─ Imaging: Well-demarcated, round to oval, uniformly radiodense (sclerotic) mass projecting from the bone surface; CT best demonstrates bony nature and lack of soft tissue component; no periosteal reaction unless fractured

─ Prognosis: Excellent, recurrence rare after complete excision

Macro ─ well-circumscribed, bosselated, round to oval, hard, bony mass; ivory-white (compact) or gritty (trabecular) cut surface

Micro ─

Composed of dense, mature lamellar bone

Two main histologic types:

─ Compact (ivory) osteoma: predominantly dense cortical-type bone with Haversian systems and minimal fibrovascular marrow spaces

─ Trabecular (spongy) osteoma: interconnecting trabeculae of mature lamellar bone separated by variable amounts of fibrovascular or fatty marrow

Osteocytes are normal; osteoblasts may line trabeculae but are bland and not prominent

No cytologic atypia, mitoses, or infiltrative growth into surrounding soft tissue

Ancillary studies ─

─ Molecular ─ APC gene mutations in Gardner syndrome-associated osteomas; sporadic osteomas typically show no specific alterations

DDx ─

─ Bone Island (Enostosis) (histologically identical but intramedullary location)

─ Osteoid Osteoma (painful, radiolucent nidus, prominent osteoblastic rimming)

─ Osteoblastoma (larger, more vascular stroma, more prominent osteoblasts)

─ Parosteal Osteosarcoma (low-grade malignant spindle cell stroma between bone trabeculae, atypia)

─ Reactive periostitis/Exostosis (history of trauma or inflammation, more organized zonal maturation)

─ Osteochondroma (cartilage cap, continuity with medullary cavity of underlying bone)

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Osteoid Osteoma

A benign bone-forming tumor characterized by a small (<2cm) radiolucent nidus, prominent reactive sclerosis, and nocturnal pain typically relieved by NSAIDs

Clinical ─

─ Predominantly affects males, typically in the 2nd and 3rd decades (ages 10-30)

─ Most common in long bones (femur, tibia proximally), also posterior elements of the spine

─ Characteristic symptom: nocturnal pain, often severe, relieved by aspirin or other NSAIDs

─ Imaging: Small, ovoid or round radiolucent nidus (<1,5-2 cm), often with central mineralization, surrounded by extensive reactive sclerosis (cortical thickening and/or periosteal reaction); CT is the best modality to visualize the nidus, especially in complex anatomical sites or when obscured by sclerosis

─ Prognosis: Excellent after complete removal or ablation of the nidus; recurrence is rare

Macro ─ nidus is a well-demarcated, reddish-brown, granular or gritty focus, usually <1,5 cm in diameter, surrounded by dense sclerotic bone

Micro ─

Nidus:

─ Interlacing trabeculae of immature woven bone and osteoid, often haphazardly arranged

─ Trabeculae are typically rimmed by a single layer of prominent, plump, active osteoblasts

─ Stroma is highly vascular, composed of loose fibrovascular connective tissue; osteoclast-like giant cells may be present

─ No cartilage formation within the nidus

─ Minimal to no cytologic atypia; mitoses are rare or absent

Surrounding bone:

─ Shows dense reactive lamellar bone (sclerosis) and/or thickened periosteum

Ancillary studies ─

─ Not typically required for diagnosis if clinical, imaging, and histologic features are characteristic

DDx ─

─ Osteoblastoma (larger size >2cm, less pain, less reactive sclerosis)

─ Brodie Abscess (intracortical abscess, central lucency with surrounding sclerosis, often history of infection)

─ Stress Fracture (linear lucency, history of repetitive activity, less well-defined nidus)

─ Intracortical Osteosarcoma (rare, malignant cytologic features, infiltrative growth)

─ Chronic Sclerosing Osteomyelitis of Garré (diffuse sclerosis, often no distinct nidus)

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Osteoblastoma

A rare, benign bone-forming tumor histologically similar to osteoid osteoma but typically larger (>2cm), with less intense pain not consistently relieved by NSAIDs, and greater growth potential

Clinical ─

─ Predominantly affects males, typically in the 2nd and 3rd decades (ages 10-30)

─ Most common in the posterior elements of the spine (vertebral arches, pedicles, transverse/spinous processes); also long bones (femur, tibia), craniofacial bones (especially mandible)

─ Symptoms: dull, aching pain, often less severe and less consistently nocturnal than osteoid osteoma; not typically relieved by aspirin/NSAIDs; may cause scoliosis or neurologic symptoms if in spine

─ Imaging: Well-circumscribed, often expansile lesion, usually >2cm; can be lytic, mixed lytic/sclerotic, or purely sclerotic; may have a thin sclerotic rim, cortical thinning or breach, and sometimes an associated soft tissue component or aneurysmal bone cyst-like changes; periosteal reaction may be present

─ Prognosis: Generally good; recurrence (10-20%) after curettage, especially for aggressive variant or incomplete excision; rare malignant transformation reported in aggressive variant

Macro ─ typically hemorrhagic, reddish-brown, granular or friable tissue; usually well-demarcated but may lack the dense surrounding sclerosis of osteoid osteoma; can be >2cm, sometimes much larger

Micro ─

─ Similar to osteoid osteoma: interconnected trabeculae of woven bone and osteoid prominently rimmed by a single layer of plump osteoblasts

─ Stroma is highly vascular and composed of loose fibrovascular connective tissue; osteoclast-like giant cells are often numerous

─ Trabeculae may be broader and more irregular than in osteoid osteoma; mineralization can be variable

─ No cartilage formation unless associated with fracture callus

─ Cytologic atypia generally absent; mitoses can be present but are not atypical

─ Aggressive (epithelioid) osteoblastoma: sheets of large epithelioid osteoblasts with prominent nucleoli, increased cellularity and mitotic activity (but no atypical mitoses); may be difficult to distinguish from osteosarcoma

Ancillary studies ─

─ Not typically required for conventional osteoblastoma

─ Molecular ─ Some cases of aggressive osteoblastoma may show USP6 gene rearrangements (seen in aneurysmal bone cyst), especially if ABC-like areas are prominent; FOS/FOSB rearrangements have been reported but are not routine diagnostic markers

DDx ─

─ Osteoid Osteoma (size <2cm, classic pain, prominent reactive sclerosis)

─ Aneurysmal Bone Cyst (can be secondary to osteoblastoma; characterized by blood-filled cystic spaces)

─ Giant Cell Tumor of Bone (epiphyseal, sheets of mononuclear cells and osteoclast-like giant cells, no prominent bone production by tumor cells)

─ Osteosarcoma (especially osteoblastoma-like osteosarcoma or aggressive osteoblastoma; malignant cytologic atypia, infiltrative growth, atypical mitoses)

─ Fibrous Dysplasia (curvilinear trabeculae of woven bone lacking osteoblastic rimming, fibrous stroma)

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Parosteal Osteoma

A benign, mature bone-forming tumor arising directly on the external surface (parosteal) of a bone, composed of dense cortical-type or trabecular bone

Clinical ─

─ Typically adults; can occur at any age

─ Most common in the skull (outer table), paranasal sinuses (especially frontal), and mandible; occasionally on the surface of long bones

─ Usually asymptomatic and discovered incidentally; may cause cosmetic deformity, headache, sinusitis, or proptosis if large or in specific locations

─ Imaging: Well-demarcated, sessile or pedunculated, uniformly dense (sclerotic) bony mass attached to the outer cortical surface of the bone by a broad base; no continuity with the medullary cavity of the underlying bone (key to differentiate from osteochondroma); no soft tissue component or aggressive features

─ Prognosis: Excellent; recurrence is rare after complete excision

Macro ─ hard, lobulated or smooth, ivory-like or cancellous bony mass arising from the bone surface; cut surface is dense white (compact) or trabecular (spongy)

Micro ─

Composed of mature lamellar bone, histologically identical to an intramedullary osteoma (bone island)

─ Compact (ivory) type: dense cortical bone with Haversian systems and scant fibrovascular marrow

─ Trabecular (spongy) type: interconnected trabeculae of lamellar bone with fatty or fibrovascular marrow spaces

No cytologic atypia or increased mitotic activity

No infiltration of underlying cortex or surrounding soft tissues

Ancillary studies ─

─ Not typically required for diagnosis

DDx ─

─ Parosteal Osteosarcoma (key DDx; shows low-grade malignant spindle cell stroma between bone trabeculae, cytologic atypia, infiltrative growth pattern)

─ Osteochondroma (has a cartilage cap and continuity with the medullary cavity of the underlying bone)

─ Myositis Ossificans (juxtacortical/soft tissue location, exhibits zonal maturation, often history of trauma)

─ Florid Reactive Periostitis (smaller bones, prominent periosteal reaction, zonal pattern histologically)

─ Reactive Exostosis/Periostitis (often related to trauma or irritation)

─ Surface manifestation of Paget Disease (disorganized mosaic pattern of lamellar bone)

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Florid Reactive Periostitis

A benign, reactive, rapidly growing fibro-osseous and sometimes cartilaginous proliferation of the periosteum, typically affecting the small tubular bones of the hands and feet

Clinical ─

─ Most common in young adults (2nd to 4th decades)

─ Frequently involves proximal phalanges of fingers, also metacarpals, metatarsals

─ Often presents with rapid onset of localized pain, swelling, and tenderness; a history of trauma is reported in about 50% of cases

─ Imaging: Fusiform, periosteal-based soft tissue mass with variable mineralization (early lesions may be purely soft tissue; later lesions show increasing ossification, often maturing from periphery inward); characteristic "saucerization" or shallow erosion of the underlying cortex without frank destruction; prominent, often lamellated or spiculated periosteal reaction is typical

─ Prognosis: Excellent; self-limiting in some cases; recurrence is uncommon after simple excision

Macro ─ firm, fusiform or plaque-like mass attached to the periosteal surface; cut surface may be gritty, grey-white, with variable fleshy areas and sometimes bluish cartilaginous foci

Micro ─

─ Exhibits a zonal architecture (maturation from superficial to deep):

─ Superficial (outer) zone: highly cellular proliferation of plump spindle cells (myofibroblasts) in a loose, myxoid, or edematous stroma, resembling nodular fasciitis; mitoses can be frequent but are not atypical; extravasated red blood cells are common

─ Intermediate zone: irregular trabeculae of woven bone and osteoid, often with prominent osteoblastic rimming; streaming pattern of bone deposition ("blue bone" appearance when osteoid is abundant and lightly mineralized) can be seen; islands of cellular hyaline cartilage undergoing endochondral ossification may be present

─ Deep (inner) zone: adjacent to the cortex, shows more mature lamellar bone trabeculae merging with the reactive periosteal bone or underlying cortex

─ Underlying cortex is typically intact, though may be eroded superficially

─ No significant cytologic atypia, atypical mitoses, or necrosis

Ancillary studies ─

─ Not typically required for diagnosis; features are predominantly reactive

DDx ─

─ Parosteal/Periosteal Osteosarcoma (lacks zonal maturation, shows cytologic atypia, infiltrative growth, atypical mitoses; key differential)

─ Bizarre Parosteal Osteochondromatous Proliferation (Nora Lesion) (more prominent and "bizarre" cartilage, often more exophytic, less spindle cell proliferation)

─ Myositis Ossificans (typically in larger muscles of extremities or trunk, more organized zonal maturation, rarely involves small bones of hands/feet)

─ Stress Fracture with callus (history, linear fracture line, more organized callus)

─ Infection (osteomyelitis with periostitis; clinical signs of infection, inflammatory infiltrate)

─ Subungual Exostosis (specific subungual location, usually toe/finger)

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Bizarre Parosteal Osteochondromatous Proliferation (Nora Lesion)

A benign, exophytic, reactive surface lesion of bone characterized by a disorganized proliferation of cartilage, bone, and spindle cells, typically occurring in the small bones of the hands and feet

Clinical ─

─ Peak incidence in young to middle-aged adults (20s-50s); no significant sex predilection

─ Most commonly involves the small tubular bones of the hands (phalanges, metacarpals) and feet (metatarsals)

─ Presents as a slowly growing, often painless or mildly painful firm swelling or mass

─ History of trauma is variable and often absent

─ Imaging: Well-circumscribed, exophytic bony mass arising from the cortical surface, often broad-based or sessile; mineralization is typically dense, irregular, and mature, sometimes described as "popcorn-like" or "cauliflower-like"; no continuity with the medullary cavity of the underlying bone (a key feature distinguishing it from osteochondroma); underlying cortex is usually intact but may be slightly eroded or "saucerized"

─ Prognosis: High local recurrence rate (30-50%) after excision, but no malignant potential

Macro ─ firm, lobulated, exophytic mass attached to the bone surface, often <3cm; cut surface shows a variegated appearance with bluish-gray cartilaginous nodules, gritty calcified areas, and white fibrous tissue admixed with bone

Micro ─

Characterized by a disorganized admixture of three components:

─ Cartilage: irregular islands and nodules of hyaline cartilage, often hypercellular; chondrocytes can be enlarged, with plump, hyperchromatic, or "bizarre" nuclei, and binucleation is common; however, mitoses are rare or absent, and true anaplasia is not seen; cartilage often has a distinct basophilic or blue tint ("blue bone" refers to the calcified cartilage and associated bone matrix)

─ Bone: irregular trabeculae of woven and lamellar bone, formed by endochondral ossification from the cartilaginous islands and by direct membranous ossification from the spindle cell stroma; osteoblastic rimming is usually present

─ Spindle cell stroma: bland, fibroblastic to myofibroblastic cells in a variably collagenous or slightly myxoid stroma, separating the bone and cartilage elements; cells lack significant atypia

No permeation of the underlying medullary bone or marrow spaces

The lesion is typically "stuck on" the cortex

Ancillary studies ─

─ Molecular ─ A subset of cases shows recurrent t(1;17)(q32;q21) translocations involving COL1A2 and USP6 genes, or other USP6 rearrangements; this finding supports a neoplastic (or at least clonally reactive) basis for some lesions, though not required for routine diagnosis

DDx ─

─ Osteochondroma (organized cartilage cap undergoing orderly endochondral ossification, continuity with underlying medullary cavity)

─ Florid Reactive Periostitis (more prominent spindle cell component resembling nodular fasciitis, less prominent and less "bizarre" cartilage, distinct zonation)

─ Parosteal Osteosarcoma (frankly malignant spindle cell stroma, infiltrative growth, atypical mitoses; key differential in larger lesions or atypical locations)

─ Periosteal Chondroma/Chondrosarcoma (predominantly cartilaginous, different type of mineralization and cortical relationship)

─ Myositis Ossificans (zonal pattern, typically intramuscular, different mineralization pattern)

─ Subungual Exostosis (specific subungual location, often fibrocartilaginous cap)

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Fracture Callus

A reparative process of woven bone, cartilage, and fibrous tissue that forms at the site of a bone fracture, ultimately remodeling into mature lamellar bone

Clinical ─

─ Occurs at any age following bone fracture

─ Site corresponds to the fractured bone

─ Presents with pain, swelling, tenderness, and immobility related to the fracture; palpable mass (callus) may develop as healing progresses

─ Imaging: Early (1-2 weeks): fracture line, soft tissue swelling, minimal periosteal reaction; Intermediate (2-6 weeks): fluffy, cloud-like or fusiform periosteal and endosteal new bone formation (callus) bridging the fracture gap, increasing mineralization and density; Late (>6 weeks): bridging callus becomes more dense, organized, and eventually remodels to an outline resembling the original bone; CT/MRI can show extent of callus and soft tissue involvement, but radiographs are often sufficient for monitoring uncomplicated healing

─ Prognosis: Excellent with proper fracture management; complications include nonunion, malunion, or infection

Macro ─ initially a hematoma, then soft fibrocartilaginous tissue (soft callus), followed by a hard, gritty, fusiform mass of bony callus surrounding and bridging the fracture site; mature callus is dense bone

Micro ─

Histologic appearance evolves over time, reflecting stages of repair:

Hematoma/Inflammatory Phase (first few days):

─ Blood clot, fibrin, necrotic debris, acute inflammatory cells (neutrophils, macrophages)

─ Proliferation of granulation tissue (capillaries, fibroblasts)

Soft Callus/Fibrocartilaginous Phase (days to weeks):

─ Proliferating spindle cells (fibroblasts, myofibroblasts) forming fibrous tissue

─ Islands of hyaline cartilage form via differentiation of mesenchymal cells (endochondral ossification component)

─ Direct bone formation (intramembranous ossification) from periosteal and endosteal osteoprogenitor cells, forming woven bone trabeculae

─ Cellular areas can be highly active with plump cells and mitoses, potentially mimicking sarcoma if out of context

Hard Callus/Bony Phase (weeks to months):

─ Mineralization of the cartilaginous matrix and replacement by woven bone (endochondral ossification)

─ Continued formation of woven bone trabeculae bridging the fracture gap

─ Osteoblastic rimming is prominent; osteoclasts resorb necrotic bone fragments

─ Cartilage islands diminish and are replaced by bone

Remodeling Phase (months to years):

─ Woven bone is gradually replaced by lamellar bone

─ Callus is resorbed and remodeled along lines of stress to restore normal bone contour and strength

─ Haversian systems re-established in cortical bone

Ancillary studies ─

─ Not typically required for diagnosis; histologic features are usually diagnostic in the context of fracture

DDx ─

─ Osteosarcoma (especially exuberant callus or if clinical history is unknown; osteosarcoma shows malignant cytologic atypia, atypical mitoses, infiltrative growth into soft tissues beyond reactive periostitis, and neoplastic bone formation directly by sarcoma cells)

─ Myositis Ossificans (if fracture extends into soft tissue; myositis ossificans has a characteristic zonal pattern and is typically intramuscular)

─ Osteomyelitis (if fracture is open or becomes secondarily infected; prominent acute/chronic inflammation, necrotic bone sequestra)

─ Chondrosarcoma (if cartilage component of callus is prominent and atypical; chondrosarcoma lacks the organized maturation to bone seen in callus and shows greater atypia)

─ Florid Reactive Periostitis (prominent spindle cell component resembling nodular fasciitis, less orderly maturation than typical callus, usually small bones of hands/feet)

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Conventional Osteosarcoma

A high-grade malignant mesenchymal tumor in which the neoplastic cells produce osteoid (immature bone) or mature bone

Clinical ─

─ Bimodal age distribution: 75% occur in patients <20 years (peak in 2nd decade, associated with pubertal growth spurt); smaller peak in older adults (>60 years, often secondary to Paget disease or radiation)

─ Slight male predominance (1,3-1,6:1)

─ Most common primary malignant bone tumor (excluding myeloma/lymphoma)

─ Most frequently arises in the metaphysis of long bones, especially around the knee (distal femur > proximal tibia > proximal humerus)

─ Presents with localized pain (often worse at night), swelling, palpable mass; pathologic fracture in 5-10%

─ Imaging: Aggressive lesion with bone destruction (lytic, sclerotic, or mixed), ill-defined margins, cortical breach, periosteal reaction (Codman triangle, sunburst, lamellated/onion-skin), and associated soft tissue mass; tumor matrix mineralization (osteoid) appears as cloud-like, fluffy, or ivory-like densities; MRI best defines intraosseous and soft tissue extent, skip metastases

─ Prognosis: Improved dramatically with neoadjuvant/adjuvant chemotherapy and surgical resection; 5-year survival ~60-70% for localized disease; poor prognosis with metastases or poor histologic response to chemotherapy

Macro ─ typically a large, destructive intramedullary tumor replacing marrow and destroying cortex, with extension into soft tissues; cut surface is variable: gritty, white-tan, firm (osteoblastic); fleshy, gray-white (fibroblastic); or gray-blue, gelatinous (chondroblastic); areas of hemorrhage and necrosis are common

Micro ─

Key diagnostic feature: direct production of osteoid matrix by malignant tumor cells

─ Osteoid is eosinophilic, amorphous, lace-like, or dense hyaline material; may mineralize to form woven bone

Three main histologic subtypes (often admixed):

─ Osteoblastic (most common, ~50%): prominent osteoid production, often in a lace-like pattern or broad sheets, by highly atypical, pleomorphic tumor cells with hyperchromatic nuclei and often bizarre mitoses

─ Chondroblastic (~25%): malignant hyaline cartilage production is a dominant feature, with areas resembling high-grade chondrosarcoma; neoplastic osteoid production must be identified elsewhere

─ Fibroblastic (~25%): spindle cell sarcoma resembling high-grade fibrosarcoma or undifferentiated pleomorphic sarcoma, with focal areas of malignant osteoid production

Other features:

─ High cellularity, marked cytologic atypia, pleomorphism, hyperchromasia, increased and atypical mitoses

─ Infiltrative growth pattern, permeating and destroying pre-existing bone trabeculae

─ Vascular invasion is common

─ Tumor necrosis (spontaneous or post-chemotherapy) is frequent

Ancillary studies ─

─ IHC: Tumor cells may express SATB2 (relatively specific for osteoblastic differentiation), alkaline phosphatase, osteocalcin, osteonectin; often variably positive for vimentin; chondroblastic areas positive for S100

─ Molecular ─ Complex karyotypes with numerous chromosomal gains and losses are characteristic; TP53 and RB1 pathway alterations are common; specific translocations are rare in conventional osteosarcoma (unlike Ewing sarcoma)

DDx ─

─ Osteoblastoma (especially aggressive osteoblastoma; osteoblastoma lacks overt malignant cytologic atypia of osteosarcoma, has organized bone formation with osteoblastic rimming, and less infiltrative growth)

─ Fracture Callus (zonal maturation, lacks malignant atypia, history of fracture)

─ Fibrous Dysplasia (curvilinear trabeculae of woven bone lacking osteoblastic rimming, bland fibrous stroma)

─ Chondrosarcoma (especially high-grade or dedifferentiated; osteosarcoma requires identification of osteoid produced by sarcoma cells, not just reactive bone)

─ Ewing Sarcoma (small round blue cells, characteristic molecular translocations like EWSR1-FLI1, usually scant or no matrix)

─ Undifferentiated Pleomorphic Sarcoma of bone (lacks osteoid production)

─ Metastatic Carcinoma (epithelial morphology, IHC positive for keratins, known primary)

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Telangiectatic Osteosarcoma

A rare, high-grade variant of osteosarcoma characterized by large, blood-filled cystic spaces separated by septa containing highly anaplastic tumor cells with minimal osteoid production

Clinical ─

─ Similar age and sex distribution to conventional osteosarcoma (most common in adolescents and young adults, slight male predominance)

─ Typically involves the metaphysis of long bones, especially femur and tibia

─ Presents with pain, swelling, and often a pathologic fracture (in 25-60% of cases, more frequent than conventional osteosarcoma)

─ Imaging: Predominantly lytic, destructive, and expansile lesion with ill-defined margins and cortical breach; often shows fluid-fluid levels on CT/MRI due to hemorrhage and layering of blood components (mimicking aneurysmal bone cyst); minimal or no visible tumor matrix mineralization is typical; MRI best shows cystic nature and soft tissue extent

─ Prognosis: Historically considered to have a worse prognosis, but with current multi-agent chemotherapy and surgery, survival rates are comparable to conventional osteosarcoma

Macro ─ grossly appears as a hemorrhagic, "blood-filled sponge" or multiloculated cystic mass with friable, fleshy septa; solid tumor areas may be minimal; extensive cortical destruction and soft tissue extension are common

Micro ─

─ Characterized by large, blood-filled sinusoidal or cystic spaces lacking an endothelial lining

─ Septa separating the cystic spaces are composed of highly anaplastic, pleomorphic malignant cells with hyperchromatic nuclei, prominent nucleoli, and frequent (often atypical) mitoses

─ Osteoid production by the tumor cells is present but often very focal, scant, and subtle; may be fine and lace-like, or small deposits on septal surfaces; careful search is often required

─ Osteoclast-like giant cells can be numerous within the septa or lining the cystic spaces

─ Necrosis is common, even without prior treatment

─ Minimal mature bone formation by the tumor

Ancillary studies ─

─ IHC: Similar to conventional osteosarcoma, tumor cells may express SATB2, alkaline phosphatase; neoplastic cells do not express endothelial markers (negative CD31/CD34 rules out true vascular tumor)

─ Molecular ─ Complex karyotypes similar to conventional osteosarcoma

DDx ─

─ Aneurysmal Bone Cyst (ABC) (key differential; ABC septa contain bland fibroblasts, osteoblasts, and osteoclast-like giant cells, but lack the high-grade anaplasia of telangiectatic osteosarcoma; minimal or no neoplastic osteoid by tumor cells in ABC; USP6 gene rearrangement in primary ABC)

─ Giant Cell Tumor of Bone (solid sheets of mononuclear stromal cells and evenly distributed osteoclast-like giant cells; lacks blood-filled cystic architecture and malignant osteoid of telangiectatic osteosarcoma; H3-3A mutations)

─ Conventional Osteosarcoma with extensive hemorrhage (may have more solid areas and more obvious osteoid)

─ Malignant Fibrous Histiocytoma/Undifferentiated Pleomorphic Sarcoma with secondary ABC-like change (lacks neoplastic osteoid production)

─ Metastatic Carcinoma with cystic/hemorrhagic changes (e,g,, renal cell carcinoma, thyroid carcinoma; look for epithelial features and IHC positivity for keratins)

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Small Cell Osteosarcoma

A rare, high-grade variant of osteosarcoma composed predominantly of small, round, undifferentiated malignant cells that produce osteoid matrix

Clinical ─

─ Similar age distribution to conventional osteosarcoma, most common in adolescents and young adults (peak in 2nd decade)

─ Slightly older mean age (mid-20s) than conventional osteosarcoma in some series

─ Most frequently involves long bones, particularly femur and tibia; can occur in flat bones

─ Presents with pain and swelling; systemic symptoms (fever, malaise) may be present, mimicking infection or Ewing sarcoma

─ Imaging: Aggressive, destructive bone lesion, often with ill-defined margins, cortical destruction, periosteal reaction, and a large soft tissue mass; appearance can be lytic, sclerotic, or mixed, often permeative; minimal or focal osteoid matrix may be visible, sometimes only on CT; can strongly mimic Ewing sarcoma or lymphoma radiologically

─ Prognosis: Generally considered similar to or slightly worse than conventional osteosarcoma when treated with similar aggressive multi-agent chemotherapy and surgery

Macro ─ gray-white, fleshy, infiltrative tumor, often with extensive soft tissue involvement; areas of hemorrhage and necrosis are common; gritty areas may correspond to osteoid production

Micro ─

─ Predominant feature is a dense proliferation of small, round to oval malignant cells with scant cytoplasm, round to irregular nuclei, finely granular or vesicular chromatin, and inconspicuous nucleoli

─ Cells may be uniform or show mild to moderate pleomorphism

─ Mitotic activity is usually high, including atypical forms

─ Crucial diagnostic feature: production of osteoid (lace-like, trabecular, or sheets) directly by the small round tumor cells; this may be very focal and require extensive sampling

─ Necrosis is common

─ Cartilaginous differentiation is rare

─ Vascular patterns can include hemangiopericytoma-like areas

Ancillary studies ─

─ IHC: Tumor cells are typically positive for vimentin; may show focal positivity for osteocalcin, osteonectin, SATB2, or alkaline phosphatase, supporting osteoblastic differentiation; CD99 may be positive (membranous pattern), causing overlap with Ewing sarcoma; negative for lymphoid markers (LCA, CD20, CD3), myogenic markers (desmin, myogenin), and most neuroendocrine markers (unlike some other small round cell tumors); FLI1 is negative (helps distinguish from Ewing sarcoma)

─ Molecular ─ Complex karyotypes similar to conventional osteosarcoma; typically lacks the specific translocations seen in Ewing sarcoma (e,g,, EWSR1-FLI1)

DDx ─

─ Ewing Sarcoma (key differential; sheets of uniform small round cells, positive for CD99 and FLI1, characteristic EWSR1 translocations, typically no osteoid production by tumor cells, though reactive bone may be present)

─ Lymphoma of Bone (sheets of atypical lymphoid cells, positive for lymphoid markers like CD45, CD20, CD3)

─ Mesenchymal Chondrosarcoma (biphasic pattern with small round cells and islands of hyaline cartilage; HEY1-NCOA2 fusion)

─ Metastatic Small Cell Carcinoma (older patients, history of primary, positive for neuroendocrine markers and keratins)

─ Neuroblastoma (younger children, often adrenal primary, rosette formation, IHC for neuroendocrine markers)

─ Conventional Osteosarcoma with areas of small cell change (look for areas with more typical osteosarcoma morphology)

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Osteopetrosis

A group of rare, hereditary bone diseases characterized by defective osteoclast function leading to impaired bone resorption, resulting in increased bone mass and density, but also brittle bones prone to fracture

Clinical ─

─ Several forms with varying inheritance patterns (autosomal recessive, autosomal dominant, X-linked) and severity

─ Autosomal Recessive Osteopetrosis (ARO, "malignant" infantile osteopetrosis): presents in infancy, severe, often fatal due to bone marrow failure (pancytopenia, infections, bleeding) and cranial nerve compression (blindness, deafness); hepatosplenomegaly from extramedullary hematopoiesis

─ Autosomal Dominant Osteopetrosis (ADO, Albers-Schönberg disease, "benign" adult osteopetrosis): milder, often diagnosed in adolescence or adulthood, sometimes incidentally; increased fracture risk, osteomyelitis (especially of mandible), cranial nerve palsies, osteoarthritis

─ Intermediate Autosomal Recessive Osteopetrosis: intermediate severity between ARO and ADO

─ Osteopetrosis with Renal Tubular Acidosis and Cerebral Calcification: associated with carbonic anhydrase II deficiency

─ Imaging: Generalized, diffuse increase in bone density (osteosclerosis) throughout the skeleton; loss of corticomedullary differentiation, "bone-within-bone" appearance (especially in vertebrae, pelvis, tubular bones); "Erlenmeyer flask" deformity of long bone metaphyses (splaying); transverse pathologic fractures ("chalkstick fractures") are common; skull base thickening and cranial nerve foramen narrowing

─ Prognosis: Variable; ARO is often fatal without bone marrow transplant; ADO has a more variable course with normal to slightly reduced lifespan, complications related to fractures and cranial nerve compression

Macro ─ bones are dense, hard, and chalky; medullary cavity is often obliterated by sclerotic bone; cut surface shows thickened cortices and dense cancellous bone

Micro ─

─ Hallmark is persistence of primary spongiosa (calcified cartilage cores within bone trabeculae) throughout the medullary cavity due to failure of osteoclastic resorption and remodeling

─ Bone trabeculae are numerous, thickened, irregular, and haphazardly arranged, often with club-shaped ends

─ Osteoclasts are usually present, often increased in number, but are functionally defective (e,g,, may lack a ruffled border or clear zone, or show abnormal morphology)

─ Intertrabecular spaces are reduced, filled with fibrous tissue or hypocellular marrow; normal hematopoiesis is severely diminished in severe forms

─ Woven bone predominates in infantile forms; lamellar bone is more common in adult forms, but still with disorganized architecture

─ Cartilage islands persist within bone trabeculae

Ancillary studies ─

─ Molecular ─ Mutations in various genes affecting osteoclast development or function (e,g,, TCIRG1, CLCN7, OSTM1, CA2, RANKL, PLEKHM1, SNX10) depending on the specific subtype of osteopetrosis

DDx ─

─ Pycnodysostosis (autosomal recessive, short stature, acro-osteolysis, open fontanelles, obtuse mandibular angle, also increased bone density but different clinical picture)

─ Engelmann-Camurati Disease (Progressive Diaphyseal Dysplasia) (symmetrical cortical thickening of long bone diaphyses, less generalized sclerosis)

─ Osteopoikilosis/Melorheostosis/Osteopathia Striata (distinct patterns of focal sclerosis, not generalized)

─ Fluorosis (chronic fluoride exposure, can cause diffuse osteosclerosis)

─ Myelofibrosis (osteosclerosis can occur but also marrow fibrosis and extramedullary hematopoiesis, different clinical/hematologic picture)

─ Diffuse Osteoblastic Metastases (e,g,, prostate cancer; typically older patients, focal rather than perfectly uniform sclerosis, positive bone scan)

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Lesions of Cartilage

Osteochondroma

A benign cartilage-capped bony projection arising from the external surface of a bone, with continuity of the cortex and medullary cavity with the underlying bone

Clinical ─

─ Most common benign bone tumor

─ Usually diagnosed in first three decades, often during periods of rapid growth (childhood/adolescence)

─ Slight male predominance for solitary lesions

─ Most commonly involves metaphysis of long bones, especially around the knee (distal femur, proximal tibia) and proximal humerus; can occur in flat bones (pelvis, scapula) or small bones

─ Often asymptomatic; may present as a painless, slow-growing mass, or cause pain due to mechanical irritation, bursa formation, fracture of the stalk, or nerve impingement

─ Imaging: Pedunculated (stalk-like) or sessile (broad-based) bony outgrowth from bone surface; cortex and medullary cavity of osteochondroma are continuous with those of the host bone; cartilage cap is usually visible on MRI (typically <1,5-2cm thick in adults, may be thicker in children); calcifications may be present in the cap

─ Prognosis: Excellent for solitary lesions; malignant transformation to secondary chondrosarcoma is rare (<1%), usually in adults, heralded by pain, growth of the lesion after skeletal maturity, or thickening of cartilage cap (>2cm in adults)

Macro ─ bony outgrowth covered by a glistening, bluish-white hyaline cartilage cap; stalk may be present; cut section shows cortical and cancellous bone continuous with host bone, and a variable thickness cartilage cap

Micro ─

Cartilage cap:

─ Resembles a disorganized epiphyseal growth plate, composed of hyaline cartilage

─ Chondrocytes are arranged in clusters or columns, especially in younger patients; may show mild atypia but lack features of malignancy (significant pleomorphism, high cellularity throughout, atypical mitoses)

─ Undergoes endochondral ossification at its base, transitioning into underlying bone

Bony stalk/base:

─ Composed of lamellar and woven bone with fatty or hematopoietic marrow, continuous with the host bone

Perichondrium covers the cartilage cap

Ancillary studies ─

─ Molecular ─ Inactivation of EXT1 or EXT2 genes (tumor suppressor genes involved in heparan sulfate biosynthesis) is found in the majority of sporadic and hereditary osteochondromas

DDx ─

─ Secondary Chondrosarcoma (arising in osteochondroma; marked increase in cartilage cap thickness, increased cellularity, significant atypia, myxoid change, invasion into underlying bone or soft tissue)

─ Parosteal Osteoma (lacks cartilage cap, no medullary continuity)

─ Bizarre Parosteal Osteochondromatous Proliferation (Nora Lesion) (small bones of hands/feet, "stuck-on" appearance, characteristic bizarre cartilage and blue bone, lacks medullary continuity)

─ Supracondylar Process of Humerus (developmental anomaly, points towards elbow joint)

─ Myositis Ossificans (juxtacortical, zonal pattern, history of trauma)

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Hereditary Multiple Osteochondromas

An autosomal dominant disorder characterized by the development of multiple osteochondromas, typically bilateral and symmetrical, leading to skeletal deformities and an increased risk of malignant transformation

Clinical ─

─ Autosomal dominant inheritance with high penetrance (variable expressivity)

─ Usually diagnosed in early childhood (by age 10 in ~80%) due to palpable masses or skeletal deformities

─ Affects males and females, though males may be more severely affected

─ Characterized by multiple osteochondromas, often numerous (>10-20), typically affecting metaphyses of long bones (around knees, ankles, shoulders, wrists), pelvis, scapulae, ribs; can cause limb length discrepancy, angular deformities (e,g,, genu valgum/varum, Madelung deformity of wrist), joint dysfunction, premature osteoarthritis, and nerve/vessel compression

─ Imaging: Multiple pedunculated or sessile osteochondromas with features similar to solitary osteochondroma (bony outgrowth with corticomedullary continuity with host bone, cartilage cap); associated skeletal deformities are common

─ Prognosis: Increased risk of malignant transformation to secondary chondrosarcoma (estimated 1-5%, higher than solitary osteochondroma), typically in adulthood, often in axial skeleton (pelvis, scapula) or proximal long bones

Macro ─ Multiple osteochondromas of varying sizes and shapes, otherwise similar to solitary osteochondroma

Micro ─

─ Histologic features of individual osteochondromas are identical to solitary osteochondroma (cartilage cap undergoing endochondral ossification, bony stalk with corticomedullary continuity)

─ Cartilage cap may appear more disorganized or cellular in some lesions, especially in younger patients, but this does not necessarily indicate malignancy without other worrisome features

Ancillary studies ─

─ Molecular ─ Germline heterozygous loss-of-function mutations in EXT1 (chromosome 8q24) or EXT2 (chromosome 11p11-p12) genes are found in ~90% of cases; these genes encode glycosyltransferases involved in heparan sulfate proteoglycan synthesis

DDx ─

─ Multiple sporadic osteochondromas (rare, lacks germline EXT mutation, usually fewer lesions)

─ Dysplasia Epiphysealis Hemimelica (Trevor Disease) (asymmetric epiphyseal osteochondromas, typically unilateral, affecting lower limb)

─ Langer-Giedion Syndrome (Trichorhinophalangeal syndrome type II) (multiple exostoses, cone-shaped epiphyses, sparse hair, characteristic facies, often with intellectual disability; TRPS1 and EXT1 contiguous gene deletion)

─ Metachondromatosis (multiple enchondromas and osteochondromas, PTPN11 mutations)

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Enchondroma

A benign intramedullary cartilaginous tumor composed of mature hyaline cartilage, typically occurring in the medullary cavity of bones

Clinical ─

─ Common benign bone tumor (10-25% of benign bone tumors)

─ Peak incidence in 2nd to 4th decades; no significant sex predilection

─ Most commonly involves small tubular bones of hands (phalanges, metacarpals) and feet (metatarsals), where they are often multiple (enchondromatosis)

─ Also occurs in long bones (femur, humerus, tibia), ribs, pelvis; rare in spine or craniofacial bones

─ Often asymptomatic, discovered incidentally or due to pathologic fracture (especially in hands/feet)

─ In long bones, may present with dull ache or pain, but severe pain is a worrisome sign for chondrosarcoma

─ Imaging: Well-circumscribed, geographic lytic lesion in the medullary cavity; often shows characteristic "rings and arcs" or stippled/popcorn calcification (matrix mineralization); may cause endosteal scalloping and mild cortical expansion, especially in small bones; cortex usually intact unless fractured; minimal or no periosteal reaction

─ Prognosis: Excellent for solitary lesions; very low risk of malignant transformation to chondrosarcoma in solitary enchondromas of long bones (<1%), slightly higher in enchondromatosis (Ollier disease, Maffucci syndrome)

Macro ─ firm, lobulated, gray-blue, translucent cartilaginous tissue within the medullary cavity; gritty calcifications may be present; usually well-demarcated from surrounding marrow and bone

Micro ─

─ Composed of lobules of mature hyaline cartilage with relatively low cellularity

─ Chondrocytes are situated within lacunae, typically small with round, dark nuclei and scant cytoplasm; binucleated cells may be present but are usually infrequent

─ Extracellular matrix is abundant, hyaline, and may show focal myxoid change or calcification (corresponding to radiologic findings)

─ Endosteal scalloping is common, but permeation of tumor through cortical bone or into Haversian systems is absent (a key feature distinguishing from low-grade chondrosarcoma)

─ Surrounding bone marrow is typically normal hematopoietic or fatty marrow

─ Enchondromas in small bones of hands/feet can show higher cellularity and more nuclear atypia than those in long bones, which can overlap with low-grade chondrosarcoma if seen in other locations

Ancillary studies ─

─ Molecular ─ Somatic heterozygous mutations in IDH1 or IDH2 genes are found in a high percentage of enchondromas (and central low-grade chondrosarcomas), suggesting they are early events in tumorigenesis

DDx ─

─ Low-Grade Central Chondrosarcoma (key differential, especially in long bones/pelvis; features favoring chondrosarcoma include pain, larger size, deep endosteal scalloping, cortical destruction/soft tissue mass, and histologically: higher cellularity, more atypia, myxoid change, permeation of host bone)

─ Bone Infarct with cartilaginous metaplasia (history of infarct, central necrotic area, cartilage is usually at periphery)

─ Chondroblastoma (epiphyseal location, characteristic "chicken-wire" calcification, different cell morphology)

─ Ollier Disease/Maffucci Syndrome (multiple enchondromas)

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Ollier Disease

A rare, non-hereditary developmental disorder characterized by multiple enchondromas (enchondromatosis) with a typically asymmetric distribution, predominantly affecting the metaphyses and diaphyses of tubular bones

Clinical ─

─ Sporadic condition, no known hereditary pattern; pathogenesis linked to somatic mosaic mutations in IDH1 or IDH2

─ Usually diagnosed in childhood or adolescence due to skeletal deformities, limb length discrepancy, or pathologic fractures

─ Affects males and females equally

─ Characterized by multiple enchondromas, often numerous and asymmetrically distributed; commonly involves tubular bones of hands and feet, long bones (femur, tibia, humerus), and flat bones (pelvis, scapula); unilateral predominance is common

─ Leads to shortened and deformed limbs, bowing, angular deformities, and limb length inequality

─ Imaging: Multiple intramedullary lytic lesions with features of enchondromas (rings and arcs calcification, endosteal scalloping); affected bones are often expanded, shortened, and deformed; characteristic "streaky" or "columnar" lucencies in metaphyses extending into diaphyses in growing bones

─ Prognosis: Increased risk of malignant transformation to chondrosarcoma (estimated 20-50% lifetime risk), typically in adulthood, often arising in larger enchondromas of long bones or pelvis; also increased risk of other neoplasms (e,g,, astrocytomas, ovarian tumors)

Macro ─ multiple masses of gray-blue, translucent cartilaginous tissue within the medullary cavities of affected bones, causing expansion and deformity; individual lesions are similar to solitary enchondromas

Micro ─

─ Histologic features of individual enchondromas are similar to solitary enchondromas: lobules of mature hyaline cartilage with low cellularity and bland chondrocytes

─ However, enchondromas in Ollier disease can exhibit greater cellularity, nuclear atypia (pleomorphism, hyperchromasia, binucleation), and disorganization than typical solitary enchondromas, making the distinction from low-grade chondrosarcoma particularly challenging, especially on limited biopsy material

─ Areas of myxoid change may be more prominent

─ Entrapment of host bone trabeculae can be seen but does not necessarily equate to chondrosarcoma in this context without other features

Ancillary studies ─

─ Molecular ─ Somatic mosaic mutations in IDH1 (most commonly R132C) or IDH2 (most commonly R172S) are found in the majority of enchondromas in Ollier disease patients; these mutations are thought to occur early in skeletal development

DDx ─

─ Low-Grade Chondrosarcoma (distinction is critical but very difficult; clinical context, imaging, and careful histologic assessment for aggressive features are paramount; pain or growth after skeletal maturity are worrisome)

─ Maffucci Syndrome (enchondromatosis associated with multiple soft tissue hemangiomas/spindle cell hemangiomas; also IDH1/IDH2 mutated)

─ Metachondromatosis (autosomal dominant; multiple enchondromas and osteochondroma-like lesions, PTPN11 mutations)

─ Fibrous Dysplasia with cartilaginous differentiation (fibrous stroma, "Chinese-letter" bone trabeculae, different imaging)

─ Generalized enchondromatosis (rare, diffuse skeletal involvement beyond typical Ollier)

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Periosteal Chondroma

A benign cartilaginous tumor arising on the surface of bone, beneath the periosteum, composed of mature hyaline cartilage

Clinical ─

─ Uncommon, accounts for <2% of all chondromas

─ Typically occurs in adolescents and young adults (10-30 years); slight male predominance

─ Most commonly involves metaphysis or diaphysis of long bones (proximal humerus, femur, tibia) and small tubular bones of hands and feet (phalanges)

─ Presents as a slow-growing, often painless or mildly painful firm swelling or mass; may cause cortical erosion

─ Imaging: Well-circumscribed, juxtacortical (surface) radiolucent lesion with a characteristic saucer-shaped erosion or excavation of the underlying cortex, often with a sclerotic rim or buttress of reactive bone at the margins; may contain chondroid matrix calcification (rings and arcs, stippled); no medullary involvement

─ Prognosis: Excellent; local recurrence is rare after complete excision; no malignant potential

Macro ─ well-demarcated, lobulated, firm, gray-blue cartilaginous mass on the bone surface, indenting the cortex; usually <3-5 cm in diameter; covered by periosteum

Micro ─

─ Composed of lobules of mature hyaline cartilage, similar to enchondroma

─ Cellularity is generally low to moderate; chondrocytes are bland with small, round nuclei; binucleation may be seen but is infrequent

─ Matrix is hyaline, may show focal myxoid change or calcification

─ Tumor is well-circumscribed, covered by periosteum, and situated on the bone surface, often eroding the underlying cortex in a saucer-like fashion

─ Reactive new bone formation may be present at the base and periphery of the lesion

─ No infiltration into underlying medullary cavity or surrounding soft tissues beyond the periosteal covering

Ancillary studies ─

─ Molecular ─ Similar to enchondromas, IDH1 or IDH2 mutations are common

DDx ─

─ Periosteal Chondrosarcoma (larger size, more aggressive imaging features like cortical destruction or soft tissue mass beyond periosteum, higher cellularity and atypia histologically)

─ Juxtacortical Chondromyxoid Fibroma (distinct lobular pattern with peripheral hypercellularity and central myxoid stroma, lacks typical chondroid calcification)

─ Periosteal Osteosarcoma (produces neoplastic osteoid, chondroblastic areas may be prominent but osteoid is key, more aggressive imaging)

─ Florid Reactive Periostitis/Nora Lesion (hands/feet, more prominent spindle cell component, bizarre cartilage, different mineralization pattern)

─ Osteochondroma (has a bony stalk with corticomedullary continuity, cartilage cap on a bony base)

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Chondroblastoma

A rare, benign cartilaginous tumor typically arising in the epiphysis or apophysis of long bones in skeletally immature individuals or young adults, characterized by sheets of chondroblasts and osteoclast-like giant cells

Clinical ─

─ Accounts for <1% of all primary bone tumors

─ Peak incidence in 2nd decade (ages 10-25); male predominance (2:1)

─ Most commonly involves epiphysis or apophysis of long bones: distal femur, proximal tibia, proximal humerus; also common in flat bones (pelvis, scapula) and tarsal/carpal bones (talus, calcaneus); rare in skull or spine

─ Presents with localized pain, often related to joint involvement; swelling, joint effusion, and limited range of motion may occur

─ Imaging: Well-circumscribed, geographic lytic lesion in the epiphysis/apophysis, often with a thin sclerotic rim; may cross the open physis into the metaphysis; matrix calcification (stippled, "chicken-wire" pattern) is present in ~50% of cases; cortical expansion may be seen; MRI shows lobulated margins, often perilesional edema

─ Prognosis: Benign, but local recurrence rates of 10-20% after curettage; aggressive variant with soft tissue extension or rare benign lung "metastases" (implants) can occur but do not usually affect overall survival; malignant transformation is exceptionally rare

Macro ─ soft, friable, gray-pink to reddish-brown tissue, often with gritty calcifications or cystic areas; usually well-demarcated

Micro ─

─ Sheets of relatively uniform, polygonal mononuclear cells (chondroblasts) with distinct cell borders, eosinophilic to clear cytoplasm, and round to ovoid nuclei with longitudinal grooves ("coffee bean" nuclei)

─ Scattered osteoclast-like multinucleated giant cells are invariably present throughout the lesion

─ Characteristic "chicken-wire" calcification: pericellular deposition of calcium around individual or small groups of chondroblasts, forming a delicate network

─ Chondroid matrix production is typically scant and immature, appearing as eosinophilic, fibrillar, or slightly basophilic material between cells; mature hyaline cartilage is uncommon

─ Mitotic figures may be present but are usually not numerous or atypical

─ Secondary aneurysmal bone cyst (ABC) changes are common (15-25% of cases)

Ancillary studies ─

─ IHC: Chondroblasts are positive for S100 protein, DOG1 (often patchy), and SOX9

─ Molecular ─ Characteristically harbors somatic heterozygous mutations in H3F3B (encoding histone H3,3 variant), most commonly K36M; less commonly H3F3A mutations

DDx ─

─ Giant Cell Tumor of Bone (epiphyseal/metaphyseal in skeletally mature, sheets of mononuclear stromal cells and more evenly distributed osteoclast-like giant cells, lacks chondroid matrix and chicken-wire calcification, H3F3A G34W/V/L/R mutations)

─ Clear Cell Chondrosarcoma (older adults, epiphyseal, malignant chondrocytes with clear cytoplasm, prominent woven bone production, lacks typical chondroblasts and chicken-wire calcification)

─ Osteosarcoma (especially chondroblastic or small cell variants; look for malignant osteoid production, greater atypia)

─ Aneurysmal Bone Cyst (if secondary ABC changes are extensive; careful search for solid chondroblastomatous areas is needed)

─ Infection/Osteomyelitis (inflammatory infiltrate, clinical signs of infection)

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Chondromyxoid Fibroma

A rare, benign cartilaginous tumor of bone characterized by a lobular architecture with myxoid and chondroid areas, often with peripheral hypercellularity and central hypocellularity within lobules

Clinical ─

─ Accounts for <1% of all primary bone tumors and <2% of benign bone tumors

─ Typically occurs in adolescents and young adults (peak in 2nd and 3rd decades); slight male predominance

─ Most commonly involves the metaphysis of long bones, especially around the knee (proximal tibia > distal femur); also occurs in small tubular bones of hands/feet, flat bones (pelvis, ribs), and rarely spine

─ Presents with localized pain and swelling, often of insidious onset and long duration

─ Imaging: Well-circumscribed, eccentric, geographic lytic lesion in the metaphysis, often with a sharply defined sclerotic rim and cortical expansion or thinning; "soap bubble" or trabeculated appearance due to internal septations; matrix calcification is typically absent or minimal (unlike enchondroma/chondrosarcoma)

─ Prognosis: Benign; local recurrence (up to 25%) after curettage, especially in younger patients or with incomplete removal; malignant transformation is exceptionally rare

Macro ─ firm, glistening, gray-white or yellowish, lobulated tissue with a distinctly myxoid or gelatinous consistency; usually well-demarcated from surrounding bone; cystic changes may be present

Micro ─

Characteristic lobular architecture:

─ Pseudolobules of tumor tissue separated by fibrous septa rich in blood vessels and sometimes containing osteoclast-like giant cells

─ Peripheral hypercellularity within lobules: spindle-shaped or stellate cells with hyperchromatic nuclei, often condensed at the edges of lobules

─ Central hypocellularity within lobules: cells are more scattered in an abundant myxoid or chondromyxoid stroma; cells here may be stellate, spindled, or occasionally more rounded with vacuolated cytoplasm (physaliphorous-like)

─ Chondroid differentiation is often focal and immature

─ Nuclear atypia and pleomorphism can be present, especially in hypercellular areas ("atypical CMF"), but significant atypia and numerous mitoses are rare and should raise concern for chondrosarcoma

─ True hyaline cartilage is usually absent or minimal

─ No "chicken-wire" calcification (unlike chondroblastoma)

Ancillary studies ─

─ IHC: Tumor cells are usually positive for S100 protein (especially in more chondroid areas), vimentin; may show focal positivity for smooth muscle actin in peripheral spindle cells

─ Molecular ─ Recurrent rearrangements involving chromosome 6, particularly involving band 6q13 (often with GRM1 gene involvement), are characteristic and support a neoplastic basis

DDx ─

─ Chondrosarcoma (low-grade central or periosteal; lacks the distinct lobular architecture with peripheral hypercellularity of CMF, often has more mature hyaline cartilage, infiltrative growth in central lesions, IDH1/2 mutations)

─ Chondroblastoma (epiphyseal, sheets of chondroblasts, chicken-wire calcification, osteoclast-like giant cells throughout, H3F3B mutations)

─ Fibrous Dysplasia with myxoid/cartilaginous change (curvilinear bone trabeculae, bland fibrous stroma, GNAS mutations)

─ Aneurysmal Bone Cyst (blood-filled cystic spaces, lacks the characteristic solid lobular pattern of CMF, though CMF can have secondary ABC changes)

─ Simple Bone Cyst (unicameral, fluid-filled, fibrous lining)

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Juxtacortical Chondromyxoid Fibroma

A very rare benign cartilaginous tumor with histologic features identical to intramedullary chondromyxoid fibroma but arising on the surface of a bone, beneath the periosteum

Clinical ─

─ Extremely rare, fewer than 30 cases reported

─ Broad age range, but often young adults (similar to intramedullary CMF)

─ Most commonly involves the surface of long bones (femur, tibia, humerus) and small tubular bones of hands and feet

─ Presents as a slow-growing, usually painless or mildly painful firm mass

─ Imaging: Well-circumscribed, juxtacortical (surface) soft tissue mass causing saucer-like erosion or scalloping of the underlying cortex, often with a sclerotic cortical rim; mineralization is typically absent or minimal; no medullary involvement

─ Prognosis: Benign; local recurrence possible after incomplete excision, similar to intramedullary CMF

Macro ─ firm, lobulated, gray-white or yellowish, myxoid/gelatinous mass on the bone surface, indenting the cortex; usually <5 cm

Micro ─

─ Histologically identical to intramedullary chondromyxoid fibroma:

─ Pseudolobular architecture with peripheral hypercellularity (spindle/stellate cells) and central hypocellularity in an abundant myxoid or chondromyxoid stroma

─ Fibrous septa with blood vessels separating lobules

─ Nuclear atypia/pleomorphism can be present but usually not marked; mitoses rare

─ Tumor is located on the bone surface, beneath the periosteum, and erodes the underlying cortex

Ancillary studies ─

─ Similar to intramedullary CMF (S100 positive, chromosome 6 rearrangements involving GRM1 may be present)

DDx ─

─ Periosteal Chondroma (composed of mature hyaline cartilage, often with calcification, lacks the characteristic myxoid stroma and biphasic cellularity of CMF lobules)

─ Periosteal Chondrosarcoma (more atypia, infiltrative growth into soft tissue beyond periosteum, larger size)

─ Periosteal Osteosarcoma (neoplastic osteoid production, different radiographic appearance)

─ Soft Tissue Myxoma/Chondromyxoid Fibroma secondarily involving bone surface (distinction can be difficult without clear origin from periosteum)

─ Florid Reactive Periostitis (zonal pattern, prominent spindle cell proliferation resembling nodular fasciitis, reactive bone formation)

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Chondrosarcoma

This section discusses: Conventional Chondrosarcoma (Central and Peripheral)

A malignant cartilaginous tumor arising either centrally within bone (central chondrosarcoma) or from the cartilage cap of a pre-existing osteochondroma (peripheral chondrosarcoma)

Clinical ─

─ Second most common primary malignant bone tumor after osteosarcoma (excluding myeloma/lymphoma)

─ Typically affects adults, peak incidence in 4th to 6th decades; rare under 20 years

─ Slight male predominance

─ Central: Most common in pelvis, femur, humerus, ribs; Peripheral: Arises from osteochondromas, so similar distribution (pelvis, scapula, proximal femur/humerus most common sites for malignant transformation)

─ Presents with insidious onset of pain, swelling, or palpable mass; pathologic fracture is uncommon

─ Central lesions may be an incidental finding or cause pain; Peripheral lesions often present with recent growth or new pain in a known osteochondroma

─ Imaging (Central): Intramedullary, geographic lytic lesion, often large (>5cm), with endosteal scalloping, cortical thickening or destruction, and often a soft tissue mass; characteristic chondroid matrix mineralization (rings and arcs, flocculent, popcorn) is key; MRI shows lobulated, high T2 signal mass

─ Imaging (Peripheral): Thickened (>2cm in adults), irregular cartilage cap on an osteochondroma, often with increased mineralization within the cap, associated soft tissue mass, or erosion of the underlying bony stalk; MRI best evaluates cap thickness and soft tissue extension

─ Prognosis: Correlates strongly with histologic grade; Grade 1: ~90% 5-year survival, rare metastases; Grade 2: ~80% 5-year survival, ~10-15% metastasis; Grade 3: ~40-50% 5-year survival, frequent metastases (lung, bone, other organs)

Macro ─ lobulated, gray-blue, translucent, firm to gelatinous cartilaginous tissue; may have gritty calcifications, cystic degeneration, myxoid areas, or necrosis (especially in higher grades); peripheral chondrosarcoma shows a thickened, irregular cartilage cap on an osteochondroma

Micro ─

Histologic grading (typically Evans Grades 1, 2, 3, or WHO Grades I, II, III) is based on cellularity, nuclear atypia, and mitotic activity:

─ Grade 1 (Low-grade): Resembles enchondroma but shows subtle aggressive features; higher cellularity than benign cartilage, mild nuclear atypia (enlarged, hyperchromatic nuclei), occasional binucleated cells; myxoid change may be present; permeation of host bone (entrapping lamellar bone trabeculae) is a key feature in central lesions distinguishing from enchondroma

─ Grade 2 (Intermediate-grade): Increased cellularity, more pronounced nuclear atypia (pleomorphism, irregular contours, prominent nucleoli), more frequent binucleation; mitoses may be present but are rare; myxoid change is more common

─ Grade 3 (High-grade): Marked hypercellularity, significant nuclear pleomorphism and atypia, easily identifiable mitoses (often >2 per 10 HPF); necrosis may be present; spindle cell change can occur

─ Peripheral chondrosarcomas arise from the cartilage cap of an osteochondroma; histologic grading is similar, with focus on atypia and cellularity within the cap; invasion into the underlying bony stalk or surrounding soft tissue is indicative of malignancy

Ancillary studies ─

─ IHC: Tumor cells are S100 positive

─ Molecular ─ Heterozygous mutations in IDH1 or IDH2 genes are very common in conventional central and peripheral chondrosarcomas (grades 1 and 2), but less frequent in grade 3 and dedifferentiated chondrosarcomas; loss of heterozygosity or mutations in TP53 and RB1 pathways, and alterations in Hedgehog signaling are associated with higher grades and progression

DDx ─

─ Enchondroma (key differential for Grade 1 central chondrosarcoma; benign, lacks permeation, less cellularity/atypia in long bones)

─ Osteochondroma (benign, for peripheral lesions; chondrosarcoma shows thickened cap with atypia)

─ Chondroblastic Osteosarcoma (younger patients, neoplastic osteoid production by malignant cells)

─ Chondroblastoma (epiphyseal, characteristic chondroblasts, chicken-wire calcification, H3F3B mutations)

─ Dedifferentiated Chondrosarcoma (abrupt transition to a high-grade non-cartilaginous sarcoma)

─ Clear Cell Chondrosarcoma (epiphyseal, characteristic clear cells, woven bone production)

─ Mesenchymal Chondrosarcoma (biphasic, small round cells and cartilage islands)

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Periosteal Chondrosarcoma

A rare, malignant cartilaginous tumor arising on the surface of bone, beneath the periosteum, typically of intermediate grade

Clinical ─

─ Uncommon, accounts for <1% of all chondrosarcomas

─ Typically affects adults, peak incidence in 3rd to 5th decades (older than periosteal chondroma)

─ Slight male predominance

─ Most commonly involves metaphysis or diaphysis of long bones (femur, humerus, tibia)

─ Presents as a slow-growing, often painful mass; symptoms may be present for months to years

─ Imaging: Well-circumscribed, juxtacortical (surface) soft tissue mass, often >5cm, causing saucer-like erosion of the underlying cortex; typically contains chondroid matrix mineralization (rings, arcs, stippled); periosteal reaction with Codman triangles may be present; cortical destruction and invasion into underlying medullary cavity are usually absent but soft tissue extension beyond periosteum is common

─ Prognosis: Intermediate between low-grade and high-grade conventional chondrosarcoma; 5-year survival ~80-90%; local recurrence is common (20-30%) if inadequately excised; distant metastases (primarily lung) occur in ~10-15% of cases

Macro ─ lobulated, firm, gray-blue to white, translucent cartilaginous mass on the bone surface, eroding the underlying cortex; may have gritty calcifications; often extends into surrounding soft tissues, pushing aside muscle

Micro ─

─ Composed of lobules of hyaline cartilage with features typically corresponding to Grade 1 or 2 conventional chondrosarcoma

─ Increased cellularity and nuclear atypia compared to periosteal chondroma (larger, more hyperchromatic, and irregular nuclei; more frequent binucleation)

─ Myxoid change in the stroma is common

─ Mitotic figures are usually infrequent but may be present

─ Tumor arises on the bone surface, beneath the periosteum, and causes saucerization of the underlying cortex; infiltration into surrounding soft tissues beyond the periosteal remnants is a key feature

─ Invasion of underlying Haversian canals or medullary bone is generally absent or very limited

Ancillary studies ─

─ IHC: Tumor cells are S100 positive

─ Molecular ─ IDH1 or IDH2 mutations are common, similar to conventional chondrosarcomas; other genetic alterations may differ from central chondrosarcomas but are not fully characterized for routine diagnosis

DDx ─

─ Periosteal Chondroma (smaller size, less cellularity and atypia, no soft tissue invasion beyond periosteum)

─ Periosteal Osteosarcoma (produces neoplastic osteoid, different radiographic appearance with perpendicular bone spicules)

─ Juxtacortical Chondromyxoid Fibroma (distinctive myxoid/chondroid lobules with peripheral hypercellularity, lacks overt malignant features of chondrosarcoma)

─ High-Grade Surface Osteosarcoma (more anaplastic, often with osteoid production)

─ Soft tissue chondrosarcoma secondarily involving bone surface (rare, distinction based on epicenter and relationship to periosteum)

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Clear Cell Chondrosarcoma

A rare, low-grade malignant cartilaginous tumor typically arising in the epiphysis of long bones, characterized by sheets of cells with abundant clear cytoplasm and deposition of fine, lace-like bone

Clinical ─

─ Accounts for ~2% of all chondrosarcomas

─ Wide age range (2nd to 8th decades), but most common in young to middle-aged adults (peak 3rd to 5th decades); strong male predominance (~3:1)

─ Predilection for epiphyses of long bones, especially proximal femur, proximal humerus, and distal femur

─ Presents with long-standing, insidious pain, often related to joint; swelling or pathologic fracture are less common

─ Imaging: Well-circumscribed, geographic lytic lesion centered in the epiphysis, often with a sclerotic rim; matrix calcification (chondroid type) is variable, may be scant or absent; cortical expansion or breach may occur; can extend across joint to involve adjacent bone

─ Prognosis: Generally better than conventional chondrosarcoma of similar grade; indolent course with potential for late local recurrence (20-30%) and rare distant metastases (<15%, usually lung or bone), often many years after initial treatment

Macro ─ firm, gritty, gray-white to tan tissue, sometimes with cystic or hemorrhagic areas; usually well-demarcated from surrounding bone

Micro ─

─ Hallmark feature: sheets of polygonal tumor cells with abundant, clear to faintly eosinophilic cytoplasm (due to glycogen content) and distinct cell membranes

─ Nuclei are central, round to oval, with vesicular chromatin and often prominent nucleoli; mild to moderate atypia

─ Mitotic activity is generally low

─ Deposition of fine, lace-like trabeculae of reactive woven bone (not neoplastic osteoid) is characteristic, often surrounding individual or small groups of tumor cells

─ Osteoclast-like multinucleated giant cells are frequently present

─ Areas resembling conventional low-grade chondrosarcoma (hyaline cartilage with mildly atypical chondrocytes) may be present, often at the periphery

─ Secondary aneurysmal bone cyst-like changes can occur

Ancillary studies ─

─ IHC: Tumor cells are S100 positive; clear cells are PAS positive (diastase sensitive) due to glycogen

─ Molecular ─ IDH1/IDH2 mutations are uncommon (unlike conventional chondrosarcoma); rearrangements involving EWSR1 gene have been reported in a subset of cases, sometimes fused with ATF1 or NR4A3 (though the latter is more typical of extraskeletal myxoid chondrosarcoma)

DDx ─

─ Chondroblastoma (younger patients, "chicken-wire" calcification, characteristic chondroblasts with grooved nuclei, H3F3B mutations)

─ Metastatic Renal Cell Carcinoma (clear cell type; older patients, history of renal mass, positive for RCC markers like PAX8, CAIX, CD10; negative for S100)

─ Osteoblastoma/Osteoid Osteoma (prominent osteoblastic rimming on bone, lacks sheets of clear cells)

─ Giant Cell Tumor of Bone (lacks clear cytoplasm and bone production by tumor stromal cells, characteristic mononuclear cells, H3F3A mutations)

─ Conventional Chondrosarcoma (may have focal clear cell change, but lacks the diffuse sheets of clear cells and lace-like bone)

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Dedifferentiated Chondrosarcoma

A highly aggressive biphasic malignant tumor composed of a well-differentiated (typically low-grade) chondrosarcoma juxtaposed with a high-grade, non-cartilaginous sarcoma

Clinical ─

─ Accounts for ~10-15% of all chondrosarcomas

─ Typically affects older adults (peak 5th to 7th decades), often a decade older than conventional chondrosarcoma

─ Slight male predominance

─ Most common in long bones (femur, humerus, tibia) and pelvis; can arise de novo or in a pre-existing chondrosarcoma (often after recurrence or radiation)

─ Presents with rapidly worsening pain, swelling, and often a large palpable mass; pathologic fracture is common (~20%)

─ Imaging: Biphasic appearance; areas typical of low-grade chondrosarcoma (lytic lesion with chondroid matrix calcification, endosteal scalloping) are juxtaposed with an aggressive, purely lytic, destructive component often with a large soft tissue mass and cortical destruction, lacking calcification; the interface between the two components is usually sharp

─ Prognosis: Very poor, dictated by the high-grade dedifferentiated component; 5-year survival rate is low (~10-25%); high rates of local recurrence and early distant metastases (lungs, bone, other organs)

Macro ─ typically a large tumor with distinct areas: firm, gray-blue, lobulated cartilaginous tissue (low-grade component) sharply demarcated from a fleshy, gray-white, often necrotic and hemorrhagic, high-grade sarcoma component; the high-grade component often forms a large soft tissue mass

Micro ─

Biphasic pattern with an abrupt interface between:

Well-differentiated chondrosarcoma component:

─ Usually low-grade (Grade 1 or 2) hyaline chondrosarcoma, with typical features (lobules of cartilage, mild to moderate atypia)

High-grade dedifferentiated component:

─ Most commonly resembles undifferentiated pleomorphic sarcoma (formerly MFH), osteosarcoma (often fibroblastic or osteoblastic type), or fibrosarcoma

─ Characterized by high cellularity, marked pleomorphism, frequent and atypical mitoses, and necrosis

─ This component is non-cartilaginous (i,e,, does not produce chondroid matrix itself)

The transition between the two components is characteristically abrupt, not gradual

Ancillary studies ─

─ IHC: Cartilaginous component is S100 positive; dedifferentiated component is typically S100 negative and its IHC profile depends on its line of differentiation (e,g,, osteosarcomatous component may be SATB2 positive)

─ Molecular ─ Complex karyotypes are common in the dedifferentiated component; IDH1/IDH2 mutations may be present in the low-grade cartilaginous part but often lost or accompanied by additional mutations (e,g,, TP53, RB1, CDKN2A) in the high-grade component, suggesting clonal evolution

DDx ─

─ Conventional High-Grade Chondrosarcoma (lacks the abrupt transition to a distinct non-cartilaginous high-grade sarcoma; atypia is within the cartilaginous component)

─ Osteosarcoma (especially chondroblastic type; osteoid is produced by the malignant spindle cells, not just a secondary high-grade sarcoma juxtaposed with cartilage)

─ Undifferentiated Pleomorphic Sarcoma/Fibrosarcoma of bone (if cartilaginous component is not sampled or recognized; imaging correlation is crucial)

─ Collision Tumor (extremely rare; two distinct primary malignancies arising contiguously)

─ Mesenchymal Chondrosarcoma (biphasic, but the non-cartilaginous component is a primitive small round cell sarcoma, not a high-grade pleomorphic sarcoma)

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Mesenchymal Chondrosarcoma

A rare, highly aggressive malignant tumor characterized by a biphasic pattern of undifferentiated small round cells admixed with islands of well-differentiated hyaline cartilage

Clinical ─

─ Accounts for <2-10% of all chondrosarcomas; rare overall

─ Wide age range, but often affects adolescents and young adults (peak 2nd and 3rd decades); no clear sex predominance, or slight female predominance in some series

─ Can arise in bone (intramedullary or juxtacortical) or extraskeletal soft tissues (especially head and neck, meninges)

─ Skeletal sites: most common in craniofacial bones (jaw, skull), ribs, pelvis, vertebrae, and long bones

─ Presents with pain, swelling, or a palpable mass; symptoms may be present for months to years

─ Imaging: Often an aggressive, destructive lesion (lytic or mixed lytic/sclerotic) with ill-defined margins, cortical destruction, and a prominent soft tissue mass; chondroid matrix calcification (stippled, rings/arcs) is present in ~50-60% of cases, often focal and corresponding to the cartilaginous islands

─ Prognosis: Poor; highly aggressive with high rates of local recurrence and distant metastases (lungs, bone, lymph nodes), often late (5-10+ years after diagnosis); 5-year survival ~40-60%, 10-year survival ~20-40%

Macro ─ firm, gray-white to tan, fleshy tumor, often with areas of hemorrhage and necrosis; visible cartilaginous nodules may be present; typically infiltrative

Micro ─

Distinctive biphasic pattern:

Undifferentiated small cell component:

─ Sheets or densely packed nests of small, round to oval cells with scant cytoplasm, dark hyperchromatic nuclei, and inconspicuous nucleoli

─ Resembles Ewing sarcoma or other small round cell tumors

─ Mitotic activity is usually high; apoptosis is common

─ Hemangiopericytoma-like vascular pattern (staghorn vessels) is often prominent within the small cell areas

Differentiated cartilaginous component:

─ Islands or nodules of relatively well-differentiated hyaline cartilage, often low-grade (resembling enchondroma or Grade 1 chondrosarcoma)

─ These cartilaginous areas are sharply demarcated from the small cell component

The proportion of the two components varies greatly; either can predominate

Ancillary studies ─

─ IHC: Small cell component is often positive for CD99 (membranous, similar to Ewing sarcoma), vimentin; may show focal S100 positivity; negative for lymphoid markers, desmin, keratins; cartilaginous component is S100 positive

─ Molecular ─ Characterized by a specific recurrent gene fusion, HEY1-NCOA2 (formerly IRF2BP2-NCOA2 or HESR1-NCOA2), resulting from inv(8)(q13q21,1) or t(8;8); this fusion is highly specific and useful for diagnosis, especially in small biopsies or cases with limited cartilage

DDx ─

─ Ewing Sarcoma (monophasic small round cell tumor, lacks cartilaginous islands, EWSR1 gene rearrangements, typically FLI1 positive)

─ Small Cell Osteosarcoma (produces neoplastic osteoid, usually lacks distinct cartilaginous islands, different molecular profile)

─ Lymphoma of Bone (positive for lymphoid markers, lacks cartilage and HEY1-NCOA2 fusion)

─ Dedifferentiated Chondrosarcoma (high-grade dedifferentiated component is typically a pleomorphic sarcoma, not a small round cell sarcoma; lacks HEY1-NCOA2 fusion)

─ Synovial Sarcoma, poorly differentiated (may have small cell areas, but often biphasic with epithelial component or monophasic spindle cells, SS18-SSX fusion)

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Giant Cell Rich Lesions of Bone

Giant Cell Tumor of Bone

A locally aggressive (rarely metastasizing) neoplasm composed of mononuclear stromal cells admixed with numerous osteoclast-like multinucleated giant cells, typically arising in the epiphysis of long bones in skeletally mature individuals

Clinical ─

─ Accounts for ~4-5% of all primary bone tumors and ~20% of benign bone tumors

─ Peak incidence in 3rd to 4th decades (ages 20-40), after physeal closure; rare in skeletally immature individuals or older adults (>55)

─ Slight female predominance

─ Most commonly involves the epiphysis/metaphysis of long bones, especially around the knee (distal femur, proximal tibia), distal radius, and proximal humerus; also occurs in sacrum and flat bones; rare in small bones of hands/feet

─ Presents with localized pain, swelling, and limited range of motion; pathologic fracture occurs in 10-15% of cases

─ Imaging: Eccentric, geographic lytic lesion in the epiphysis extending to the subarticular bone, usually with well-defined but non-sclerotic margins; cortical expansion, thinning, and breach are common; soft tissue extension may occur; no matrix mineralization is typical; MRI shows solid, often heterogeneous mass, may have secondary aneurysmal bone cyst changes with fluid-fluid levels

─ Prognosis: Benign, but locally aggressive with a high local recurrence rate (15-50%) after curettage; lung "metastases" (benign implants) occur in ~2-5% of cases, usually with indolent course but can rarely be fatal; malignant transformation (primary or secondary, often post-radiation) is rare (<1%)

Macro ─ soft, friable, reddish-brown to tan hemorrhagic tissue; may have cystic areas (secondary ABC changes) or yellowish areas (xanthoma cells); usually destroys cortex and may extend into soft tissue

Micro ─

Two main cell populations:

Mononuclear stromal cells:

─ The neoplastic component; plump, ovoid to spindle-shaped cells with indistinct cell borders, vesicular nuclei, and small nucleoli; mitoses are usually present and can be numerous, but atypical mitoses are rare

Osteoclast-like multinucleated giant cells:

─ Large cells with numerous (often >10-20) bland, centrally clustered nuclei similar to those of the mononuclear cells; evenly distributed throughout the tumor

─ Stroma is highly vascular with thin-walled capillaries; areas of hemorrhage, hemosiderin deposition, and foamy macrophages (xanthoma cells) are common

─ Secondary aneurysmal bone cyst (ABC) changes (blood-filled cystic spaces lined by fibrous septa with giant cells) are frequent and can be extensive

─ Reactive woven bone may be present at the periphery or within septa of ABC areas, but neoplastic bone/cartilage production is absent

─ Necrosis can occur, especially in larger tumors

Ancillary studies ─

─ IHC: Mononuclear stromal cells are positive for RANKL; osteoclast-like giant cells express RANK (receptor for RANKL); histone H3,3 G34W/V immunostain is highly specific for the neoplastic stromal cells in most GCTB

─ Molecular ─ Majority of cases harbor somatic heterozygous mutations in H3F3A gene (encoding histone H3,3 variant), most commonly p,Gly34Trp (G34W) or p,Gly34Val (G34V); these mutations are highly specific for GCTB among giant cell-rich lesions

DDx ─

─ Aneurysmal Bone Cyst (ABC) (especially solid variant or if secondary ABC changes are extensive in GCTB; ABC lacks the diffuse sheets of neoplastic mononuclear cells, primary ABC has USP6 rearrangement)

─ Chondroblastoma (skeletally immature, epiphyseal, sheets of chondroblasts with grooved nuclei, chicken-wire calcification, S100+, H3F3B mutations)

─ Brown Tumor of Hyperparathyroidism (history of hyperparathyroidism, often multiple lesions, abundant hemosiderin, fibrosis, prominent osteoclastic resorption, no H3F3A mutation)

─ Giant Cell Reparative Granuloma (typically jaws or small bones of hands/feet, zonal architecture, more fibrous stroma, hemosiderin common)

─ Nonossifying Fibroma (metaphyseal, storiform spindle cells, foamy macrophages, less prominent/evenly distributed giant cells)

─ Malignant Giant Cell Tumor of Bone (rare; overt sarcomatous stroma juxtaposed with conventional GCTB areas)

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Giant Cell Reparative Granuloma (Central and Peripheral)

A benign, reactive, intraosseous lesion characterized by a proliferation of fibroblastic spindle cells, hemorrhage, hemosiderin deposition, and osteoclast-like multinucleated giant cells, most commonly occurring in the jawbones (central) or gingiva/alveolar mucosa (peripheral)

Clinical ─

─ Central GCRG: Typically affects children and young adults (peak 2nd-3rd decades); female predominance; most common in mandible (anterior to molars) > maxilla

─ Peripheral GCRG (Epulis): More common than central GCRG; occurs over a wider age range, but also common in young adults; female predominance; arises in gingiva or alveolar ridge, often associated with irritation or trauma (e,g,, tooth extraction)

─ Presents as a painless or mildly painful swelling; may cause tooth displacement or malocclusion (central); peripheral lesions are exophytic, reddish-purple, often ulcerated masses

─ Imaging (Central GCRG): Well-demarcated, unilocular or multilocular radiolucency, often with cortical expansion and thinning; may show ill-defined margins if aggressive; tooth displacement is common; roots may be resorbed

─ Prognosis: Good; treated by curettage or local excision; recurrence rates are higher for central GCRG (10-25%, up to 50% for aggressive lesions) than for peripheral GCRG (<10%)

Macro ─ soft, friable, reddish-brown to hemorrhagic tissue; peripheral lesions are polypoid or nodular masses on gingiva

Micro ─

─ Cellular proliferation of bland ovoid to spindle-shaped fibroblastic/myofibroblastic cells in a variably collagenous stroma

─ Numerous osteoclast-like multinucleated giant cells, often clustered around areas of hemorrhage or in a haphazard distribution

─ Prominent hemorrhage, extravasated red blood cells, and hemosiderin deposition are characteristic features

─ Reactive woven bone or osteoid formation is common, often at the periphery or within fibrous septa

─ Stroma can be loose and edematous or more densely fibrous

─ Mitotic activity may be present but atypical mitoses are absent

─ No significant cytologic atypia or pleomorphism in the mononuclear cells (unlike GCTB)

─ Zonal pattern may be seen with more cellular areas and more fibrous areas

─ Peripheral GCRG is histologically similar but arises in soft tissue overlying bone, may cause superficial bone erosion

Ancillary studies ─

─ Not typically required for diagnosis; diagnosis is based on clinicopathologic and radiographic features

─ Molecular ─ Some studies suggest USP6 gene rearrangements (as seen in ABC) can occur in a subset of aggressive craniofacial GCRGs, but this is not a consistent finding and its significance is debated; generally distinct from GCTB (H3F3A negative)

DDx ─

─ Giant Cell Tumor of Bone (GCTB) (rare in jaws, typically epiphyseal in long bones of skeletally mature, diffuse sheets of neoplastic mononuclear cells with evenly distributed giant cells, lacks prominent hemorrhage/hemosiderin of GCRG, H3F3A mutated)

─ Brown Tumor of Hyperparathyroidism (histologically identical to GCRG; requires clinical/serum evaluation for hyperparathyroidism)

─ Aneurysmal Bone Cyst (ABC) (blood-filled cystic spaces, fibrous septa may resemble GCRG, but GCRG is predominantly solid; GCRG can have secondary ABC changes)

─ Cherubism (bilateral, symmetric jaw involvement in children, specific genetic basis, histologically similar to GCRG)

─ Fibrous Dysplasia (curvilinear bone trabeculae in fibrous stroma, lacks prominent giant cells and hemorrhage of GCRG)

─ Central Odontogenic Fibroma (if in jaw, different stromal appearance, odontogenic epithelium may be present)

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Brown Tumor of Hyperparathyroidism

A focal, reactive, intraosseous lesion rich in osteoclast-like giant cells, hemorrhage, and hemosiderin, occurring in the setting of persistent hyperparathyroidism (primary, secondary, or tertiary)

Clinical ─

─ Occurs in patients with hyperparathyroidism (elevated parathyroid hormone - PTH)

─ Primary HPT: adenoma, hyperplasia, or carcinoma of parathyroid glands

─ Secondary HPT: most commonly due to chronic renal failure; also vitamin D deficiency, malabsorption

─ Tertiary HPT: autonomous PTH secretion after prolonged secondary HPT

─ Can affect any bone, but common sites include jawbones (mandible, maxilla), pelvis, ribs, clavicles, and long bones (especially femur, tibia)

─ Often multiple lesions; may present as painful swelling, palpable mass, or pathologic fracture; symptoms of hypercalcemia or underlying renal disease may be present

─ Imaging: Well-demarcated, expansile lytic lesions, can be unilocular or multilocular; cortical thinning or breach may occur; other radiographic signs of hyperparathyroidism often present (subperiosteal bone resorption, osteopenia, "salt-and-pepper" skull, loss of lamina dura)

─ Prognosis: Lesions typically regress or resolve with successful treatment of the underlying hyperparathyroidism (e,g,, parathyroidectomy, management of renal disease)

Macro ─ soft, friable, reddish-brown to brown (due to hemosiderin) tissue; may be cystic or hemorrhagic

Micro ─

─ Histologically identical to Giant Cell Reparative Granuloma (GCRG)

─ Cellular proliferation of bland ovoid to spindle-shaped fibroblastic cells

─ Numerous osteoclast-like multinucleated giant cells, often clustered around areas of hemorrhage

─ Abundant extravasated red blood cells and hemosiderin pigment (giving the "brown" color)

─ Reactive woven bone or osteoid formation is common

─ Fibrous stroma, which can be loose or dense

─ Cystic degeneration may be present

─ No significant cytologic atypia or pleomorphism

Ancillary studies ─

─ Clinical correlation is key: requires evidence of hyperparathyroidism (elevated serum PTH, often elevated calcium and alkaline phosphatase, low/normal phosphorus in primary HPT)

─ Histology alone cannot distinguish Brown Tumor from GCRG

DDx ─

─ Giant Cell Reparative Granuloma (GCRG) (histologically identical; GCRG occurs in patients without hyperparathyroidism)

─ Giant Cell Tumor of Bone (GCTB) (different cell population, less hemorrhage/hemosiderin, H3F3A mutated)

─ Aneurysmal Bone Cyst (ABC) (predominantly cystic, different septal histology, though Brown Tumor can have secondary ABC changes)

─ Langerhans Cell Histiocytosis (eosinophilic granuloma) (Langerhans cells with grooved nuclei, eosinophils, CD1a/Langerin positive)

─ Metastatic Carcinoma with giant cells (e,g,, giant cell carcinoma of lung/thyroid; epithelial atypia, IHC for keratins)

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Spindle cell lesions

Fibrous Dysplasia

A benign, developmental, non-neoplastic fibro-osseous lesion characterized by replacement of normal bone with an immature fibrous stroma and disorganized trabeculae of woven bone

Clinical ─

─ Can be monostotic (single bone, ~70-80%) or polyostotic (multiple bones, ~20-30%)

─ Monostotic: common, often asymptomatic, discovered incidentally in adolescents/young adults

─ Polyostotic: presents earlier, may cause deformities, fractures, pain; can be associated with McCune-Albright syndrome (polyostotic FD, café-au-lait skin pigmentation, endocrine abnormalities like precocious puberty) or Mazabraud syndrome (polyostotic FD with intramuscular myxomas)

─ Any bone can be affected; common sites: ribs, femur (especially proximal), tibia, craniofacial bones (maxilla, skull base), humerus, pelvis

─ Imaging: Variable appearance; typically intramedullary lesion with "ground glass" or hazy opacity, often expansile with cortical thinning but intact cortex; well-defined or ill-defined margins; "Shepherd's crook" deformity of proximal femur is characteristic in polyostotic disease; craniofacial lesions are often densely sclerotic ("pagetoid")

─ Prognosis: Generally good; lesions often stabilize after skeletal maturity; risk of pathologic fracture, deformity; malignant transformation (to osteosarcoma, fibrosarcoma, chondrosarcoma) is rare (<1% in monostotic, ~4% in McCune-Albright)

Macro ─ firm, gritty, gray-white to yellowish tissue replacing normal bone; affected bone may be expanded or deformed; cystic areas can be present

Micro ─

─ Hallmark: Irregular, curvilinear trabeculae of immature woven bone ("Chinese letters," "alphabet soup," "C-shapes") within a moderately cellular, bland fibrous stroma

─ Bone trabeculae typically lack prominent osteoblastic rimming (bone appears to arise directly from fibrous stroma by metaplasia)

─ Fibrous stroma is composed of bland spindle cells with ovoid to spindle-shaped nuclei, minimal atypia, and low mitotic activity; collagen deposition varies from loose to dense

─ Vascularity is usually moderate

─ Islands of hyaline cartilage (fibrocartilaginous dysplasia) may be present, especially in craniofacial or polyostotic lesions, but should not be the dominant component

─ Cystic degeneration and secondary aneurysmal bone cyst-like changes can occur

─ Foamy macrophages and scattered osteoclast-like giant cells may be present

Ancillary studies ─

─ Molecular ─ Caused by somatic activating missense mutations in the GNAS gene (encoding Gs alpha subunit of G-protein coupled receptors), leading to increased intracellular cAMP; mutations occur post-zygotically, resulting in mosaicism (not heritable)

DDx ─

─ Ossifying Fibroma (craniofacial; more common in mandible, typically well-circumscribed radiographically, histologically shows lamellar bone with prominent osteoblastic rimming, lacks "Chinese letter" bone, no GNAS mutation)

─ Low-Grade Central Osteosarcoma (infiltrative growth, permeation of host bone, cytologic atypia in spindle cells, often MDM2/CDK4 amplified, no GNAS mutation)

─ Osteofibrous Dysplasia (almost exclusively anterior tibia/fibula in children, prominent zonal architecture with peripheral osteoblastic rimming, keratin-positive spindle cells, no GNAS mutation)

─ Paget Disease of Bone (older adults, mosaic pattern of lamellar bone, prominent cement lines, active osteoblasts and osteoclasts)

─ Bone Infarct with ossification (necrotic marrow, irregular calcification and ossification at periphery)

─ Healing Fracture Callus (history of fracture, more organized bone and cartilage formation, zonation)

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Osteofibrous Dysplasia

A rare, benign, self-limiting fibro-osseous lesion almost exclusively affecting the cortex of the tibia and/or fibula in children, characterized by a zonal architecture with osteoblastic rimming of bone trabeculae and scattered keratin-positive spindle cells

Clinical ─

─ Typically presents in first decade of life (most <10 years old, mean age ~5 years); rare in adults

─ Slight male predominance

─ Almost exclusively involves anterior cortex of tibia (most common) and/or fibula; usually diaphysis or metadiaphysis

─ Presents as a painless bowing or swelling of the lower leg; pathologic fracture is uncommon

─ Natural history often involves progression during childhood, then stabilization or regression after puberty

─ Imaging: Eccentric, intracortical, well-circumscribed lytic lesion with a sclerotic rim, causing fusiform expansion and anterior bowing of tibia/fibula; may be multiloculated ("soap bubble" appearance); cortex is often thinned but intact

─ Prognosis: Excellent; many lesions stabilize or regress spontaneously after skeletal maturity; recurrence after curettage is common if performed before skeletal maturity; association with adamantinoma is debated (some consider OFD-like areas part of adamantinoma spectrum, or OFD a precursor)

Macro ─ firm, gritty, gray-white to tan tissue confined to the cortex; may cause bony expansion

Micro ─

Characteristic zonal architecture (maturation from center to periphery):

─ Central zone: loose, moderately cellular fibrous stroma with slender, haphazardly arranged trabeculae of immature woven bone; osteoblastic rimming may be less prominent centrally

─ Peripheral zone: more mature, lamellar bone trabeculae, often arranged parallel to the cortical surface, with prominent osteoblastic rimming; fibrous stroma may be more collagenized

─ Overall: Interconnecting trabeculae of woven and lamellar bone within a fibrous stroma of bland spindle cells

─ Prominent osteoblastic rimming of bone trabeculae by plump, active osteoblasts is a key feature throughout most of the lesion

─ Scattered single epithelial cells or small nests of cells positive for cytokeratin are often present within the fibrous stroma (distinguishes from fibrous dysplasia on IHC)

─ No significant cytologic atypia or high mitotic activity

Ancillary studies ─

─ IHC: Spindle cells are vimentin positive; scattered stromal cells are positive for cytokeratins (e,g,, AE1/AE3, CAM5,2), distinguishing it from fibrous dysplasia

─ Molecular ─ Lacks GNAS mutations found in fibrous dysplasia; relationship to adamantinoma is complex, adamantinoma has more complex genetic changes including gains of chromosomes 7, 8, 12, 19, 21

DDx ─

─ Fibrous Dysplasia (lacks prominent osteoblastic rimming, lacks zonal architecture, lacks keratin-positive stromal cells, GNAS mutated)

─ Adamantinoma (biphasic tumor with overtly epithelial nests/cords and fibrous stroma; OFD-like areas can be present in adamantinoma, but adamantinoma is malignant, occurs in older patients, and shows more aggressive imaging)

─ Ossifying Fibroma (typically craniofacial, different radiographic appearance in long bones, usually more lamellar bone centrally)

─ Healing Fracture Callus (history of trauma, different zonation with cartilage often present)

─ Nonossifying Fibroma (different histology: storiform spindle cells, foam cells, giant cells, no significant bone production)

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Ossifying Fibroma (Craniofacial)

A benign, well-demarcated, fibro-osseous neoplasm primarily affecting the craniofacial bones, particularly the jawbones, characterized by a fibrous stroma containing varying amounts of woven and lamellar bone, often with osteoblastic rimming

Clinical ─

─ Typically occurs in young to middle-aged adults (peak 2nd to 4th decades); female predominance

─ Most common in mandible (especially premolar/molar region) > maxilla; less commonly involves other craniofacial bones (ethmoid, sphenoid, frontal sinus)

─ Presents as a slow-growing, usually painless, expansile swelling or asymptomatic incidental radiographic finding; may cause tooth displacement, malocclusion, or facial asymmetry

─ Juvenile Ossifying Fibroma (trabecular and psammomatoid variants) is a more aggressive subtype in children/adolescents with higher recurrence rates

─ Imaging: Well-circumscribed, expansile lesion, often round or ovoid, with variable radiodensity depending on degree of mineralization (can be radiolucent, mixed, or radiopaque); typically has a sclerotic rim or capsule; may displace or resorb tooth roots; distinct from surrounding bone (does not blend imperceptibly like fibrous dysplasia)

─ Prognosis: Benign; treated by enucleation or local excision; recurrence is uncommon for conventional type (5-20%) but higher for juvenile variants

Macro ─ well-encapsulated, firm, gritty, gray-white to yellowish tumor; often shells out easily from surrounding bone; may contain small cystic spaces or hemorrhagic areas

Micro ─

─ Cellular fibrous stroma composed of bland spindle to stellate shaped fibroblasts, with variable collagen content

─ Contains varying amounts of mineralized tissue, which can be:

─ Irregular trabeculae of woven bone

─ More mature lamellar bone, often with prominent osteoblastic rimming

─ Spheroidal or "psammoma-like" calcifications (especially in psammomatoid juvenile ossifying fibroma)

─ Cementum-like material (acellular, rounded, basophilic deposits) may be present (historically leading to terms like cemento-ossifying fibroma)

─ Stroma is typically more cellular than in fibrous dysplasia, especially in juvenile variants

─ Osteoclast-like giant cells may be present, particularly around bone trabeculae

─ Cystic degeneration can occur

─ No significant cytologic atypia or high mitotic activity in conventional type; juvenile variants can be more cellular and mitotically active but lack malignant features

Ancillary studies ─

─ Not typically required for diagnosis of conventional ossifying fibroma; diagnosis is based on clinicopathologic and radiographic correlation

─ Molecular ─ Conventional ossifying fibroma is genetically distinct from fibrous dysplasia (no GNAS mutations); some harbor HRPT2 gene mutations (especially in HPT-Jaw Tumor Syndrome); juvenile ossifying fibromas may have different genetic alterations (e,g,, MDM2 amplification in some psammomatoid variants)

DDx ─

─ Fibrous Dysplasia (key differential, especially in maxilla; FD has "ground glass" appearance, blends with host bone, lacks prominent osteoblastic rimming, characteristic "Chinese letter" bone, GNAS mutated)

─ Osteofibrous Dysplasia (long bones of children, specific zonal architecture, keratin-positive cells)

─ Low-Grade Central Osteosarcoma (infiltrative margins, cytologic atypia, MDM2/CDK4 amplified)

─ Cementoblastoma (attached to tooth root, radiolucent rim, specific histology)

─ Periapical Cemento-osseous Dysplasia (multiple lesions at apices of mandibular anterior teeth, self-limiting)

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Nonossifying Fibroma (Metaphyseal Fibrous Defect)

A common, benign, self-limiting fibroblastic lesion of bone, typically occurring in the metaphysis of long bones in children and adolescents, characterized by a storiform proliferation of spindle cells, osteoclast-like giant cells, and foamy macrophages

Clinical ─

─ Very common; estimated to occur in 30-40% of children >2 years old, often an incidental finding

─ Most common in first two decades of life (peak 10-15 years); usually regresses spontaneously and ossifies by early adulthood

─ Slight male predominance

─ Most frequently involves metaphysis of long bones, especially around the knee (distal femur > proximal tibia); also distal tibia, proximal humerus

─ Usually asymptomatic; may present with mild pain or pathologic fracture if large (>50% of bone diameter or >3-4 cm)

─ Multiple lesions can occur, sometimes associated with neurofibromatosis type 1 or Jaffe-Campanacci syndrome (multiple NOFs, café-au-lait spots, other developmental anomalies)

─ Imaging: Eccentric, well-circumscribed, geographic lytic lesion in the metaphysis, often with a thin sclerotic rim and a scalloped inner margin; typically abuts or is within the cortex, causing slight cortical expansion but no periosteal reaction unless fractured; MRI shows variable signal intensity depending on cellularity and lipid content

─ Prognosis: Excellent; most lesions involute spontaneously with age and are replaced by bone; pathologic fractures heal well; recurrence after curettage is rare

Macro ─ soft, friable, yellowish-brown to reddish-brown tissue, often well-demarcated; may contain hemorrhagic areas

Micro ─

─ Cellular proliferation of bland spindle cells (fibroblasts) arranged in a characteristic storiform (cartwheel or "pinwheel") pattern

─ Numerous osteoclast-like multinucleated giant cells are scattered throughout the lesion

─ Clusters of foamy macrophages (xanthoma cells) containing lipid are a common and characteristic feature

─ Hemosiderin deposition is often present, contributing to the brown color grossly

─ Stroma is variably collagenous; mitoses may be present but are not atypical and usually infrequent

─ No significant cytologic atypia or pleomorphism

─ Reactive woven bone may be seen at the periphery, especially in healing or ossifying lesions, but is not produced by the neoplastic spindle cells

─ "Fibrous cortical defect" is often used for smaller (<2-3 cm), purely cortical lesions with identical histology; NOF is used for larger lesions that extend into the medullary cavity

Ancillary studies ─

─ Not typically required; diagnosis is usually made on characteristic clinical and radiographic features, with histology confirming in biopsied cases

DDx ─

─ Benign Fibrous Histiocytoma of Bone (histologically very similar or identical; BFH tends to occur in older patients, different locations like flat bones, and may be painful, but distinction can be controversial and based on clinicoradiographic context)

─ Giant Cell Tumor of Bone (epiphyseal in skeletally mature, diffuse sheets of neoplastic mononuclear cells and more evenly distributed giant cells, lacks storiform pattern and prominent foamy cells, H3F3A mutated)

─ Langerhans Cell Histiocytosis (Langerhans cells with grooved nuclei, eosinophils, CD1a/Langerin positive)

─ Fibrous Dysplasia (curvilinear woven bone trabeculae, different fibrous stroma, GNAS mutated)

─ Aneurysmal Bone Cyst (can have solid areas resembling NOF, but ABC is predominantly cystic with blood-filled spaces)

─ Desmoplastic Fibroma (more collagenous, lacks prominent giant cells and foamy cells)

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Benign Fibrous Histiocytoma of Bone

A rare, benign intraosseous neoplasm composed of fibroblastic spindle cells, histiocyte-like cells, osteoclast-like giant cells, and foamy macrophages, with a storiform pattern; histologically similar to nonossifying fibroma but often occurring in older individuals and different skeletal sites

Clinical ─

─ Uncommon; much rarer than nonossifying fibroma

─ Can occur over a wide age range, but typically affects adults (3rd to 6th decades), older than typical NOF patients

─ No clear sex predilection

─ Can involve almost any bone; common sites include long bones (femur, tibia, humerus - often diaphysis or metaphysis), flat bones (pelvis, ribs, scapula), and spine; epiphyseal involvement can occur

─ Often presents with pain, unlike asymptomatic NOF; pathologic fracture can occur

─ Imaging: Well-circumscribed, geographic lytic lesion, often with a sclerotic rim; can be central or eccentric, may cause cortical expansion or thinning; no aggressive periosteal reaction unless fractured; appearance can be very similar to NOF, but location and patient age differ

─ Prognosis: Benign; local recurrence after curettage is reported (5-20%) but is generally low; no malignant potential

Macro ─ firm, yellowish-gray to tan-brown tissue; may appear lobulated or hemorrhagic

Micro ─

─ Histologically very similar or identical to Nonossifying Fibroma (NOF):

─ Cellular proliferation of bland spindle cells (fibroblasts) arranged in a storiform pattern

─ Admixed osteoclast-like multinucleated giant cells, foamy macrophages (xanthoma cells), and hemosiderin pigment

─ Stroma is variably collagenous

─ Mitotic activity is usually low, and atypical mitoses are absent

─ No significant cytologic atypia

─ Some authors suggest BFH may have a more prominent fibrous component and less prominent giant cells/xanthoma cells compared to NOF, but overlap is considerable

─ Distinction from NOF is largely based on clinicoradiographic context (age, location, symptoms) rather than definitive histologic differences

Ancillary studies ─

─ Not typically required; diagnosis is based on integration of histologic, clinical, and radiographic features

DDx ─

─ Nonossifying Fibroma (NOF) (key differential, often histologically indistinguishable; NOF is metaphyseal in children/adolescents and usually asymptomatic)

─ Giant Cell Tumor of Bone (GCTB) (different mononuclear cell population, lacks prominent storiform pattern and foamy cells, H3F3A mutated)

─ Desmoplastic Fibroma of Bone (more collagenous, paucicellular, lacks giant cells and foamy cells)

─ Fibrous Dysplasia (curvilinear woven bone trabeculae, different stroma)

─ Undifferentiated Pleomorphic Sarcoma of Bone (malignant fibrous histiocytoma) (overtly malignant cytologic features, pleomorphism, atypical mitoses, necrosis)

─ Langerhans Cell Histiocytosis (Langerhans cells, eosinophils)

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Desmoplastic Fibroma of Bone

A rare, benign but locally aggressive intraosseous fibroblastic neoplasm, characterized by bland spindle cells producing abundant collagen; considered the intraosseous counterpart of soft tissue desmoid-type fibromatosis

Clinical ─

─ Rare, accounts for <0,1% of all primary bone tumors

─ Wide age range, but most common in adolescents and young adults (peak 2nd-3rd decades)

─ No significant sex predilection

─ Most frequently involves mandible, followed by long bones (femur, tibia, humerus - often metaphysis or diaphysis) and pelvis

─ Presents with localized pain, swelling, or a palpable mass; pathologic fracture is uncommon

─ Imaging: Well-circumscribed, geographic lytic lesion, often expansile with cortical thinning or breach; internal appearance is typically radiolucent with coarse trabeculations or "soap bubble" appearance; lacks matrix mineralization; MRI shows low to intermediate signal on T1 and variable signal on T2 (depending on cellularity/collagen content)

─ Prognosis: Benign (does not metastasize), but has a high rate of local recurrence (20-70%) if not completely excised with wide margins, due to its infiltrative nature

Macro ─ firm, rubbery, gray-white, fibrous tissue; often appears well-demarcated but may show microscopic infiltration at margins; cut surface is typically whorled or trabeculated

Micro ─

─ Composed of relatively hypocellular to moderately cellular proliferation of bland, uniform spindle cells (fibroblasts and myofibroblasts) with elongated, tapering nuclei and scant cytoplasm

─ Cells are arranged in sweeping fascicles or a vaguely storiform pattern, set in an abundant, densely collagenous (desmoplastic) stroma

─ No significant cytologic atypia, hyperchromasia, or pleomorphism

─ Mitotic activity is very low or absent; atypical mitoses are not seen

─ Vascularity is typically inconspicuous, with small, slit-like vessels

─ Infiltrative growth pattern at the periphery, with tumor cells extending between and entrapping pre-existing host bone trabeculae

─ No bone or cartilage production by the tumor cells themselves

Ancillary studies ─

─ IHC: Spindle cells are positive for vimentin; may show focal positivity for smooth muscle actin and muscle specific actin (consistent with myofibroblastic differentiation); negative for S100, keratins, desmin

─ Molecular ─ Similar to desmoid-type fibromatosis of soft tissue, mutations in CTNNB1 (encoding beta-catenin) or APC gene are found in a significant proportion of cases, leading to nuclear beta-catenin accumulation by IHC

DDx ─

─ Low-Grade Central Osteosarcoma (produces neoplastic bone, cytologic atypia, MDM2/CDK4 amplified)

─ Fibrous Dysplasia (produces curvilinear woven bone, different stroma, GNAS mutated)

─ Nonossifying Fibroma/Benign Fibrous Histiocytoma (storiform pattern, giant cells, foamy cells, less collagen)

─ Fibrosarcoma of Bone (low-grade variant; more cellular, more atypia, herringbone pattern, higher mitotic rate; distinction can be difficult on small biopsies)

─ Intraosseous schwannoma (wavy nuclei, Verocay bodies, S100 positive)

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Fibromyxoma of Bone (Intraosseous Myxoma)

A rare, benign intraosseous neoplasm composed of bland spindle to stellate shaped cells set in an abundant myxoid stroma, lacking significant fibroblastic or chondroid differentiation; its existence as a distinct primary bone entity is debated by some

Clinical ─

─ Extremely rare as a primary bone tumor, especially outside the jawbones (where odontogenic myxoma is a distinct entity)

─ Reported cases in extragnathic skeleton occur over a wide age range, typically in adults

─ No clear sex predilection from limited data

─ Skeletal sites include long bones (femur, tibia), pelvis, ribs, and small bones

─ Often presents with nonspecific pain or swelling; may be an incidental finding

─ Imaging: Well-circumscribed, geographic lytic lesion, often expansile with cortical thinning; may have a sclerotic rim and internal septations ("soap bubble" appearance); typically no matrix mineralization; MRI shows high T2 signal intensity due to myxoid matrix

─ Prognosis: Benign; local recurrence is possible after curettage, especially if incompletely excised; no metastatic potential

Macro ─ soft, gelatinous, glistening, gray-white to translucent tissue; often well-demarcated or pseudoencapsulated

Micro ─

─ Hypocellular proliferation of bland, small spindle-shaped or stellate cells with inconspicuous nuclei and scant cytoplasm

─ Cells are loosely arranged within an abundant, avascular or poorly vascularized, myxoid (mucoid or "slimy") extracellular matrix

─ Minimal collagen deposition; delicate reticulin fibers may be present around cells

─ No significant cytologic atypia, pleomorphism, or mitotic activity

─ No true cartilage, bone, or well-formed fibrous tissue production by the tumor cells (key to distinguish from other myxoid lesions)

─ Vascularity is typically scant, with delicate, thin-walled capillaries

─ May show infiltrative margins into surrounding marrow spaces

Ancillary studies ─

─ IHC: Spindle cells are positive for vimentin; may show focal smooth muscle actin; negative for S100, keratins, desmin, CD34 (in most areas)

─ Special stains: Alcian blue or colloidal iron highlights the myxoid matrix (hyaluronic acid)

DDx ─

─ Chondromyxoid Fibroma (CMF) (lobular architecture, peripheral hypercellularity, more chondroid areas, S100 positive, chromosome 6 rearrangements)

─ Myxoid Chondrosarcoma (malignant, more cellularity and atypia, presence of true hyaline cartilage lobules, infiltrative growth)

─ Fibrous Dysplasia with extensive myxoid change (will have areas of "Chinese letter" bone and more fibrous stroma, GNAS mutation)

─ Myxoid Liposarcoma (metastatic or very rarely primary; contains lipoblasts, characteristic vascular pattern, FUS-DDIT3 or EWSR1-DDIT3 fusion)

─ Intraosseous Ganglion Cyst (juxta-articular, acellular or paucicellular mucin, fibrous pseudocapsule, no true neoplastic cells)

─ Myxofibrosarcoma (metastatic or rarely primary; more cellular, more atypia, curvilinear vessels, more collagen)

─ Odontogenic Myxoma (if in jaw; specific clinical/radiographic context, may have odontogenic epithelial remnants)

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Myofibromatosis of Bone

A rare benign mesenchymal proliferation of myofibroblasts that can occur as solitary or multiple lesions in bone, soft tissue, or viscera, typically in infancy and early childhood; bone involvement is uncommon

Clinical ─

─ Solitary myofibroma of bone is very rare; multicentric myofibromatosis with bone involvement is also uncommon

─ Most cases present in infancy or early childhood (often congenital or within first 2 years of life); can occur in older children and adults

─ No clear sex predilection, or slight male predominance

─ Bone lesions most commonly affect craniofacial bones (skull, mandible), followed by long bones (femur, tibia) and vertebrae

─ May present as a painless swelling, palpable mass, or an incidental radiographic finding; pathologic fractures are rare; visceral involvement in generalized infantile myofibromatosis can be life-threatening

─ Imaging: Well-demarcated, lytic lesions in bone, often with a sclerotic rim; may be expansile and cause cortical thinning; central lucency with peripheral sclerosis ("targetoid" appearance) has been described

─ Prognosis: Solitary bone lesions are benign and may regress spontaneously; multicentric disease without visceral involvement also has a good prognosis; generalized infantile myofibromatosis with visceral involvement has a higher mortality rate due to organ compromise

Macro ─ firm, gray-white, whorled or nodular tissue; usually well-circumscribed within bone

Micro ─

Biphasic pattern often observed, especially at low power:

─ Cellular areas: Densely packed spindle cells (myofibroblasts) arranged in short fascicles, whorls, or a vaguely storiform pattern; cells have elongated, tapering nuclei, pale eosinophilic cytoplasm, and indistinct cell borders

─ Paucicellular/Myoid areas: Less cellular zones with plumper, more eosinophilic cells resembling smooth muscle cells, often around hemangiopericytoma-like vessels

─ Hemangiopericytoma-like vascular pattern (branching, "staghorn" vessels) is a characteristic

Myofibromatosis of Bone

A rare benign feature, particularly in cellular areas

─ Mitotic activity is usually low, and atypical mitoses are absent

─ No mesenchymal proliferation characterized by myofibroblastic differentiation, which can occur as solitary (myofibroma) or multiple lesions significant cytologic atypia or pleomorphism

─ Stroma is variably collagenous, can be hyalinized, (myofibromatosis) affecting bone, soft tissue, and viscera, primarily in infancy and childhood

especially in paucicellular areas; myxoid change is uncommon

─ Necrosis and calcification can occur, especially in largerClinical ─

─ Solitary bone lesions are very rare; more commonly, bone involvement is part of multic or older lesions

Ancillary studies ─

─ IHC: Spindle cells are consistently positive for ventric myofibromatosis

─ Predominantly affects infants and young children (most <2 years old); congenital casesimentin and smooth muscle actin (SMA); variably positive for muscle specific actin (MSA) and desmin (often are common

─ Solitary myofibroma of bone can occur in older children and adults but is exceptional

─ No in more myoid areas); negative for S100, keratins, CD34 (except in vessels)

DD clear sex predilection for solitary bone lesions; slight male predominance in generalized myofibromatosis

─ Skeletal sites: cranx ─

─ Infantile Fibrosarcoma (more cellular, herringbone pattern, higher mitotic rate, infiltrative growth, ofteniofacial bones (mandible, skull) are most common for solitary bone lesions; long bones, ribs, vertebrae can also be affected, ETV6-NTRK3 fusion; important differential in infants)

─ Desmoplastic Fibroma especially in multicentric disease

─ Presents as a firm, painless or mildly painful swelling/mass; may be an incidental radiographic of Bone (more uniformly collagenous, less cellular, lacks biphasic pattern and hemangiopericytoma-like vessels, nuclear finding; visceral involvement in generalized infantile myofibromatosis can be life-threatening

─ Imaging: Well-demarcated, l beta-catenin in many cases)

─ Fibrous Dysplasia (produces woven bone, different stroma)

─ Leiomyytic lesions in bone, often with a sclerotic rim; may be expansile and cause cortical thinning; central "targetoma of Bone (rare, more uniform smooth muscle differentiation, lacks biphasic pattern)

─ Solitary Fibrous-like" calcification has been described in some soft tissue lesions and rarely in bone

─ Prognosis: Sol Tumor (CD34 positive, STAT6 positive, different morphology)

─ Langerhans Cell Histiocytosis (Langerhans cells, eosinophils, CD1a/Langerin positive)

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itary bone myofibromas are benign with low recurrence after excision; multicentric disease without visceral involvement generally has good prognosis with

Liposclerosing Myxoid Fibrous Tumor (LSMFT)

An uncommon, benign spontaneous regression of many lesions; generalized infantile myofibromatosis with visceral involvement has higher morbidity/mortality

Macro fibro-osseous lesion of bone with a complex and variable histologic appearance, typically occurring in the intertrochanteric region of the proximal femur, and associated with a risk of malignant transformation

Clinical ─

─ Typically affects middle-aged to ─ firm, well-circumscribed, gray-white to tan nodular or infiltrative tissue; cut surface is older adults (peak 4th-6th decades); slight male predominance

─ Strong predilection for the intertrochan often whorled or fascicular

Micro ─

Biphasic pattern typically observed:

1teric region of the proximal femur; rarely occurs in other sites (e,g,, ilium, humerus,. Myofibroblastic component:

─ Fascicles and whorls of uniform spindle cells with eosinophilic cytoplasm ribs)

─ Often an incidental radiographic finding; may present with chronic, dull pain or pathologic fracture (less common)

─ Imaging and elongated, tapering ("cigar-shaped") nuclei; minimal atypia and low mitotic activity

─ Res: Well-circumscribed, geographic lesion in the intertrochanteric femur, usually with a prominent, thick sclerotic rim;embles smooth muscle or infantile fibromatosis

Primitive mesenchymal/perivascular component:

─ Less differentiated, more rounded to ovoid cells with scant cytoplasm and hyperchromatic nuclei, often arranged around thin-walled, internal appearance is variable, often mixed lytic and sclerotic, may have areas of fat density on CT or MRI, branching (hemangiopericytoma-like) blood vessels

─ Stroma is variably collagenous, myxoid change (high T2 signal on MRI), and/or cystic degeneration; "ring and arc" calc can be myxoid in areas

─ Necrosis can be present, especially in larger lesions or in the moreification may be present

─ Prognosis: Benign, but has a significant risk (10-15%) of malignant transformation (dedifferentiation) to a high-grade sarcoma (most commonly osteosarcoma or undifferentiated ple cellular perivascular areas

─ Calcification may occur

─ Bone lesions show tumor replacing normal marrow and boneomorphic sarcoma); requires long-term follow-up

Macro ─ firm to gritty, yellowish-gray, often with a pushing border but can be infiltrative

Ancillary studies ─

─ IHC: Spindle cells (myofibroblasts) are consistently positive for vimentin and smooth muscle actin (SMA); variable positivity for muscle to tan tissue; often heterogeneous with fatty, fibrous, myxoid, and ossified areas; cystic changes may be present

Micro ─ specific actin (MSA) and desmin (more often positive in perivascular cells); negative for S100, kerat

Complex and variable histology, often a mixture of several patterns within the same lesion:

─ Myxoid/ins, CD34 (except vessels)

─ Molecular ─ Some familial cases of infantile myofibromatosis haveFibromyxoid areas: Hypocellular to moderately cellular spindle or stellate cells in an abundant myxoid or collagenous stroma; can resemble fibromyxoma or fibrous dysplasia with myxoid change

─ Lipomatous areas shown mutations in PDGFRB or NOTCH3; somatic PDGFRB mutations also found in sporadic solitary myofibromas

DDx ─

─ Infantile Fibrosarcoma (more: Mature adipose tissue, often with areas of fat necrosis, foamy macrophages, and lipomembranous change (cystic cellular, herringbone pattern, higher mitotic rate, ETV6-NTRK3 fusion)

─ Desmoplastic Fibroma spaces lined by hyaline membranes)

─ Ischemic-like ossification: Irregular trabeculae of woven of Bone (more densely collagenous, paucicellular, lacks biphasic pattern and prominent hemangiopericytoma-like vessels, nuclear beta-catenin in many)

─ Leiomyoma/Leiomyosarcoma of Bone (rare bone, often acellular or paucicellular, sometimes with prominent cement lines, resembling Paget disease of bone or bone infarct

─ Fibrous dysplasia-like areas: Curvilinear trabeculae of woven bone in a fibrous stroma, but; more distinct smooth muscle features, more atypia in leiomyosarcoma)

─ Fibrous Dysplasia ( often with more prominent osteoblastic rimming than typical fibrous dysplasia

─ Xanthomatous areas: Aggregates of foif bone formation is reactive around myofibroma; FD has characteristic woven bone)

─ Hemangiopericytoma (nowamy macrophages

─ Cystic degeneration and aneurysmal bone cyst-like changes can occur

─ Cytologic atypia is generally absent part of solitary fibrous tumor spectrum; diffuse hemangiopericytoma-like pattern, CD34+, STAT6 in the benign components; mitotic activity is low

─ Dedifferentiation: Areas of abrupt transition to a high-grade sarcoma (e,g,, osteosarcoma, undifferentiated pleomorphic sarcoma, fibrosarcoma)

Ancillary studies ─ +)

─ Langerhans Cell Histiocytosis (if many eosinophils and histiocyte-like cells are present; look

─ IHC: Spindle cells are vimentin positive; S100 may highlight adipocytes; MDM2/CDK4 are for Langerhans cells, CD1a/Langerin+)

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Liposclerosing Myxoid Fibrous Tumor (LSMFT)

A benign, complex typically negative in the benign components (helps distinguish dedifferentiated LSMFT with osteosarcomatous component from primary osteosarcoma with fibro-osseous lesion of bone with a striking predilection for the intertrochanteric region of the femur MDM2/CDK4 amplification)

─ Molecular ─ GNAS mutations (characteristic of fibrous dysplasia) are often found,, characterized by a variable admixture of lipomatous, myxoid, fibrous, and osseous (often ischemic-like suggesting LSMFT may be a complex variant or a "traumatized" form of fibrous dysplasia with secondary changes

DDx ─ or Pagetoid) components

Clinical ─

─ Typically affects middle-aged to older adults (peak

─ Fibrous Dysplasia (especially with cystic or myxoid change; LSMFT has more complex/4th to 6th decades); slight male predominance

─ Strong predilection for the intertrochanteric region of the proximal femur (>90% of cases); rarely occurs in other sites (e,g,, ilium, ribs, humerus)

─ Oftenmixed histology, prominent fat, and ischemic-like ossification not typical of FD alone)

─ Intraosseous Lipoma (pred an incidental radiographic finding; may present with chronic, dull hip or groin pain, sometimes for years; pathologic fracture is uncommonominantly mature fat; LSMFT is more heterogeneous)

─ Bone Infarct (necrotic marrow and bone but can occur

─ Imaging: Well-demarcated, geographic lytic lesion in the femoral neck/intertrochanteric region, usually, often with peripheral reactive changes; LSMFT is a distinct proliferative lesion)

─ Simple Bone Cyst with fracture/ with a thick, complete sclerotic rim; internal matrix is variable: can be radiolucent (fatty/myxoid), hazyischemic changes (more purely cystic, different lining)

─ Paget Disease of Bone (mosaic pattern of lam/ground-glass, or have areas of dense sclerosis/calcification; "ring sign" of peripheral ossification is characteristicellar bone, active osteoblasts/osteoclasts; LSMFT bone is more ischemic-like or FD-like)

─ Dedifferentiated Sarcoma (if only high-grade component is sampled; must look for underlying LSMFT features)

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Fibrosarcoma of Bone

A malignant mesenchymal tumor composed on CT; MRI shows heterogeneous signal reflecting the mixed components (fat, myxoid, fibrous, bone)

─ Prognosis: Benign, but has a risk of malignant transformation (dedifferentiation) to sarcoma (most commonly osteosarcoma or und of fibroblastic spindle cells arranged in a characteristic herringbone pattern, producing collagen but no bone or cartilage; its existence as a distinct primaryifferentiated pleomorphic sarcoma) in 10-15% of cases, especially if large or symptomatic; careful follow-up is recommended

bone entity separate from undifferentiated pleomorphic sarcoma with fibroblastic features is debated

Clinical ─

─ RareMacro ─ variegated appearance; firm, gritty, yellowish-white tissue with gelatinous (myxoid) areas, accounts for <5% of primary malignant bone tumors; incidence has declined as many historical cases are now reclassified (, fatty (lipomatous) foci, and sometimes cystic change; usually well-demarcated by a sclerotic bonye,g,, as MFH/UPS or fibroblastic osteosarcoma)

─ Typically affects adults ( shell

Micro ─

Highly variable histology, with an admixture of different patterns and components:

─ Lippeak 3rd to 6th decades); slight male predominance

─ Most common in metaphysis or diaphysis of long bones (femur, tibia, humerus); also occurs in jawbones and pelvis

─ Presents with pain and swelling, often ofomatous areas: mature adipose tissue, sometimes with fat necrosis or atrophy

─ Myxoid areas: hypocellular, loose several months' duration; pathologic fracture can occur

─ Can be primary (arising de novo) or secondary (arising in pre-existing conditions like Paget disease, bone infarct, irradiated bone, or chronic osteomyelitis)

─ Imaging myxoid stroma with bland spindle or stellate cells, resembling fibromyxoma or myxoid liposarcoma (but without lipoblasts)

─ Fibrous areas: bland fibroblastic spindle cells in a collagenous stroma, may resemble: Destructive, lytic lesion with ill-defined margins and cortical destruction; often has a permeative or "m fibrous dysplasia or desmoplastic fibroma

─ Osseous component: irregular trabeculae of woven or lamellar bone, often with featuresoth-eaten" appearance; soft tissue extension is common; no tumor matrix mineralization (unless secondary to fracture callus or arising resembling:

─ Ischemic bone: acellular bone, empty lacunae, surrounding fibrovascular tissue in Pagetoid bone)

─ Prognosis: Generally poor, especially for high-grade lesions; 5-year survival ~

─ Paget-like bone: thickened trabeculae with irregular cement lines (mosaic pattern)

─ Fib30-50%; depends on grade and stage; better prognosis for low-grade lesions and those amenable to widerous dysplasia-like bone: curvilinear trabeculae of woven bone (but often with some osteoblastic rimming, surgical excision

Macro ─ firm, gray-white, fleshy or fibrous tumor; often infiltrative with areas of hemorrhage and necrosis, especially in high-grade lesions

Micro ─

─ Composed of malignant unlike classic FD)

─ Xanthoma cells (foamy macrophages) may be present

─ Cystic degeneration spindle cells (fibroblasts) with varying degrees of cellularity, atypia, and mitotic activity, producing collagen and aneurysmal bone cyst-like changes can occur

─ Overall bland cytology; mitoses are rare

─ Characteristic herringbone pattern: spindle cells arranged in intersecting fascicles at acute angles

─ Low-grade fibrosarcoma: Rescillary studies ─

─ Not typically required for diagnosis if classic clinicoradiographic features are present

─ Molecular ─ Someembles desmoplastic fibroma but with higher cellularity, more nuclear atypia (enlarged, hyperchromatic, irregular nuclei studies suggest GNAS mutations (as seen in fibrous dysplasia) can be found in a subset of LSMFT, supporting), and discernible mitotic activity; collagen production is usually abundant

─ High-grade fibrosarcoma: More cellular the idea that some may represent a variant or end-stage of fibrous dysplasia; however, this is not consistent across all cases

DD, more pleomorphic, with higher mitotic rates (often numerous and atypical mitoses); collagen production may be less prominent;x ─

─ Fibrous Dysplasia (especially if FD-like bone is prominent; LSMFT has necrosis is common

─ No production of neoplastic bone or cartilage (essential to distinguish from fibroblastic osteosarcoma or dedifferentiated chondrosarcoma)

Ancillary studies ─

─ IHC: Spindle cells are positive more complex histology with lipomatous/myxoid areas and often ischemic/Pagetoid bone, thicker sclerotic rim)

─ Intra for vimentin; may show focal positivity for smooth muscle actin; negative for S100, keratins, desosseous Lipoma (predominantly mature fat, less complex histology, calcification may be central nidus-like)

─ Bonemin, CD34, and specific markers of other sarcomas (e,g,, SOX10 for MP Infarct (necrotic marrow and bone, serpiginous calcified rim, lacks the diverse benign proliferative components of LSMFT)

─ SimpleNST, STAT6 for SFT)

─ Molecular ─ No specific recurrent translocations or mutations are consistently associated with primary Bone Cyst with fracture/ischemia (if cystic changes are prominent in LSMFT)

─ Paget Disease of Bone (if fibrosarcoma of bone; genetic profile is often complex, especially in high-grade lesions

DDx ─ Pagetoid bone is extensive; Paget disease has characteristic osteoclastic activity and different radiographic distribution)

─ Low

─ Fibroblastic Osteosarcoma (produces neoplastic osteoid directly by malignant spindle cells; careful search for osteoid is crucial)

─ Undifferentiated Pleomorphic Sarcoma (UPS) of bone (more pleomorphic, less uniform-Grade Central Osteosarcoma (if osseous component is prominent; LGCOS has infiltrative growth and cytologic atypia, MDM2/CDK4 amplified)

─ Malignant transformation within LSMFT (look for areas of high-grade sarcoma) herringbone pattern, often more bizarre giant cells; distinction can be subjective and controversial, some consider fibrosarcoma a variant

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Fibrosarcoma of Bone

A malignant mesenchymal of UPS)

─ Desmoplastic Fibroma of Bone (blander cytology, very low mitotic rate, more uniform tumor composed of fibroblastic spindle cells arranged in fascicles, often with a herringbone pattern, that produces collagen but not collagen, often nuclear beta-catenin)

─ Malignant Peripheral Nerve Sheath Tumor (MPNST) (ar osteoid or cartilage; its existence as a distinct primary bone entity separate from undifferentiated pleomorphic sarcoma or fibroblastic osteosarcoma is increasingly debated

Clinical ─

─ Rare, accounts for <5% of primary malignant bone tumors (ising from nerve or in NF1 patient, often wavy nuclei, S100 positive in ~50%)

─ Synovhistorical data, incidence likely lower with current stricter criteria)

─ Wide age range, but most common in adults (peak ial Sarcoma (monophasic spindle cell type; may show herringbone pattern but often positive for keratins/EMA, characteristic SS18-SSX fusion)

─ Leiomyosarcoma of Bone (blunter nuclei4th to 6th decades); slight male predominance

─ Can arise de novo (primary) or as a secondary malignancy in pre-existing conditions (Paget disease, bone infarct, irradiated bone, chronic osteomyelitis)

─ Most, more eosinophilic cytoplasm, desmin/caldesmon positive)

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Undifferentiated Pleomorphic Sarcoma of Bone (formerly Malignant Fibrous Histiocytoma of Bone)

A high frequently involves metaphysis or diaphysis of long bones (femur, tibia, humerus); also pelvis, jaw-grade, aggressive malignant mesenchymal tumor of bone composed of undifferentiated pleomorphic spindle and polygonal cells, often with a storiform pattern,bones

─ Presents with pain, swelling, and palpable mass; pathologic fracture can occur

─ Imaging: Agg lacking a specific line of differentiation; essentially a diagnosis of exclusion

Clinical ─

─ Relatively uncommon,ressive, destructive lytic lesion with ill-defined, permeative margins; cortical destruction and soft tissue extension are common; accounts for ~2-5% of primary malignant bone tumors; incidence has decreased with reclassification of many former "MFH" cases

─ Typically no tumor matrix mineralization (a key feature distinguishing it from osteosarcoma); periosteal reaction may be present

─ Prognosis: affects older adults (peak 5th to 7th decades); slight male predominance

─ Most common in long bones (femur, Generally poor, similar to high-grade osteosarcoma or undifferentiated pleomorphic sarcoma; 5-year survival rates tibia, humerus - often metaphysis or diaphysis); also occurs in pelvis and jawbones

─ Presents with pain, swelling, and often a palpable mass; pathologic fracture is common (20-30%)

─ Can historically ~25-40%; depends on grade and stage; secondary fibrosarcomas often have worse prognosis

Macro be primary (de novo) or secondary (arising in Paget disease, bone infarct, irradiated bone, or rarely ─ fleshy, gray-white to tan, firm or soft infiltrative tumor; often with areas of hemorrhage and necrosis

Micro from dedifferentiation of a benign lesion)

─ Imaging: Aggressive, destructive lytic lesion with ill-defined margins, cortical destruction, and a prominent soft tissue mass; often permeative or "moth-eaten" appearance; no tumor ─

─ Cellular proliferation of spindle cells (fibroblasts) arranged in intersecting fascicles, classically forming a "herringbone" pattern matrix mineralization (unless secondary to fracture or pre-existing Pagetoid bone)

─ Prognosis: Poor; similar

─ Cells have elongated, tapering nuclei, variably hyperchromatic, with minimal to moderate atypia in low-grade lesions to other high-grade sarcomas like conventional osteosarcoma; 5-year survival ~20-40%; high, and significant pleomorphism in high-grade lesions

─ Cytoplasm is usually scant and eosinophilic

─ Mit rates of local recurrence and distant metastases (lungs most common)

Macro ─ fleshy, gray-white tootic activity varies with grade; atypical mitoses are seen in high-grade tumors

─ Collagen production is variable, from tan tumor, often with extensive hemorrhage and necrosis; infiltrative margins and large soft tissue component are typical

Micro ─ scant to abundant (desmoplastic areas)

─ Crucially, no production of neoplastic osteoid or cartilage by the tumor cells (distinguishes from osteosarcoma and chondrosarcoma)

─ Necrosis and vascular invasion are common in

─ Highly cellular, malignant neoplasm characterized by marked pleomorphism and a haphazard or storiform arrangement of cells

─ high-grade lesions

─ Low-grade fibrosarcoma: resembles desmoplastic fibroma but with higher Tumor cells are typically undifferentiated, spindle-shaped, ovoid, or polygonal, with hyperchromatic, irregular, often cellularity, more atypia, and higher mitotic rate

─ High-grade fibrosarcoma: significant pleomorphism, high mitotic rate, necrosis; may overlap significantly with undifferentiated pleomorphic sarcoma

Ancillary studies ─

bizarre nuclei, and prominent nucleoli

─ Multinucleated tumor giant cells are common

─ Mitotic activity is usually─ IHC: Tumor cells are positive for vimentin; may show focal positivity for smooth muscle actin; negative for S high, including numerous atypical mitoses

─ Necrosis is a frequent finding

─ Stroma is variably collagen100, keratins, desmin, CD34, and specific markers of other sarcomas (e,g,, SATous; myxoid areas or inflammatory infiltrates (including foamy macrophages or eosinophils) may be present B2 for osteosarcoma)

─ Molecular ─ No specific recurrent translocations are consistently identified for primary fib

─ By definition, there is no identifiable specific line of differentiation (e,g,, no definitive osteoid, cartilage, musclerosarcoma of bone, unlike some soft tissue fibrosarcoma variants or other sarcomas

DDx ─, or neural differentiation by morphology or IHC after adequate sampling)

─ Variants described in soft tissue (e,g,, stor

─ Fibroblastic Osteosarcoma (key differential; osteosarcoma produces neoplastic osteoid, even if focaliform-pleomorphic, myxoid, giant cell, inflammatory) are less formally applied to bone lesions, with stor; SATB2 can be helpful)

─ Undifferentiated Pleomorphic Sarcoma (UPS) of Bone (formerlyiform-pleomorphic being the most common pattern

Ancillary studies ─

─ IHC: Diagnosis of exclusion; tumor cells are positive for vimentin; may show focal/patchy positivity for smooth muscle actin, CD6 MFH; often histologically indistinguishable from high-grade fibrosarcoma, UPS may have more prominent pleomorphism and storiform pattern8 (histiocytic marker, but not specific for true histiocytic differentiation); crucially, negative for keratins (; some consider high-grade fibrosarcoma part of UPS spectrum)

─ Desmoplastic Fibroma of Bone (lowto exclude sarcomatoid carcinoma), S100 (to exclude MPNST/melanoma), desmin/-grade, paucicellular, abundant collagen, lacks significant atypia/mitoses, nuclear beta-catenin oftenmyogenin (to exclude rhabdomyosarcoma), specific osteoblastic/chondroblastic markers if osteosarcoma/chondrosarcoma variants are considered

─ Molecular ─ Highly complex and heterogeneous karyotypes with numerous chromosomal positive)

─ Malignant Peripheral Nerve Sheath Tumor (MPNST) (may have herringbone pattern; look for association gains and losses; no specific recurrent translocations identify UPS

DDx ─

─ High-Grade Osteosarcoma (especially fibroblastic or pleomorphic types; careful search for neoplastic osteoid is critical)

─ Dedifferentiated Chondrosarcoma (requires with nerve, neurofibromatosis, S100 positivity often patchy or lost in high-grade MPNST)

─ Synovial identification of a low-grade cartilaginous component)

─ Fibrosarcoma of Bone (high-grade; Sarcoma (monophasic spindle cell type; may have herringbone pattern; positive for keratins/EMA, t(X more uniform herringbone pattern, less pleomorphism; distinction can be subjective)

─ Leiomyosarcoma of Bone (high-grade;;18) translocation)

─ Leiomyosarcoma of Bone (blunt-ended nuclei, more eosinophilic cytoplasm, des requires convincing myogenic differentiation by IHC)

─ Rhabdomyosarcoma (pleomorphic type; requires rhabdomyoblasticmin/caldesmon positive)

Media

**Und differentiation)

─ Metastatic Sarcomatoid Carcinoma or Melanoma (IHC for keratins, melanifferentiated Pleomorphic Sarcoma of Bone (formerly Malignant Fibrous Histiocytoma of Bone)**

A highocytic markers, and clinical history are crucial)

Media

Infantile Fibrosarcoma

A rare malignant spindle cell neoplasm of infancy and early childhood, histologically resembling adult fibrosarcoma but typically with a more favorable prognosis and characterized by a recurrent ETV6-NTRK3 gene fusion

Clinical ─

─ Rare; most common soft tissue sarcoma in first year of life, but primary bone involvement is exceptionally rare (few case reports)

─ Typically presents at birth or within the first 2 years of life (congenital fibrosarcoma)

─ No clear sex predilection

─ Primary bone lesions reported in long bones (femur, humerus) and skull

─ Usually presents as a rapidly growing, painless or mildly painful mass; may be large at diagnosis

─ Imaging (bone lesions): Destructive, lytic lesion with ill-defined margins, cortical destruction, and often a significant soft tissue component; periosteal reaction may be present; can mimic other aggressive tumors of infancy

─ Prognosis: Better than adult fibrosarcoma; despite aggressive local growth and potential for recurrence, metastases are uncommon (<10-15%) if completely excised; overall survival is good, especially with modern multimodal therapy (surgery +/- chemotherapy)

Macro ─ fleshy, gray-white, often unencapsulated tumor; may have areas of hemorrhage, necrosis, or cystic change, especially in larger lesions

Micro ─

─ Cellular proliferation of relatively uniform spindle cells with ovoid to tapering nuclei, vesicular chromatin, and inconspicuous nucleoli

─ Cells are typically arranged in intersecting fascicles, often forming a "herringbone" pattern, similar to adult fibrosarcoma

─ Cytoplasm is usually scant and pale eosinophilic

─ Mitotic activity is generally brisk and easily identifiable, but atypical mitoses are usually not prominent

─ Stroma is variably collagenous; myxoid change can be present

─ Infiltrative growth pattern is common

─ Lymphoplasmacytic infiltrate may be present, sometimes prominent

─ Necrosis can occur, particularly in larger or rapidly growing tumors

─ No significant pleomorphism or bizarre tumor cells (unlike some adult sarcomas)

Ancillary studies ─

─ IHC: Spindle cells are positive for vimentin; may show focal positivity for smooth muscle actin; negative for S100, desmin, myogenin, keratins, CD34

─ Molecular ─ Characteristic and diagnostic recurrent translocation t(12;15)(p13;q25) resulting in an ETV6-NTRK3 gene fusion is present in most cases; this can be detected by RT-PCR or FISH

DDx ─

─ Myofibromatosis (infantile myofibroma) (biphasic pattern with myofibroblastic and hemangiopericytoma-like areas, less uniformly cellular and less aggressive than infantile fibrosarcoma, lacks ETV6-NTRK3 fusion)

─ Spindle Cell Rhabdomyosarcoma (requires rhabdomyoblastic differentiation by morphology or IHC for myogenin/MyoD1)

─ Malignant Peripheral Nerve Sheath Tumor (rare in this age group; look for association with nerve or NF1, S100 positivity often patchy)

─ Primitive Myxoid Mesenchymal Tumor of Infancy (PMMTI) (prominent myxoid stroma, often BCOR gene alterations, different immunoprofile)

─ Lipofibromatosis (infiltrative proliferation of adipose tissue and bland fibroblasts, different morphology)

Media

Juxtacortical Chondromyxoid Fibroma

A very rare benign cartilaginous tumor with histologic features identical to intramedullary chondromyxoid fibroma but arising on the surface of a bone, beneath the periosteum

Clinical ─

─ Extremely rare, fewer than 30 cases reported

─ Broad age range, but often young adults (similar to intramedullary CMF)

─ Most commonly involves the surface of long bones (femur, tibia, humerus) and small tubular bones of hands and feet

─ Presents as a slow-growing, usually painless or mildly painful firm mass

─ Prognosis: Benign; local recurrence possible after incomplete excision, similar to intramedullary CMF

Macro ─ firm, lobulated, gray-white or yellowish, myxoid/gelatinous mass on the bone surface, indenting the cortex; usually <5 cm

Micro ─

─ Histologically identical to intramedullary chondromyxoid fibroma:

─ Pseudolobular architecture with peripheral hypercellularity (spindle/stellate cells) and central hypocellularity in an abundant myxoid or chondromyxoid stroma

─ Fibrous septa with blood vessels separating lobules

─ Nuclear atypia/pleomorphism can be present but usually not marked; mitoses rare

─ Tumor is located on the bone surface, beneath the periosteum, and erodes the underlying cortex

Ancillary studies ─

─ Similar to intramedullary CMF (S100 positive, chromosome 6 rearrangements involving GRM1 may be present)

DDx ─

─ Periosteal Chondroma (composed of mature hyaline cartilage, often with calcification, lacks the characteristic myxoid stroma and biphasic cellularity of CMF lobules)

─ Periosteal Chondrosarcoma (more atypia, infiltrative growth into soft tissue beyond periosteum, larger size)

─ Periosteal Osteosarcoma (neoplastic osteoid production, different radiographic appearance)

─ Soft Tissue Myxoma/Chondromyxoid Fibroma secondarily involving bone surface (distinction can be difficult without clear origin from periosteum)

─ Florid Reactive Periostitis (zonal pattern, prominent spindle cell proliferation resembling nodular fasciitis, reactive bone formation)

Media

Cortical Irregularity Syndrome (Periosteal Desmoid)

A benign, reactive fibro-osseous lesion occurring at characteristic sites of tendon or ligamentous insertion, typically the posteromedial aspect of the distal femur, related to chronic stress or avulsion injury

Clinical ─

─ Common incidental finding, especially in adolescents and young adults involved in athletic activities (estimated 11% of males, 3,5% of females aged 10-20)

─ Most characteristic location is the posteromedial aspect of the distal femoral metaphysis, at or near the insertion of the adductor magnus tendon or medial head of gastrocnemius

─ Usually asymptomatic; may cause localized pain or tenderness, especially with activity

─ Self-limiting; often resolves spontaneously with cessation of activity or skeletal maturity

─ Imaging: Irregular, saucer-like cortical excavation or spiculated periosteal reaction at the characteristic location; underlying bone marrow is usually normal; MRI may show edema in the lesion and adjacent soft tissues if symptomatic

─ Prognosis: Excellent; benign and self-limiting; no treatment usually required unless symptomatic

Macro ─ Biopsy material (rarely obtained) consists of fragments of fibrous tissue and reactive bone

Micro ─

─ Reactive fibroblastic proliferation with bland spindle cells and varying amounts of collagen

─ Admixed reactive woven bone trabeculae, often with osteoblastic rimming

─ Areas of mature lamellar bone may be present

─ Cartilage is typically absent, or only small foci of fibrocartilage at tendon insertion site

─ Mild chronic inflammation may be present

─ No significant cytologic atypia, pleomorphism, or atypical mitoses (though reactive atypia can sometimes be seen)

─ Not a true desmoid tumor (fibromatosis) despite historical name

Ancillary studies ─

─ Not typically required; diagnosis is usually made on characteristic clinical and radiographic features and location

DDx ─

─ Osteosarcoma (especially surface osteosarcomas like parosteal or periosteal; osteosarcoma shows malignant cytologic features, neoplastic osteoid, and more aggressive imaging; crucial to recognize benign nature of cortical irregularity to avoid misdiagnosis)

─ Avulsion Fracture with callus (acute history of injury, more organized callus formation)

─ Chronic Osteomyelitis with periostitis (clinical signs of infection, inflammatory infiltrate)

─ Fibrous Dysplasia (intramedullary lesion, characteristic "ground glass" bone)

─ Nonossifying Fibroma (intracortical/medullary, different histology)

Media

Hemangioma of Bone

A benign vascular tumor composed of blood-filled vessels lined by bland endothelial cells, representing the most common benign vascular tumor of bone

Clinical ─

─ Common; often an incidental finding, especially in vertebrae (present in 10-12% of spines at autopsy)

─ Can occur at any age, but most symptomatic lesions present in middle-aged adults (4th-6th decades)

─ Slight female predominance for symptomatic vertebral lesions

─ Most common in vertebrae (especially thoracic and lumbar spine, typically involving body) and skull (calvarium); less commonly in long bones, ribs, pelvis

─ Usually asymptomatic; symptomatic lesions may cause pain (due to bone expansion or pathologic fracture), or neurologic symptoms if vertebral lesion causes cord/nerve root compression

─ Imaging (Vertebra): Characteristic "corduroy cloth" or "jailhouse stripes" appearance on plain radiographs and CT (thickened vertical trabeculae); "polka-dot" sign on axial CT; MRI shows high T1 signal (due to fat content in stroma) and high T2 signal (due to slow blood flow); avid enhancement with contrast

─ Imaging (Skull): Well-circumscribed, lytic lesion, often with a "sunburst" or "honeycomb" pattern of radiating bony spicules

─ Imaging (Long bones): Lytic lesion, often expansile, may have a "soap bubble" or trabeculated appearance

─ Prognosis: Excellent; most are asymptomatic and require no treatment; symptomatic lesions can be treated with embolization, radiation, vertebroplasty, or surgical decompression/resection

Macro ─ reddish-brown, hemorrhagic, spongy or cavernous tissue; may be well-circumscribed or infiltrative within bone

Micro ─

Composed of benign vascular channels; main histologic types:

─ Cavernous hemangioma (most common in vertebrae): Large, dilated, thin-walled vascular spaces filled with blood, lined by a single layer of flat, bland endothelial cells; separated by fibrous stroma or bone trabeculae

─ Capillary hemangioma (more common in skull/skin): Proliferation of small, capillary-sized vessels lined by bland endothelial cells, often in a lobular arrangement

─ Mixed capillary and cavernous patterns are common

─ Stroma between vessels may contain mature adipose tissue (especially in vertebral lesions), fibrous tissue, or hematopoietic marrow

─ Reactive woven or lamellar bone may be present surrounding vascular channels

─ No cytologic atypia, significant mitotic activity, or endothelial multilayering

Ancillary studies ─

─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FLI1

DDx ─

─ Lymphangioma of Bone (lymph-filled channels, D2-40/podoplanin positive endothelial cells, often lack red blood cells)

─ Angiosarcoma (malignant cytologic features, infiltrative growth, necrosis, atypical mitoses, endothelial multilayering)

─ Skeletal Angiomatosis/Gorham-Stout Disease (multicentric vascular lesions, often with lytic/resorptive changes)

─ Metastatic Renal Cell Carcinoma (can be highly vascular and mimic hemangioma; look for epithelial atypia, clear cells, PAX8/CAIX positivity)

─ Aneurysmal Bone Cyst (blood-filled cystic spaces but septa contain fibroblasts, giant cells, and woven bone, not primarily vascular channels; USP6 rearrangement)

Media

Lymphangioma of Bone

A rare benign vascular tumor composed of lymphatic-like channels lined by bland endothelial cells, occurring as solitary or multiple (lymphangiomatosis) intraosseous lesions

Clinical ─

─ Very rare primary bone tumor; bone lacks intrinsic lymphatics, so origin is debated (possibly from periosteal lymphatics or congenital malformation)

─ Most present in first two decades of life; no clear sex predilection

─ Can affect any bone, but most common in long bones (femur, tibia, humerus), pelvis, ribs, and vertebrae

─ Often multicentric (lymphangiomatosis), may be associated with soft tissue lymphangiomas or cystic hygroma

─ Solitary lesions often asymptomatic or cause mild pain/swelling; multiple lesions (lymphangiomatosis) can cause more significant symptoms, pathologic fractures, skeletal deformities, or chylous effusions (if thoracic involvement)

─ Gorham-Stout disease (massive osteolysis, vanishing bone disease) is considered by some to be a form of aggressive lymphangiomatosis

─ Imaging: Well-demarcated, lytic, often expansile lesions; can be unilocular or multilocular ("soap bubble" appearance); typically no matrix mineralization or significant periosteal reaction unless fractured; MRI shows high T2 signal cystic spaces

─ Prognosis: Generally good for solitary lesions; lymphangiomatosis can be progressive and difficult to manage, especially with extensive skeletal or visceral involvement; Gorham-Stout disease has a variable, often poor prognosis

Macro ─ spongy, cystic tissue containing clear or chylous fluid; may be poorly demarcated and infiltrative, especially in lymphangiomatosis

Micro ─

─ Composed of irregular, dilated, thin-walled vascular channels resembling lymphatic vessels

─ Channels are lined by a single layer of flat, bland endothelial cells with inconspicuous nuclei

─ Lumina typically contain proteinaceous, eosinophilic lymph fluid; may contain scattered lymphocytes; red blood cells are usually sparse or absent (helps distinguish from hemangioma)

─ Stroma between channels is loose, fibroconnective tissue, may contain lymphoid aggregates or smooth muscle fibers in vessel walls

─ Interstitial bone trabeculae may be resorbed or thinned

─ No cytologic atypia or significant mitotic activity

Ancillary studies ─

─ IHC: Endothelial cells are positive for lymphatic markers D2-40 (podoplanin) and LYVE-1, in addition to general endothelial markers (CD31, ERG); this helps distinguish from hemangioma

DDx ─

─ Hemangioma of Bone (blood-filled channels, lacks lymphatic marker expression)

─ Aneurysmal Bone Cyst (blood-filled cystic spaces, lacks true endothelial lining, septa with fibroblasts/giant cells)

─ Simple Bone Cyst (unicameral, fluid-filled, fibrous lining, no endothelial cells)

─ Skeletal Angiomatosis (if multiple lesions; term often used broadly for multicentric vascular lesions, which can be hemangiomatous or lymphangiomatous)

─ Cystic Fibrous Dysplasia (if cystic changes are prominent; look for characteristic woven bone and fibrous stroma)

Media

Arteriovenous Malformation of Bone

A rare congenital vascular anomaly characterized by abnormal direct connections between arteries and veins within bone, bypassing the normal capillary bed

Clinical ─

─ Very rare as a primary intraosseous lesion; more commonly, bone is secondarily involved by a soft tissue AVM

─ Usually presents in childhood or young adulthood; no clear sex predilection

─ Most commonly affects craniofacial bones (mandible, maxilla), vertebrae, and long bones

─ May present with pain, swelling, palpable thrill or bruit, localized warmth, pulsatile mass, or bleeding (e,g,, gingival bleeding if in jaw); high-flow lesions can cause cardiac overload or limb hypertrophy

─ Neurologic symptoms can occur with vertebral AVMs due to cord/nerve compression or vascular steal phenomenon

─ Imaging: Complex lytic lesion with multiple tortuous vascular channels and enlarged feeding arteries and draining veins; angiography is definitive for diagnosis and mapping; CT/MRI can show bone destruction, serpiginous flow voids, and soft tissue extension

─ Prognosis: Variable; depends on size, location, and flow dynamics; risk of hemorrhage, neurologic compromise, or cardiac failure in high-flow lesions; treatment often involves embolization +/- surgical resection, which can be challenging with high recurrence rates

Macro ─ a tangle of abnormal, dilated, thick-walled arteries and thin-walled, often dilated, "arterialized" veins; bone may be eroded or replaced by vascular channels

Micro ─

─ Characterized by a malformed tangle of thick-walled arteries and thin-walled, often dilated, "arterialized" veins, with direct arteriovenous shunts

─ Arteries show muscular hypertrophy and elastic lamina abnormalities; veins may show intimal thickening and muscularization

─ Intervening capillary bed is absent or poorly developed

─ Endothelial lining of vessels is bland

─ Surrounding bone may show reactive changes, resorption, or sclerosis

─ Thrombosis, hemorrhage, and hemosiderin deposition can be present

─ No neoplastic proliferation of endothelial cells

Ancillary studies ─

─ IHC: Endothelial cells positive for CD31, CD34, ERG, FLI1; smooth muscle actin highlights vessel walls

─ Imaging (angiography) is crucial for diagnosis and pre-treatment planning

DDx ─

─ Hemangioma of Bone (neoplastic proliferation of capillaries or cavernous channels, not direct AV shunts)

─ Aneurysmal Bone Cyst (blood-filled cystic spaces, septa with fibroblasts/giant cells, lacks true arterial and venous structures)

─ Angiosarcoma (malignant endothelial cells, infiltrative growth, atypia, mitoses)

─ Vascular-rich metastatic carcinoma (e,g,, renal cell carcinoma; epithelial atypia, IHC for keratins/PAX8)

─ Fibrous Dysplasia (can be hypervascular, but different underlying histology)

Media

Skeletal Angiomatosis (including Gorham-Stout Disease / Vanishing Bone Disease)

A rare condition characterized by benign, diffuse or multicentric proliferation of vascular (hemangiomatous and/or lymphangiomatous) channels within bone, often associated with soft tissue and visceral involvement; Gorham-Stout disease represents a subtype with progressive osteolysis

Clinical ─

─ Rare; usually presents in childhood or adolescence, but can occur at any age

─ No clear sex predilection

─ Canset 10 affect any part of the skeleton, often polyostotic and involving contiguous bones or an entire region (e,g,, limb, hem

markdown

Arteriovenous Malformation of Bone

A rare congenital vascular anomaly characterized by abnormal direct connections between arteries and veins within bone, bypassing the normal capillary bed

Clinical ─ipelvis, shoulder girdle)

─ Clinical presentation is highly variable, depending on site and extent of involvement: pain, swelling, pathologic

─ Very rare as a primary intraosseous lesion; more commonly, bone is secondarily involved by a soft tissue A fractures, skeletal deformities, lymphedema (if lymphatic predominant); chylous effusions (pleural, pericardial, peritonealVM

─ Usually presents in childhood or young adulthood; no clear sex predilection

─ Most commonly affects) can occur with thoracic or extensive involvement

─ Gorham-Stout Disease (Massive Osteolysis, Vanishing Bone Disease craniofacial bones (mandible, maxilla), vertebrae, and long bones

─ May present with pain, swelling, palpable): progressive resorption and disappearance of affected bone(s), leading to severe deformity and functional impairment; often involves ribs, scapula, pelvis thrill or bruit, localized warmth, pulsatile mass, or bleeding (e,g,, gingival bleeding if in jaw); high, vertebrae, long bones

─ Imaging: Multiple lytic lesions, often expansile, with well-defined or ill-flow lesions can cause cardiac overload or limb hypertrophy

─ Neurologic symptoms can occur with vertebral AVMs due to cord-defined margins; "honeycomb" or "soap bubble" appearance; cortical thinning and destruction are common; Gorham-Stout shows/nerve compression or vascular steal phenomenon

─ Imaging: Complex lytic lesion with multiple tortuous vascular channels and enlarged progressive osteolysis with "tapering" or "pointed" ends of affected bones, eventually leading to complete disappearance of bone; soft feeding arteries and draining veins; angiography is definitive for diagnosis and mapping; CT/MRI can show bone destruction, serpiginous flow voids, tissue involvement is common

─ Prognosis: Highly variable; some cases are indolent or stabilize; Gorham-Stout disease is often progressive and soft tissue extension

─ Prognosis: Variable; depends on size, location, and flow dynamics; risk of hemorrhage, neurologic and can be debilitating or fatal due to complications (e,g,, respiratory compromise from chylothorax, spinal instability)

Macro compromise, or cardiac failure in high-flow lesions; treatment often involves embolization +/- surgical resection, which can be challenging with ─ affected bone is replaced by spongy, reddish-brown (hemangiomatous) or pale, cystic (lymphangiomatous) vascular tissue; in Gorham-Stout, bone is progressively resorbed and replaced by fibrous and vascular tissue

Micro high recurrence rates

Macro ─ a tangle of abnormal, dilated, thick-walled arteries and thin-walled, ─

─ Proliferation of benign vascular channels, which can be:

─ Hemangiomatous: often dilated, "arterialized" veins; bone may be eroded or replaced by vascular channels

Micro ─ capillary-sized or cavernous blood vessels lined by bland endothelial cells, similar to hemangioma of bone

─

─ Characterized by a malformed tangle of thick-walled arteries and thin-walled, often dilated, "arterialized" veins, Lymphangiomatous: dilated, irregular lymphatic-like channels lined by bland endothelial cells, containing lymph fluid, similar to lymph with direct arteriovenous shunts

─ Arteries show muscular hypertrophy and elastic lamina abnormalities; veins may show intimal thickeningangioma of bone

─ Mixed hemangio-lymphangiomatous patterns are common

─ Vessels infiltrate and muscularization

─ Intervening capillary bed is absent or poorly developed

─ Endothelial lining of vessels is bland

─ Sur and replace normal bone marrow and trabeculae

─ In Gorham-Stout disease, there is prominent osteoclastic activityrounding bone may show reactive changes, resorption, or sclerosis

─ Thrombosis, hemorrhage, and hemosiderin deposition can be present

─ No neoplastic proliferation of endothelial cells

Ancillary studies ─

─ IHC: Endothelial cells positive for CD31, CD34, ERG, FLI1; smooth muscle actin highlights vessel walls

─ leading to bone resorption, and the vascular proliferation is often predominantly lymphangiomatous; affected areas eventually replaced by fibrous tissue with residual Imaging (angiography) is crucial for diagnosis and pre-treatment planning

DDx ─

─ Hem vascular channels

─ Stroma is usually loose fibroconnective tissue; lymphoid aggregates may be present

─ No cytologicangioma of Bone (neoplastic proliferation of capillaries or cavernous channels, not direct AV shunts)

─ A atypia or significant mitotic activity

Ancillary studies ─

─ IHC: Endothelial cells positiveneurysmal Bone Cyst (blood-filled cystic spaces, septa with fibroblasts/giant cells, lacks true arterial and venous for general endothelial markers (CD31, ERG); lymphatic channels also positive for D2-40 (podoplanin) and LY structures)

─ Angiosarcoma (malignant endothelial cells, infiltrative growth, atypia, mitoses)

─ VascularVE-1

DDx ─

─ Multifocal Hemangiomas or Lymphangiomas (angi-rich metastatic carcinoma (e,g,, renal cell carcinoma; epithelial atypia, IHC for keratins/PAX8)

─ Fibrous Dysplasia (can be hypervascular, but different underlying histology)

Media

omatosis implies more diffuse/extensive involvement than discrete multiple lesions)

─ Metastatic Disease (especially lytic metastases

Skeletal Angiomatosis (including Gorham-Stout Disease / Vanishing Bone Disease)

Clinical; clinical history, primary tumor search)

─ Langerhans Cell Histiocytosis (different cell population, characteristic IHC ─

─ Rare; usually presents in childhood or adolescence, but can occur at any age

─ No clear)

─ Fibrous Dysplasia (can be polyostotic and lytic, but different histology and matrix)

─ Oste sex predilection

─ Can affect any part of the skeleton, often polyostotic and involving contiguous bones oromyelitis (if lytic and destructive; clinical signs of infection, inflammatory infiltrate)

Media

an entire region (e,g,, limb, hemipelvis, shoulder girdle)

─ Clinical presentation is highly variable, depending on site and extent of involvement: pain, swelling, pathologic fractures, skeletal deformities, lymphedema (

Epithelioid Hemangioma of Bone

A benign, locally aggressive vascular neoplasm composedif lymphatic predominant); chylous effusions (pleural, pericardial, peritoneal) can occur with thoracic or extensive involvement

─ Gorham-Stout Disease (Massive Osteolysis, Vanishing Bone Disease): progressive resorption and disappearance of epithelioid endothelial cells, often with an inflammatory infiltrate including eosinophils; previously known by various names including angiolymphoid hyperplasia of affected bone(s), leading to severe deformity and functional impairment; often involves ribs, scapula, pelvis, vertebrae with eosinophilia and histiocytoid hemangioma

Clinical ─

─ Uncommon; affects, long bones

─ Imaging: Multiple lytic lesions, often expansile, with well-defined or ill-defined margins; "honeycomb" or "soap bubble" appearance; cortical thinning and destruction are common; Gorham-Stout shows progressive oste adults (peak 3rd to 5th decades), slight male predominance

─ Most commonly involves bones of the handsolysis with "tapering" or "pointed" ends of affected bones, eventually leading to complete disappearance of bone; and feet (phalanges, metacarpals/tarsals), long bones (tibia, femur), and vertebrae; skull soft tissue involvement is common

─ Prognosis: Highly variable; some cases are indolent or stabilize; Gorham-Stout disease is often and ribs less common

─ Often multicentric (~20-50%), involving multiple bones or bone and soft tissue/ progressive and can be debilitating or fatal due to complications (e,g,, respiratory compromise from chylothorax, spinal instability)

Macro ─ affected bone is replaced by spongy, reddish-brown (hemangiomatous) orskin sites

─ Presents with pain and swelling; pathologic fracture can occur

─ Peripheral blood eosinophilia may be present in some pale, cystic (lymphangiomatous) vascular tissue; in Gorham-Stout, bone is progressively resorbed and replaced by fibrous and vascular tissue

Micro ─

─ Proliferation of benign vascular channels, which can be:

cases (formerly linked to angiolymphoid hyperplasia with eosinophilia)

─ Imaging: Well-circumscribed, geographic lytic lesion ─ Hemangiomatous: capillary-sized or cavernous blood vessels lined by bland endothelial cells, similar to hemangioma of bone

─, often eccentric and expansile, with a thin sclerotic rim; may cause cortical thinning or breach; no aggressive peri Lymphangiomatous: dilated, irregular lymphatic-like channels lined by bland endothelial cells, containing lymph fluid, similar to lymphosteal reaction typically; can mimic other benign or low-grade malignant tumors

─ Prognosis: Benign butangioma of bone

─ Mixed hemangio-lymphangiomatous patterns are common

─ Channels infiltrate can be locally recurrent after curettage (10-15%); metastases do not occur; rare reports of regression and replace normal bone marrow and bone trabeculae

─ In Gorham-Stout disease, there is prominent

Macro ─ soft, friable, reddish-brown or tan tissue; often well-demarcated; osteoclastic activity and bone resorption, with replacement by loose fibrovascular tissue and dilated lymphatic-like channels

─ No may be hemorrhagic

Micro ─

─ Characterized by a proliferation of plump, epithelioid endothelial cytologic atypia or significant mitotic activity in the endothelial cells

Ancillary studies ─

─ IHC: Hemangiomatous channels positive for CD31, CD34, ERG; Lymphangiomatous channels positive for D2-40 (podoplanin cells lining vascular channels or forming solid nests/cords

─ Endothelial cells have abundant eosinophilic cytoplasm, round), LYVE-1, in addition to general endothelial markers

DDx ─

─ Multif to oval vesicular nuclei, and often prominent nucleoli; intracytoplasmic vacuoles (primitive lumens) are common

─ Vascularocal Hemangiomas or Lymphangiomas (distinction from angiomatosis can be arbitrary and depends on extent/diffuseness)

─ Langerhans Cell Histiocytosis (can be lytic and multicentric, but different histology channels are typically small, capillary-sized or slightly larger, often irregular; "hobnailing" of endothelial cells into with Langerhans cells and eosinophils)

─ Metastatic Disease (especially lytic metastases; typically older patients, different histology) lumens is characteristic

─ Stroma is loose, edematous, or hyalinized, and often contains a prominent inflammatory infiltrate

─ Fibrous Dysplasia (polyostotic; different radiographic appearance, "ground glass" bone, woven bone trab rich in eosinophils and lymphocytes; plasma cells and mast cells may also be present

─ Mitotic activity is usually loweculae in fibrous stroma)

─ Other causes of osteolysis (e,g,, infection, inflammatory conditions;, and atypical mitoses are absent

─ No significant cytologic atypia or pleomorphism beyond the epithelioid appearance

─ Solid sheets of epithelioid cells can be seen, mimicking carcinoma

Ancillary studies clinical context and specific histologic features differ)

Media

**E─

─ IHC: Epithelioid endothelial cells are strongly positive for general endothelial markers (CD31, CDpithelioid Hemangioma of Bone**

A benign, locally aggressive vascular neoplasm composed of epithelioid endothelial34, ERG, FLI1); may also express cytokeratins (AE1/AE3, CAM cells, typically forming small vessels, often associated with an inflammatory infiltrate

Clinical ─

─ Uncommon5,2) in a subset of cases (potential pitfall)

─ Molecular ─ Some cases show *; accounts for <1% of primary bone tumors

─ Typically affects adults (peak 3rd to 5th decades); slight male predominance

─ Most common in long bones (femur, tibia, humerus), bonesFOS* or FOSB gene rearrangements, suggesting a neoplastic basis; ZFP36-FOSB fusion has been described

DDx ─

─ Epithelioid Hemangioendothelioma (more of hands and feet (phalanges, metatarsals/carpals), and vertebrae; can be multifocal (~20%)

─ Presents with localized pain and swelling; pathologic fracture is uncommon

─ Skin and soft tissue lesions (ang myxohyaline/chondroid stroma, often more infiltrative, WWTR1-CAMTA1 or YAP1-TFE3 fusions)

─ Epithelioid Angiosarcoma (frankly malignant cytologiciolymphoid hyperplasia with eosinophilia) may be associated

─ Imaging: Well-circumscribed, geographic lytic lesion, features, high mitotic rate, necrosis, infiltrative destructive growth)

─ Metastatic Carcinoma (especially epithel often with a thin sclerotic rim; may be expansile and cause cortical thinning; no aggressive periosteal reaction unlessioid types; IHC for specific carcinoma markers, negative for consistent endothelial markers, clinical history)

─ Langerhans Cell Histi fractured; MRI shows variable signal, often avid enhancement

─ Prognosis: Benign, but local recurrence can occur (1ocytosis (if eosinophils are prominent; Langerhans cells have characteristic grooved nuclei, CD1a/Langerin positive)

─ Oste0-15%) after curettage; rarely, multifocal lesions can be more problematic; malignant transformation is notomyelitis with prominent eosinophils (clinical signs of infection, mixed inflammatory infiltrate, no neoplastic epithelioid endothelial cells)

Media ─ placeholderrecognized

Macro ─ soft, friable, reddish-brown to gray-tan tissue; usually well-dem

Kaposiform Hemangioendothelioma of Bone

A rare, locallyarcated; may appear hemorrhagic

Micro ─

─ Proliferation of small to medium-sized blood aggressive vascular neoplasm of intermediate malignancy, typically occurring in infants and children, characterized by infiltrating nodules of spindle cells and slit vessels, often in a lobular or nodular arrangement

─ Vessels are lined by plump, epithelioid endothelial cells with abundant-like vascular spaces; primary bone involvement is exceptional

Clinical ─

─ Very rare, especially eosinophilic cytoplasm, round to oval vesicular nuclei, and often prominent nucleoli; cells may bulge into vascular lumens ("hob as a primary bone tumor; most arise in soft tissue (skin, deep soft tissue, retroperitoneum, mediastinum)

─ Prednail" appearance)

─ Intracytoplasmic vacuoles (representing primitive lumen formation) are characteristic

─ Stominantly affects infants and young children (most <2 years old, many congenital); rare in older children/adults

─ Noroma is variably edematous, fibrous, or hyalinized, and typically contains a prominent inflammatory infiltrate rich in eosin clear sex predilection

─ Primary bone involvement is extremely rare, reported in long bones and vertebrae

─ Oftenophils and lymphocytes; lymphoid follicles may be present

─ Mitotic activity is usually low; atypical mitoses are absent associated with Kasabach-Merritt phenomenon (consumptive coagulopathy with profound thrombocytopenia and microangiopathic hemolytic

─ No significant cytologic atypia or pleomorphism beyond the epithelioid appearance

─ Solid sheets of epit anemia), especially in large or visceral lesions

─ Presents as a rapidly growing, firm, infiltrative mass, often violaceous or echelioid cells can occur focally but are not the dominant pattern (distinction from epithelioid angiosarcoma)

Ancchymotic if cutaneous

─ Imaging (if bone involved): Aggressive, lytic lesion with ill-defined margins,illary studies ─

─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FL cortical destruction, and often a large soft tissue mass; may be expansile; periosteal reaction can be present

─ PrognI1; may also express keratins focally (pitfall for metastatic carcinoma)

─ Molecular ─ Recurrent FOSB gene rearrangements (often with WWTR1 or ZEB2 partners) have been identifiedosis: Locally aggressive with high recurrence rates; mortality is often due to Kasabach-Merritt phenomenon or organ compromise from in a subset of cutaneous and soft tissue epithelioid hemangiomas; data on bone lesions is limited

DD infiltrative growth, rather than true metastasis (which is rare)

Macro ─ poorly circumscribed, firm, fleshyx ─

─ Epithelioid Angiosarcoma (more cytologic atypia, pleomorphism, infiltr, reddish-brown to violaceous infiltrative mass; may show areas of hemorrhage

Micro ─

ative growth, necrosis, higher mitotic rate, endothelial multilayering)

─ Epithelioid Hemangioendothelioma (different stromal matrix - often hyaline or myxochondroid, more prominent cords and nests of epithelioid cells, specificCharacteristic features include:

─ Infiltrating nodules or sheets of relatively uniform spindle cells with scant cytoplasm and ovoid to elongated translocations like WWTR1-CAMTA1)

─ Metastatic Carcinoma (especially clear cell renal nuclei

─ Spindle cells form poorly defined fascicles and surround slit-like or crescentic vascular channels, which often cell carcinoma or squamous cell carcinoma; look for more definitive epithelial features, IHC for keratins usually more diffuse, specific markers like PAX8, p63)

─ Langerhans Cell Histiocytosis (if eosinophils are very prominent; contain red blood cells

─ Admixed clusters or lobules of more epithelioid or rounded endothelial cells forming glomerul Langerhans cells have grooved nuclei, CD1a/Langerin positive)

─ Osteomyelitis with prominentoid structures or small capillary-like vessels are common

─ Intracytoplasmic hyaline globules (PAS-positive, eosinophils (clinical signs of infection, mixed inflammatory infiltrate, absence of neoplastic epithelioid endothelial cells)

Media ─ placeholderdiastase-resistant) may be present in tumor cells

─ Hemosiderin deposition is common

─ Mit

Kaposiform Hemangioendothelioma of Bone

A rare, locallyotic activity is variable, can be brisk, but atypical mitoses are usually not prominent

─ Minimal cytologic atypia overall aggressive vascular neoplasm of borderline malignancy, typically occurring in childhood, characterized by infiltrative nodules of slit-like vascular channels and spindle

─ Platelet trapping within vascular channels can be seen, especially in cases with Kasabach-Merritt phenomenon cells; primary bone involvement is exceptionally rare

Clinical ─

─ Very rare, especially as a primary bone tumor; most

Ancillary studies ─

─ IHC: Spindle and epithelioid endothelial cells are positive for general endothelial markers (CD31, CD34, ERG, FLI1); D2-40 (pod commonly arises in skin and soft tissues of trunk, extremities, and retroperitoneum

─ Predominantly affects infants and young children (most <2 years old); can be congenital

─ No clear sex predilection

─ Skeoplanin) is often positive, suggesting lymphatic differentiation in some components; GLUT1 is typically negative (helps distinguish from infantile hemangioma); HHV-8 is negative (distinguishes from Kaposi sarcoma)

─ Molecular ─ No specific recurrentletal involvement is usually secondary from an overlying soft tissue lesion; primary bone lesions are exceptional (reports in long bones, vertebrae)

─ Often translocations identified; some studies suggest involvement of lymphatic development pathways

DDx ─

─ Inf associated with Kasabach-Merritt phenomenon (consumptive coagulopathy with thrombocytopenia and microangiopathic hemolytic anemia) ifantile Hemangioma (especially cellular phase; GLUT1 positive, lacks the infiltrative nodules and slit-like spaces of K large or visceral

─ Presents as a rapidly growing, firm, often violaceous mass or plaque

─ Imaging (HE)

─ Kaposi Sarcoma (HHV-8 positive, characteristic slit-like spaces and hyaline globules,bone lesions): Lytic, destructive lesion with ill-defined margins, cortical erosion, and often a large associated soft tissue mass; usually older/immunocompromised patients for classic/AIDS-related types)

─ Spindle Cell Hemangioma (well may be expansile

─ Prognosis: Locally aggressive with high recurrence rates; mortality can occur due to Kasabach-Merritt phenomenon-formed cavernous vessels admixed with spindle cell areas, often phleboliths, different age group)

─ Tu or involvement of vital organs; metastases are rare but have been reported

Macro ─ firm, infiltrative, poorly circumscribed, reddish-brown to violaceous mass; may have areas of hemorrhage

Micro ─

fted Angioma (histologically similar/identical to KHE, some consider them part of same spectrum; often smaller─ Infiltrative, lobulated or nodular growth pattern

─ Composed of two main components:

1, more superficial lesions)

─ Infantile Fibrosarcoma (herringbone pattern, ETV6-NTRK. Slit-like vascular channels: Irregular, compressed vascular spaces lined by bland spindle endothelial cells, often forming small,3 fusion)

─ Other Spindle Cell Sarcomas (if atypia is more pronounced)

Media

Epithelioid Hemangioendothelioma of Bone

A rare poorly defined nodules ("glomeruloid" structures)

Spindle cell proliferation: Sheets and fascicles of relatively malignant vascular tumor of intermediate grade, characterized by epithelioid endothelial cells arranged in cords and nests within a myxohy uniform spindle cells with scant cytoplasm and ovoid to elongated nuclei, surrounding the vascular channels; may resemble Kaposi sarcoma aline or chondroid-like stroma; can be multicentric and metastasize

Clinical ─

─ Rare, accounts for <1% of primary bone malignancies

─ Affects adults over a wide age range (peak

─ Extravasated red blood cells and hemosiderin deposition are common

─ Eosinophilic hyaline globules (3rd to 5th decades); slight female predominance

─ Most commonly involves long bones (femur, tibia, humerus), spine, andintracytoplasmic or extracellular) may be present

─ Mitotic activity is variable but usually not high; atypical mitoses are rare

─ No significant cytologic atypia or pleomorphism

─ Lymphatic-like channels may be present at pelvis; can also occur in ribs, clavicle, small bones

─ Often multicentric at presentation (~30-50%), involving the periphery

Ancillary studies ─

─ IHC: Spindle endothelial cells are positive for CD31, multiple bones or bone and soft tissue/viscera (liver, lung are common visceral sites)

─ Presents CD34, ERG, FLI1; lymphatic markers like D2-40 and LYVE-1 may be positive in some areas, particularly in lymphatic-like channels; negative for HHV-8 (distinction from Kaposi sarcoma) and with pain, swelling, or pathologic fracture; symptoms may be present for months to years

─ Imaging: Geographic l GLUT1 (distinction from infantile hemangioma)

DDx ─

─ Kaposi Sarcoma (HHytic lesions, often multiple, with well-defined or ill-defined margins; may have a thin sclerotic rim orV-8 positive, characteristic slit-like spaces with extravasated RBCs and hyaline globules, but different clinical context and cortical expansion/destruction; soft tissue extension can occur; no characteristic matrix mineralization, but stroma can appear dense

─ Progn viral association)

─ Infantile Hemangioma (cellular phase; GLUT1 positive, lacks the infiltrative nodulesosis: Intermediate malignancy; indolent course in many, but ~20-30% develop metastases (lung, liver and prominent spindle cell component of KHE)

─ Tufted Angioma (similar histology with "cannonball, lymph nodes, bone) and ~10-20% die of disease; multicentricity at presentation is a" nodules of capillaries, but usually cutaneous and less infiltrative)

─ Spindle Cell Hemangioma (distinct poor prognostic factor

Macro ─ firm, gray-white to tan, often infiltrative tumor; may have a cavernous vessels admixed with spindle cells, often with phleboliths)

─ Angiosarcoma (more gelatinous or chondroid appearance; hemorrhage and necrosis are uncommon

Micro ─

─ Characteristic cords cytologic atypia, necrosis, higher mitotic rate)

Media

##, strands, and nests of epithelioid endothelial cells embedded in an abundant myxohyaline or chondroid-like stroma Epithelioid Hemangioendothelioma of Bone

A rare malignant vascular tumor of borderline or low-grade malignancy, composed of epithelioid endothelial cells arranged in cords, nests, or strands within a characteristic hyaline or myxochond

─ Tumor cells are polygonal to ovoid with abundant eosinophilic cytoplasm, round to oval vesicular nuclei, and often prominent nucleroid stroma

Clinical ─

─ Uncommon; accounts for <1% of primary bone tumors

─ Typically affectsoli; intracytoplasmic vacuoles (primitive vascular lumens) are a key feature, sometimes containing red blood cells

─ Minimal well adults (peak 3rd to 5th decades); no clear sex predilection

─ Most common in long bones (femur, tibia, humerus), vertebrae, and pelvis; often multifocal (30-50% of cases), which may-formed vascular channels; tumor grows by infiltration

─ Stroma is typically pale blue to gray, myxoid, or hyalinized, resembling cartilage matrix but S100 negative

─ Mitotic activity is usually low (< represent metastatic disease rather than true multicentricity

─ Presents with pain, swelling, or pathologic fracture; symptoms may be present1-2 per 10 HPF); atypical mitoses are rare

─ Mild to moderate cytologic atypia; for months to years

─ Imaging: Geographic lytic lesions, often multiple, with well-defined or ill-defined margins; significant pleomorphism is uncommon

─ Inflammatory infiltrate is usually sparse

Ancillary studies ─

─ IHC: Epithelioid endothelial cells are consistently positive for general endothelial markers (CD31, CD34, ERG, FLI may have a sclerotic rim or cortical expansion; matrix calcification is usually absent; MRI shows intermediate T1 and high T2 signal,1); often positive for cytokeratins (AE1/AE3, CAM5,2) in ~3 avid enhancement

─ Prognosis: Variable; considered borderline/low-grade malignancy; 5-year survival ~0-50% of cases (potential diagnostic pitfall); S100 is negative

─ Molecular ─ Characteristic70-80%; metastases (lungs, liver, lymph nodes, other bones) occur in 20-30% of cases recurrent translocation t(1;3)(p36;q25) resulting in a *WWTR1-CAM; multifocal disease at presentation has a worse prognosis

Macro ─ firm, gray-white to tanTA1* gene fusion is found in most cases; a less common YAP1-TFE3 fusion t(X;11)(p11;q22) is seen in a subset with different morphology (more, often gelatinous or chondroid-like tissue; usually infiltrative within bone; may have hemorrhagic areas

Micro ─ vasoformative)

DDx ─

─ Metastatic Carcinoma (especially adenocarcinoma with sign

─ Characteristic growth pattern: nests, cords, strands, or single files of epithelioid endothelial cells embedded in an abundantet ring cells or mucinous carcinoma; strong/diffuse keratin positivity, negative for consistent endothelial markers, clinical history) hyaline, myxoid, or chondroid-like stroma

─ Tumor cells are polygonal to ovoid with ample

─ Epithelioid Hemangioma (more well-formed vessels, prominent eosinophilic inflammatory infiltrate, lacks my eosinophilic to clear cytoplasm, round to oval vesicular nuclei, and often prominent nucleoli; mild to moderate atypia xohyaline/chondroid stroma, different molecular if tested)

─ Epithelioid Angiosarcoma (more

─ Intracytoplasmic vacuoles or lumina (representing primitive vessel formation) are a key feature, sometimes containing red atypia, higher mitotic rate, necrosis, solid sheets, less prominent myxohyaline stroma)

─ My blood cells

─ Mitotic activity is generally low; atypical mitoses are rare

─ Stroma is oftenxoid Chondrosarcoma (lobules of hyaline cartilage with myxoid change, S100 positive, EWSR1-NR4A3 fusion)

─ Chordoma (if in axial skeleton; physalip prominent and can be densely hyalinized, resembling amyloid, or have a myxoid/chondroid appearance

─ Inhorous cells, S100 and brachyury positive, different stroma)

Mediafiltrative growth pattern, permeating host bone trabeculae

─ Necrosis is uncommon

Ancillary studies

Pseudomyogenic Hemangioendothelioma of Bone

A rare vascular neoplasm of intermediate (rarely metastasizing) malignancy, characterized by infiltrating fascicles of plump spindle and epithelioid cells with eosinophilic cytoplasm, often multifocal and involving skin, soft tissue, and bone

Clinical ─

─ Rare; bone involvement is uncommon, usually secondary to soft tissue lesions or part of multifocal disease

─ Primarily affects young to middle-aged adults (peak 2nd to 4th decades); strong male predominance (~4:1)

─ Often presents as multiple, asynchronous lesions in different tissue planes (skin, subcutaneous tissue, muscle, bone) within a single anatomic region (e,g,, lower limb)

─ Skeletal sites include long bones (tibia, femur), and small bones of hands/feet

─ Lesions are often painful or tender nodules/plaques; can be slow-growing or rapidly enlarging

─ Imaging (bone lesions): Lytic, often well-circumscribed lesions; may be expansile and cause cortical thinning or breach; periosteal reaction is uncommon; multifocal bone involvement can occur

─ Prognosis: Indolent course; locally recurrent (up to 60%) and new lesions in the same region are common; distant metastases are very rare (<5%), but have been reported to lymph nodes and lung; no reported disease-related deaths

Macro ─ poorly circumscribed, firm, gray-white to tan-red infiltrative nodules or plaques in soft tissue or bone

Micro ─

─ Infiltrating fascicles and sheets of plump spindle cells and more rounded epithelioid cells

─ Cells have abundant, deeply eosinophilic, glassy cytoplasm resembling skeletal muscle (hence "pseudomyogenic") and large, vesicular nuclei with prominent nucleoli; mild to moderate pleomorphism

─ Nuclear atypia is generally mild; mitotic activity is variable but usually low, atypical mitoses are rare

─ Cells are loosely cohesive, often with intercellular edema or clefting

─ Poorly formed vascular channels or intracytoplasmic lumens are usually inconspicuous or absent (distinction from other epithelioid vascular tumors)

─ Stroma is variably fibrous or edematous, often with a prominent acute and chronic inflammatory infiltrate, including numerous neutrophils and eosinophils

─ Necrosis is uncommon

Ancillary studies ─

─ IHC: Tumor cells are consistently positive for keratins (AE1/AE3, CAM5,2 - often strong and diffuse) and FLI1 (nuclear); frequently positive for CD31; ERG is often positive; negative for CD34, S100, desmin, myogenin, smooth muscle actin, HHV-8

─ Molecular ─ Characterized by recurrent translocations involving the SERPINE1 gene on 7q22 and the FOSB gene on 19q13, most commonly t(7;19)(q22;q13) leading to SERPINE1-FOSB fusion

DDx ─

─ Epithelioid Sarcoma (keratin positive, but often shows granuloma-like nodules with central necrosis, loss of INI1 expression, negative for endothelial markers)

─ Epithelioid Hemangioma (prominent well-formed vessels, characteristic hobnail cells, eosinophilic infiltrate, lacks diffuse sheets of pseudomyogenic cells, FOS/FOSB rearrangements without SERPINE1)

─ Epithelioid Angiosarcoma (more cytologic atypia, higher mitotic rate, better-formed vascular channels, infiltrative destructive growth, keratin positivity less consistent/strong)

─ Rhabdomyosarcoma (especially spindle cell or pleomorphic types; requires myogenic differentiation by IHC - desmin, myogenin, MyoD1)

─ Metastatic Carcinoma (keratin positive, but negative for endothelial markers, clinical history)

Media

Kaposi Sarcoma of Bone

A low-grade malignant vascular neoplasm linked to Human Herpesvirus-8 (HHV-8) infection, characterized by proliferating spindle cells forming slit-like vascular spaces; primary bone involvement is rare, usually occurring in the context of disseminated disease

Clinical ─

─ Four main clinical-epidemiologic forms:

1, Classic (older men of Mediterranean/Eastern European descent, indolent skin lesions on lower extremities)

2, Endemic (African; children and young adults, can be aggressive with lymph node/visceral involvement)

3, Iatrogenic (immunosuppression-associated, e,g,, transplant recipients)

4, AIDS-related (most common form in Western countries, can be aggressive and disseminated)

─ Bone involvement is uncommon overall (<5-10%), most frequent in endemic African and advanced AIDS-related forms; very rare as a primary isolated bone lesion

─ Skeletal sites: often affects distal extremities (hands, feet), but can involve any bone, including long bones, pelvis, spine, jaw

─ Presents with painful, lytic bone lesions, often multiple; soft tissue swelling or skin lesions are usually associated; pathologic fractures can occur

─ Imaging: Lytic lesions, often with ill-defined margins, cortical erosion or destruction; can be expansile or permeative; periosteal reaction is uncommon; "flame-shaped" or "bubbly" lucencies described

─ Prognosis: Variable, depends on clinical form and extent of disease; classic form is often indolent; AIDS-related and endemic forms can be aggressive, especially with visceral involvement; highly active antiretroviral therapy (HAART) has dramatically improved prognosis in AIDS-related KS

Macro ─ reddish-purple to brown, hemorrhagic nodules or plaques; in bone, replaces marrow and erodes cortex

Micro ─

Characteristic features, often seen in different stages/lesions:

─ Patch/Plaque stage: Proliferation of irregular, jagged, thin-walled vascular channels dissecting collagen, often around pre-existing vessels ("promontory sign"); mild spindle cell proliferation and inflammatory infiltrate (lymphocytes, plasma cells)

─ Nodule/Tumor stage: Denser proliferation of spindle cells arranged in short, intersecting fascicles, surrounding slit-like vascular spaces containing red blood cells

─ Spindle cells have ovoid to elongated nuclei, minimal atypia, and inconspicuous cytoplasm

─ Extravasated red blood cells and hemosiderin deposition are prominent

─ Eosinophilic hyaline globules (PAS-positive, diastase-resistant) are characteristic, found intracellularly or extracellularly

─ Mitotic activity is generally low

─ Lymphoplasmacytic infiltrate is common

Ancillary studies ─

─ IHC: Spindle cells are positive for endothelial markers (CD31, CD34, ERG, FLI1) and lymphatic markers (D2-40/podoplanin, LYVE-1); crucial diagnostic feature is strong nuclear positivity for HHV-8 (LANA-1) in tumor cells

DDx ─

─ Angiosarcoma (more cytologic atypia, necrosis, higher mitotic rate, endothelial multilayering, HHV-8 negative)

─ Spindle Cell Hemangioma (well-formed cavernous vessels admixed with spindle cells, often phleboliths, HHV-8 negative)

─ Kaposiform Hemangioendothelioma (infancy/childhood, glomeruloid structures, lacks consistent HHV-8 positivity)

─ Fibrosarcoma/Other Spindle Cell Sarcomas (negative for endothelial markers and HHV-8)

─ Bacillary Angiomatosis (infection by Bartonella henselae/quintana in immunocompromised; neutrophilic infiltrate, granular amphophilic material, organisms seen on Warthin-Starry stain)

Media

Angiosarcoma of Bone

A rare, high-grade malignant vascular neoplasm arising within bone, characterized by anastomosing vascular channels lined by atypical endothelial cells

Clinical ─

─ Rare, accounts for <1% of all primary malignant bone tumors

─ Wide age range, but most common in adults (peak 4th to 6th decades); slight male predominance

─ Can arise in any bone, but most frequent in long bones (femur, tibia, humerus), pelvis, and vertebrae; often multicentric at presentation (up to 30-50%), which may represent metastases or true multifocal primary disease

─ Can be primary (de novo) or secondary (arising in chronic lymphedema, irradiated bone, bone infarct, pre-existing benign vascular lesion like hemangioma, or associated with foreign material)

─ Presents with pain, swelling, and palpable mass; pathologic fracture is common; systemic symptoms like fever or weight loss may occur

─ Imaging: Aggressive, destructive lytic lesion with ill-defined, permeative margins and cortical destruction; soft tissue extension is common; no specific matrix mineralization; periosteal reaction is variable; can be expansile or purely infiltrative

─ Prognosis: Poor; highly aggressive tumor with high rates of local recurrence and early distant metastases (lungs, liver, bone, lymph nodes); 5-year survival rates generally <20-30%, worse for multicentric or high-grade lesions

Macro ─ fleshy, hemorrhagic, often necrotic, poorly demarcated infiltrative mass; replaces bone marrow and destroys cortex; may have cystic areas

Micro ─

─ Characterized by irregular, anastomosing vascular channels infiltrating bone and soft tissue

─ Vascular channels are lined by atypical, malignant endothelial cells which can be:

─ Plump and epithelioid with abundant eosinophilic cytoplasm, large vesicular nuclei, and prominent nucleoli

─ More spindled with hyperchromatic nuclei

─ Endothelial cells often show multilayering, tufting, or papillary formations into vascular lumens

─ Cytologic atypia ranges from moderate to marked pleomorphism

─ Mitotic activity is usually high, including atypical mitoses

─ Necrosis and hemorrhage are common

─ Well-formed vasoformative areas may be focal, with other areas showing solid sheets of anaplastic cells (poorly differentiated angiosarcoma)

─ Intracytoplasmic lumens or red blood cells within tumor cells can be seen

Ancillary studies ─

─ IHC: Malignant endothelial cells are positive for general endothelial markers (CD31, CD34, ERG, FLI1); factor VIII-related antigen is less sensitive but more specific; cytokeratin positivity can be seen in epithelioid variants (pitfall for carcinoma)

DDx ─

─ Epithelioid Hemangioendothelioma (less cytologic atypia, characteristic myxohyaline/chondroid stroma, specific translocations)

─ Epithelioid Hemangioma (benign, prominent eosinophilic infiltrate, lacks overt malignant features)

─ Metastatic Carcinoma (especially poorly differentiated or vasoformative types; strong/diffuse keratin positivity, negative for consistent endothelial markers, clinical history)

─ Metastatic Melanoma (can be vasoformative and pleomorphic; S100/melanocytic markers positive)

─ Other High-Grade Sarcomas with epithelioid features (e,g,, epithelioid sarcoma; distinct immunoprofile, often INI1 loss in epithelioid sarcoma)

─ Kaposi Sarcoma (HHV-8 positive, characteristic slit-like spaces and hyaline globules)

Media

Ewing Sarcoma

A highly aggressive, malignant small round blue cell tumor of bone and soft tissue, characterized by specific chromosomal translocations involving the EWSR1 gene (or rarely FUS) and a member of the ETS family of transcription factors

Clinical ─

─ Second most common primary malignant bone tumor in children and adolescents (after osteosarcoma)

─ Peak incidence in 2nd decade (80% <20 years old); rare in children <5 years and adults >30 years

─ Slight male predominance (1,5:1)

─ More common in Caucasians; rare in individuals of African or Asian descent

─ Most commonly arises in diaphysis or metadiaphysis of long bones (femur, tibia, humerus), pelvis (ilium, ischium, pubis), and ribs; can occur in almost any bone, including vertebrae, scapula, clavicle, small bones of hands/feet

─ Presents with localized pain and swelling, often intermittent and present for months; systemic symptoms (fever, weight loss, fatigue, anemia, leukocytosis) are common (20-30%) and can mimic infection (osteomyelitis)

─ Palpable soft tissue mass is often present; pathologic fracture is uncommon

─ Imaging: Destructive, permeative ("moth-eaten") lesion in bone with ill-defined margins, cortical destruction, and often a large associated soft tissue mass; characteristic aggressive periosteal reaction ("onion-skin" lamellation, "hair-on-end" spiculation, Codman triangle); no tumor matrix mineralization (lesion is lytic), but reactive sclerosis can occur

─ Prognosis: Significantly improved with multi-agent chemotherapy combined with surgery and/or radiation; 5-year survival for localized disease ~70-80%; poor prognosis with metastases at diagnosis (25-30% of patients), large tumor size, axial location, older age, poor response to chemotherapy

Macro ─ soft, fleshy, gray-white to tan tumor, often with extensive hemorrhage and necrosis; infiltrates medullary cavity and permeates cortex, frequently forming a large soft tissue mass

Micro ─

─ Diffuse sheets of uniform, small, round to oval cells with scant, poorly defined cytoplasm (often clear or vacuolated due to glycogen)

─ Nuclei are round to oval, with finely granular ("powdery" or "salt-and-pepper") chromatin, inconspicuous nucleoli, and smooth nuclear membranes

─ Mitotic activity is variable but usually present; atypical mitoses are uncommon

─ Cells are closely packed, with minimal intervening stroma; necrosis is common, often extensive

─ Homer-Wright rosettes (indicative of neuroectodermal differentiation) may be present in a subset of cases (formerly PNET variant)

─ Atypical Ewing Sarcoma: larger cells, more nuclear pleomorphism, prominent nucleoli, increased mitotic activity

─ Adamantinoma-like Ewing Sarcoma: rare variant with biphasic pattern (epithelial-like nests in a spindle cell stroma)

Ancillary studies ─

─ IHC: Strong membranous positivity for CD99 (MIC2 gene product) in >95% of cases (not specific, also positive in lymphoblastic lymphoma, other small round cell tumors); nuclear positivity for FLI1 (if EWSR1-FLI1 fusion) or ERG (if EWSR1-ERG fusion); may show focal positivity for keratins, S100, or neuroendocrine markers (especially in PNET variant); negative for LCA, desmin, myogenin

─ Special stains: PAS stain is positive for cytoplasmic glycogen (diastase sensitive) in many cases

─ Molecular ─ Definitive diagnosis relies on detection of characteristic translocations: most common is t(11;22)(q24;q12) leading to EWSR1-FLI1 fusion (>85% of cases); other fusions include EWSR1-ERG (~5-10%), and rare fusions involving EWSR1 with ETV1, ETV4, FEV, or FUS with FEV or ERG

DDx ─

─ Other Small Round Blue Cell Tumors:

─ Lymphoma of Bone (especially lymphoblastic lymphoma; LCA+, TdT+, CD99+, specific lymphoid markers, lacks EWSR1 fusion)

─ Small Cell Osteosarcoma (produces neoplastic osteoid, usually SATB2+, lacks EWSR1 fusion)

─ Mesenchymal Chondrosarcoma (biphasic with cartilage islands, HEY1-NCOA2 fusion)

─ Rhabdomyosarcoma (especially alveolar or embryonal; myogenic differentiation by IHC - desmin, myogenin, MyoD1)

─ Neuroblastoma (younger children, Homer-Wright rosettes, IHC for neuroendocrine markers, MYCN amplification)

─ Desmoplastic Small Round Cell Tumor (intra-abdominal, characteristic polyphenotypic IHC, EWSR1-WT1 fusion)

─ Osteomyelitis (inflammatory infiltrate, no true neoplastic cells, culture may be positive)

Media

Primary Bone Lymphoma

A malignant lymphoid neoplasm arising primarily within bone, without evidence of nodal or extranodal disease elsewhere at diagnosis or within 6 months; most are diffuse large B-cell lymphomas

Clinical ─

─ Rare, accounts for ~3-7% of all primary bone malignancies and <5% of extranodal lymphomas

─ Wide age range, but most common in middle-aged to older adults (peak 5th-7th decades); slight male predominance

─ Can affect any bone, but most frequent in femur, pelvis, humerus, tibia, and vertebrae (long bones > flat bones); usually monostotic, but can be polyostotic (~10-20%)

─ Presents with localized bone pain (often worse at night), swelling, or palpable mass; pathologic fracture occurs in 10-20%; systemic B-symptoms (fever, night sweats, weight loss) are uncommon (<10-15%) in primary bone disease

─ Imaging: Destructive, permeative ("moth-eaten") lytic lesion with ill-defined margins and often a large associated soft tissue mass; cortical destruction is common; periosteal reaction can be present (lamellated or spiculated); sclerosis is uncommon unless treated or in specific subtypes (e,g,, Hodgkin lymphoma); MRI best defines intraosseous and soft tissue extent

─ Prognosis: Varies by lymphoma subtype and stage; overall 5-year survival for primary diffuse large B-cell lymphoma of bone is ~50-60%, better than nodal DLBCL of similar stage; better prognosis for localized disease, younger age, and B-cell phenotype

Macro ─ fleshy, gray-white to tan, infiltrative tumor replacing bone marrow and often extending into soft tissues; areas of necrosis may be present

Micro ─

Histologic subtype dictates morphology; most common is Diffuse Large B-cell Lymphoma (DLBCL):

─ Diffuse infiltrate of large, atypical lymphoid cells with round, irregular, or cleaved nuclei, vesicular chromatin, and prominent nucleoli

─ Cytoplasm is scant to moderate, basophilic or amphophilic

─ Mitotic activity is usually high; apoptosis is common

─ Cells efface normal bone marrow architecture and permeate between bone trabeculae, which may be thickened or resorbed

─ Necrosis and fibrosis can be prominent

Other less common subtypes include:

─ Follicular lymphoma, anaplastic large cell lymphoma, T-cell lymphoma, Burkitt lymphoma, Hodgkin lymphoma (rare as primary bone lesion)

Ancillary studies ─

─ IHC: Essential for classification; DLBCL cells are typically positive for pan-B-cell markers (CD20, CD79a, PAX5) and often BCL6, MUM1; may express BCL2, CD10; Ki-67 proliferation index is usually high; negative for T-cell markers (CD3, CD5), myeloid markers, and cytokeratins

─ Flow cytometry on fresh tissue can confirm clonality and immunophenotype

─ Molecular/Cytogenetics: Cloncal immunoglobulin gene rearrangements confirm B-cell lineage; specific translocations are associated with certain subtypes (e,g,, t(14;18) involving BCL2 in follicular lymphoma, t(8;14) involving MYC in Burkitt lymphoma, ALK rearrangements in anaplastic large cell lymphoma)

DDx ─

─ Ewing Sarcoma (CD99+, FLI1+, characteristic EWSR1 fusion, lacks lymphoid markers)

─ Small Cell Osteosarcoma (produces osteoid, SATB2+, lacks lymphoid markers)

─ Metastatic Small Cell Carcinoma (keratin+, neuroendocrine markers+, lacks lymphoid markers)

─ Chronic Osteomyelitis (mixed inflammatory infiltrate with plasma cells, lymphocytes, neutrophils; no atypical clonal lymphoid population; cultures may be positive)

─ Langerhans Cell Histiocytosis (Langerhans cells with grooved nuclei, eosinophils, CD1a/Langerin+)

─ Myeloma/Plasmacytoma (sheets of plasma cells, CD138+, monoclonal immunoglobulin expression)

Media

Plasma Cell Myeloma (Multiple Myeloma)

A malignant neoplasm of plasma cells characterized by clonal proliferation within the bone marrow, often multifocal, associated with monoclonal immunoglobulin production, and causing end-organ damage

Clinical ─

─ Most common primary malignant tumor of bone (if considered a bone tumor rather than hematologic malignancy)

─ Peak incidence in 6th-7th decades (median age ~65-70 years); rare <40 years

─ Male predominance; higher incidence in African Americans

─ Typically multifocal involvement of axial skeleton (vertebrae, ribs, skull, pelvis) and proximal long bones (femur, humerus) due to predilection for red marrow

─ Presents with bone pain (most common symptom, ~70%), pathologic fractures, fatigue (anemia), recurrent infections (immunodeficiency), hypercalcemia, and renal insufficiency (CRAB criteria: Calcium elevation, Renal insufficiency, Anemia, Bone lesions)

─ Monoclonal gammopathy (M-protein in serum and/or urine) is present in >98% of cases

─ Imaging: Multiple, well-circumscribed, "punched-out" lytic lesions without sclerotic rims are classic ("pepper-pot skull"); diffuse osteopenia is common; expansile lesions and pathologic fractures can occur; MRI is more sensitive for detecting early marrow involvement and extramedullary disease than plain radiographs or CT

─ Prognosis: Variable, depends on stage, cytogenetics, and response to therapy; incurable but treatable; median survival ~5-7 years with modern therapies; high-risk cytogenetics (e,g,, del(17p), t(4;14), t(14;16)) associated with poorer outcome

Macro ─ soft, gelatinous, reddish-gray to tan tumor tissue replacing bone marrow; can cause bone destruction and soft tissue masses

Micro ─

─ Diffuse or nodular infiltrate of neoplastic plasma cells replacing normal bone marrow

─ Plasma cells are typically recognizable by their eccentric nuclei, "clock-face" or "cartwheel" chromatin, distinct Golgi hof (perinuclear pale zone), and basophilic cytoplasm; however, morphology can be variable:

─ Mature/Well-differentiated: Resemble normal plasma cells

─ Immature/Plasmablastic: Larger cells, more open chromatin, prominent nucleoli, higher N/C ratio (associated with more aggressive disease)

─ Anaplastic/Pleomorphic: Marked nuclear atypia, bizarre multinucleated cells

─ Russell bodies (intracytoplasmic eosinophilic inclusions of immunoglobulin) or Dutcher bodies (intranuclear inclusions) may be present

─ Amyloid deposition (AL type) can occur in stroma or vessel walls

─ Mitotic activity is variable

Ancillary studies ─

─ IHC: Plasma cells are positive for CD138, CD79a (subset), MUM1; cytoplasmic monoclonal immunoglobulin (kappa or lambda light chain restriction is diagnostic of clonality); CD20 is usually negative (unlike some B-cell lymphomas); CD56 is often aberrantly expressed

─ Serum/urine protein electrophoresis and immunofixation detect and characterize M-protein

─ Bone marrow aspirate/biopsy for plasma cell percentage and cytogenetics (FISH for prognostic markers)

DDx ─

─ Monoclonal Gammopathy of Undetermined Significance (MGUS) (M-protein <3g/dL, bone marrow plasma cells <10%, no end-organ damage)

─ Smoldering Multiple Myeloma (M-protein >=3g/dL and/or bone marrow plasma cells 10-60%, no end-organ damage)

─ Solitary Plasmacytoma of Bone (single lesion, no systemic myeloma criteria)

─ Reactive Plasmacytosis (e,g,, in chronic osteomyelitis, autoimmune disease; polyclonal plasma cells, no M-protein)

─ Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia (lymphoid cells with plasmacytoid differentiation, IgM M-protein, MYD88 L265P mutation)

─ Other B-cell Lymphomas with plasmacytic differentiation

Media

Solitary Plasmacytoma of Bone

A localized, clonal proliferation of plasma cells within a single bone lesion, without evidence of systemic multiple myeloma at diagnosis

Clinical ─

─ Uncommon, accounts for ~3-5% of all plasma cell neoplasms

─ Median age at diagnosis ~55-60 years (younger than multiple myeloma)

─ Male predominance (2:1)

─ Most commonly involves vertebrae (especially thoracic spine), followed by pelvis, ribs, femur, humerus, sternum, skull

─ Presents with localized bone pain or pathologic fracture; neurologic symptoms can occur with vertebral lesions causing cord/nerve compression

─ By definition, diagnosis requires: single bone lesion, no evidence of other bone lesions on skeletal survey/MRI, normal bone marrow aspirate/biopsy (<10% plasma cells, no clonal atypia), absent or low level M-protein (if present, typically IgG), no CRAB criteria (hypercalcemia, renal insufficiency, anemia due to myeloma)

─ Imaging: Well-circumscribed, expansile lytic lesion, often with a "soap bubble" or trabeculated appearance; may have a sclerotic rim; cortical thinning or destruction and soft tissue extension can occur

─ Prognosis: Higher risk of progression to multiple myeloma (median time ~2-3 years, ~50-70% progress within 10 years); factors associated with progression include persistent M-protein after treatment, older age, larger tumor size, and possibly MRI findings of occult marrow involvement; local control with radiation therapy is excellent

Macro ─ soft, friable, reddish-gray to tan tumor tissue; similar to multiple myeloma lesions but localized

Micro ─

─ Histologically identical to plasma cell myeloma: diffuse or nodular infiltrate of clonal plasma cells

─ Plasma cells can range from mature-appearing to anaplastic

─ Important to assess cellularity and degree of atypia, though these do not reliably predict progression

─ Surrounding bone marrow should be free of significant plasmacytosis

Ancillary studies ─

─ IHC: Plasma cells positive for CD138, MUM1, monoclonal cytoplasmic immunoglobulin (kappa or lambda light chain restriction)

─ Staging workup is crucial to exclude systemic myeloma: skeletal survey, MRI of spine/pelvis, bone marrow aspirate/biopsy, serum/urine protein electrophoresis and immunofixation, serum free light chain assay, complete blood count, serum calcium, creatinine

DDx ─

─ Multiple Myeloma (requires systemic involvement/criteria)

─ Reactive Plasmacytosis (polyclonal, associated with inflammation/infection)

─ Lymphoplasmacytic Lymphoma involving bone (different immunophenotype, often IgM M-protein)

─ Other bone tumors that can be lytic and expansile (e,g,, GCTB, ABC, metastatic carcinoma; histology and IHC differ)

Media

Langerhans Cell Histiocytosis

A clonal neoplastic proliferation of Langerhans cells (specialized dendritic cells) admixed with eosinophils, lymphocytes, plasma cells, and neutrophils; can affect bone, skin, lymph nodes, and other organs

Clinical ─

─ Rare disorder; incidence ~1-2 per million in children, less common in adults

─ Most common in children (peak 1-4 years); can occur at any age

─ Slight male predominance

─ Bone is the most commonly affected site (in ~80% of cases); can be unifocal (single bone lesion, often termed "eosinophilic granuloma") or multifocal (multiple bone lesions, or bone + other organ involvement)

─ Skeletal sites: skull (calvarium, mandible - "floating teeth"), femur, pelvis, ribs, vertebrae ("vertebra plana" - collapsed vertebral body) are common

─ Presents with localized bone pain, swelling, or palpable mass; pathologic fracture can occur; systemic symptoms (fever, weight loss) more common in multifocal/multisystem disease

─ Skin involvement: seborrheic dermatitis-like rash, papules, pustules

─ Other organ involvement: lymphadenopathy, hepatosplenomegaly, pulmonary infiltrates, diabetes insipidus (pituitary involvement)

─ Hand-Schüller-Christian disease (historic triad: skull defects, exophthalmos, diabetes insipidus) and Letterer-Siwe disease (aggressive multisystem disease in infants) are severe forms of LCH

─ Imaging: Well-demarcated, "punched-out" lytic lesions in bone, often with beveled edges or endosteal scalloping; periosteal reaction (lamellated or solid) can be present, especially in long bones; soft tissue mass may be associated; vertebral lesions can cause collapse

─ Prognosis: Highly variable; unifocal bone LCH ("eosinophilic granuloma") has excellent prognosis, often self-healing; multifocal bone disease has good prognosis but higher recurrence; multisystem LCH, especially with organ dysfunction (liver, lung, hematopoietic system), has guarded prognosis, particularly in infants

Macro ─ soft, friable, yellowish-tan to hemorrhagic tissue; may appear granular or necrotic

Micro ─

─ Diagnostic cell is the Langerhans cell: medium to large cells with abundant, pale eosinophilic cytoplasm, indistinct cell borders, and characteristic longitudinally grooved or indented ("coffee bean" or reniform) nuclei with fine chromatin and small nucleoli

─ Langerhans cells are admixed with a variable number of eosinophils (often numerous and a prominent feature), lymphocytes, plasma cells, neutrophils, and non-Langerhans histiocytes (macrophages)

─ Osteoclast-like giant cells may be present

─ Necrosis and fibrosis can occur, especially in older or treated lesions

─ Infiltrative growth pattern, replacing normal marrow

Ancillary studies ─

─ IHC: Langerhans cells are positive for CD1a (strong membranous), Langerin (CD207 - cytoplasmic/Golgi), and S100 protein (nuclear and cytoplasmic)

─ Electron Microscopy (historic): Birbeck granules (tennis-racket shaped intracytoplasmic organelles) are pathognomonic but EM is rarely needed with IHC

─ Molecular ─ Activating somatic mutations in BRAF (most commonly V600E) are found in ~50-60% of LCH cases, particularly in high-risk multisystem disease; mutations in MAP2K1 (MEK1) can occur in BRAF-wildtype cases

DDx ─

─ Osteomyelitis (especially eosinophilic osteomyelitis; prominent inflammatory infiltrate, but lacks atypical Langerhans cells, no CD1a/Langerin positivity)

─ Ewing Sarcoma (small round blue cells, CD99+, FLI1+, lacks eosinophils and typical Langerhans cells)

─ Lymphoma of Bone (atypical lymphoid cells, specific lymphoid markers)

─ Non-Langerhans Cell Histiocytoses (e,g,, Rosai-Dorfman disease, Erdheim-Chester disease; different morphology and immunophenotype - see specific entries)

─ Metastatic Carcinoma (epithelial atypia, keratin+)

Media

Erdheim-Chester Disease

A rare, non-Langerhans cell histiocytosis characterized by infiltration of tissues by lipid-laden (foamy) histiocytes, leading to fibrosis and organ dysfunction; bone involvement is characteristic and often pathognomonic

Clinical ─

─ Very rare; ~500-600 cases reported worldwide

─ Typically affects middle-aged to older adults (peak 5th-7th decades, median age ~50-60 years); slight male predominance

─ Multisystemic disease; bone involvement is present in >95% of cases and is often the presenting feature

─ Most characteristic skeletal involvement: bilateral, symmetrical osteosclerosis of the diaphyses and metaphyses of long bones (especially femur, tibia, fibula), typically sparing the epiphyses

─ Other common sites: retroperitoneum (causing "coated aorta" and hydronephrosis), cardiovascular system (pericardial/myocardial infiltration, valvular disease), lungs (interstitial infiltrates), CNS (diabetes insipidus, cerebellar ataxia, pyramidal signs), orbits (exophthalmos), skin (xanthelasmas, papules)

─ Presents with bone pain (most common symptom), fatigue, weight loss, fever; other symptoms depend on organ involvement (e,g,, dyspnea, ataxia, visual disturbances, renal colic)

─ Imaging (Bone): Bilateral, symmetrical, dense cortical and medullary osteosclerosis of long bone diaphyses/metaphyses is pathognomonic on plain radiographs and bone scan (intense, symmetrical uptake); CT shows cortical thickening and medullary sclerosis; MRI shows low T1 and T2 signal in sclerotic areas

─ Prognosis: Variable; chronic progressive disease; median survival ~3-8 years from diagnosis historically, but improving with targeted therapies; mortality often due to cardiovascular, pulmonary, or neurological complications

Macro ─ affected tissues are often indurated, yellowish-white, and fibrotic

Micro ─

─ Infiltrate of lipid-laden (foamy) histiocytes with small, centrally or eccentrically located nuclei and abundant, pale, vacuolated cytoplasm

─ Histiocytes are admixed with variable numbers of lymphocytes, plasma cells, and sometimes eosinophils; Touton-type giant cells (multinucleated foamy histiocytes) may be present

─ Background stroma is often fibrotic, sometimes densely sclerotic (especially in bone lesions)

─ Emperipolesis (intact inflammatory cells within histiocyte cytoplasm) is typically absent (unlike Rosai-Dorfman disease)

─ No granuloma formation or significant necrosis typically

Ancillary studies ─

─ IHC: Foamy histiocytes are positive for CD68, CD163 (macrophage markers); negative for CD1a and Langerin (distinguishing from LCH) and S100 (usually negative or weakly positive, distinguishing from Rosai-Dorfman disease)

─ Molecular ─ Activating somatic mutations in BRAF (V600E) are found in ~50-70% of ECD cases; mutations in other MAPK pathway genes (NRAS, KRAS, MAP2K1) can occur in BRAF-wildtype cases; these mutations support a neoplastic basis for ECD

DDx ─

─ Langerhans Cell Histiocytosis (LCH) (Langerhans cells with grooved nuclei, eosinophils, CD1a/Langerin+, BRAF V600E can also occur in LCH, but clinical/radiographic picture differs)

─ Rosai-Dorfman Disease (sinus histiocytosis with massive lymphadenopathy; characteristic large histiocytes with emperipolesis, S100+, CD68+, CD1a-)

─ Xanthogranulomatous Inflammation (e,g,, xanthogranulomatous pyelonephritis; often associated with infection/obstruction, mixed inflammatory infiltrate with foamy macrophages, but lacks systemic involvement and specific bone sclerosis of ECD)

─ Storage Diseases (e,g,, Gaucher disease, Niemann-Pick disease; specific enzyme deficiencies, characteristic cell morphology, clinical context)

─ Myelofibrosis with osteosclerosis (hematologic abnormalities, different marrow infiltrate)

─ Paget Disease of Bone (mosaic pattern of lamellar bone, different radiographic pattern)

Media

Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman Disease)

A rare, benign, idiopathic histiocytic proliferative disorder characterized by massive, painless cervical lymphadenopathy and distinctive histologic features including emperipolesis; extranodal involvement, including bone, occurs in a significant subset of cases

Clinical ─

─ Rare disorder; precise incidence unknown

─ Primarily affects children and young adults (most <20 years old); can occur at any age

─ Slight male predominance; more common in individuals of African descent

─ Classic presentation: massive, bilateral, painless cervical lymphadenopathy; fever, malaise, weight loss, polyclonal hypergammaglobulinemia, elevated ESR may be present

─ Extranodal involvement in ~40-45% of cases, can occur with or without lymphadenopathy; common extranodal sites: skin, soft tissue, upper respiratory tract (nasal cavity, paranasal sinuses), orbit, bone, CNS, testes

─ Bone involvement in ~10-20% of cases, often multifocal; most common skeletal sites are long bones, skull, vertebrae, small bones of hands/feet

─ Bone lesions typically present as lytic areas with pain or swelling; pathologic fractures are rare

─ Imaging (Bone): Well-demarcated lytic lesions, often with a sclerotic rim; can be expansile; periosteal reaction is uncommon; may mimic LCH, lymphoma, or metastatic disease

─ Prognosis: Generally good; most cases are self-limiting with spontaneous remission over months to years, especially nodal disease; extranodal disease, particularly CNS or multisystem involvement, can be more persistent or associated with higher morbidity; mortality is rare

Macro ─ enlarged lymph nodes are matted, firm, yellow-white on cut surface; extranodal lesions are often ill-defined, firm, tan-white masses

Micro ─

Hallmark features, especially in involved lymph nodes:

─ Dilated sinuses filled with numerous large, distinctive histiocytes (Rosai-Dorfman cells)

─ Rosai-Dorfman cells: large histiocytes with abundant, pale eosinophilic to clear cytoplasm, round to oval vesicular nuclei, and small nucleoli

─ Emperipolesis: presence of intact, viable lymphocytes, plasma cells, and occasionally neutrophils or red blood cells within the cytoplasm of Rosai-Dorfman cells (pathognomonic feature)

─ Background infiltrate of mature plasma cells and lymphocytes is typically prominent

─ Fibrosis may be present in older lesions

─ In bone lesions: similar infiltrate of Rosai-Dorfman cells with emperipolesis, plasma cells, and lymphocytes replacing normal marrow; lytic bone destruction

─ No significant cytologic atypia, pleomorphism, or high mitotic activity in Rosai-Dorfman cells

Ancillary studies ─

─ IHC: Rosai-Dorfman histiocytes are strongly positive for S100 protein (nuclear and cytoplasmic) and CD68 (macrophage marker); also positive for CD163; negative for CD1a and Langerin (distinguishing from LCH)

─ Emperipolesis is best appreciated on H&E stained sections

DDx ─

─ Langerhans Cell Histiocytosis (LCH) (Langerhans cells with grooved nuclei, eosinophils, CD1a/Langerin+, S100+ but different morphology and emperipolesis usually absent)

─ Erdheim-Chester Disease (foamy histiocytes, fibrosis, characteristic bone sclerosis, S100 usually negative or weak, CD1a-)

─ Hodgkin Lymphoma (Reed-Sternberg cells, specific immunophenotype with CD30/CD15)

─ Reactive Lymphadenopathy (e,g,, infectious mononucleosis; different cytologic features, lack of prominent emperipolesis by large S100+ histiocytes)

─ Malignant Histiocytic Sarcoma (rare; overtly malignant cytologic features)

─ Hemophagocytic Lymphohistiocytosis (different clinical context, hemophagocytosis not emperipolesis, often different immunophenotype)

Media

Adamantinoma

A rare, low-grade malignant biphasic tumor of bone, characterized by nests and strands of epithelial-like cells within a fibrous stroma, almost exclusively occurring in the tibia

Clinical ─

─ Very rare, accounts for <0,5% of all primary malignant bone tumors

─ Wide age range, but most common in adolescents and young adults (peak 2nd to 5th decades)

─ Slight male predominance

─ Strong predilection for the diaphysis (often anterior cortex) of the tibia (>85-90% of cases); fibula is the second most common site (often synchronously with tibia); exceptionally rare in other bones (e,g,, humerus, ulna, femur, ribs, foot bones)

─ Presents with insidious onset of localized pain and swelling, often present for years before diagnosis; pathologic fracture can occur

─ Imaging: Eccentric, well-circumscribed, often multiloculated ("soap bubble") lytic lesion in the anterior tibial diaphysis, causing cortical expansion and thinning; may have a sclerotic rim; internal septations are common; soft tissue extension can occur in more aggressive lesions; periosteal reaction is variable

─ Prognosis: Indolent but persistent tumor with a high rate of local recurrence (20-30%) after inadequate excision; distant metastases (lungs, lymph nodes, other bones) occur in ~15-30% of cases, often many years after initial diagnosis; overall survival is better than for high-grade sarcomas if completely resected

Macro ─ firm, gray-white to yellowish, often lobulated or cystic tumor; infiltrates cortex and may extend into medullary cavity or soft tissue

Micro ─

Biphasic pattern with epithelial and fibrous stromal components:

1, Epithelial component:

─ Nests, strands, tubules, or islands of epithelial-like cells with varying morphologies:

─ Basaloid: peripheral palisading of small cells with dark nuclei and scant cytoplasm

─ Squamoid: larger cells with more eosinophilic cytoplasm, intercellular bridges, and sometimes keratin pearl formation

─ Spindle cell: elongated cells, can mimic sarcoma

─ Tubular/glandular: cuboidal to columnar cells forming gland-like structures

─ Nuclei are generally bland to mildly atypical; mitoses are usually infrequent

2, Fibrous stromal component:

─ Bland fibroblastic spindle cells in a variably collagenous (often desmoplastic) or myxoid stroma

─ Stroma may resemble fibrous dysplasia or desmoplastic fibroma

─ Osteofibrous dysplasia (OFD)-like areas: characterized by woven bone trabeculae rimmed by osteoblasts within a fibrous stroma, are commonly found at the periphery of adamantinoma or as a predominant component in "differentiated" or "OFD-like" adamantinoma (relationship is complex and debated)

─ Vascular invasion can be seen

Ancillary studies ─

─ IHC: Epithelial cells are consistently positive for cytokeratins (especially broad-spectrum, CK5/6, CK14, CK19) and EMA; often positive for p63; fibrous stroma is vimentin positive; S100 and endothelial markers are negative in epithelial cells

─ Molecular ─ Complex karyotypes with recurrent gains of chromosomes 7, 8, 12, 19, 21 and losses of other chromosomes have been reported; no single pathognomonic translocation identified

DDx ─

─ Osteofibrous Dysplasia (OFD) (key differential; OFD is benign, typically in younger children, anterior tibia, zonal architecture, prominent osteoblastic rimming, keratin-positive cells are scattered single cells not cohesive nests/strands as in adamantinoma)

─ Fibrous Dysplasia (lacks epithelial component, characteristic woven bone in fibrous stroma, GNAS mutation)

─ Metastatic Carcinoma (especially squamous cell carcinoma or adenocarcinoma; older patients, clinical history, IHC profile will differ - e,g,, specific organ markers, often more atypia)

─ Synovial Sarcoma (biphasic type; epithelial component forms glands/clefts, spindle cells are more uniform, characteristic t(X;18) SS18-SSX fusion)

─ Vascular Tumors (e,g,, epithelioid hemangioendothelioma can have epithelial-like cells and occur in tibia; positive for endothelial markers)

─ Ameloblastoma (if in jaw; histologically similar but different clinical/radiographic context)

Media

Mastocytosis of Bone

A rare disorder characterized by clonal, neoplastic proliferation of mast cells in one or more organs, including bone marrow; bone involvement can range from asymptomatic infiltrates to destructive lesions

Clinical ─

─ Systemic mastocytosis (SM) is rare; bone involvement is common in SM (reported in up to 70-100% of adult SM patients if systematically screened)

─ Can occur at any age, but adult-onset SM is more common than pediatric

─ No clear sex predilection for SM overall

─ Bone marrow is a primary site of involvement in SM; skeletal lesions can be focal or diffuse

─ Presents with symptoms related to mast cell mediator release (e,g,, flushing, pruritus, abdominal pain, diarrhea, syncope, anaphylaxis), cytopenias (due to marrow infiltration), or bone pain/fractures

─ Skin involvement (urticaria pigmentosa) is common, especially in pediatric mastocytosis and indolent SM in adults

─ Imaging: Variable; can show osteopenia, focal lytic lesions, diffuse or focal osteosclerosis, or mixed lytic/sclerotic pattern; "salt-and-pepper" appearance of vertebrae described; bone scan often shows increased uptake

─ Prognosis: Highly variable, depends on subtype of mastocytosis; Indolent SM has good prognosis with normal life expectancy; Aggressive SM and Mast Cell Leukemia have poor prognosis

Macro ─ bone marrow may appear normal, fibrotic, or replaced by yellowish-tan infiltrates

Micro ─

─ Diagnostic feature: aggregates or diffuse infiltrates of atypical mast cells in bone marrow or other tissues

─ Mast cells are typically round to spindle-shaped, with centrally or eccentrically located round nuclei and abundant granular cytoplasm (granules are metachromatic with Giemsa or toluidine blue)

─ Atypical features in SM: spindle shape, hypogranularity, abnormal nuclear contours, clustering (>15 mast cells)

─ Bone marrow infiltrates are often paratrabecular or perivascular; can be associated with fibrosis, eosinophilia, and lymphoid aggregates

─ Osteosclerosis or osteolysis can be seen in surrounding bone trabeculae

Ancillary studies ─

─ IHC: Mast cells are positive for tryptase (most specific), chymase, CD117 (c-kit), and often CD25 (aberrantly expressed in neoplastic mast cells, useful marker); CD2 may also be aberrantly expressed

─ Special Stains: Giemsa or toluidine blue demonstrates metachromatic cytoplasmic granules

─ Serum tryptase levels are often elevated and correlate with mast cell burden

─ Molecular ─ Activating point mutations in the KIT gene (encoding c-kit receptor tyrosine kinase) are found in >80-90% of adult SM cases, most commonly D816V in exon 17; this mutation confers resistance to imatinib

DDx ─

─ Reactive Mast Cell Hyperplasia (e,g,, in response to inflammation, allergy, or neoplasm; mast cells are typically not atypical, not clustered, CD25 negative, no KIT D816V mutation)

─ Myeloid Neoplasms (e,g,, myelodysplastic syndrome, myeloproliferative neoplasm, acute myeloid leukemia; different morphology and immunophenotype, specific cytogenetic/molecular findings)

─ Lymphoma/Leukemia involving marrow (specific lymphoid/myeloid markers)

─ Langerhans Cell Histiocytosis (if eosinophils are prominent; Langerhans cells have characteristic morphology and CD1a/Langerin positivity)

─ Carcinoid Tumor metastatic to bone (neuroendocrine markers, different morphology, lacks mast cell granules)

Media

Osteomyelitis

Inflammation of bone and bone marrow, almost always due to infection by pyogenic bacteria, mycobacteria, fungi, or other microorganisms

Clinical ─

─ Can occur at any age; different patterns and causative organisms depending on age and route of infection

─ Acute hematogenous osteomyelitis: most common in children (metaphysis of long bones) and elderly (vertebrae)

─ Osteomyelitis due to contiguous spread: from adjacent soft tissue infection, penetrating trauma, or surgery (e,g,, open fractures, prosthetic joint infections)

─ Osteomyelitis due to vascular insufficiency: typically in diabetic patients (feet)

─ Presents with localized pain, tenderness, swelling, erythema, warmth; fever, malaise, leukocytosis may be present (especially in acute hematogenous form); chronic osteomyelitis may present with draining sinus tracts, bone deformity, or recurrent flares

─ Imaging: Early (first 1-2 weeks): soft tissue swelling, subtle osteopenia; Later: lytic bone destruction, periosteal reaction (lamellated or spiculated), cortical thickening, sequestrum (necrotic bone fragment) formation, involucrum (new bone shell around sequestrum); Brodie abscess (intracortical abscess with sclerotic rim) can occur in subacute/chronic forms; MRI is most sensitive for early detection of marrow edema, abscess formation, and soft tissue extent

─ Prognosis: Generally good with appropriate antimicrobial therapy and surgical debridement if needed; chronic osteomyelitis can be difficult to eradicate and lead to long-term morbidity (nonunion, deformity, sinus tracts, rarely squamous cell carcinoma in sinus tract or amyloidosis)

Macro ─ pus, necrotic bone (sequestrum), granulation tissue, fibrotic and sclerotic bone in chronic cases; involucrum formation

Micro ─

Acute Osteomyelitis:

─ Necrotic bone trabeculae with empty lacunae

─ Dense infiltrate of neutrophils (pus) in marrow spaces and Haversian canals

─ Edema, hemorrhage, and vascular congestion

─ Bacteria may be visible (Gram stain, specific stains for fungi/mycobacteria if suspected)

Chronic Osteomyelitis:

─ Necrotic bone (sequestrum) surrounded by granulation tissue and viable bone (involucrum)

─ Predominantly chronic inflammatory infiltrate: lymphocytes, plasma cells, histiocytes; neutrophils may still be present, especially during acute flares

─ Fibrosis of marrow spaces; reactive new bone formation (sclerosis)

─ Draining sinus tracts lined by squamous epithelium or granulation tissue

─ Specific granulomatous inflammation in tuberculous or fungal osteomyelitis (caseating or non-caseating granulomas, specific organisms on stains/culture)

Ancillary studies ─

─ Microbiology: Crucial for identification of causative organism and antibiotic susceptibility testing (culture of bone biopsy, pus, or blood)

─ Special Stains: Gram stain for bacteria; Ziehl-Neelsen or Fite stain for mycobacteria; GMS or PAS stain for fungi

─ PCR for specific organisms may be useful in culture-negative cases

DDx ─

─ Ewing Sarcoma/Lymphoma (can mimic osteomyelitis clinically and radiologically with permeative lesion and periostitis; biopsy shows malignant small round cells, not inflammatory infiltrate)

─ Langerhans Cell Histiocytosis (especially eosinophilic granuloma; lytic lesion, can have prominent eosinophils, but Langerhans cells are diagnostic)

─ Osteoid Osteoma/Osteoblastoma (sclerotic lesions with nidus, different histology)

─ Bone Infarct (necrotic bone, but sterile, no inflammatory infiltrate unless secondarily infected)

─ Aggressive Bone Tumors causing lytic destruction (e,g,, osteosarcoma, GCTB; neoplastic cells, not primary inflammation)

─ SAPHO Syndrome (Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis) (chronic inflammatory bone lesions, often sterile, associated skin findings)

Media

Unicameral Bone Cyst (Simple Bone Cyst)

A common, benign, fluid-filled, unilocular cystic lesion of bone, typically occurring in the metaphysis of long bones in children and adolescents

Clinical ─

─ Common, accounts for ~3% of all biopsied primary bone lesions

─ Most common in first two decades of life (80% <20 years old, peak 5-15 years); rare in adults

─ Male predominance (2-3:1)

─ Strong predilection for metaphysis of long bones, especially proximal humerus (>50%) and proximal femur (~25%); less commonly calcaneus, tibia, fibula, pelvis, ribs

─ Usually asymptomatic, often discovered incidentally or due to pathologic fracture (presenting feature in ~60-70%)

─ Lesions adjacent to physis are "active" (tend to enlarge as bone grows); lesions that have migrated away from physis into diaphysis are "latent" (tend to stabilize or involute)

─ Imaging: Well-circumscribed, central, geographic lytic lesion in metaphysis, often expansile with cortical thinning but intact cortex; typically unilocular (single cavity); thin sclerotic rim may be present; no matrix mineralization or significant periosteal reaction unless fractured; "fallen fragment" sign (displaced cortical fragment within cyst lumen after fracture) is pathognomonic; MRI shows fluid signal (low T1, high T2)

─ Prognosis: Excellent; most lesions heal after pathologic fracture or resolve spontaneously after skeletal maturity; treatment (curettage, bone grafting, steroid/marrow injection) for symptomatic or large lesions at risk of fracture; recurrence rates higher in younger patients with active cysts (up to 25-50%)

Macro ─ cyst cavity contains clear, yellowish (serous) or serosanguinous fluid; lined by a thin, gray-white fibrous membrane; bony ridges or septa may be present on inner surface

Micro ─

─ Cyst wall is lined by a thin layer of loose, fibrovascular connective tissue; no true epithelial or endothelial lining

─ Lining may contain scattered bland fibroblasts, myofibroblasts, and occasional osteoclast-like giant cells

─ Fibrinoid material, often calcified (resembling cementum-like deposits), may be present on or within the cyst wall (can be mistaken for osteoid if prominent)

─ Hemosiderin deposition and foamy macrophages can be seen, especially after fracture or hemorrhage

─ Reactive woven bone may be present in the cyst wall or adjacent bone

─ Fluid content is acellular or paucicellular

─ No significant cytologic atypia or mitotic activity

Ancillary studies ─

─ Not typically required; diagnosis is usually made on characteristic clinical and radiographic features

DDx ─

─ Aneurysmal Bone Cyst (ABC) (multiloculated, blood-filled cystic spaces with characteristic septa containing fibroblasts/giant cells/woven bone, fluid-fluid levels on MRI, USP6 rearrangement)

─ Fibrous Dysplasia (especially cystic variant; woven bone trabeculae in fibrous stroma, "ground glass" appearance)

─ Chondromyxoid Fibroma (lobulated myxochondroid tissue, different cell morphology)

─ Intraosseous Ganglion Cyst (juxta-articular epiphyseal/subchondral location, more viscous mucoid content)

─ Giant Cell Tumor of Bone (older patients, epiphyseal, solid tumor with characteristic mononuclear and giant cells)

─ Langerhans Cell Histiocytosis (lytic lesion, but infiltrate of Langerhans cells and eosinophils)

Media

Aneurysmal Bone Cyst

A benign, expansile, locally destructive cystic lesion of bone composed of blood-filled spaces separated by fibrous septa containing fibroblasts, osteoclast-like giant cells, and reactive woven bone; can be primary or secondary to another bone lesion

Clinical ─

─ Uncommon, accounts for ~1-2% of all primary bone tumors

─ Most common in first two decades of life (80% <20 years old, peak 10-20 years); no significant sex predilection

─ Can affect any bone, but most frequent in metaphysis of long bones (femur, tibia, humerus), vertebrae (posterior elements), and pelvis

─ Presents with localized pain, swelling, and often rapid growth; pathologic fracture occurs in ~10% of cases; neurologic symptoms can occur with vertebral lesions

─ Primary ABC (~70%): arises de novo; Secondary ABC (~30%): arises in association with another pre-existing bone lesion (e,g,, giant cell tumor, chondroblastoma, fibrous dysplasia, osteoblastoma, osteosarcoma)

─ Imaging: Eccentric, expansile, geographic lytic lesion, often with a markedly thinned but intact cortical shell ("eggshell" rim); may cause significant bone "blowout"; characteristic fluid-fluid levels on CT and MRI (due to layering of blood products of different ages) are highly suggestive but not pathognomonic; internal septations are common; aggressive periosteal reaction can occur

─ Prognosis: Benign, but can be locally destructive; local recurrence rates after curettage are significant (20-50%), especially for large or incompletely excised lesions; treatment options include curettage with bone grafting/cement, sclerotherapy, embolization (for difficult locations), or rarely en bloc resection; spontaneous regression is rare

Macro ─ "blood-filled sponge" appearance; multiloculated cystic mass containing dark, unclotted blood or serosanguinous fluid; separated by thin, tan-white fibrous septa; bone shell is often very thin

Micro ─

─ Multiloculated cystic spaces filled with blood, lacking a true endothelial lining

─ Septa separating the cystic spaces are composed of:

─ Bland spindle cells (fibroblasts and myofibroblasts)

─ Numerous osteoclast-like multinucleated giant cells, often clustered along septal surfaces or around hemorrhage

─ Reactive woven bone or osteoid, often lining the septa or forming irregular trabeculae within them; osteoblastic rimming is common

─ Hemosiderin pigment and areas of hemorrhage are prominent

─ Capillaries and small blood vessels are present within septa

─ Mitotic activity can be present in spindle cells but atypical mitoses are absent

─ No significant cytologic atypia or pleomorphism in the mononuclear cells (unless it is secondary to a malignant tumor)

─ Solid variant of ABC: rare, predominantly solid lesion with histology similar to the septa of conventional ABC (can be difficult to distinguish from giant cell reparative granuloma or solid areas of GCTB)

─ "Blue bone" (chondroid-like matrix) may be present within septa

Ancillary studies ─

─ Molecular ─ Primary ABCs are characterized by recurrent rearrangements of the USP6 gene (on chromosome 17p13), most commonly with the CDH11 gene (osteoblast cadherin, on 16q22), leading to CDH11-USP6 fusion; this can be detected by FISH or RT-PCR and helps distinguish primary ABC from secondary ABC (which lacks USP6 rearrangement) and other histologic mimics

DDx ─

─ Telangiectatic Osteosarcoma (key differential; malignant, septa contain highly anaplastic cells producing neoplastic osteoid, high mitotic rate, lacks consistent USP6 rearrangement)

─ Giant Cell Tumor of Bone (GCTB) (solid sheets of neoplastic mononuclear cells and evenly distributed giant cells; secondary ABC changes can be extensive in GCTB, requiring careful search for diagnostic GCTB areas; GCTB has H3F3A mutations)

─ Simple Bone Cyst (unicameral, serous fluid, thin fibrous lining, lacks blood-filled spaces and characteristic septa of ABC)

─ Chondroblastoma (epiphyseal, sheets of chondroblasts, chicken-wire calcification, can have secondary ABC)

─ Fibrous Dysplasia with secondary ABC changes (look for characteristic woven bone in fibrous stroma)

─ Other benign or malignant tumors with secondary ABC changes (e,g,, osteoblastoma, chondromyxoid fibroma, osteosarcoma; primary lesion's histology should be identifiable)

Media

Intraosseous Ganglion Cyst

A benign, cystic lesion occurring within bone, typically in a subchondral or epiphyseal location adjacent to a joint, filled with viscous mucoid material and lined by fibrous tissue; considered the intraosseous counterpart of a soft tissue ganglion cyst

Clinical ─

─ Uncommon; true incidence unknown as many are asymptomatic and incidental

─ Most common in middle-aged to older adults (peak 4th to 6th decades); can occur at any age

─ No clear sex predilection, or slight female predominance

─ Strong predilection for subchondral bone of epiphyses or apophyses, adjacent to a joint; most common sites are medial malleolus of tibia, femoral neck/head, proximal tibia (around knee), carpal bones (especially lunate, scaphoid), acetabulum

─ Often asymptomatic and discovered incidentally; may present with chronic, dull ache or pain related to the adjacent joint, often exacerbated by activity; rarely causes swelling or limited range of motion

─ Pathologic fracture is very rare

─ Imaging: Well-circumscribed, geographic lytic lesion, often round or oval, with a thin, prominent sclerotic rim; typically unilocular, but may appear multilocular due to bony ridges; located eccentrically in subchondral bone, immediately adjacent to a joint (but usually not communicating directly with joint space, unlike osteoarthritic subchondral cysts); no matrix mineralization or aggressive features

─ Prognosis: Excellent; benign lesion; treatment (curettage and bone grafting) is usually curative if symptomatic; recurrence is uncommon

Macro ─ cyst cavity contains clear, yellowish, viscous, gelatinous (mucoid) material, similar to soft tissue ganglion; lined by a thin, white, fibrous pseudocapsule; surrounding bone is often sclerotic

Micro ─

─ Cyst wall is composed of dense, hypocellular, collagenous fibrous tissue; no true epithelial or synovial lining

─ Inner surface of the cyst may be lined by flattened fibroblasts or myofibroblasts, or be acellular

─ Cyst lumen contains acellular, pale eosinophilic or basophilic, mucoid/myxoid material (precipitated mucin)

─ Scattered histiocytes or chronic inflammatory cells may be present in the cyst wall

─ Surrounding bone trabeculae often show reactive sclerosis

─ No significant cytologic atypia, mitotic activity, or features of other specific bone lesions

Ancillary studies ─

─ Not typically required; diagnosis is based on characteristic clinicopathologic and radiographic features

DDx ─

─ Subchondral Cyst of Osteoarthritis (degenerative joint cyst; associated with other signs of osteoarthritis like joint space narrowing, osteophytes; often communicates with joint space; may have more inflammatory lining)

─ Simple Bone Cyst (typically metaphyseal in children, serous fluid, different lining histology with fibrin-like deposits)

─ Aneurysmal Bone Cyst (blood-filled, different septal histology, often more expansile)

─ Epidermal Inclusion Cyst (phalanges, skull; lined by keratinizing squamous epithelium)

─ Non-neoplastic bone marrow edema/subchondral stress reaction (MRI findings, lacks true cyst on histology)

─ Brodie Abscess (if appears cystic; signs of infection, inflammatory infiltrate)

─ Benign fibrous histiocytoma/Nonossifying fibroma (if near joint; different solid histology)

Media

Epidermal Inclusion Cyst of Bone

A rare, benign cystic lesion occurring within bone, lined by keratinizing stratified squamous epithelium and filled with keratin debris; thought to arise from traumatic implantation or sequestration of epidermal elements

Clinical ─

─ Rare as an intraosseous lesion

─ Wide age range, but most common in adults (peak 3rd to 5th decades)

─ Male predominance, likely related to higher incidence of penetrating trauma

─ Strong predilection for distal phalanges of fingers and toes (especially terminal tuft), likely due to susceptibility to trauma; also occurs in skull (calvarium, especially frontal and parietal bones), and rarely other sites

─ Often presents as a slow-growing, firm, painless or mildly painful swelling; may cause nail deformity if in distal phalanx; can become secondarily infected

─ History of prior penetrating trauma to the area is common but not always elicited

─ Imaging: Well-circumscribed, geographic lytic lesion, often with a thin sclerotic rim; may be expansile and cause cortical thinning or erosion; no matrix mineralization or aggressive periosteal reaction; in phalanges, typically located in terminal tuft

─ Prognosis: Excellent; benign lesion; treated by curettage or local excision, which is usually curative; recurrence is rare if completely excised

Macro ─ cyst cavity contains cheesy, yellow-white, keratinous material; lined by a gray-white, often friable membrane

Micro ─

─ Cyst wall is lined by stratified squamous epithelium, similar to epidermis, with a distinct granular cell layer and keratin production (orthokeratosis or parakeratosis)

─ Cyst lumen is filled with abundant, laminated keratin flakes and desquamated squamous cells

─ Epidermal appendages (hair follicles, sebaceous glands, sweat glands) are absent (distinguishes from dermoid cyst)

─ Surrounding bone may show reactive changes, including fibrosis and chronic inflammation, especially if cyst has ruptured

─ Foreign body giant cell reaction to keratin debris is common if cyst wall is breached

─ No cytologic atypia or malignancy

Ancillary studies ─

─ Not typically required; diagnosis is based on characteristic histologic features and location

DDx ─

─ Dermoid Cyst of Bone (rare; similar squamous lining but also contains skin appendages like hair follicles/sebaceous glands in the wall)

─ Cholesteatoma (of temporal bone/middle ear; destructive lesion lined by keratinizing squamous epithelium, but specific clinical/anatomical context)

─ Squamous Cell Carcinoma metastatic to bone or primary intraosseous SCC (rare; malignant cytologic features, infiltrative growth, atypia, mitoses)

─ Ameloblastoma/Adamantinoma (if in jaw or tibia respectively; different epithelial morphology, odontogenic or biphasic features)

─ Intraosseous Ganglion Cyst (phalanges; mucoid content, fibrous lining, no squamous epithelium)

─ Glomus Tumor (phalanges; painful, different histology with nests of glomus cells)

─ Enchondroma (phalanges; cartilaginous matrix, different imaging)

Media

Schwannoma of Bone (Neurilemmoma)

A benign nerve sheath tumor composed of Schwann cells, arising primarily within bone or secondarily invading bone from an adjacent soft tissue or nerve root; primary intraosseous schwannomas are rare

Clinical ─

─ Rare as a primary intraosseous tumor, accounting for <1% of all primary bone tumors

─ Wide age range (most common in adults 20-50 years); no significant sex predilection

─ Primary intraosseous lesions most commonly affect mandible and sacrum; can also occur in long bones (femur, humerus, tibia), vertebrae, ribs, pelvis, and small bones of hands/feet

─ Schwannomas arising from spinal nerve roots can erode adjacent vertebrae ("dumbbell" tumor)

─ Often asymptomatic and discovered incidentally; may present with localized pain, swelling, or paresthesias if nerve involvement; neurologic symptoms common with spinal lesions

─ Rarely associated with Neurofibromatosis type 2 (NF2), in which case multiple schwannomas (especially bilateral vestibular schwannomas) are characteristic

─ Imaging: Well-circumscribed, geographic lytic lesion, often expansile with cortical thinning and a sclerotic rim; may appear multiloculated; "target sign" on MRI (peripheral high T2 signal, central low T2 signal) can be suggestive but is not specific; cystic change and hemorrhage common in larger lesions; enhancement is often heterogeneous

─ Prognosis: Excellent; benign lesion; malignant transformation is exceedingly rare (except possibly in NF2); local recurrence is uncommon after complete excision; curettage may suffice for small, well-defined lesions

Macro ─ well-circumscribed, encapsulated (if soft tissue origin, capsule may be less distinct in primary bone lesions), firm, gray-white to yellowish, often glistening or myxoid tumor; cystic degeneration and hemorrhage are common in larger lesions

Micro ─

Characteristic biphasic pattern of Antoni A and Antoni B areas:

─ Antoni A areas: Densely cellular, composed of spindle cells with elongated, wavy or buckled nuclei and indistinct eosinophilic cytoplasm, arranged in short fascicles or whorls; nuclear palisading around acellular eosinophilic zones (Verocay bodies) is a hallmark feature but not always present

─ Antoni B areas: Less cellular, loose, myxoid stroma with more randomly arranged spindle cells, often with smaller, darker nuclei; microcystic change is common

─ Blood vessels are often prominent, thick-walled, and hyalinized

─ Degenerative changes are common: cystic degeneration, hemorrhage, hemosiderin deposition, stromal hyalinization, calcification, and ancient change (nuclear atypia/pleomorphism without increased mitoses in long-standing lesions)

─ Foamy macrophages may be present

─ Mitotic activity is typically very low

Ancillary studies ─

─ IHC: Schwann cells are diffusely and strongly positive for S100 protein (nuclear and cytoplasmic); often positive for SOX10; variably positive for GFAP; negative for keratins, desmin, smooth muscle actin

─ Molecular ─ Inactivation of the NF2 tumor suppressor gene (on chromosome 22q) by mutation or loss of heterozygosity is characteristic of most sporadic and NF2-associated schwannomas

DDx ─

─ Neurofibroma (if primary bone lesion or involving bone; more infiltrative, wavy spindle cells in a loose collagenous/myxoid stroma, admixed axons, S100 often stains only a subset of cells, associated with NF1)

─ Malignant Peripheral Nerve Sheath Tumor (MPNST) (more cellularity, atypia, higher mitotic rate, necrosis, infiltrative growth; S100 often lost or focal/weak; distinction from schwannoma with ancient change can be difficult)

─ Leiomyoma/Leiomyosarcoma (blunt-ended nuclei, eosinophilic cytoplasm, desmin/actin positive, S100 negative)

─ Fibrosarcoma/Other Spindle Cell Sarcomas (S100 negative, different morphology)

─ Meningioma (if in skull/spine; EMA positive, characteristic whorls and psammoma bodies)

─ Desmoplastic Fibroma (more collagenous, lacks Antoni A/B areas, S100 negative)

Media

Lipoma of Bone (Intraosseous and Parosteal)

A benign tumor composed of mature adipose tissue, occurring within the medullary cavity (intraosseous lipoma) or on the surface of bone (parosteal lipoma); primary intraosseous lipomas are rare

Clinical ─

─ Intraosseous lipoma: Rare, <0,1% of primary bone tumors; wide age range (most common in adults 30-60 years); no clear sex predilection

─ Parosteal lipoma: Also rare; typically affects adults

─ Intraosseous sites: Most common in calcaneus (neutral triangle), proximal femur (intertrochanteric region), fibula, tibia, ribs; can occur in almost any bone

─ Parosteal sites: Most common on surface of femur, tibia, humerus, radius

─ Often asymptomatic and discovered incidentally; may cause mild, dull pain or swelling, especially larger lesions or those causing nerve compression (parosteal); pathologic fracture is very rare for intraosseous lipoma

─ Imaging (Intraosseous): Well-circumscribed, geographic lytic lesion, often with a thin sclerotic rim; central area shows fat density on CT and fat signal on MRI (high T1, intermediate to high T2, suppresses with fat saturation); characteristic central calcification or ossification ("cockade" sign or target-like nidus) can be present, especially in calcaneus; cystic degeneration and cortical expansion may occur

─ Imaging (Parosteal): Well-circumscribed, predominantly fatty mass on bone surface, may cause extrinsic erosion or scalloping of cortex, or reactive periosteal new bone formation; underlying cortex is intact

─ Prognosis: Excellent; benign lesion; malignant transformation (to liposarcoma) is exceedingly rare, if ever, for true primary bone lipomas; treatment (curettage or excision) usually reserved for symptomatic lesions or if diagnosis is uncertain

Macro ─ lobulated, soft, yellow, fatty tissue, similar to subcutaneous lipoma; intraosseous lesions may be contained by a thin fibrous capsule or sclerotic bone; parosteal lesions are attached to periosteum

Micro ─

─ Composed of lobules of mature adipocytes (fat cells) with small, eccentric, bland nuclei and abundant clear cytoplasm

─ Adipocytes are uniform in size and shape, though some variation can occur

─ Thin fibrous septa containing delicate capillaries separate fat lobules

─ Intraosseous lipoma:

─ Often shows areas of fat necrosis, calcification, ossification (metaplastic bone), and cystic degeneration (lipomembranous change, oil cysts) - corresponding to "involutional" stages

─ Entrapped or reactive bone trabeculae may be present within the fatty tissue

─ Scant hematopoietic marrow elements may be seen at the periphery

─ Parosteal lipoma:

─ Mature adipose tissue adjacent to periosteum; may contain reactive bone or cartilage

─ No lipoblasts, significant cytologic atypia, or increased mitotic activity (distinguishes from liposarcoma)

Ancillary studies ─

─ Not typically required if imaging is characteristic of fat; diagnosis is largely clinicoradiologic with histologic confirmation if biopsied

─ Molecular ─ Chromosomal rearrangements involving 12q13-15 (region of MDM2 and HMGA2 genes) are common in soft tissue lipomas; similar findings may occur in bone lipomas, but data is limited; helps distinguish from normal marrow fat

DDx ─

─ Bone Infarct (necrotic marrow and bone, serpiginous calcified rim, lacks proliferative mature adipocytes as the primary component)

─ Intraosseous Hemangioma (if fatty stroma is prominent; vascular channels are key feature)

─ Liposclerosing Myxoid Fibrous Tumor (LSMFT) (intertrochanteric femur, complex mixed histology, GNAS mutations common)

─ Well-Differentiated Liposarcoma/Atypical Lipomatous Tumor (ALT) (if primary in bone, extremely rare; ALT typically shows atypical spindle cells, fibrous bands, and scattered lipoblasts; MDM2/CDK4 amplification is characteristic; important differential for parosteal fatty lesions)

─ Normal marrow fat (especially in older individuals or fatty marrow conversion; lipoma is a discrete mass-forming lesion)

─ Fibrous Dysplasia with fatty change (characteristic woven bone in fibrous stroma)

Media

Leiomyosarcoma of Bone (Primary)

A rare, malignant mesenchymal tumor arising primarily within bone, characterized by spindle cells showing smooth muscle differentiation

Clinical ─

─ Extremely rare, accounts for <0,7% of all primary malignant bone tumors

─ Typically affects adults (peak 4th to 6th decades); no clear sex predilection, or slight male predominance in some series

─ Most common in metaphysis or diaphysis of long bones, especially around the knee (distal femur, proximal tibia); can also occur in pelvis, jawbones, and vertebrae

─ Presents with localized pain and swelling, often of several months' duration; pathologic fracture can occur

─ Diagnosis of primary bone leiomyosarcoma requires exclusion of metastasis from a soft tissue or visceral primary (especially uterus, retroperitoneum, gastrointestinal tract)

─ Imaging: Aggressive, destructive lytic lesion with ill-defined, permeative margins and cortical destruction; soft tissue extension is common; no specific tumor matrix mineralization; periosteal reaction may be present

─ Prognosis: Generally poor, similar to other high-grade bone sarcomas; 5-year survival rates historically ~20-50%; depends on grade, stage, and completeness of surgical resection; high rates of local recurrence and distant metastases (lungs most common)

Macro ─ fleshy, gray-white to tan, firm or soft infiltrative tumor; often with areas of hemorrhage and necrosis; replaces bone marrow and destroys cortex

Micro ─

─ Composed of malignant spindle cells arranged in intersecting fascicles, often with a herringbone pattern (similar to fibrosarcoma) or whorled pattern

─ Tumor cells have elongated, "cigar-shaped" (blunt-ended) nuclei with vesicular or hyperchromatic chromatin and eosinophilic, fibrillar cytoplasm

─ Nuclear atypia and pleomorphism vary with grade; high-grade lesions show significant pleomorphism, bizarre nuclei, and increased N/C ratio

─ Mitotic activity is usually high, including atypical mitoses, especially in high-grade tumors

─ Necrosis is common in high-grade lesions

─ Vascular invasion may be present

─ No production of neoplastic bone or cartilage (distinguishes from osteosarcoma or chondrosarcoma)

─ Epithelioid variant is rare, composed of polygonal cells with eosinophilic cytoplasm

Ancillary studies ─

─ IHC: Crucial for diagnosis; tumor cells are positive for smooth muscle actin (SMA) and muscle specific actin (MSA); desmin positivity is variable (often positive but can be focal or negative, especially in high-grade tumors); caldesmon is often positive and more specific for smooth muscle differentiation; negative for S100, keratins, CD34, SOX10

─ Electron Microscopy (historic): Shows features of smooth muscle differentiation (abundant thin filaments with focal densities, pinocytotic vesicles, incomplete basal lamina)

DDx ─

─ Metastatic Leiomyosarcoma (most important differential; requires clinical exclusion of primary elsewhere, especially uterus/retroperitoneum)

─ Fibrosarcoma of Bone (histologically similar spindle cell pattern, but negative for smooth muscle markers)

─ Undifferentiated Pleomorphic Sarcoma (UPS) of Bone (more pleomorphic, lacks consistent smooth muscle differentiation by IHC)

─ Malignant Peripheral Nerve Sheath Tumor (MPNST) (may have fascicular pattern, S100 often positive focally, association with nerve or NF1)

─ Synovial Sarcoma (monophasic spindle cell type; often keratin/EMA positive, t(X;18) fusion)

─ Fibroblastic Osteosarcoma (if osteoid production is focal or missed; leiomyosarcoma does not produce osteoid)

Media

Liposarcoma of Bone (Primary)

An exceedingly rare malignant mesenchymal tumor arising primarily within bone, characterized by adipocytic differentiation with lipoblasts; most cases likely represent metastases or direct extension from soft tissue liposarcoma

Clinical ─

─ Exceptionally rare as a primary bone tumor; true incidence is difficult to determine due to rarity and strict diagnostic criteria (exclusion of soft tissue primary)

─ Reported cases occur over a wide age range, typically in adults

─ Skeletal sites include long bones (femur, tibia, humerus), pelvis, and ribs

─ Often presents with pain and swelling; pathologic fracture can occur

─ Diagnosis requires rigorous exclusion of a soft tissue primary or metastasis, which are far more common

─ Imaging: Lytic, destructive lesion, often with ill-defined margins and cortical destruction; soft tissue extension is common; fatty components may be visible on CT/MRI (fat density/signal), but this is not always present, especially in high-grade or non-lipogenic subtypes; no specific tumor matrix mineralization

─ Prognosis: Generally poor, similar to high-grade soft tissue liposarcomas or other primary bone sarcomas; depends on histologic subtype, grade, and stage

Macro ─ fleshy, yellowish-gray to white tumor; may have overtly fatty areas, myxoid/gelatinous regions, or firm fibrous/sarcomatous areas; often infiltrative with necrosis and hemorrhage

Micro ─

Histologic subtypes similar to soft tissue liposarcoma; diagnosis relies on identification of lipoblasts (immature fat cells with scalloped, hyperchromatic nuclei indented by cytoplasmic lipid vacuoles):

─ Well-differentiated liposarcoma / Atypical Lipomatous Tumor (WDL/ALT): composed of mature adipose tissue with scattered atypical spindle cells and adipocytes, fibrous septa; lipoblasts may be rare

─ Dedifferentiated liposarcoma: WDL/ALT component juxtaposed with a high-grade non-lipogenic sarcoma (most commonly resembling UPS or fibrosarcoma)

─ Myxoid liposarcoma: bland spindle/stellate cells in a prominent myxoid stroma with a characteristic plexiform ("chicken-wire") capillary network; lipoblasts are often present, typically univacuolated or multivacuolated signet-ring like cells

─ Round cell liposarcoma: high-grade variant of myxoid liposarcoma, with increased cellularity, sheets of primitive round cells, and decreased myxoid stroma

─ Pleomorphic liposarcoma: high-grade sarcoma with marked pleomorphism and numerous bizarre lipoblasts

─ Primary intraosseous liposarcoma is most often reported as pleomorphic or myxoid/round cell type; WDL/ALT type is exceptionally rare in bone as a primary tumor

Ancillary studies ─

─ IHC: Lipoblasts and atypical adipocytes are S100 positive; MDM2 and CDK4 are overexpressed/amplified in WDL/ALT and dedifferentiated liposarcoma (very useful for this subtype)

─ Molecular:

─ WDL/ALT & Dedifferentiated: Amplification of 12q13-15 region (containing MDM2, CDK4, HMGA2 genes) is characteristic

─ Myxoid/Round Cell: Recurrent translocation t(12;16)(q13;p11) resulting in FUS-DDIT3 fusion, or less commonly t(12;22)(q13;q12) with EWSR1-DDIT3 fusion

─ Pleomorphic: Complex karyotypes, no specific recurrent translocations

DDx ─

─ Metastatic Liposarcoma from soft tissue (most crucial differential; often indistinguishable histologically)

─ Intraosseous Lipoma with atypia or fat necrosis (benign, lacks true lipoblasts and malignant features)

─ Bone Infarct with fatty marrow (necrotic fat, lacks viable lipoblasts)

─ Other sarcomas with clear cell or vacuolated features (e,g,, clear cell chondrosarcoma, metastatic renal cell carcinoma; distinguished by IHC and specific features)

─ Myxoid tumors of bone (e,g,, chondromyxoid fibroma, fibromyxoma; lack lipoblasts and specific molecular alterations of myxoid liposarcoma)

Media

Rhabdomyosarcoma of Bone (Primary)

An exceedingly rare, highly aggressive malignant mesenchymal tumor arising primarily within bone, characterized by skeletal muscle differentiation (rhabdomyoblasts)

Clinical ─

─ Exceptionally rare as a primary bone tumor; most bone involvement by rhabdomyosarcoma is metastatic (especially alveolar RMS in children) or by direct extension from a soft tissue primary

─ Reported primary bone cases occur over a wide age range, but often in children and young adults (similar to soft tissue RMS)

─ Skeletal sites include long bones (femur, tibia), pelvis, vertebrae, and skull

─ Presents with rapidly progressive pain and swelling; pathologic fracture can occur

─ Diagnosis requires strict exclusion of soft tissue primary or metastasis

─ Imaging: Aggressive, destructive lytic lesion with ill-defined, permeative margins, cortical destruction, and a large associated soft tissue mass; no specific tumor matrix mineralization

─ Prognosis: Generally poor, similar to high-grade soft tissue rhabdomyosarcomas or other primary bone sarcomas; depends on histologic subtype, stage, and response to multimodal therapy

Macro ─ fleshy, gray-white to tan-pink, infiltrative tumor; often with extensive necrosis and hemorrhage

Micro ─

Histologic subtypes similar to soft tissue rhabdomyosarcoma; diagnosis relies on identification of rhabdomyoblasts (cells with eosinophilic cytoplasm, eccentric nuclei, and sometimes cross-striations):

─ Embryonal rhabdomyosarcoma: most common type in soft tissue, rare as primary bone; alternating cellular and myxoid areas with small round to spindle cells and scattered rhabdomyoblasts (tadpole, strap, or spider cells); cambium layer may be present

─ Alveolar rhabdomyosarcoma: nests of primitive round cells separated by fibrous septa, resembling pulmonary alveoli; rhabdomyoblasts may be sparse; high-grade features

─ Pleomorphic rhabdomyosarcoma: rare in children, more common in adults; sheets of large, bizarre, pleomorphic cells with abundant eosinophilic cytoplasm, frequent rhabdomyoblasts; high-grade

─ Spindle cell/sclerosing rhabdomyosarcoma: variants with spindle cell morphology and often prominent collagenous stroma

─ Bone invasion is common in all types if primary in bone

Ancillary studies ─

─ IHC: Essential for diagnosis; tumor cells (especially rhabdomyoblasts) are positive for myogenic markers: desmin, myogenin (Myf4 - nuclear), MyoD1 (nuclear), muscle specific actin (MSA); myoglobin is less sensitive

─ Electron Microscopy (historic): Shows sarcomeric differentiation (thin and thick filaments, Z-bands)

─ Molecular:

─ Alveolar RMS: Characterized by recurrent translocations involving FOXO1 gene with PAX3 (t(2;13)(q35;q14)) or PAX7 (t(1;13)(p36;q14))

─ Embryonal RMS: Often shows allelic loss at 11p15,5 and gain of chromosomes 2, 8, 12, 13, 20

─ Spindle cell/sclerosing RMS: May have MYOD1 mutations or fusions involving VGLL2, SRF, NCOA2

DDx ─

─ Metastatic Rhabdomyosarcoma (most important differential)

─ Ewing Sarcoma/Other Small Round Blue Cell Tumors (if rhabdomyoblasts are sparse or morphology is primitive; distinguished by IHC and molecular)

─ Osteosarcoma (especially small cell or pleomorphic types; osteosarcoma produces osteoid)

─ Undifferentiated Pleomorphic Sarcoma (UPS) of Bone (lacks definitive myogenic differentiation)

─ Lymphoma of Bone (positive for lymphoid markers)

─ Granulocytic Sarcoma (myeloid markers)

Media

Malignant Peripheral Nerve Sheath Tumor of Bone (Primary)

A rare, aggressive malignant mesenchymal tumor arising primarily within bone, showing Schwann cell differentiation or arising from a pre-existing neurofibroma or schwannoma within bone

Clinical ─

─ Extremely rare as a primary intraosseous tumor; most MPNSTs arise in soft tissue, often associated with peripheral nerves or Neurofibromatosis type 1 (NF1)

─ Reported primary bone cases occur over a wide age range, but often in adults

─ Skeletal sites include mandible, long bones (femur, tibia), vertebrae, and sacrum

─ May present with pain, swelling, palpable mass, or neurologic symptoms if nerve root/cord compression

─ Higher risk in patients with NF1 (MPNST is a known complication of NF1, though primary bone MPNST in NF1 is still rare)

─ Imaging: Aggressive, destructive lytic lesion with ill-defined, permeative margins, cortical destruction, and often a large associated soft tissue mass; can be expansile; no specific tumor matrix mineralization

─ Prognosis: Generally poor, similar to high-grade soft tissue MPNSTs; 5-year survival rates ~30-50%; high rates of local recurrence and distant metastases (lungs, liver, bone)

Macro ─ fleshy, gray-white to tan, infiltrative tumor; often with areas of necrosis and hemorrhage; may appear to arise from or encase an intraosseous nerve

Micro ─

─ Cellular proliferation of malignant spindle cells with features suggestive of Schwann cell differentiation:

─ Cells are typically arranged in intersecting fascicles, often with a "herringbone" or storiform pattern; may also show areas of alternating cellularity (hypercellular and hypocellular/myxoid zones)

─ Nuclei are elongated, wavy, buckled, or comma-shaped, with irregular contours and hyperchromasia

─ Cytoplasm is usually scant and eosinophilic

─ Mitotic activity is generally high, including atypical mitoses

─ Necrosis is common

─ Perivascular accentuation of tumor cells can be seen

─ Evidence of origin from a nerve or pre-existing benign nerve sheath tumor (neurofibroma, schwannoma) is supportive but often absent in primary bone lesions

─ High-grade features: marked pleomorphism, epithelioid morphology (rare), or heterologous differentiation (e,g,, rhabdomyosarcomatous - "Triton tumor", chondrosarcomatous, osteosarcomatous) can occur

Ancillary studies ─

─ IHC: Spindle cells are positive for S100 protein in ~50-70% of cases (often patchy and weak, especially in high-grade tumors); SOX10 is more sensitive and specific for Schwannian differentiation; GFAP may be positive; loss of H3K27me3 expression by IHC is a relatively specific marker for MPNST (especially in NF1 setting); negative for keratins, desmin, actin, CD34 (except vessels)

─ Molecular ─ Associated with inactivation of NF1 tumor suppressor gene (in NF1-associated and ~50% of sporadic MPNSTs) and/or CDKN2A/B (p16/p14arf); PRC2 complex gene alterations (SUZ12, EED) are also common

DDx ─

─ Fibrosarcoma of Bone (S100/SOX10 negative, lacks wavy nuclei, no association with NF1)

─ Undifferentiated Pleomorphic Sarcoma (UPS) of Bone (S100/SOX10 negative, more pleomorphic, less fascicular)

─ Synovial Sarcoma (monophasic spindle cell type; often keratin/EMA positive, t(X;18) fusion)

─ Leiomyosarcoma of Bone (smooth muscle markers positive, blunt-ended nuclei)

─ Melanoma (metastatic or rarely primary; S100/SOX10 positive, but also positive for melanocytic markers like HMB-45, Melan-A)

─ Schwannoma with ancient change (benign, degenerative atypia but low mitoses, lacks infiltrative growth, diffuse S100)

Media

Avascular Necrosis of Bone (Bone Infarct)

Death of bone tissue (osteocytes and marrow) due to interruption of blood supply; can be traumatic or non-traumatic, focal or diffuse

Clinical ─

─ Common; incidence varies greatly depending on underlying cause and site

─ Non-traumatic causes: corticosteroid use (most common non-traumatic), alcoholism, sickle cell disease, Gaucher disease, pancreatitis, caisson disease (decompression sickness), radiation therapy, chemotherapy, systemic lupus erythematosus, coagulopathies, hyperlipidemia, idiopathic

─ Traumatic causes: fractures (especially femoral neck, scaphoid, talus), dislocations

─ Common sites: femoral head (most frequent symptomatic site), humeral head, femoral condyles, talus, carpal bones (scaphoid, lunate - Kienböck's disease), small bones of feet (e,g,, navicular - Köhler's disease; metatarsal heads - Freiberg's infraction)

─ Presents with pain, often insidious onset, exacerbated by activity or weight-bearing; limited range of motion; asymptomatic in early stages or small infarcts

─ Untreated osteonecrosis of weight-bearing joints (especially femoral head) often progresses to subchondral collapse, articular cartilage degeneration, and secondary osteoarthritis

─ Imaging: Early: radiographs often normal; MRI is most sensitive, showing marrow edema (high T2, low T1), then characteristic "double line sign" (serpiginous inner bright T2 line of granulation tissue, outer dark T2 line of sclerosis) on T2-weighted images separating viable from necrotic bone; Bone scan shows initial "cold spot" (decreased uptake) followed by increased uptake (reactive hyperemia/repair)

─ Later radiographic signs: increased density (sclerosis) of necrotic bone, subchondral lucency ("crescent sign" - impending collapse), flattening/collapse of articular surface, joint space narrowing, osteophytes (secondary osteoarthritis)

─ Prognosis: Depends on size, location, stage at diagnosis, and underlying cause; early intervention (e,g,, core decompression) may prevent collapse in some femoral head lesions; established collapse often requires joint replacement

Macro ─ infarcted area is often wedge-shaped (base towards articular surface), pale yellow, opaque, and relatively firm; may be demarcated by a hyperemic rim of granulation tissue; subchondral fracture and cartilage collapse are seen in later stages

Micro ─

─ Necrosis of osteocytes: empty lacunae within bone trabeculae (hallmark feature)

─ Necrosis of bone marrow: adipocytes lose nuclei, appearing as "ghost cells" or empty spaces; hematopoietic cells disappear; stroma becomes amorphous and eosinophilic

─ Surrounding reactive changes:

─ Hyperemia and vascular proliferation at the margin of the infarct

─ Inflammatory infiltrate (macrophages, lymphocytes, plasma cells)

─ Creeping substitution: apposition of new viable woven bone onto dead trabeculae by osteoblasts (repair process)

─ Fibrosis of marrow spaces

─ Dystrophic calcification can occur within necrotic marrow fat (saponification) or bone

─ Subchondral fracture (separation of necrotic bone from overlying cartilage)

─ Articular cartilage overlying infarct initially remains viable (nourished by synovial fluid) but may degenerate or detach with subchondral collapse

Ancillary studies ─

─ Not typically required for diagnosis; imaging and clinical context are usually sufficient

DDx ─

─ Transient Osteoporosis of the Hip/Regional Migratory Osteoporosis (diffuse marrow edema on MRI, resolves spontaneously, no true necrosis)

─ Stress Fracture (different location/pattern of marrow edema, fracture line may be visible)

─ Osteomyelitis (clinical signs of infection, inflammatory infiltrate with neutrophils, positive cultures)

─ Bone Tumors (neoplastic cells, destructive growth pattern; some tumors can cause secondary infarct)

─ Gaucher Disease (Gaucher cells in marrow, characteristic "Erlenmeyer flask" deformity)

Media

Paget Disease of Bone

A chronic, focal disorder of bone remodeling characterized by excessive osteoclastic bone resorption followed by disorganized and excessive new bone formation, resulting in enlarged, deformed, and weakened bones

Clinical ─

─ Common in older adults (rare <40 years, prevalence increases with age, affecting ~1-3% of individuals >55 years in some populations)

─ More common in individuals of Anglo-Saxon descent (UK, USA, Australia, New Zealand, Western Europe); rare in Asia, Africa, Scandinavia

─ Slight male predominance

─ Can be monostotic (single bone, ~15-30%) or polyostotic (multiple bones); most common sites are pelvis, femur, spine (vertebrae), skull, and tibia

─ Often asymptomatic, discovered incidentally on radiographs or due to elevated serum alkaline phosphatase

─ Symptomatic patients may present with bone pain (most common), bone deformity (bowing of long bones, skull enlargement), pathologic fractures ("chalkstick" fractures), arthritis in adjacent joints, hearing loss (skull involvement), or neurologic complications (e,g,, nerve root/spinal cord compression, basilar invagination)

─ Warmth over affected bone due to increased vascularity

─ Imaging: Three phases are described:

1, Lytic phase (early, osteoclastic dominant): "blade of grass" or "flame-shaped" advancing lytic wedge in long bones; osteoporosis circumscripta in skull (well-demarcated lucency)

2, Mixed phase: coarsened trabeculae, cortical thickening, bone expansion, areas of lysis and sclerosis

3, Sclerotic phase (late, osteoblastic dominant): dense, sclerotic, enlarged bone; "cotton wool" appearance in skull; "ivory vertebra"

─ Bone scan shows intense uptake in affected areas

─ Prognosis: Generally good for asymptomatic or mildly symptomatic disease; complications include fractures, deformities, arthritis, neurologic deficits, high-output cardiac failure (rare, with extensive skeletal involvement), and malignant transformation (sarcoma, most commonly osteosarcoma) in <1% of patients (Paget sarcoma)

Macro ─ affected bone is enlarged, thickened, and deformed; cortex is often porous and cancellous bone is coarse and sclerotic; cut surface may show a mosaic pattern; increased vascularity

Micro ─

Key feature is disorganized bone remodeling with a characteristic "mosaic" or "jigsaw puzzle" pattern of lamellar bone:

─ Irregularly shaped cement lines (reversal lines) outlining haphazardly arranged packets of lamellar bone, reflecting previous resorption and apposition

─ Increased osteoclastic activity: osteoclasts are often numerous, large, and contain increased numbers of nuclei (up to 100 nuclei/cell); viral-like nuclear inclusions may be seen on EM (paramyxovirus-like) but are not specific

─ Increased osteoblastic activity: plump osteoblasts line bone trabeculae, producing abundant new bone

─ Bone marrow is typically replaced by loose, highly vascular fibroconnective tissue (fibrosis)

─ Woven bone may be present, especially in active phases, but mature lamellar bone with mosaic pattern dominates in established disease

─ In lytic phase: predominantly osteoclastic resorption with fibrous replacement of marrow

─ In sclerotic phase: dense, thickened trabeculae with mosaic pattern, reduced marrow spaces

Ancillary studies ─

─ Serum alkaline phosphatase (ALP): often markedly elevated, reflects increased osteoblastic activity; useful for diagnosis and monitoring treatment response

─ Urinary hydroxyproline or other bone resorption markers (e,g,, N-telopeptide) may be elevated

─ Molecular ─ SQSTM1/p62 gene mutations are found in a significant proportion of familial (20-50%) and sporadic (5-10%) Paget disease, predisposing to increased NF-κB signaling and osteoclast activity; viral infection (e,g,, measles, canine distemper) has been hypothesized as a cofactor but remains controversial

DDx ─

─ Osteoblastic Metastases (especially prostate cancer; can cause diffuse sclerosis, but typically lacks bone expansion and mosaic pattern, different clinical context)

─ Fibrous Dysplasia (woven bone in fibrous stroma, "Chinese letters," lacks mosaic pattern and prominent osteoclasts, GNAS mutation)

─ Chronic Osteomyelitis with sclerosis (inflammatory infiltrate, sequestra, clinical signs of infection)

─ Myelofibrosis with osteosclerosis (hematologic abnormalities, different marrow infiltrate)

─ Osteosarcoma (Paget sarcoma; malignant cells producing osteoid, arises in background of Paget disease)

─ Hyperparathyroidism (osteitis fibrosa cystica; increased osteoclastic resorption, fibrosis, brown tumors, but different pattern of bone changes)

Media

Metastatic Carcinoma to Bone

The most common malignant tumor involving bone, resulting from hematogenous spread of a carcinoma from a distant primary site

Clinical ─

─ Most common in adults >40 years; incidence increases with age

─ Common primary sites metastasizing to bone: prostate, breast, lung, kidney, thyroid (acronym "PB KTL" - P B Kills The Lungs)

─ Skeletal sites: axial skeleton (vertebrae, pelvis, ribs, skull) and proximal long bones (femur, humerus) are most frequently involved due to abundant red marrow and specific homing mechanisms

─ Can be osteolytic (bone-destroying), osteoblastic (bone-forming), or mixed; depends on primary tumor type and interactions with bone microenvironment

─ Presents with bone pain (most common symptom), pathologic fractures, spinal cord/nerve root compression, hypercalcemia of malignancy; may be an incidental finding or the first manifestation of an occult primary cancer

─ Imaging: Highly variable; lytic lesions are often "punched-out" or permeative with ill-defined margins; blastic lesions appear as focal or diffuse areas of increased density; mixed patterns are common; cortical destruction and soft tissue extension are frequent; bone scan is sensitive for detecting blastic and most lytic lesions (increased uptake); MRI is excellent for marrow involvement and soft tissue extent

─ Prognosis: Generally poor, indicates advanced systemic disease (Stage IV); median survival varies greatly depending on primary tumor type, extent of bone disease, presence of visceral metastases, and treatment response; can range from months (e,g,, lung cancer) to several years (e,g,, some breast or prostate cancers)

Macro ─ tumor tissue replaces bone marrow; can be soft, fleshy, gray-white, hemorrhagic, or necrotic; bone may be destroyed (lytic) or thickened and sclerotic (blastic)

Micro ─

─ Infiltrate of malignant epithelial cells (carcinoma cells) within bone marrow spaces and Haversian canals, often replacing normal hematopoietic tissue and bone trabeculae

─ Morphology of metastatic carcinoma usually resembles that of the primary tumor (e,g,, adenocarcinoma, squamous cell carcinoma, small cell carcinoma, urothelial carcinoma)

─ Carcinoma cells typically form nests, glands, cords, sheets, or grow as single files, depending on primary type

─ Cytologic features of malignancy: nuclear atypia (pleomorphism, hyperchromasia, irregular contours, prominent nucleoli), increased N/C ratio, mitotic activity (often including atypical mitoses)

─ Stroma is variable, can be desmoplastic (fibrous) or scant

─ Osteolytic metastases: associated with increased osteoclastic bone resorption, often stimulated by tumor-secreted factors (e,g,, PTHrP, interleukins)

─ Osteoblastic metastases: associated with increased osteoblastic new bone formation, often stimulated by tumor-secreted factors (e,g,, endothelin-1, Wnt pathway activators); reactive woven bone is deposited on pre-existing trabeculae

Ancillary studies ─

─ IHC: Essential for determining primary site of origin if unknown, or confirming metastasis if primary is known; panel of antibodies typically includes:

─ Cytokeratins (AE1/AE3, CAM5,2, CK7, CK20) to confirm epithelial nature and suggest origin (e,g,, CK7+/CK20- common in breast/lung, CK7-/CK20+ common in colorectal)

─ Organ-specific markers (e,g,, PSA/PSAP for prostate, TTF-1/Napsin A for lung adenocarcinoma, GATA3/mammaglobin for breast, PAX8/CAIX for renal cell, thyroglobulin/TTF-1 for thyroid, CDX2 for colorectal, uroplakin for urothelial)

DDx ─

─ Primary Bone Sarcoma (e,g,, osteosarcoma, chondrosarcoma, Ewing sarcoma; mesenchymal origin, different histology and IHC profile, usually younger patients for many types)

─ Plasma Cell Myeloma (sheets of plasma cells, CD138+, monoclonal immunoglobulin)

─ Lymphoma of Bone (atypical lymphoid cells, LCA+, specific lymphoid markers)

─ Osteomyelitis (inflammatory infiltrate, no malignant epithelial cells, cultures may be positive)

─ Paget Disease of Bone (if sclerotic; mosaic pattern of lamellar bone, characteristic osteoclasts/osteoblasts)

─ Benign bone lesions mimicking lytic metastases (e,g,, enchondroma, fibrous dysplasia, GCTB; specific benign histology)

Media

Metastatic Sarcoma to Bone

Rare event where a sarcoma originating in soft tissue or another bone metastasizes to a distant skeletal site; much less common than metastatic carcinoma to bone

Clinical ─

─ Overall rare; bone is not a common site for sarcoma metastasis (lungs are most frequent)

─ Most likely to metastasize to bone: osteosarcoma (bone-to-bone metastasis), Ewing sarcoma, rhabdomyosarcoma, undifferentiated pleomorphic sarcoma (UPS), leiomyosarcoma, synovial sarcoma

─ Usually occurs in patients with known high-grade sarcoma and advanced disease

─ Skeletal sites: similar to metastatic carcinoma (axial skeleton, proximal long bones)

─ Presents with bone pain, pathologic fracture, or identified during staging/surveillance imaging

─ Imaging: Typically aggressive, destructive lytic lesions; may show features reminiscent of the primary sarcoma if it produces matrix (e,g,, osteoid in metastatic osteosarcoma)

─ Prognosis: Generally very poor, indicates disseminated, aggressive disease

Macro ─ fleshy, infiltrative tumor mass; appearance depends on primary sarcoma type

Micro ─

─ Histology of the bone metastasis resembles that of the primary sarcoma

─ Requires careful comparison with the primary tumor histology if available

─ For example:

─ Metastatic osteosarcoma: malignant spindle cells producing osteoid

─ Metastatic Ewing sarcoma: sheets of small round blue cells

─ Metastatic rhabdomyosarcoma: rhabdomyoblasts with skeletal muscle differentiation

─ Metastatic UPS: pleomorphic spindle and polygonal cells

─ Infiltration and destruction of host bone trabeculae and marrow

Ancillary studies ─

─ IHC: Profile should match the primary sarcoma; crucial if primary is unknown or histology is ambiguous (e,g,, S100 for MPNST, desmin/myogenin for rhabdomyosarcoma, smooth muscle markers for leiomyosarcoma, CD99/FLI1 for Ewing sarcoma)

─ Molecular: Detection of specific translocations or mutations known in the primary sarcoma can confirm metastatic nature (e,g,, EWSR1 fusion in Ewing, SS18-SSX in synovial sarcoma, MDM2 amplification in dedifferentiated liposarcoma component if that metastasizes)

DDx ─

─ Primary Bone Sarcoma (especially if a solitary bone lesion and primary sarcoma history is remote or unknown; careful clinicopathologic correlation needed; some sarcomas like osteosarcoma can present with synchronous bone metastases)

─ Metastatic Carcinoma (epithelial morphology, keratin positive)

─ Lymphoma/Myeloma (specific lymphoid/plasma cell markers)

─ High-grade transformation of a benign bone lesion (e,g,, Paget sarcoma, dedifferentiated chondrosarcoma; look for underlying benign/low-grade lesion)

Media

Metastatic Melanoma to Bone

Metastasis of malignant melanoma (a neuroectodermal tumor of melanocytes) to bone; bone metastases are relatively uncommon but can occur in advanced disease

Clinical ─

─ Bone metastases occur in ~7-15% of patients with disseminated melanoma

─ Usually occurs in patients with known advanced (Stage IV) cutaneous, mucosal, or uveal melanoma

─ Can affect any bone, but common sites include vertebrae, pelvis, ribs, femur, skull

─ Often multiple lesions; may be osteolytic, osteoblastic (rare), or mixed

─ Presents with bone pain, pathologic fracture, or neurologic symptoms (spinal cord compression)

─ Imaging: Typically lytic, destructive lesions with ill-defined margins; can be expansile; MRI is sensitive for marrow involvement; PET/CT useful for staging and detecting occult metastases

─ Prognosis: Poor when bone metastases are present; median survival is often <6-12 months, though newer targeted therapies and immunotherapies are improving outcomes for some patients

Macro ─ tumor tissue is often pigmented (brown-black) if melanotic, but can be amelanotic (fleshy, gray-white); infiltrates and destroys bone

Micro ─

Histology of metastatic melanoma can be highly variable:

─ Composed of malignant melanocytes, which can be:

─ Epithelioid: large polygonal cells with abundant eosinophilic cytoplasm, large vesicular nuclei, and prominent eosinophilic nucleoli

─ Spindled: elongated cells arranged in fascicles, resembling fibrosarcoma or MPNST

─ Small cell/Nevoid: smaller cells with scant cytoplasm and round nuclei

─ Mixed patterns are common

─ Melanin pigment (fine brown granules) may be present in cytoplasm of tumor cells, but many metastases are amelanotic (lacking visible pigment)

─ Nuclear atypia, pleomorphism, and mitotic activity (including atypical mitoses) are usually prominent

─ Intranuclear cytoplasmic inclusions are common

─ Infiltration and destruction of host bone and marrow

Ancillary studies ─

─ IHC: Essential for diagnosis, especially in amelanotic or poorly differentiated cases; tumor cells are positive for melanocytic markers: S100 protein (diffuse, strong), SOX10 (nuclear), Melan-A (MART-1), HMB-45; tyrosinase may also be positive; negative for keratins, lymphoid markers, most mesenchymal markers (except S100/SOX10)

─ Molecular ─ Somatic mutations in BRAF (most commonly V600E, in ~50% of cutaneous melanomas), NRAS (~15-20%), or KIT (in acral/mucosal/chronic sun-damaged skin melanomas) are common and have therapeutic implications (targeted inhibitors)

DDx ─

─ Primary Bone Sarcoma (especially pleomorphic types like UPS or spindle cell osteosarcoma; distinguished by IHC and specific features)

─ Metastatic Carcinoma (especially poorly differentiated or spindle cell types; keratin positive, melanocytic markers negative)

─ Lymphoma of Bone (LCA+, specific lymphoid markers)

─ Angiosarcoma (if epithelioid and hemorrhagic; endothelial markers positive)

─ Clear Cell Sarcoma of Soft Tissue (melanocytic differentiation, EWSR1-ATF1 or EWSR1-CREB1 fusion, typically arises in tendons/aponeuroses of distal extremities, S100/melanocytic markers positive)

Media

Metastatic Neuroblastoma to Bone

Metastasis of neuroblastoma (a malignant embryonal tumor of the sympathetic nervous system) to bone; bone marrow and cortical bone are common sites of metastasis in advanced-stage neuroblastoma, particularly in children

Clinical ─

─ Neuroblastoma is the most common extracranial solid tumor of childhood

─ Bone metastases are present in >50% of patients with high-risk neuroblastoma (Stage 4) at diagnosis or relapse

─ Primarily affects infants and young children (median age at diagnosis ~18-24 months)

─ Arises from sympathetic ganglia (adrenal medulla most common, also paraspinal ganglia in abdomen, thorax, neck, pelvis)

─ Skeletal metastases most commonly involve skull (orbital "racoon eyes", periorbital ecchymosis), long bones (metaphyses), vertebrae, pelvis, ribs

─ Presents with bone pain (limping, refusal to walk), palpable masses, or symptoms related to marrow infiltration (pancytopenia); systemic symptoms (fever, weight loss) may be present

─ Imaging: Lytic, permeative lesions in bone, often multiple and symmetrical; cortical destruction and periosteal reaction (lamellated or spiculated) are common; soft tissue masses associated with bone lesions; "sunburst" appearance in skull; MRI is sensitive for marrow involvement; MIBG (metaiodobenzylguanidine) scan is specific for neuroblastoma and useful for staging/detecting metastases

─ Prognosis: Presence of bone/bone marrow metastases is a major poor prognostic factor (defines high-risk disease); outcome depends on age, stage, MYCN amplification status, and response to therapy; intensive multimodal therapy (chemotherapy, surgery, radiation, stem cell transplant, immunotherapy) is used for high-risk disease

Macro ─ infiltrative, soft, gray-white to tan tumor tissue in bone marrow; may cause bone destruction

Micro ─

─ Composed of small, round blue cells with scant cytoplasm, round to oval hyperchromatic nuclei, and finely granular ("salt-and-pepper") chromatin; nucleoli are inconspicuous

─ Cells are often arranged in diffuse sheets, nests, or lobules

─ Homer-Wright rosettes (tumor cells arranged around a central fibrillary meshwork of neuritic processes) are characteristic but not always present

─ Neuropil (eosinophilic, fibrillar material representing neuritic processes) is a key diagnostic feature when present

─ Ganglion cell differentiation (larger cells with more cytoplasm, vesicular nuclei, prominent nucleoli) may be seen, especially after therapy or in maturing tumors

─ Stroma is typically scant and fibrovascular

─ Bone marrow infiltration is common, replacing normal hematopoietic elements

Ancillary studies ─

─ IHC: Tumor cells are positive for neuroendocrine markers (synaptophysin, chromogranin A - often focal), neuron-specific enolase (NSE), PGP9,5; often positive for CD56; NB84 is a relatively specific marker; negative for LCA, CD99 (usually), desmin, myogenin, keratins

─ Electron Microscopy (historic): Shows neurosecretory granules and neuritic processes

─ Molecular ─ MYCN gene amplification (detected by FISH or PCR) is a critical prognostic marker (associated with aggressive disease and poor outcome); other genetic alterations include deletions of 1p, 11q, gains of 17q

DDx ─

─ Other Small Round Blue Cell Tumors of Childhood:

─ Ewing Sarcoma (CD99+, FLI1+, EWSR1 fusion)

─ Lymphoma/Leukemia (LCA+, specific lymphoid/myeloid markers)

─ Rhabdomyosarcoma (especially embryonal; myogenic markers positive)

─ Medulloblastoma (metastatic; similar histology but arises in CNS, often GFAP+)

─ Wilms Tumor (metastatic; triphasic pattern usually, WT1+)

─ Osteomyelitis (inflammatory infiltrate, no neoplastic cells)

Media

Pigmented Villonodular Synovitis (Tenosynovial Giant Cell Tumor, Diffuse Type)

A rare, benign but locally aggressive neoplastic proliferation of synovial lining cells, histiocytes, osteoclast-like giant cells, and hemosiderin-laden macrophages, diffusely involving the synovium of a joint, bursa, or tendon sheath

Clinical ─

─ Uncommon; incidence ~1,8 per million per year

─ Typically affects young to middle-aged adults (peak 3rd to 4th decades); no clear sex predilection

─ Most commonly involves large joints, especially knee (~75-80%), followed by hip, ankle, shoulder, elbow; rarely small joints

─ Can be intra-articular (most common) or extra-articular (involving bursae or diffusely along tendon sheaths)

─ Presents with insidious onset of monoarticular pain, swelling, joint effusion (often hemorrhagic or serosanguinous), and limited range of motion; palpable mass may be present

─ Imaging: Plain radiographs may be normal or show soft tissue swelling, joint effusion, and juxta-articular osteopenia; characteristic well-defined, often multiple, pressure erosions or cysts on both sides of the joint without significant joint space narrowing are highly suggestive, especially if hemosiderin is seen on MRI; MRI is imaging modality of choice: shows diffuse synovial thickening with characteristic low signal intensity on T1 and T2-weighted images due to hemosiderin deposition (susceptibility artifact on gradient echo sequences); areas of higher signal on T1 (hemorrhage) or T2 (fluid, inflammation) can also be present; avid enhancement after contrast

─ Prognosis: Benign (does not metastasize), but locally aggressive with a high rate of local recurrence (20-50%) after synovectomy, especially if complete excision is difficult; can cause significant joint destruction and disability over time

Macro ─ diffuse, thickened, nodular or shaggy (villous) synovium, often with a characteristic reddish-brown to yellowish-brown discoloration due to hemosiderin and lipid deposition; joint effusion is common

Micro ─

─ Diffuse proliferation of synovial-like mononuclear cells, histiocytes, osteoclast-like multinucleated giant cells, foamy macrophages (xanthoma cells), and siderophages (hemosiderin-laden macrophages) within synovial stroma

─ Mononuclear cells (likely neoplastic component) are ovoid to spindle-shaped with vesicular nuclei and pale eosinophilic cytoplasm; mitoses can be present but are usually not numerous or atypical

─ Osteoclast-like giant cells are scattered throughout

─ Abundant hemosiderin pigment, both intracellular (in siderophages) and extracellular, is a hallmark feature and responsible for the brown color and MRI appearance

─ Foamy macrophages are common, forming sheets or clusters

─ Synovial lining may show hyperplasia and villous projections

─ Stroma is variably fibrous, sometimes with hyalinization

─ Infiltration into subsynovial fat, joint capsule, and adjacent bone (causing erosions) is common

─ No significant cytologic atypia or pleomorphism to suggest malignancy

Ancillary studies ─

─ IHC: Mononuclear cells and giant cells are positive for CD68 (macrophage marker); a subset of mononuclear cells may express CSF1 (colony-stimulating factor 1); negative for keratins, S100, desmin, actin (except vessels)

─ Prussian blue stain highlights hemosiderin deposits

─ Molecular ─ Most cases (both diffuse and localized TGCT) harbor a specific translocation, t(1;2)(p13;q37), resulting in a fusion of the CSF1 gene with the COL6A3 gene, leading to CSF1 overexpression and recruitment of non-neoplastic CSF1R-expressing cells (macrophages, giant cells)

DDx ─

─ Localized Nodular Tenosynovitis (Giant Cell Tumor of Tendon Sheath) (more common, well-circumscribed nodule attached to tendon sheath, usually hands/feet, histologically similar but localized and less infiltrative)

─ Hemophilic Arthropathy (history of hemophilia, recurrent hemarthrosis, hemosiderin deposition, synovial hypertrophy, but lacks the characteristic neoplastic mononuclear cell proliferation of PVNS)

─ Rheumatoid Arthritis/Other Inflammatory Synovitis (prominent chronic inflammation, lymphoid follicles, pannus formation, different immunophenotype, lacks diffuse sheets of mononuclear cells/giant cells of PVNS)

─ Synovial Hemangioma (proliferation of blood vessels, not mononuclear cells/giant cells, though hemosiderin can be present)

─ Synovial Sarcoma (malignant spindle cell tumor, biphasic pattern with epithelial component or monophasic spindle cells, t(X;18) SS18-SSX fusion, keratin/EMA positive)

─ Malignant Tenosynovial Giant Cell Tumor (very rare, arises in background of PVNS, shows overt sarcomatous transformation)

Media

Giant Cell Tumor of Tendon Sheath (Tenosynovial Giant Cell Tumor, Localized Nodular Type)

A common, benign neoplastic proliferation of synovial-like mononuclear cells, histiocytes, osteoclast-like giant cells, and hemosiderin-laden macrophages, forming a well-circumscribed nodule attached to a tendon sheath, most frequently in the hands and feet

Clinical ─

─ Most common soft tissue tumor of the hand

─ Typically affects adults (peak 3rd to 5th decades); slight female predominance

─ Most commonly involves fingers (volar aspect) and toes; less commonly wrists, ankles, knees, hips

─ Presents as a slow-growing, firm, usually painless or mildly tender, mobile nodule attached to a tendon sheath or joint capsule

─ Imaging: Plain radiographs are often normal or may show a non-specific soft tissue mass, occasionally with pressure erosion of adjacent bone; ultrasound shows a well-defined hypoechoic nodule; MRI shows a well-circumscribed mass with low to intermediate signal on T1 and variable (often low due to hemosiderin) signal on T2, avid enhancement

─ Prognosis: Benign; local recurrence is common (10-30%, up to 50% in some series) after marginal excision, especially if incompletely removed or multinodular; malignant transformation is exceedingly rare

Macro ─ well-circumscribed, firm, lobulated nodule, typically 0,5-3 cm in diameter; cut surface is variegated, yellowish-brown to reddish-brown, often with areas of fibrosis or cystic change; attached to tendon sheath or joint capsule

Micro ─

─ Histologically similar to diffuse-type TGCT (PVNS), but forms a well-circumscribed, often pseudoencapsulated nodule

─ Composed of a mixture of:

─ Mononuclear cells (synovial-like stromal cells and histiocytes): ovoid to spindle-shaped with vesicular nuclei and pale eosinophilic cytoplasm

─ Osteoclast-like multinucleated giant cells: scattered throughout, variable in number

─ Foamy macrophages (xanthoma cells): often present in clusters

─ Siderophages (hemosiderin-laden macrophages): contributing to brown color

─ Cells are arranged in sheets, vague fascicles, or a storiform pattern

─ Stroma is variably fibrous, collagenous, or hyalinized; cleft-like spaces may be present

─ Hemosiderin deposition is usually prominent

─ Mitotic activity is generally low; no atypical mitoses

─ No significant cytologic atypia or pleomorphism

─ Less infiltrative than diffuse-type TGCT

Ancillary studies ─

─ IHC: Mononuclear cells and giant cells are CD68 positive; a subset of mononuclear cells may express CSF1

─ Prussian blue stain highlights hemosiderin

─ Molecular ─ Similar to diffuse-type TGCT, most cases harbor the t(1;2)(p13;q37) translocation resulting in CSF1-COL6A3 fusion

DDx ─

─ Diffuse-Type TGCT (PVNS) (more extensive, infiltrative involvement of synovium, typically large joints, histologically similar but diffuse architecture)

─ Fibroma of Tendon Sheath (paucicellular, densely collagenous spindle cell lesion, lacks prominent giant cells, foamy cells, and hemosiderin)

─ Nodular Fasciitis (more myxoid stroma, plump myofibroblasts, extravasated RBCs, lacks prominent giant cells/hemosiderin)

─ Foreign Body Granuloma (if prominent giant cells; look for foreign material, different stromal cells)

─ Benign Fibrous Histiocytoma (soft tissue; similar storiform pattern and giant cells, but typically lacks the prominent hemosiderin and synovial-like mononuclear cells of TGCT)

Media

Malignant Tenosynovial Giant Cell Tumor

An extremely rare sarcoma arising in association with a pre-existing benign tenosynovial giant cell tumor (localized or diffuse type), or de novo with features reminiscent of TGCT but with overt malignancy

Clinical ─

─ Exceedingly rare; precise incidence unknown, only small case series and case reports exist

─ Typically affects adults, often in a slightly older age group than benign TGCT

─ Arises in sites typical for benign TGCT (joints, tendon sheaths), most commonly knee, hip, ankle, hand/foot

─ May present as a rapidly enlarging mass, increased pain, or recurrence in a patient with a history of benign TGCT; can also arise de novo

─ Imaging: Often shows features of a large, aggressive soft tissue mass with bone destruction, ill-defined margins, and heterogeneous signal on MRI; may have areas resembling underlying benign TGCT (e,g,, hemosiderin) but also overtly sarcomatous components

─ Prognosis: Aggressive sarcoma with high rates of local recurrence and distant metastases (lungs, lymph nodes); overall prognosis is poor, significantly worse than benign TGCT

Macro ─ large, fleshy, often hemorrhagic and necrotic tumor mass; may show areas reminiscent of benign TGCT (yellow-brown nodules) juxtaposed with frankly sarcomatous tissue

Micro ─

Biphasic pattern often seen, with:

1, Areas resembling conventional benign Tenosynovial Giant Cell Tumor (localized or diffuse type):

─ Mononuclear cells, osteoclast-like giant cells, foamy macrophages, hemosiderin

2, Malignant (sarcomatous) component:

─ Abrupt transition to a high-grade sarcoma, most commonly resembling undifferentiated pleomorphic sarcoma (UPS), fibrosarcoma, or less commonly osteosarcoma or rhabdomyosarcoma (if heterologous differentiation)

─ Sarcomatous areas show high cellularity, marked cytologic atypia, pleomorphism, frequent and atypical mitoses, and often necrosis

─ Some cases may be entirely sarcomatous (de novo malignant TGCT) but retain some subtle features or immunophenotypic markers suggestive of TGCT lineage (e,g,, focal hemosiderin, scattered giant cells, CSF1 expression)

Ancillary studies ─

─ IHC: Sarcomatous component's IHC depends on its line of differentiation; benign TGCT-like areas show CD68 positivity; CSF1 expression may be retained in some malignant cells

─ Molecular ─ The CSF1-COL6A3 fusion may be present in some cases, especially those clearly arising from benign TGCT, but additional complex genetic alterations are expected in the sarcomatous component

DDx ─

─ Benign Tenosynovial Giant Cell Tumor with reactive atypia (e,g,, after trauma or biopsy; atypia is usually focal and lacks the overt anaplasia and high mitotic rate of sarcoma)

─ Other High-Grade Sarcomas arising in soft tissue/joint (e,g,, UPS, synovial sarcoma, fibrosarcoma; if no clear pre-existing or co-existing benign TGCT component, distinction can be very difficult and may rely on subtle clues or molecular findings if TGCT lineage is suspected)

─ Metastatic Sarcoma or Carcinoma involving synovium (clinical history, IHC profile)

─ Pigmented Villonodular Synovitis with florid reactive changes (can be very cellular and mitotically active, but lacks the anaplasia of true sarcoma)

Media

Synovial Chondromatosis

A benign, typically monoarticular condition characterized by metaplastic formation of multiple cartilaginous nodules within the synovial membrane of a joint, bursa, or tendon sheath; these nodules can detach and become loose bodies

Clinical ─

─ Uncommon; precise incidence unknown

─ Typically affects adults (peak 3rd to 5th decades); male predominance (2:1)

─ Most common in large joints: knee (>50%), hip, elbow, shoulder, ankle; rarely small joints or temporomandibular joint

─ Primary synovial chondromatosis: idiopathic metaplastic process

─ Secondary synovial chondromatosis: arises in context of pre-existing joint disease (e,g,, osteoarthritis, trauma, AVN, osteochondritis dissecans), loose bodies are often derived from damaged articular cartilage

─ Presents with insidious onset of joint pain, swelling, stiffness, limited range of motion, crepitus, and locking or catching (due to loose bodies)

─ Imaging: Plain radiographs are diagnostic if cartilaginous nodules are calcified/ossified, showing multiple, round to oval intra-articular loose bodies of similar size and density; pressure erosions on adjacent bone may occur; MRI shows multiple lobulated nodules within distended joint/bursa, low to intermediate T1 signal, high T2 signal (cartilage), signal voids if calcified/ossified

─ Prognosis: Benign; symptoms often progressive if untreated; treatment is arthroscopic or open synovectomy with removal of loose bodies; recurrence is common (10-30%), especially if synovectomy is incomplete; malignant transformation to synovial chondrosarcoma is rare (<1-5%), usually in long-standing, recurrent primary disease

Macro ─ synovium is thickened, nodular, and contains numerous embedded or attached cartilaginous nodules; multiple free loose bodies (cartilaginous or osteocartilaginous) of varying size (mm to cm) are present in the joint space; loose bodies are typically smooth, glistening, white or bluish-gray

Micro ─

─ Nodules of hyaline cartilage within the synovial stroma or as free intra-articular bodies

─ Cartilage nodules are typically well-circumscribed, often with a lobulated contour

─ Chondrocytes are arranged in clusters (clones) within lacunae, similar to normal articular cartilage or enchondroma; nuclei are usually small, round, and bland

─ In primary synovial chondromatosis, cartilage can be hypercellular with mild to moderate nuclear atypia (enlargement, hyperchromasia, binucleation), especially in active lesions; this atypia can be worrisome but is generally considered benign in this context and lacks features of chondrosarcoma (significant pleomorphism, mitoses, permeation)

─ Periphery of nodules may show endochondral ossification, forming osteocartilaginous loose bodies

─ Synovial lining may be hyperplastic; stroma may show fibrosis or mild chronic inflammation

─ In secondary synovial chondromatosis, loose bodies are often derived from degenerated articular cartilage and may show degenerative atypia; underlying osteoarthritis features are present

Ancillary studies ─

─ Not usually required for diagnosis if classic clinicopathologic features are present

─ Molecular ─ Some cases of primary synovial chondromatosis show clonal chromosomal abnormalities (e,g,, involving chromosome 6), supporting a neoplastic basis for at least a subset

DDx ─

─ Synovial Chondrosarcoma (malignant; more pronounced cytologic atypia, high cellularity, mitoses, myxoid change, spindle cell change, necrosis, invasion of underlying bone or soft tissue; distinction from floridly atypical primary SC can be difficult)

─ Osteoarthritis with loose bodies (secondary SC; features of OA in joint, loose bodies derived from degenerated cartilage, less cellular/atypical than primary SC nodules)

─ Traumatic osteochondral fragments (history of trauma, may resemble loose bodies)

─ Synovial Osteochondromas (rare, true osteochondromas arising from synovium, different structure)

─ Tumoral Calcinosis (periarticular calcific masses, not intra-articular cartilage nodules)

Media

Synovial Chondrosarcoma

A rare malignant cartilaginous tumor arising from the synovium of a joint, bursa, or tendon sheath; can arise de novo (primary synovial chondrosarcoma) or from malignant transformation of pre-existing synovial chondromatosis (secondary synovial chondrosarcoma)

Clinical ─

─ Extremely rare; accounts for a very small fraction of all chondrosarcomas

─ Typically affects adults, often in a slightly older age group than primary synovial chondromatosis if arising secondarily

─ Most common in large joints (knee, hip, shoulder)

─ Primary: presents as a slow-growing painful mass with joint swelling and limited motion

─ Secondary: often a history of long-standing synovial chondromatosis with recent change in symptoms (increased pain, rapid growth of mass)

─ Imaging: Destructive intra-articular or juxta-articular mass with chondroid matrix mineralization (rings and arcs, stippled); bone erosion and soft tissue extension are common; may see residual features of synovial chondromatosis (multiple loose bodies) in secondary cases

─ Prognosis: Aggressive malignancy; high rates of local recurrence and distant metastases (lungs); prognosis depends on histologic grade and completeness of surgical resection; generally poor compared to conventional chondrosarcoma of bone of similar grade

Macro ─ large, lobulated, gray-blue, translucent cartilaginous mass diffusely involving synovium or forming a discrete tumor; areas of necrosis, hemorrhage, or myxoid change may be present; may infiltrate surrounding tissues and bone

Micro ─

─ Malignant hyaline cartilage tumor with features similar to intramedullary chondrosarcoma, but arising in synovium

─ Histologic grading (Grade 1, 2, or 3) based on cellularity, nuclear atypia, and mitotic activity is important

─ Increased cellularity, nuclear pleomorphism (enlarged, hyperchromatic, irregular nuclei), frequent binucleation, and identifiable mitoses are features of malignancy

─ Myxoid change in the stroma, spindle cell transformation, and necrosis are associated with higher grade and worse prognosis

─ Invasion of underlying bone, joint capsule, or surrounding soft tissues is common

─ In secondary synovial chondrosarcoma, areas of pre-existing benign synovial chondromatosis (bland cartilaginous nodules) are seen juxtaposed with the malignant chondrosarcomatous component; transition may be gradual or abrupt

Ancillary studies ─

─ IHC: Tumor cells are S100 positive

─ Molecular ─ IDH1/IDH2 mutations can occur, similar to conventional chondrosarcomas of bone; genetic alterations associated with higher grade (e,g,, TP53, CDKN2A loss) may be present

DDx ─

─ Synovial Chondromatosis (benign; atypia, if present, is usually mild and focal, lacks overt malignant features like high mitotic rate, significant pleomorphism, necrosis, or destructive invasion; distinguishing floridly atypical SC from low-grade synovial chondrosarcoma can be very difficult)

─ Soft Tissue Chondrosarcoma secondarily involving joint (if epicenter is unclear)

─ Metastatic Chondrosarcoma to synovium (rare, history of primary chondrosarcoma elsewhere)

─ Synovial Sarcoma with cartilaginous metaplasia (rare; synovial sarcoma is biphasic or monophasic spindle cell, t(X;18) positive)

─ Tumoral Calcinosis (calcific deposits, not true cartilage)

Media

Synovial Sarcoma (Intra-articular/Juxta-articular)

A malignant mesenchymal tumor with variable epithelial differentiation, characterized by a specific t(X;18) translocation; primary intra-articular synovial sarcoma is rare, most arise in deep soft tissues adjacent to joints

Clinical ─

─ Rare as a primary intra-articular tumor; overall, synovial sarcoma accounts for ~5-10% of all soft tissue sarcomas

─ Typically affects adolescents and young adults (peak 15-40 years); slight male predominance

─ True intra-articular lesions are uncommon; more often, juxta-articular soft tissue synovial sarcomas may secondarily involve or appear to arise from the joint capsule or synovium

─ Most common joints involved are knee, followed by hip, ankle, elbow, shoulder

─ Presents as a slow-growing, often painful mass or with joint swelling, pain, and limited range of motion; symptoms may be present for months to years

─ Imaging: Often a well-circumscribed, multilobulated soft tissue mass adjacent to or within a joint; may show heterogeneous signal on MRI (reflecting cystic areas, hemorrhage, fibrosis); calcifications are common (~30%) and can be fine, stippled, or coarse; bone erosion or invasion can occur in ~20-50% of cases, especially with intra-articular lesions or large juxta-articular tumors

─ Prognosis: Aggressive sarcoma; 5-year survival ~50-75%, 10-year survival ~35-60%; depends on size, grade (if applicable, though most are considered high-grade), presence of metastases at diagnosis, and completeness of surgical resection; high rates of local recurrence and distant metastases (lungs, bone, lymph nodes)

Macro ─ firm, gray-white to tan, often lobulated or pseudoencapsulated mass; cut surface may show cystic areas, hemorrhage, necrosis, or calcification; intra-articular lesions infiltrate synovium and joint structures

Micro ─

Two main histologic patterns (often admixed):

1, Biphasic synovial sarcoma:

─ Composed of both spindle cell and epithelial components

─ Spindle cells: relatively uniform, ovoid to elongated cells with scant cytoplasm, arranged in dense fascicles or sheets

─ Epithelial cells: polygonal to cuboidal or columnar cells forming glands, nests, cords, or lining cleft-like spaces; may show glandular, papillary, or solid patterns

2, Monophasic synovial sarcoma:

─ Composed predominantly or exclusively of the spindle cell component; epithelial differentiation is minimal or absent by light microscopy (may require IHC or EM to confirm)

─ Most common type overall

─ Poorly differentiated synovial sarcoma: rare variant with high-grade features, often small round cell or large cell epithelioid morphology, increased mitotic activity, and necrosis; may lose typical immunophenotype

─ Stroma is variably collagenous or myxoid; prominent hemangiopericytoma-like vascular pattern can be seen

─ Mast cells are often numerous

─ Calcification (focal or extensive) can occur

Ancillary studies ─

─ IHC: Essential for diagnosis, especially in monophasic or poorly differentiated types; spindle cells and epithelial cells are typically positive for cytokeratins (AE1/AE3, CAM5,2 - often focal in spindle cells) and EMA; TLE1 (nuclear stain) is a sensitive but not entirely specific marker; CD99 and BCL2 are often positive but nonspecific; S100 protein may be focally positive in a subset; negative for most other sarcoma markers

─ Molecular ─ Definitive diagnosis relies on detection of the characteristic translocation t(X;18)(p11,2;q11,2) resulting in a fusion of the SS18 (SYT) gene on chromosome 18 with an SSX gene (SSX1, SSX2, or rarely SSX4) on chromosome X; this can be detected by FISH or RT-PCR

DDx ─

─ Malignant Peripheral Nerve Sheath Tumor (MPNST) (if spindle cell predominant; MPNST often S100+, SOX10+, lacks consistent keratin/EMA, no SS18-SSX fusion)

─ Fibrosarcoma (S100/keratin/EMA negative, lacks SS18-SSX fusion)

─ Leiomyosarcoma (smooth muscle markers positive)

─ Unclassified Spindle Cell Sarcoma (diagnosis of exclusion if IHC/molecular are uninformative)

─ Biphasic tumors (e,g,, adenocarcinoma with spindle cell component, mesothelioma; distinguished by IHC profile and clinical context)

─ Solitary Fibrous Tumor (CD34+, STAT6+, characteristic morphology)

Media

Synovial Hemangioma

A benign vascular tumor composed of blood-filled vessels, arising from the synovial membrane of a joint, bursa, or tendon sheath; can be localized or diffuse

Clinical ─

─ Rare; true incidence unknown

─ Typically affects children and young adults (most <30 years old); no clear sex predilection

─ Most common in the knee joint (>50%), followed by elbow, ankle, wrist, fingers, hip

─ Localized type: more common, presents as a discrete, often pedunculated intra-articular mass

─ Diffuse type: less common, involves a large portion or all of the synovium, can be more infiltrative

─ Presents with recurrent joint pain, swelling, hemarthrosis (bloody joint effusion), and limited range of motion; symptoms often exacerbated by activity; palpable mass may be present with localized type

─ Imaging: Plain radiographs may be normal or show soft tissue swelling, joint effusion, or juxta-articular osteopenia; phleboliths (calcified thrombi within vessels) are a characteristic but uncommon finding; MRI is imaging modality of choice: shows lobulated intra-articular mass or diffuse synovial thickening with characteristic serpentine vascular channels that are low signal on T1, high signal on T2, and show avid enhancement; signal voids due to high flow may be seen

─ Prognosis: Benign; local recurrence is common after incomplete excision, especially for diffuse type; arthroscopic or open synovectomy is treatment of choice; embolization may be used for large or difficult lesions

Macro ─ localized type: well-circumscribed, often pedunculated, reddish-purple to brown, spongy or lobulated mass; Diffuse type: thickened, shaggy, reddish-brown synovium with diffuse vascular engorgement

Micro ─

─ Composed of a proliferation of benign blood vessels within synovial stroma; histologic types similar to soft tissue hemangiomas:

─ Cavernous hemangioma (most common): large, dilated, thin-walled vascular spaces lined by flat endothelial cells, filled with blood

─ Capillary hemangioma: lobules of small, capillary-sized vessels lined by bland endothelial cells

─ Arteriovenous hemangioma (mixed): features of both capillary and cavernous types, with some thick-walled arterial vessels and thin-walled venous channels

─ Synovial stroma surrounding vessels is often edematous or fibrotic, may contain hemosiderin-laden macrophages (due to recurrent hemorrhage) and chronic inflammatory cells

─ Synovial lining may be hyperplastic and form villous projections

─ No cytologic atypia, significant mitotic activity, or endothelial multilayering

─ Phleboliths (organized, calcified thrombi) may be present within vascular lumens

Ancillary studies ─

─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FLI1

DDx ─

─ Pigmented Villonodular Synovitis (PVNS)/Diffuse TGCT (sheets of mononuclear cells, giant cells, hemosiderin, foamy cells; lacks the prominent vascular proliferation of hemangioma, though both can have hemosiderin)

─ Lipoma Arborescens (frond-like synovial proliferation with mature adipose tissue, not primarily vascular)

─ Inflammatory Synovitis (e,g,, RA; prominent chronic inflammation, synovial hyperplasia, pannus, but lacks the neoplastic vascular proliferation)

─ Arteriovenous Malformation (AVM) involving joint (direct AV shunts, malformed vessels, not a true neoplasm of capillaries/cavernous channels)

─ Angiosarcoma of synovium (exceedingly rare; malignant endothelial cells, atypia, mitoses, infiltrative growth)

Media

Lipoma Arborescens

A rare, benign, intra-articular lesion characterized by diffuse, villous or frond-like proliferation of the synovium with replacement of subsynovial connective tissue by mature adipose tissue

Clinical ─

─ Rare; true incidence unknown, often an underrecognized cause of chronic joint effusion

─ Typically affects adults (peak 4th to 6th decades); slight male predominance

─ Most common in the knee joint, especially suprapatellar pouch; less commonly hip, shoulder, elbow, ankle, wrist; rarely bilateral

─ Often associated with underlying joint pathology (osteoarthritis, rheumatoid arthritis, trauma, meniscal tear), suggesting it may be a reactive process (synovial lipomatous metaplasia) rather than a true neoplasm, though this is debated

─ Presents with insidious onset of painless or mildly painful joint swelling, recurrent effusions, and limited range of motion; locking or crepitus may occur

─ Imaging: Plain radiographs may be normal or show soft tissue swelling/effusion, and signs of underlying OA if present; MRI is characteristic and diagnostic: frond-like, villous synovial mass with signal intensity identical to subcutaneous fat on all sequences (high T1, intermediate to high T2, suppresses with fat saturation); joint effusion is common

─ Prognosis: Benign; symptoms often relieved by synovectomy (arthroscopic or open); recurrence is rare if completely excised

Macro ─ diffuse thickening of synovium with innumerable, yellow, finger-like or frond-like villous projections filled with fat; resembles a "leafy tree" (arborescens); joint often contains serous or serosanguinous effusion

Micro ─

─ Villous or papillary synovial fronds lined by unremarkable synovial lining cells (1-2 layers thick)

─ Subsynovial connective tissue within the fronds is almost entirely replaced by mature, benign adipose tissue (lobules of adipocytes)

─ Adipocytes are univacuolated with small, eccentric, bland nuclei, identical to normal fat cells

─ Capillaries and small venules are present within the fatty stroma

─ Mild chronic inflammation (lymphocytes, plasma cells) may be present in the stroma or around vessels

─ No lipoblasts, cytologic atypia, significant mitotic activity, or necrosis (distinguishes from liposarcoma)

─ Underlying synovium may show features of associated conditions like OA or RA

Ancillary studies ─

─ Not usually required if imaging is characteristic; S100 protein will highlight adipocytes

DDx ─

─ Synovial Lipoma (true benign neoplasm of fat; typically a discrete, localized, encapsulated fatty mass within the joint, not a diffuse villous proliferation of synovium)

─ Pigmented Villonodular Synovitis (PVNS)/Diffuse TGCT (hemosiderin deposition causing low T1/T2 signal, different cell population)

─ Synovial Hemangioma (vascular proliferation, different MRI signal, not primarily fatty)

─ Inflammatory Synovitis (e,g,, RA; prominent inflammation, synovial hyperplasia, pannus, but not diffuse fatty replacement)

─ Osteoarthritis with prominent synovial effusion (synovial hypertrophy is less frond-like and not primarily fatty)

─ Well-differentiated Liposarcoma involving joint (exceedingly rare; look for atypical cells, fibrous bands, MDM2 amplification)

Media

Infantile Hamartoma of the Chest Wall

A rare, benign, congenital lesion of the ribs in infants, characterized by a disorganized admixture of cartilage, bone, and mesenchymal spindle cells, often with secondary aneurysmal bone cyst-like changes

Clinical ─

─ Rare; most cases present at birth or within the first year of life

─ No clear sex predilection

─ Almost exclusively involves ribs, often multiple contiguous ribs; typically posterior or lateral aspect of chest wall

─ Usually presents as a firm, fixed, painless mass on the chest wall; may cause respiratory distress if very large and compressing lung, or chest wall deformity

─ Imaging: Expansile, often large, multiloculated mass arising from ribs, with variable calcification/ossification; may show cortical destruction and soft tissue extension, mimicking a malignant tumor; MRI shows heterogeneous signal with solid and cystic (ABC-like) components

─ Prognosis: Benign; local recurrence is possible after incomplete excision, but complete resection is usually curative; no metastatic potential; spontaneous regression has been rarely reported

Macro ─ firm, lobulated, gray-white to tan mass expanding and replacing ribs; cut surface shows a variegated appearance with cartilaginous nodules, bony spicules, fibrous areas, and often blood-filled cystic spaces (ABC-like changes)

Micro ─

─ Disorganized admixture of three main components:

1, Cartilage: Irregular islands and nodules of hyaline cartilage, often hypercellular with mild chondrocyte atypia (enlarged, hyperchromatic nuclei, binucleation), resembling enchondroma or low-grade chondrosarcoma if viewed in isolation; areas of endochondral ossification are common

2, Bone: Immature woven bone and mature lamellar bone trabeculae, often admixed with the cartilage and fibrous tissue

3, Spindle cell stroma: Bland fibroblastic or primitive mesenchymal spindle cells, often with a myxoid background; can be cellular but lacks significant atypia or high mitotic activity

─ Aneurysmal bone cyst (ABC)-like changes are very common and can be extensive: blood-filled cystic spaces separated by fibrous septa containing fibroblasts, osteoclast-like giant cells, and reactive bone (similar to ABC)

─ Entire lesion is a disorganized, hamartomatous proliferation, not a true neoplasm with clonal growth

Ancillary studies ─

─ Not typically required for diagnosis if clinical, imaging, and histologic features are classic for this entity in an infant chest wall

─ IHC: Cartilage is S100 positive; spindle cells are vimentin positive

DDx ─

─ Chondrosarcoma (extremely rare in infants; would show more overt malignant cytologic features, destructive growth, lacks the disorganized admixture of infantile hamartoma)

─ Osteosarcoma (also extremely rare in infants; malignant osteoid production by sarcoma cells)

─ Mesenchymal Chondrosarcoma (biphasic with small round cells and cartilage; very rare in infants)

─ Aneurysmal Bone Cyst (if ABC changes are predominant; look for solid hamartomatous areas)

─ Fibrous Dysplasia with cartilage (FD has characteristic woven bone in fibrous stroma, GNAS mutation)

─ Ewing Sarcoma/Other Small Round Blue Cell Tumors (different morphology, specific IHC/molecular)

Media

Ecchordosis Physaliphora

A benign congenital remnant of notochordal tissue, typically found as an incidental, asymptomatic gelatinous nodule on the clivus or sacrococcygeal region, attached to dura

Clinical ─

─ Incidental finding in up to 2% of autopsies, particularly at the clivus

─ Believed to be a developmental rest of notochordal tissue that failed to regress

─ Most common location is the dorsal surface of the clivus (spheno-occipital region), attached to the dura mater; less commonly found in the sacrococcygeal area

─ Almost always asymptomatic and discovered incidentally at autopsy or on imaging performed for other reasons

─ Rarely, large lesions may cause symptoms due to compression of adjacent structures (e,g,, brainstem, cranial nerves)

─ Imaging: Well-demarcated, lobulated, non-enhancing lesion on CT/MRI; typically T1 hypointense and markedly T2 hyperintense (due to high water content of gelatinous matrix); usually located extradurally, often protruding through a small dural defect; no bone destruction or aggressive features

─ Prognosis: Benign and static lesion; no treatment required if asymptomatic; surgical excision may be considered for rare symptomatic cases, but recurrence is possible if incompletely removed

Macro ─ soft, gelatinous, translucent, lobulated nodule or mass, typically small (a few mm to 1-2 cm, rarely larger); attached to the dura

Micro ─

─ Composed of clusters and cords of physaliphorous cells embedded in an abundant, loose myxoid stroma

─ Physaliphorous cells: large, vacuolated cells with abundant, clear to pale eosinophilic, bubbly cytoplasm (due to intracytoplasmic mucin) and small, central, bland nuclei; resemble mature notochordal cells

─ Cells are arranged in small groups or cords, often within a delicate fibrous network

─ Stroma is abundant, hypocellular, and myxoid or gelatinous

─ No significant cytologic atypia, pleomorphism, or mitotic activity

─ No bone destruction or infiltration of surrounding tissues (lesion is well-circumscribed by dura or fibrous tissue)

─ Lacks the lobular architecture, infiltrative growth, and increased cellularity/atypia of chordoma

Ancillary studies ─

─ IHC: Physaliphorous cells are positive for S100 protein, cytokeratins (especially broad-spectrum, CK18, CAM5,2), EMA, and brachyury (a specific marker of notochordal differentiation)

DDx ─

─ Chordoma (key differential; malignant, invasive, destructive lesion with lobular architecture, more cellularity, often mild to moderate atypia, myxoid stroma but also more solid areas; important to distinguish based on imaging and lack of bone destruction in ecchordosis)

─ Benign Notochordal Cell Tumor (intraosseous lesion, different imaging and location, though histologically similar cell type)

─ Meningioma (especially chordoid or clear cell variants; arises from dura, different IHC profile - EMA+, S100 variable, brachyury negative)

─ Metastatic Mucinous Adenocarcinoma (can have physaliphorous-like cells; IHC for specific carcinoma markers, brachyury negative, clinical history)

─ Chondrosarcoma (if myxoid and near skull base; S100+, but lacks physaliphorous cells and brachyury, different matrix)

Media

Benign Notochordal Cell Tumor

A rare, benign intraosseous lesion of the axial skeleton composed of physaliphorous cells identical to those of ecchordosis physaliphora and chordoma, but lacking the aggressive features of chordoma; considered by some to be an intraosseous counterpart of ecchordosis physaliphora or a precursor to chordoma

Clinical ─

─ Rare; incidence not well established, many are likely incidental findings or misdiagnosed

─ Typically affects adults (mean age ~50-60 years); can occur over a wide age range

─ No clear sex predilection

─ Almost exclusively involves vertebral bodies (clivus, cervical, thoracic, lumbar, sacrum); often found incidentally during imaging for back pain or other reasons

─ Usually asymptomatic; may cause mild, nonspecific pain; no neurologic symptoms or bone destruction unless associated with a chordoma

─ Imaging: Well-circumscribed, intraosseous lesion with sclerotic margins and no cortical destruction or soft tissue extension; typically T1 hypointense and T2 hyperintense on MRI, similar to ecchordosis and chordoma, but confined to bone without aggressive features

─ Prognosis: Benign; most are stable or slow-growing; relationship to chordoma is debated (some consider it a precursor lesion, others a distinct benign entity); malignant transformation to chordoma has been rarely documented, so follow-up is often recommended

Macro ─ not usually encountered as a gross surgical specimen unless an incidental finding in a resection for another reason; if seen, would be gelatinous or mucoid tissue within bone

Micro ─

─ Intraosseous proliferation of physaliphorous cells similar to those in ecchordosis physaliphora and conventional chordoma

─ Cells are large, with abundant clear, bubbly (vacuolated) cytoplasm and small, central, bland nuclei

─ Arranged in sheets, cords, or small clusters within the bone marrow spaces, often admixed with hematopoietic or fatty marrow

─ Myxoid stroma is usually scant or absent between the cells within the marrow spaces (unlike the abundant stroma of ecchordosis or chordoma)

─ No significant cytologic atypia, pleomorphism, or mitotic activity

─ No lobular architecture, bone destruction, or infiltration of surrounding soft tissues (key features distinguishing from chordoma)

─ Entraps pre-existing host bone trabeculae without destroying them

Ancillary studies ─

─ IHC: Physaliphorous cells are positive for S100 protein, cytokeratins (broad-spectrum, CK18), EMA, and brachyury (nuclear staining)

DDx ─

─ Chordoma (especially early or low-grade; chordoma shows lobular architecture, infiltrative destructive growth, often more cellularity/atypia, and typically a more prominent myxoid stroma)

─ Ecchordosis Physaliphora (extradural, dural-based lesion, not intraosseous, though cell type is identical)

─ Metastatic Carcinoma (especially clear cell renal cell carcinoma or mucinous adenocarcinoma; IHC for specific carcinoma markers, brachyury negative)

─ Chondrosarcoma (if focal physaliphorous-like cells are present; look for typical cartilaginous matrix, different IHC)

─ Normal notochordal remnants (microscopic rests, not a discrete lesion)

Media

Chordoma

A rare, locally aggressive to malignant neoplasm of notochordal origin, characterized by physaliphorous cells in a myxoid stroma, arising exclusively in the axial skeleton

Clinical ─

─ Rare, accounts for ~1-4% of all primary malignant bone tumors

─ Peak incidence in 5th to 7th decades (median age ~55-65 years); rare <30 years

─ Male predominance (1,5-2:1)

─ Arises exclusively along the axial skeleton, in remnants of the notochord:

─ Sacrococcygeal region (~50% of cases)

─ Spheno-occipital region (clivus, skull base) (~35% of cases)

─ Mobile spine (vertebrae - cervical > lumbar > thoracic) (~15% of cases)

─ Presents with slow onset of symptoms related to location and compression of adjacent structures:

─ Sacrococcygeal: low back pain, sciatica, constipation, urinary/fecal incontinence, palpable presacral mass

─ Skull base: headaches, cranial nerve palsies (diplopia, facial pain/numbness, dysphagia, hoarseness), visual disturbances, pituitary dysfunction

─ Mobile spine: neck/back pain, radiculopathy, myelopathy, cord compression

─ Imaging: Destructive, often large, midline or paramidline mass causing bone lysis and often a significant soft tissue component; CT shows bone destruction, soft tissue mass, and often intratumoral calcifications (sequestered bone fragments); MRI shows T1 hypointense, T2 hyperintense lobulated mass with heterogeneous enhancement; avid enhancement of septa

─ Prognosis: Locally aggressive with high rates of local recurrence after surgery (30-70%); distant metastases (lungs, liver, bone, lymph nodes) occur in ~20-40% of cases, often late in the disease course; 5-year survival ~60-80%, 10-year survival ~40-50%; poor prognostic factors include large size, sacral location, incomplete resection, dedifferentiation, certain molecular markers

Macro ─ lobulated, gelatinous, translucent, gray-white to bluish-gray tumor; often with areas of hemorrhage, necrosis, or cystic change; typically causes extensive bone destruction and forms a large soft tissue mass

Micro ─

Characteristic features:

─ Lobular architecture: tumor grows in distinct lobules separated by fibrous septa

─ Physaliphorous cells: large, polygonal cells with abundant, clear, bubbly (vacuolated) cytoplasm due to intracytoplasmic mucin, and small, central, often bland nuclei; these are the hallmark cells and resemble mature notochordal cells

─ Smaller, non-vacuolated epithelioid or spindle cells with eosinophilic cytoplasm may also be present

─ Cells are arranged in cords, nests, sheets, or a reticular pattern within an abundant extracellular myxoid stroma

─ Myxoid stroma is Alcian blue positive

─ Cytologic atypia is usually mild to moderate; mitotic activity is generally low, but can be higher in aggressive or dedifferentiated variants

─ Bone destruction and infiltration of surrounding soft tissues are common

─ Variants:

─ Chondroid chordoma: contains islands of hyaline cartilage (S100+, brachyury negative) admixed with typical chordoma areas; more common in skull base, may have slightly better prognosis

─ Dedifferentiated chordoma: rare, aggressive variant with abrupt transition from conventional chordoma to a high-grade sarcoma (e,g,, UPS, fibrosarcoma, osteosarcoma); very poor prognosis

Ancillary studies ─

─ IHC: Tumor cells are consistently positive for cytokeratins (broad-spectrum, AE1/AE3, CAM5,2, CK18, CK19), EMA, S100 protein, and brachyury (nuclear stain; highly specific and sensitive marker for notochordal differentiation)

DDx ─

─ Chondrosarcoma (especially myxoid or dedifferentiated variants; key differential, especially in skull base/spine; chondrosarcoma is S100+, brachyury negative, lacks true physaliphorous cells, different matrix properties)

─ Metastatic Mucinous Adenocarcinoma (can have signet ring cells mimicking physaliphorous cells; IHC for specific carcinoma markers like CDX2, CK20, and brachyury negativity are crucial)

─ Metastatic Renal Cell Carcinoma (clear cell type; PAX8+, CAIX+, brachyury negative)

─ Ecchordosis Physaliphora/Benign Notochordal Cell Tumor (benign, lack bone destruction and infiltrative growth, less cellular, less atypia, though share IHC profile)

─ Myxopapillary Ependymoma (if in sacrococcygeal region; GFAP+, different morphology)

─ Chordoid Meningioma (skull base; EMA+, S100 variable, brachyury negative, lacks physaliphorous cells)

Media

Degenerative Joint Disease (Osteoarthritis)

A common, chronic disorder characterized by progressive loss of articular cartilage, subchondral bone remodeling, and synovial inflammation, leading to joint pain, stiffness, and functional impairment

Clinical ─

─ Most common form of arthritis; leading cause of disability in older adults

─ Prevalence increases with age (rare <40 years, common >60 years); affects women more than men, especially after menopause

─ Primary (idiopathic) OA: no identifiable cause, likely multifactorial (age, genetics, mechanical stress)

─ Secondary OA: due to pre-existing joint abnormality or injury (e,g,, trauma, developmental dysplasia, inflammatory arthritis, AVN, metabolic disorders)

─ Most commonly affects weight-bearing joints (knees, hips) and hands (DIP, PIP, 1st CMC joints); also spine (facet joints, intervertebral discs), shoulders, feet

─ Presents with insidious onset of joint pain (worse with activity, relieved by rest), stiffness (especially morning stiffness <30 min, or after inactivity - "gelling"), limited range of motion, crepitus, and joint deformity (e,g,, Heberden's/Bouchard's nodes in hands, varus/valgus deformity of knee)

─ Imaging: Cardinal radiographic features include:

1, Joint space narrowing (asymmetric)

2, Subchondral sclerosis (increased bone density beneath cartilage)

3, Osteophyte formation (bony spurs at joint margins)

4, Subchondral cyst formation (geodes)

─ MRI can show cartilage defects, bone marrow lesions (edema-like), meniscal tears, synovial effusion/hypertrophy earlier than radiographs

─ Prognosis: Chronic, progressive disorder; no cure; management focuses on symptom relief, improving function, and slowing progression (lifestyle modification, physical therapy, analgesics, NSAIDs, intra-articular injections, joint replacement surgery for end-stage disease)

Macro ─ articular cartilage shows fibrillation (surface fraying), erosion, ulceration, and loss, exposing underlying eburnated (ivory-like, polished) subchondral bone; osteophytes at joint margins; subchondral cysts may be visible; synovium may be thickened and hyperemic

Micro ─

Articular cartilage changes:

─ Early: superficial fibrillation, chondrocyte cloning (clusters), increased water content, loss of proteoglycans

─ Progressive: deeper clefts and fissures extending to subchondral bone, loss of chondrocytes, cartilage thinning and erosion

─ Late: full-thickness cartilage loss, exposure of subchondral bone

Subchondral bone changes:

─ Sclerosis: thickening of bone trabeculae due to increased osteoblastic activity

─ Cysts (geodes): fluid-filled cavities within subchondral bone, often with a fibrous lining, resulting from intrusion of synovial fluid or bone necrosis

Osteophytes:

─ Bony outgrowths at joint margins, formed by endochondral ossification of new cartilage and fibrocartilage

Synovial changes:

─ Mild to moderate synovial hyperplasia and villous hypertrophy

─ Chronic inflammation (lymphocytes, plasma cells)

─ Fibrosis of joint capsule

─ Loose bodies (cartilage or osteocartilaginous fragments) may be present in joint space or embedded in synovium

Ancillary studies ─

─ Not usually required for diagnosis of primary OA; lab tests (ESR, CRP, RF, ANA) are typically normal or negative, used to exclude inflammatory arthritis

─ Synovial fluid analysis: non-inflammatory or mildly inflammatory (WBC <2000/μL, predominantly mononuclear cells)

DDx ─

─ Inflammatory Arthritis (e,g,, Rheumatoid Arthritis, Psoriatic Arthritis, Gout, Pseudogout): more prominent synovial inflammation, specific clinical/serologic/crystal findings, different radiographic patterns (e,g,, erosions in RA, symmetrical joint space narrowing)

─ Septic Arthritis: acute onset, fever, markedly inflammatory synovial fluid, positive cultures

─ Avascular Necrosis (especially early stages before collapse; can lead to secondary OA)

─ Neuropathic Arthropathy (Charcot joint): severe joint destruction, instability, often less pain than expected for degree of damage, underlying neurologic disorder

─ Hemochromatosis/Wilson's Disease/Ochronosis (metabolic arthropathies causing secondary OA, specific clinical/lab findings)

Media

Rheumatoid Arthritis

A chronic, systemic autoimmune inflammatory disease primarily affecting synovial joints, leading to progressive cartilage and bone destruction, joint deformity, and functional disability; can also have extra-articular manifestations

Clinical ─

─ Affects ~0,5-1% of adult population worldwide; peak onset 30-50 years

─ Female predominance (2-3:1)

─ Genetic predisposition (HLA-DRB1 shared epitope alleles) and environmental factors (e,g,, smoking, infections) play a role in pathogenesis

─ Characterized by symmetric polyarthritis, typically involving small joints of hands (MCP, PIP) and feet (MTP), wrists, elbows, shoulders, knees, ankles; DIP joints usually spared (unlike OA)

─ Presents with insidious onset of joint pain, stiffness (especially morning stiffness >1 hour), swelling, warmth, and tenderness; fatigue, malaise, low-grade fever may be present

─ Joint deformities develop over time (e,g,, ulnar deviation, swan neck/boutonniere deformities of fingers, rheumatoid nodules)

─ Extra-articular manifestations: rheumatoid nodules (subcutaneous, visceral), vasculitis, sicca syndrome (Sjögren's), interstitial lung disease, pericarditis, scleritis, Felty's syndrome (RA, splenomegaly, neutropenia)

─ Imaging: Early: soft tissue swelling, periarticular osteopenia; Later: symmetric joint space narrowing, marginal bone erosions (at bare areas where synovium contacts bone), subluxations/deformities; MRI is more sensitive for early synovitis, tenosynovitis, and erosions

─ Prognosis: Chronic, progressive disease; modern "treat-to-target" strategies with early use of DMARDs (disease-modifying antirheumatic drugs, e,g,, methotrexate) and biologic agents (e,g,, TNF inhibitors, rituximab) have significantly improved outcomes, reducing joint damage and disability; untreated RA leads to severe joint destruction and functional loss

Macro ─ Synovium is markedly thickened, hyperemic, edematous, and forms exuberant villous projections (pannus) that grow over and erode articular cartilage and underlying bone; joint effusions are common; articular cartilage is eroded and destroyed; bone shows erosions and osteoporosis

Micro ─

Synovitis is the hallmark:

─ Synovial lining cell hyperplasia (increased layers of synoviocytes) and hypertrophy

─ Dense inflammatory infiltrate in subsynovial stroma, composed primarily of lymphocytes (T and B cells, often forming lymphoid follicles with germinal centers) and plasma cells; macrophages, mast cells, and neutrophils also present

─ Increased vascularity (angiogenesis)

─ Fibrin deposition on synovial surface and within stroma

Pannus formation:

─ Proliferating, invasive synovial tissue (pannus) extending over articular cartilage, composed of fibroblasts, macrophages, inflammatory cells, and new blood vessels; directly erodes cartilage and bone through production of enzymes (MMPs, cathepsins) and cytokines (TNF-α, IL-1, IL-6)

Articular cartilage destruction:

─ Loss of proteoglycans, chondrocyte apoptosis/necrosis, direct erosion by pannus

Bone erosions:

─ Occur at joint margins (bare areas) and subchondral bone, mediated by osteoclasts activated by RANKL produced by synovial fibroblasts and T cells

Rheumatoid nodules (if present, typically subcutaneous over pressure points):

─ Central fibrinoid necrosis surrounded by palisading histiocytes and a cuff of chronic inflammatory cells

Ancillary studies ─

─ Serology: Rheumatoid Factor (RF - autoantibody against Fc portion of IgG) positive in ~70-80% (not specific); Anti-citrullinated protein antibodies (ACPA, e,g,, anti-CCP) positive in ~60-70% (more specific than RF, associated with more aggressive disease)

─ Inflammatory markers: Elevated ESR and CRP common during active disease

─ Synovial fluid analysis: Inflammatory (WBC 2,000-75,000/μL, predominantly neutrophils)

DDx ─

─ Other Inflammatory Polyarthritides:

─ Psoriatic Arthritis (asymmetric, DIP involvement, dactylitis, enthesitis, skin/nail psoriasis, RF often negative)

─ Systemic Lupus Erythematosus (SLE) Arthritis (often non-erosive or Jaccoud's arthropathy, other systemic features of SLE, specific autoantibodies like ANA, anti-dsDNA)

─ Spondyloarthropathies (e,g,, Ankylosing Spondylitis, Reactive Arthritis; axial involvement, enthesitis, HLA-B27 association, RF negative)

─ Crystal Arthropathies (Gout, Pseudogout; crystal identification in synovial fluid, different radiographic features)

─ Osteoarthritis (less inflammation, DIP/PIP/1st CMC involvement in hands, osteophytes, asymmetric joint space narrowing, RF/ACPA negative)

─ Septic Arthritis (acute monoarthritis, fever, markedly inflammatory synovial fluid, positive cultures)

Media

Septic Arthritis

Inflammation of a joint caused by infection with microorganisms, most commonly bacteria; a rheumatologic emergency requiring prompt diagnosis and treatment to prevent irreversible joint damage

Clinical ─

─ Can occur at any age, but more common in young children, elderly, and immunocompromised individuals

─ Risk factors: pre-existing joint disease (e,g,, RA, OA), prosthetic joint, IV drug use, recent joint surgery/injection, skin infection, bacteremia from distant site, diabetes, immunosuppression

─ Most common causative organisms: Staphylococcus aureus (most frequent overall); Streptococcus species (especially in children); Neisseria gonorrhoeae (sexually active young adults - gonococcal arthritis); Gram-negative bacilli (elderly, IV drug users, immunocompromised); less commonly Haemophilus influenzae (unvaccinated children), fungi, mycobacteria, viruses

─ Typically presents as acute monoarthritis (single joint involvement in ~80-90%) with severe joint pain, swelling, warmth, erythema, and markedly restricted range of motion; fever and systemic signs of infection (malaise, leukocytosis) are common

─ Most commonly affects large joints: knee (>50%), hip, shoulder, wrist, ankle, elbow; polyarticular involvement is more common in patients with RA or sepsis

─ Imaging: Early radiographs may only show soft tissue swelling and joint effusion; later (7-14 days), joint space narrowing (due to cartilage destruction), periarticular osteopenia, and marginal/subchondral bone erosions may become evident; MRI is sensitive for detecting joint effusion, synovitis, cartilage damage, and associated osteomyelitis or soft tissue abscesses

─ Prognosis: Depends on promptness of diagnosis and treatment, virulence of organism, and host factors; untreated or delayed treatment can lead to rapid, irreversible cartilage and bone destruction, joint deformity, ankylosis, sepsis, and even death; with appropriate antibiotics and drainage, good outcome is possible, but residual joint damage occurs in 25-50% of cases

Macro ─ joint effusion is typically purulent (turbid, yellowish-green pus); synovium is acutely inflamed (hyperemic, edematous, thickened); articular cartilage appears dull, eroded, and may be destroyed; underlying bone may show erosions or signs of osteomyelitis

Micro ─

Synovial fluid:

─ Markedly inflammatory: high white blood cell count (WBC typically >50,000/μL, often >100,000/μL) with >90% neutrophils; low glucose compared to serum; poor mucin clot; Gram stain may identify organisms (positive in ~30-50% of bacterial arthritis); culture is usually positive

Synovial membrane biopsy:

─ Acute synovitis: marked edema, vascular congestion, and dense infiltration by neutrophils; synovial lining cell hyperplasia and necrosis may be present

─ Fibrinopurulent exudate on synovial surface

─ In later stages or chronic infection: chronic inflammatory infiltrate (lymphocytes, plasma cells), granulation tissue formation, fibrosis, and pannus-like synovial proliferation may occur

Articular cartilage:

─ Chondrocyte necrosis, loss of proteoglycans, enzymatic degradation of matrix by bacterial and host enzymes (MMPs, aggrecanases), leading to full-thickness cartilage destruction

Underlying bone:

─ Subchondral bone erosion, osteoclastic resorption, and potentially contiguous osteomyelitis with neutrophilic infiltrate and bone necrosis

Ancillary studies ─

─ Synovial Fluid Analysis: Essential for diagnosis (cell count with differential, Gram stain, crystal analysis to exclude crystal arthropathy, culture and sensitivity)

─ Blood Cultures: May be positive, especially in hematogenous septic arthritis

─ Inflammatory Markers: Elevated ESR and CRP are typical

DDx ─

─ Crystal Arthropathy (Gout, Pseudogout): acute monoarthritis, but synovial fluid shows crystals (urate or CPPD) and typically lower WBC count than septic arthritis (though overlap exists); Gram stain/culture negative

─ Reactive Arthritis (Reiter's syndrome): oligoarthritis, often asymmetric, follows urogenital/gastrointestinal infection, associated with enthesitis, dactylitis, extra-articular features (uveitis, urethritis), HLA-B27 common; synovial fluid inflammatory but sterile

─ Rheumatoid Arthritis (acute flare): can mimic septic monoarthritis, but RA is usually polyarticular and symmetric; synovial fluid inflammatory, RF/ACPA may be positive

─ Hemarthrosis (e,g,, due to trauma, coagulopathy): bloody joint effusion, less inflammatory WBC count

─ Lyme Arthritis: oligoarthritis, history of tick bite/erythema migrans, positive Lyme serology; synovial fluid inflammatory, PCR for Borrelia burgdorferi may be positive

─ Osteoarthritis (acute flare with effusion): less inflammatory synovial fluid, radiographic signs of OA

Media

Neuropathic Joint (Charcot Joint)

A progressive, destructive arthropathy resulting from impaired sensory innervation to a joint, leading to loss of protective reflexes, recurrent microtrauma, and ultimately severe joint disorganization

Clinical ─

─ Develops in individuals with underlying neurological disorders causing sensory neuropathy:

─ Diabetes mellitus (most common cause in Western countries, typically affecting foot and ankle - "diabetic foot")

─ Syringomyelia (typically affecting shoulder, elbow - upper limb Charcot)

─ Tabes dorsalis (tertiary syphilis; typically affecting knee, hip - lower limb Charcot)

─ Other causes: spinal cord injury, peripheral nerve injury, leprosy, Charcot-Marie-Tooth disease, alcoholism, congenital insensitivity to pain

─ Typically presents with a swollen, warm, erythematous, and often unstable joint, but with disproportionately little pain (due to sensory loss); crepitus and deformity are common

─ "Bag of bones" feel on palpation due to joint instability and fragmentation

─ Imaging: Characterized by the "6 D's" of destruction:

1, Distension (joint effusion)

2, Density (sclerosis, osteophytes)

Debris (intra-articular loose bodies, bony fragments)

4, Dislocation (subluxation)

5, Disorganization (loss of normal joint architecture)

6, Destruction (severe articular cartilage and bone damage)

─ Radiographs show marked joint destruction, sclerosis, fragmentation, osteophytosis, subluxation, and soft tissue swelling with calcific debris; can be hypertrophic (bone-forming) or atrophic (bone-resorbing) patterns

─ Prognosis: Chronic, progressive condition; often leads to severe deformity, instability, and functional impairment; high risk of secondary infection, ulceration, and amputation (especially in diabetic foot)

Macro ─ severe joint disorganization with cartilage loss, bone fragmentation, osteophytes, loose bodies, thickened joint capsule, and often large effusions; bone may be sclerotic or resorbed

Micro ─

─ Marked articular cartilage destruction, often with full-thickness loss and eburnation of underlying bone

─ Subchondral bone sclerosis, cyst formation, and microfractures

─ Extensive bone and cartilage debris embedded within the synovium and joint capsule, often eliciting a foreign body giant cell reaction

─ Synovial hyperplasia and chronic inflammation (lymphocytes, plasma cells)

─ Fibrosis and thickening of the joint capsule and ligaments

─ Heterotopic ossification may be present in periarticular soft tissues

─ Underlying nerve pathology (if biopsied, which is rare) would show features of the specific neuropathy

Ancillary studies ─

─ Clinical evaluation for underlying neurologic disorder is key

─ Nerve conduction studies/EMG can confirm neuropathy

─ Synovial fluid is usually non-inflammatory or mildly inflammatory, may contain cartilage/bone fragments

DDx ─

─ Septic Arthritis (acute, painful, febrile, purulent synovial fluid, positive cultures; can co-exist with Charcot joint, especially in diabetic foot)

─ Severe Osteoarthritis (less destructive, more pain relative to damage, lacks the extensive debris and disorganization of Charcot)

─ Rheumatoid Arthritis (symmetric polyarthritis, inflammatory synovial fluid, erosions, specific serology)

─ Crystal Arthropathy (acute flares, crystal identification in synovial fluid)

─ Avascular Necrosis with collapse (can lead to severe joint damage, but usually more localized, specific imaging features of AVN)

Media

Gout (Monosodium Urate Crystal Deposition Disease)

A metabolic disorder characterized by hyperuricemia and deposition of monosodium urate (MSU) crystals in and around joints and soft tissues, leading to recurrent acute inflammatory arthritis (gouty arthritis), chronic tophaceous gout, and urate nephropathy

Clinical ─

─ Most common inflammatory arthritis in men >40 years; prevalence increases with age

─ Male predominance (3-4:1 before menopause, evens out later); rare in premenopausal women

─ Risk factors: hyperuricemia (due to overproduction or underexcretion of uric acid), genetic predisposition, high purine diet (red meat, seafood, alcohol - especially beer), obesity, hypertension, diuretic use, renal insufficiency, certain medications

─ Acute gouty arthritis: sudden onset of severe joint pain, swelling, warmth, erythema (often mimicking cellulitis); typically monoarticular, most common site is first metatarsophalangeal joint (podagra, ~50% of first attacks); also affects midfoot, ankle, knee, wrist, fingers; attacks are self-limiting (days to weeks) but recurrent

─ Intercritical gout: asymptomatic periods between acute attacks

─ Chronic tophaceous gout: develops after years of recurrent gout; characterized by deposition of MSU crystals (tophi) in synovium, cartilage, bone, tendons, bursae, and subcutaneous tissue (especially helix of ear, olecranon bursa, extensor surfaces of forearms/fingers); tophi are firm, non-tender nodules, may ulcerate and discharge chalky material

─ Associated conditions: urate nephrolithiasis, chronic urate nephropathy, hypertension, cardiovascular disease, metabolic syndrome

─ Imaging (Acute): Soft tissue swelling, joint effusion; radiographs often normal

─ Imaging (Chronic tophaceous): "Punched-out" bone erosions with sclerotic margins and overhanging edges (rat-bite erosions), often juxta-articular, caused by tophi; joint space usually preserved until late; soft tissue masses (tophi) may be visible, sometimes with calcification; dual-energy CT can specifically identify urate deposits

─ Prognosis: Good with appropriate management (lifestyle modification, urate-lowering therapy); untreated chronic gout leads to progressive joint damage, deformity, disability, and renal complications

Macro ─ tophi are chalky white, pasty or firm deposits of MSU crystals; synovial fluid during acute attack is inflammatory and may be cloudy

Micro ─

Synovial fluid (acute attack):

─ Inflammatory effusion (WBC often >20,000/μL, predominantly neutrophils)

─ MSU crystals: needle-shaped, negatively birefringent under polarized light (yellow when parallel to compensator axis, blue when perpendicular)

Tophi/Synovial biopsy:

─ Aggregates of acicular (needle-shaped) MSU crystals, often arranged in radiating clusters (sheaves)

─ Crystals are typically dissolved out during routine formalin fixation and paraffin embedding, leaving amorphous eosinophilic or basophilic spaces (ghosts of crystals) surrounded by a foreign body giant cell granulomatous reaction (palisading histiocytes, lymphocytes, plasma cells)

─ Alcohol fixation better preserves MSU crystals

─ Fibrosis and chronic inflammation around tophi

─ Cartilage and bone erosion by tophaceous deposits

Ancillary studies ─

─ Synovial Fluid Analysis: Demonstration of MSU crystals is diagnostic gold standard

─ Serum Uric Acid: Often elevated (>6,8 mg/dL), but can be normal during acute attack; hyperuricemia alone is not diagnostic of gout

─ 24-hour Urinary Uric Acid: To differentiate overproducers from underexcreters (guides urate-lowering therapy choice)

DDx ─

─ Pseudogout (CPPD crystal deposition disease): acute monoarthritis, but synovial fluid shows rhomboid-shaped, positively birefringent CPPD crystals

─ Septic Arthritis: acute monoarthritis, fever, purulent synovial fluid, positive Gram stain/culture

─ Cellulitis (if overlying skin erythema is prominent): no joint effusion, different clinical picture

─ Rheumatoid Arthritis (if polyarticular chronic gout): different joint distribution, erosions, serology (RF/ACPA)

─ Osteoarthritis with acute flare: less inflammatory synovial fluid, radiographic signs of OA

Media

Calcium Pyrophosphate Dihydrate Crystal Deposition Disease (Pseudogout/CPPD)

A common metabolic arthropathy characterized by deposition of calcium pyrophosphate dihydrate (CPPD) crystals in articular cartilage (chondrocalcinosis) and other periarticular tissues, leading to a spectrum of clinical manifestations including acute inflammatory arthritis (pseudogout), chronic degenerative arthropathy, and asymptomatic chondrocalcinosis

Clinical ─

─ Prevalence increases markedly with age (rare <50 years, ~10-15% in ages 65-75, up to 50% in >85 years)

─ No clear sex predilection

─ Most cases are idiopathic (sporadic); can be associated with metabolic disorders (hyperparathyroidism, hemochromatosis, hypomagnesemia, hypophosphatasia), trauma, osteoarthritis, or be familial (autosomal dominant, mutations in ANKH gene)

─ Clinical presentations:

1, Asymptomatic chondrocalcinosis (most common): incidental radiographic finding

2, Acute CPPD crystal arthritis (Pseudogout): sudden onset of severe monoarticular or oligoarticular inflammatory arthritis, mimicking gout; most common in knee, wrist, shoulder, ankle, elbow; attacks are self-limiting (days to weeks) but can be recurrent

3, Chronic CPPD crystal inflammatory arthritis: chronic polyarticular inflammation resembling rheumatoid arthritis, with symmetric involvement of wrists, MCPs, PIPs, knees

4, CPPD arthropathy with severe osteoarthritis: progressive degenerative joint disease, often in atypical joints for OA (e,g,, wrist, MCPs, shoulder, elbow, ankle) or with more severe changes than typical OA (e,g,, prominent subchondral cysts, "squared-off" bone ends)

─ Imaging: Chondrocalcinosis (calcification of hyaline and fibrocartilage) is the hallmark radiographic finding: linear or punctate calcific densities in articular cartilage (especially knee, wrist, hip, shoulder), menisci of knee, triangular fibrocartilage of wrist, symphysis pubis, intervertebral discs; dual-energy CT can also detect CPPD deposits

─ Prognosis: Variable; asymptomatic chondrocalcinosis requires no treatment; pseudogout attacks are self-limiting but recurrent; chronic CPPD arthropathy can lead to significant joint damage and disability, similar to severe OA

Macro ─ chalky white, punctate or linear deposits of CPPD crystals within cartilage or synovium; synovial fluid during acute attack is inflammatory

Micro ─

Synovial fluid (acute attack):

─ Inflammatory effusion (WBC often 10,000-50,000/μL, predominantly neutrophils)

─ CPPD crystals: rhomboid-shaped, rod-shaped, or acicular; weakly positively birefringent under polarized light (blue when parallel to compensator axis, yellow when perpendicular)

Cartilage/Synovial biopsy:

─ Deposits of CPPD crystals within cartilage matrix or synovium

─ Crystals are often rhomboid or rod-shaped, appearing as basophilic granular material on H&E (if not dissolved) or bright, refractile crystals under polarized light

─ In cartilage, crystals are often in superficial or mid-zones, can be associated with chondrocyte necrosis or cloning

─ In synovium, crystals may elicit a mild chronic inflammatory or foreign body giant cell reaction, or be relatively acellular; acute neutrophilic infiltrate during pseudogout attacks

Ancillary studies ─

─ Synovial Fluid Analysis: Demonstration of CPPD crystals is diagnostic gold standard

─ Radiographs: To detect chondrocalcinosis

─ Serum calcium, phosphate, magnesium, iron/ferritin, alkaline phosphatase: to screen for associated metabolic disorders

DDx ─

─ Gout (acute monoarthritis, but MSU crystals in synovial fluid, different radiographic erosions if tophaceous)

─ Septic Arthritis (acute monoarthritis, fever, purulent synovial fluid, positive Gram stain/culture)

─ Rheumatoid Arthritis (if chronic polyarticular CPPD; RA has erosions, specific serology, different crystal findings)

─ Osteoarthritis (can coexist with CPPD or be mimicked by chronic CPPD arthropathy; radiographic chondrocalcinosis helps distinguish)

─ Hydroxyapatite Deposition Disease (calcific periarthritis, different crystal morphology if identifiable)

Media

Hydroxyapatite Deposition Disease (Calcific Tendinitis/Periarthritis)

A common condition characterized by deposition of basic calcium phosphate crystals, primarily hydroxyapatite (HA), in periarticular soft tissues, especially tendons and bursae, leading to acute or chronic inflammation and pain

Clinical ─

─ Common, especially in middle-aged individuals (peak 40-60 years)

─ Female predominance for symptomatic disease in some studies

─ Most cases are idiopathic; can be associated with trauma, repetitive microtrauma, certain metabolic conditions (e,g,, chronic renal failure, hyperparathyroidism), or degenerative changes in tendons

─ Most common site is shoulder rotator cuff tendons (especially supraspinatus - calcific tendinitis of shoulder); also common in hip (gluteal tendons), elbow, wrist, hand, foot, neck (longus colli tendinitis)

─ Clinical presentations:

1, Asymptomatic calcific deposits (incidental radiographic finding)

2, Acute calcific periarthritis: sudden onset of severe pain, tenderness, and restricted motion, often mimicking gout or septic arthritis; due to rupture of calcific deposit into bursa or surrounding tissue, causing intense inflammation

Chronic calcific periarthritis: chronic, dull ache or pain, often worse with activity or at night; may cause impingement symptoms

─ Imaging: Radiographs show amorphous, "cloud-like" or "fluffy," well-demarcated calcific deposits in tendons, bursae, or other periarticular soft tissues; deposits can vary in size and density, may become more defined and dense as they mature or resorb; ultrasound can also detect and guide aspiration/lavage; MRI not usually needed but shows low signal calcification with surrounding edema/inflammation if symptomatic

─ Prognosis: Often self-limiting; acute attacks usually resolve in days to weeks; chronic symptoms may persist; calcific deposits can spontaneously resorb over time; treatment includes NSAIDs, corticosteroid injections, physical therapy, needle aspiration/lavage, or rarely surgical excision for refractory cases

Macro ─ calcific deposits are typically pasty, chalky-white, or toothpaste-like material when acute or liquid; can become firm, gritty, or rock-hard when chronic or mature

Micro ─

─ Deposits of basic calcium phosphate crystals, primarily hydroxyapatite (HA), but may also include octacalcium phosphate and tricalcium phosphate

─ HA crystals are very small (nanometer-sized) and not individually visible by light microscopy; appear as amorphous, granular, basophilic (purple-staining on H&E) material

─ Crystals are not birefringent under polarized light (distinction from MSU and CPPD)

─ Deposits are often surrounded by a foreign body giant cell reaction, histiocytes (macrophages), lymphocytes, and plasma cells, especially in symptomatic or resorbing lesions

─ Fibroblastic proliferation and neovascularization may be present around deposits

─ Underlying tendon may show degenerative changes (tendinosis)

─ Acute calcific periarthritis: shows intense acute inflammatory infiltrate (neutrophils) in addition to crystals and chronic inflammation

Ancillary studies ─

─ Crystal analysis (if material aspirated): HA crystals require specialized techniques for definitive identification (e,g,, alizarin red S stain for calcium, electron microscopy, X-ray diffraction, infrared spectroscopy); not routinely done in most labs

─ Diagnosis is usually based on characteristic clinical and radiographic findings

DDx ─

─ Gout/Pseudogout (if acute inflammatory monoarthritis; crystal analysis of synovial fluid or aspirate is key)

─ Septic Arthritis/Bursitis (fever, systemic signs, purulent aspirate, positive cultures)

─ Rotator Cuff Tear/Tendinopathy (without calcification; MRI or ultrasound findings differ)

─ Osteoarthritis with osteophytes (osteophytes are bony, different radiographic appearance)

─ Tumoral Calcinosis (large, lobulated periarticular calcific masses, often in specific locations like hips/shoulders/elbows, typically in setting of renal failure or genetic disorders of phosphate metabolism; HA crystals but different clinical entity)