend into soft tissue if bone fracture; skull lesions have area of lucency with hole-in-hole appearance due to different rates of destruction of two tables of bone in skull
Treatment: excision, but may recur; also small doses of radiation
Excellent prognosis
Case reports: 8 year old boy with vertebral lesion (Archives 2003;127:e235)
Multiple bone involvement
Also called multiple or polyostotic eosinophilic granuloma, Hand-Schuller-Christian disease
May cause proptosis, diabetes insipidus, chronic otitis media
Prolonged clinical course with regression and relapse
Usually favorable outcome
Multiple organ involvement
Lung and skin most commonly involved in addition to bone; also lymphadenopathy, diabetes insipidus
Poor prognostic factors: < 18 months old at diagnosis, hepatomegaly, anemia, bone marrow involvement, thrombocytopenia, hemorrhagic skin lesions
Histologic features not predictive of clinical course
Very rare as primary tumor of bone, resembles soft tissue counterpart
Mean age 44 years, range 13-77 years; no gender preference
Often jaw, femur or other long bones
May occur post-radiation therapy
75% high grade, predicts recurrence and metastases
Micro images: quiz case
Positive stains: smooth muscle actin, desmin, h-caldesmon, vimentin, variable keratin and S100
Negative stains: p53 (usually)
EM: cytoplasmic microfilaments with focal densities
DD: metastatic leiomyosarcoma, particularly in women
References: AJSP 1997;21:1281, Archives 1996;120:671, Hum Path 1994;25:1205
top
Very rare, usually ages 30’s and
40’s
Often involves calcaneus; also femur, tibia; almost all cases are intramedullary
Usually asymptomatic and an incidental finding
Xray: sharply outlined lytic lesion with rarefaction of bone, central area of calcification
Case report of intracortical lipoma in femur of 74 year old woman (AJSP 2002;26:804)
Micro: mature adipose tissue, no hematopoietic elements; variable hemorrhage, fat necrosis, calcification, reactive bone formation
References: AJSP 1992;16:401, Archives 1992;116:947
Very rare
Usually represents metastatic disease or extension from soft tissue tumor
Malignant fibrous histiocytoma (MFH)
Mean age 34-40 years but all ages, no gender predominance
Sites: metaphysis of long bones, jaw
Associated with bone infarcts (30%), foreign bodies, radiation (15%, AJSP 1986;10:9), Paget’s disease, dedifferentiation or transformation of chondrosarcoma, chordoma or giant cell tumor
Behaves like a high grade sarcoma with a poor prognosis, particularly for older patients and secondary sarcomas
Five year survival of 78% if prominent chronic inflammatory infiltrate
Xray: lytic process with destruction of cortex
Gross: large, tan-white, hemorrhagic, fish-flesh appearance with bone destruction and extension into soft tissue; yellow discoloration in areas of foam cells; usually NOT multicentric
Gross images: MFH surrounding femur
Micro: resembles similar soft tissue tumor; storiform pattern of malignant appearing fibroblasts and myofibroblasts with benign or malignant giant cells; no areas typical of osteosarcoma or chondrosarcoma (by definition)
Micro images: MFH with whorling spindle cells; inflammatory MFH; post-Paget’s disease
DD: fibrosarcoma (less pleomorphism, no giant cells), fibroblastic osteosarcoma (matrix production), lymphoma, metastatic sarcomatoid carcinoma (must rule out in patients age 60+ years)
References: AJSP 1985;9:853, Hum Path 1979;10:57
Malignant peripheral nerve sheath tumor
Primary tumors are rare; usually in mandible or maxilla
Case reports: distal femur of 28 year old man with no stigmata of neurofibromatosis (Archives 1995;119:367)
Also called Gorham’s disease
Resembles skeletal angiomatosis, but probably not a vascular neoplasm
Cause unknown
Gross: destructive reabsorption of a whole bone or several bones, with replacement by heavily vascularized fibrous tissue
Also called Leri's disease, flowing periosteal hyperostosis
Usually apparent in early childhood, 50% develop symptoms by age 20
Incidence of 0.9 cases per million
May have associated vascular malformations or hemangiomas, aneurysms, neurofibromatosis, linear scleroderma, tuberous sclerosis, focal subcutaneous fibrosis
Causes pain, joint stiffness, progressive deformity
Xray: sclerotic bone lesions that resemble dripping wax
Micro: variable marrow fibrosis, markedly irregular bone with mixed lamellar and woven bone; soft tissue masses with osteocartilagenous, fibrovascular and adipose tissue
References: more information
Most common malignant bone tumor is metastatic carcinoma
In adults, 80% from prostate, breast, kidney, lung or thyroid
In children, from neuroblastoma, Wilm’s tumor, osteosarcoma, Ewing’s/PNET or rhabdomyosarcoma
Intraspinal seeding may occur along Batson’s plexus of veins
Positive isotope bone scans (versus myeloma)
Sarcomatoid carcinoma: consider if patient 60+ years with spindling bone malignancy; cells usually plumper than bone sarcomas and accompanied by carcinoma; renal cell carcinoma is most common primary site
Common sites: axial skeleton, proximal femur, proximal humerus; usually marrow; very rare to be distal to elbow or knee
Solitary metastases: kidney, thyroid
Small bones of hands and feet: colon, lung, kidney
Blastic lesions: prostate, carcinoid tumor, neuroendocrine tumors
Xray images: metastatic breast carcinoma to vertebrae
Treatment: radiation therapy for pain relief and to prevent fracture of weight bearing bones
Case reports: benign metastasizing pleomorphic adenoma of salivary gland of 37 year old man to vertebrae (Archives 2003;127:887), metastatic basal cell carcinoma to vertebrae in nevoid basal cell carcinoma syndrome (Archives 2004;128:819)
Gross images: metastatic prostate carcinoma; metastases to vertebrate
Micro images: metastatic basal cell carcinoma in nevoid basal cell carcinoma syndrome - figure 1: pelvic CT scan; 2: Diff-Quik smears; 3: H&E; 4: AE1-AE3+)
Virtual slides: metastatic carcinoma (unspecified)
DD: myeloma (negative isotope bone scan, monoclonal protein in serum or urine)
References: more information
Rare, women in 60’s and 70’s
Distal femur, tibia and iliac bones
Xray: well-demarcated lytic destructive lesions without periosteal reaction, may extend into soft tissue
Treatment: wide resection, may have distant metastases
Micro: mixture of cell-rich fascicular area and hypocellular fibrous area; fascicular area has interlacing fascicles and storiform areas of tumor cells with eosinophilic spindled and wavy cytoplasm and variable inflammatory cells; variable pleomorphism and large cells with hyperchromatic nuclei; hypocellular areas are collagenous, hyaline scar-like and rarely keloid-like, with focal coagulation necrosis; infiltrative growth at periphery; reactive bone but no malignant osteoid
Positive stains: vimentin, muscle specific actin (HHF35), alpha-smooth muscle actin, calponin, desmin
Negative stains: high molecular weight caldesmon
DD: inflammatory myofibroblastic tumor (no necrosis), leiomyosarcoma (h-caldesmon+), MFH of bone (more prominent anaplasia, multinucleated giant cells), fibrosarcoma (negative for muscle markers, no inflammatory infiltrate)
References: AJSP 2001; 25: 1501
Benign behavior
Resembles soft tissue myxomas
Xray: expansile lesion of distal long bones
Xray: intraosseous lytic lesion; may enlarge intervertebral foramina as dumbbell lesion
References: more information
Also called von Recklinghausen’s disease of bone
See also Brown tumor of hyperthyroidism
Micro: increased bone cell activity, peritrabecular fibrosis, cystic brown tumors
Rare congenital bone tumor presenting with painless mass
Associated with Carney complex (familial lentinginous and multiorgan tumor syndrome, AJSP 2001;25:164)
Sites: nasal region, tibia, radius
Treatment: resection, but recurs if incompletely excised
Gross: gelatinous, cartilaginous, bony
Micro: sheets and lobules of bland cells in myxomatous, cartilaginous, osseous, and hyaline fibrous matrix; low to moderate cellularity; erodes bone and frequently extends into soft tissue
Phosphaturic mesenchymal tumor - bone chapter
Extremely rare
Median age 53 years, range 9-80 years, slight female predominance
Causes rickets or osteomalacia by producing a renal phosphaturic substance that reduces tubal phosphate reabsorption, causing low serum phosphate and resulting oncogenic osteomalacia; also low serum 1,25 dihydroxyvitamin D (Pediatr Dev Pathol 2000;3:61)
Most cases of tumor associated oncogenic osteomalacia are due to phosphaturic mesenchymal tumor which produces fibroblast growth factor-23 (a protein that inhibits renal tubular epithelial phosphate transport, AJSP 2004;28:1) or dentin matrix protein 1 (Mod Path 2004;17:573)
Usually benign
Case reports: Case of Week #63, 36 year old woman with muscle pain and weakness (Archives 2002;126:1245)
Treatment: complete excision causes dramatic reversal of signs and symptoms (AJSP 1989;13:588)
Gross: 2-14 cm, arises in soft tissue and bone
Micro: hypocellular tumor of bland spindled cells with small nuclei, indistinct nucleoli, osteoclast-like giant cells, myxoid change, hemangiopericytoma-like vessels, distinctive “grungy” calcified matrix, fat, microcysts, hemorrhage, incomplete rim of membranous ossification, metaplastic bone; infiltrative; no/rare mitotic activity, no atypia
Phosphaturic mesenchymal tumor (continued)
Micro images: image #1; #2; #3; #4; #5; giant cells
malignant: rare cases with nuclear atypia, 5+ mitotic figures/10 HPF, high cellularity, resembles MFH
Positive stains: fibroblast growth factor-23 (AJSP 2004;28:1), dentin matrix protein 1 (Mod Path 2004;17:573)
DD: mesenchymal tumors (hemangiopericytoma, osteosarcoma, giant cell tumor)
References: Cancer 1987;59:1442
Latent period usually 14 years after radiation of bone tumor (giant cell tumor) or non-bone tumor
Survival is similar to osteosarcoma, regardless of histology
Micro: high grade sarcoma, either fibrosarcoma, osteosarcoma or malignant fibrous histiocytoma
References: more information
Case reports: 7 year old girl with destructive tumor of femoral diaphysis (AJSP 1996;20:239)
Also called neurilemoma
Very rare as primary tumor of bone, <100 cases reported
Often mandible
Sacral masses may be huge and simulate malignancy
Xray: extremely well circumscribed
Treatment: conservative excision, good prognosis
Micro: spindle cell lesions with palisading growth pattern
Micro images: palisading growth and Verocay bodies; thick walled blood vessels
Positive stains: S100
References: Hum Path 1984;15:551, more information
Sinus histiocytosis with massive lymphadenopathy
Also called Rosai-Dorfman disease
Rare; unknown cause
Skeleton is fifth most common site of extranodal involvement
Micro: fibrosis, polyclonal plasma cells, lymphocytes, histiocytes, lymphocytophagocytosis by histiocytes
Positive stains: S100 (histiocytes)
Also called simple cyst
Benign, usually medulla of metaphysis of proximal humerus and femur; also calcaneus
Usually males (75%) under 20 years old
Presents with advanced lesion, often with pathologic fracture
Xray: thin cortex, but without periosteal bone proliferation or expansion of bone
Treatment: curettage, replace cyst with bone chips
Poor prognostic factors: cyst near epiphysis
Gross: cyst with clear-yellow fluid lined by brown fibrous membrane
Micro: cyst lined by spindle cells and occasional giant cells; connective tissue with prominent vasculature, hemosiderin, cholesterol clefts; surrounding bone may be dense with irregular cement lines
Micro images: quiz case; wall of cyst #1; #2
References: more information
Xray images: growth into tibia
Case reports: periosteal tumor of tibia (Hum Path 1995;26:460)
Also called Dupuytren’s exostosis
Rare, osteochondroma-like lesion under nail bed, usually of great toe
A type of myositis ossificans
Appears to be neoplastic based on t(X;6) present
Usually male teenagers/young adults
Painful, slow growing, may produce ulceration of nail
May be associated with local trauma, infection or chronic irritation
Xray: calcifying lesion projecting from distal phalanx
Xray images: toenail lesion
Treatment: simple excision, may recur, particularly with incomplete excision; does not transform
Micro: spindle cell proliferation on surface of cartilage, resembling a cap, with underlying trabecular bone formation; may be hypercellular and mitotically active
Micro images: 19 year old woman with thumb lesion
Molecular: t(X;6) (AJSP 2004;28:1033)
DD: osteochondroma (different location, no spindle cell proliferation), sarcoma (marked atypia)
References: AJSP 1988;12:368
Rare; well circumscribed nail bed lesion producing lytic defects in underlying bone
Rapidly progressive
Benign, excision is curative
Xray: well defined defect in bone
Micro: proliferation of squamous cells with abundant pink cytoplasm and marked keratinization, resembling cutaneous lesion
DD: squamous cell carcinoma (usually a chronic problem, tends to permeate bone)
65% male, age 20+ years
Usually solitary; affects pelvis, ribs, skull
Xray: well defined, expansile lytic lesion, often with sclerotic margin
Micro: foam cells, multinucleated giant cells, cholesterol clefts, fibrosis
DD: sinus histiocytosis with massive lymphadenopathy, Langerhans cell histiocytosis with secondary xanthomatous change, post-traumatic dysplasia, benign fibrous histiocytoma
Miscellaneous
Classification excludes lymphoma and myeloma
AJCC 7th edition: changes from AJCC 6th are in Stage III, which must be G3 or G4
Primary tumor (pT)
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
T1: Tumor 8 cm or less in greatest dimension
T2: Tumor more than 8 cm in greatest dimension
T3: Discontinuous tumors in the primary bone site
Regional lymph nodes (pN)
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis
Note: because of the rarity of lymph node involvement in bone sarcomas, the designation NX may not be appropriate, and cases should be considered N0 unless clinical node involvement is clearly evident
Distant metastasis (pM)
M0: No distant metastasis
M1: Distant metastasis
M1a: Lung
M1b: Other distant sites
Stage grouping
IA : T1 N0 M0, well to moderately differentiated/low grade (G1, G2, GX)
IB : T2-3 N0 M0, well to moderately differentiated/low grade (G1, G2, GX)
IIA : T1 N0 M0, poorly differentiated/undifferentiated/high grade (G3, G4)
IIB : T2 N0 M0, poorly differentiated/undifferentiated/high grade (G3, G4)
III : T3 N0 M0, G3, G4
IVA : Any T N0 M1a, any grade
IVB : Any T N1 Any M, any grade or Any T Any N M1b any grade
Enneking staging
Uses histologic grade and anatomic location of tumor
Grade: well differentiated / low grade (tumor cells resemble cells from which they are thought to arise); poorly differentiated / high grade (can barely recognize what normal counterpart of tumor cell would be); also graded as 1-4 (1-2: low grade, 3-4: high grade)
Anatomic location: one compartment (confined to bone) or two compartments (tumor has broken through bone into soft tissue)
Staging same as TNM except that T1 means one compartment and T2 means 2 or more compartments; stage IIIA is any grade and T1 M1 and stage IIIB is any grade and T2 M1
Margins
Intralesional margin: microscopic evidence of lesion at margin after debulking or curetting
Marginal margin: lesion is shelled out, usually within a pseudocapsule; no normal tissue is removed
Wide margin: tumor with pseudocapsule, reactive zone and cuff of normal tissue is removed
Radical margin: entire compartment with tumor is removed (does not refer necessarily to the surgery, but the tumor location and tissue removed)
International staging system
Stage I: serum beta2 microglobulin < 3.5 mg/L and serum albumin 3.5 g/dL or more
Stage II: not stage I or III
Consists of either serum beta2 microglobulin < 3.5 mg/L but serum albumin < 3.5 g/dL or serum beta2 microglobulin 3.5 to < 5.5 mg/L irrespective of the serum albumin level
Stage III: serum beta2 microglobulin 5.5 mg/L or more
References: J Clin Oncol 2005;23:3412
Durie-Salmon staging system
Stage I: hemogloblin > 10.0 g/dL, serum calcium ≤12 mg/dL, normal bone xrays or a solitary bone lesion, IgG < 5 g/dL, IgA < 3 g/dL and urine M-protein < 4g/24 hours
Stage II: not stage I or III
Stage III: one or more of the following: hemoglobin < 8.5 g/dL, serum calcium > 12 mg/dL, advanced lytic bone lesions, IgG > 7 g/dL, IgA > 5 g/dL or urine M-protein > 12 g/24 hours
Note: patients are further subclassified per stage grouping as either (A) serum creatinine < 2.0 mg/dL or (B) serum creatinine ≥ 2.0 mg/dL
References: Cancer 1975;36:842
Organ
Site (include laterality if appropriate)
Procedure
Tumor diagnosis
Tumor size (1 dimension is mandatory, 2-3 dimensions if possible)
Histologic grade (low/high grade or I, II, III or IV)
Chemotherapy response:
I: no chemotherapy effect
IIA: some necrosis, more than 50% viable tumor
IIB: 3-50% viable tumor
III: less than 3% viable tumor but scattered foci present
IV: no viable tumor noted
Tumor extent:
surface only, cortex only, through cortex, into soft tissue, satellite lesions, invades or crosses joint spaces
Margins:
proximal, distal, distance of tumor to closest surgical margin, involvement of neurovascular bundle at margin
Lymph nodes: number positive, number examined, extracapsular extension, largest nodal metastasis
Staging (see above)
Results of special studies
Optional features
Name structures with gross involvement of tumor
Cystic change, hemorrhage, tumor necrosis (in non-chemotherapy cases)
Large or small vessel invasion present/absent/indeterminate
References: Hum Path 2004;35:1173
General
Orient specimen using identifiable landmarks
Measure specimen (each fragment)
Note gross characteristics including color (dead bone is yellow-tan), localized lesions, sclerotic areas, calcification, cystic changes, necrosis
Radiographs or photographs of sliced bone specimens may be helpful (particularly for nidus of osteoid osteoma)
Use scalpel tip to tease out fleshy areas (except near tumors) for nondecalcified fixation
Histomorphometry may be helpful for metabolic bone diseases (see Sternberg page 246 for more details)
Submit fresh tissue for ancillary studies, as needed
Decalcification
20% formic acid in 10% formalin (400 ml of formic acid in 1600 ml of 10% formalin)
Fix bone first, decalcify slices but not entire specimen in adequate amount of formic acid, change solution (dissolved calcium neutralizes the acid), wash thoroughly to remove acid
Small specimens may require only a few hours
Check specimen periodically to avoid excessive decalcification
Bone biopsy
Divide needle biopsy longitudinally with a fine-toothed saw if 5 mm or more in diameter
Dissect out soft tissue and process separately without decalcification
Open biopsy and curettage
Separated calcified from noncalcified tissue and process separately
Femoral head
Hold specimen with a clamp or vice, and cut through center of articular surface with band saw
Then make another parallel cut 3 mm from the first cut
Submit abnormal areas, articular surface and synovium
Bone resection for tumor
Review Xrays
Check prior biopsy sites
Identify lymph node groups, dissect and place in separate containers
Ink and examine margins (scoop bone marrow from end margin)
Dissect away soft tissue, leaving bone and soft tissue extension of tumor (margins of soft tissue are examined at frozen section)
Examine major vessels and nerve trunks (limb specimens)
Determine position of tumor with respect to other landmarks present
Bivalve tumor with band saw (anterior-posterior or what exposes most of the bone tumor)
Describe status of cortex near tumor
Cut through joint if no apparent tumor
If joint contains apparent tumor, make cross section through adjacent non-involved bone, then open and examine joints
Obtain 3-4 mm sections of tumor using band saw or handheld saw
Wash with running water, brush cut surfaces of bone with a nail brush to remove bone dust
Check for satellite lesions (examine under Wood’s light if tetracycline was administered)
Calculate %necrosis in post-chemotherapy specimens
(1) for osteosarcoma and Ewing’s sarcoma, sample completely a slice of the tumor using a grid pattern diagram
(2) take additional blocks perpendicular to previous ones to evaluate tumor in 3 dimensions
(3) examine blocks from soft tissue, tumor/nodal interface, cortex, subcortical marrow, pericartilaginous regions, necrotic areas, ligaments
(4) necrosis is defined as follows:
Osteoblastic and chondroblastic osteosarcomas: empty lacunae or ghost cells
Fibroblastic and small cell osteosarcomas and Ewing’s sarcoma: fibrous and granulation tissue replacing cellular tumor
Telangiectatic osteosarcoma: residual cystic spaces with blood or hemosiderin
Note: post-chemotherapy atypia is NOT counted as necrosis
Sections to submit
4 or more sections of tumor (representative, including dissimilar areas; tumor and cortex, medulla, articular cartilage, periosteum, soft tissue, epiphyseal line)
Tumor and margin
Osseous margin of resection
Prior biopsy sites
Other abnormal areas
Lymph nodes
References: Hum Path 2004;35:1173
End of Bone chapter
