Benign tumor composed of mature adipocytes
Clinical ─ Most common soft tissue tumor; typically adults 40-60 years; superficial (subcutaneous, esp upper back, neck, shoulders) or deep (eg, intramuscular)
Macro ─ Well-circumscribed, encapsulated, soft, lobulated, yellow mass
Micro

─ Sheets of univacuolated mature adipocytes, uniform in size and shape
─ Thin fibrous capsule and delicate fibrous septa dividing lobules
─ Capillary vascular network
─ No significant atypia, pleomorphism, or lipoblasts
─ Variants include angiolipoma, myolipoma, spindle cell/pleomorphic lipoma, chondroid lipoma, intramuscular lipoma (infiltrative growth pattern into skeletal muscle)
Ancillary studies ─
─ IHC: S100 positive in adipocyte nuclei and cytoplasm
─ Molecular: HMGA2 (12q15) rearrangements common, especially in conventional lipomas; MDM2 and CDK4 amplification absent (distinguishes from atypical lipomatous tumor)
DDx

─ Atypical lipomatous tumor / Well-differentiated liposarcoma (variation in adipocyte size, hyperchromatic stromal cells, lipoblasts, MDM2/CDK4 amplification)
─ Lipomatosis (diffuse overgrowth of mature adipose tissue without a discrete mass)
─ Normal adipose tissue (lipoma is a discrete, circumscribed mass)
─ Hibernoma (contains brown fat cells)
─ Angiomyolipoma (contains prominent thick-walled vessels and smooth muscle, HMB45 positive)
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Dermal Lipoma

Benign tumor composed of mature adipocytes located within the dermis
Clinical ─ Common, adults; often small papules or nodules on the skin, particularly neck, trunk, and extremities
Macro ─ Typically small, yellowish, poorly circumscribed dermal nodules; may lack obvious encapsulation if purely dermal
Micro

─ Mature adipocytes infiltrating dermal collagen bundles
─ Often unencapsulated or poorly encapsulated within the dermis
─ Adipocytes are of uniform size and shape without atypia
─ May be associated with adnexal structures
Ancillary studies ─
─ IHC: S100 positive in adipocytes
─ Molecular: Generally not characterized by specific recurrent alterations, but can show HMGA2 rearrangements like other lipomas
DDx

─ Lipoma (conventional) (typically subcutaneous, encapsulated)
─ Nevus lipomatosus superficialis (congenital lesion, ectopic fat in dermis, often papillated surface)
─ Cutaneous neurofibroma with fatty overgrowth (contains spindle cells, S100 positive wavy nuclei, embedded axons)
─ Angiolipoma (contains capillary proliferation and fibrin thrombi)
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Angiolipoma

Benign adipocytic tumor composed of mature fat and a prominent proliferation of small capillary-sized blood vessels, often containing fibrin thrombi
Clinical ─ Typically young adults (20s-30s); M>F; subcutaneous tissue, commonly forearm, trunk, neck; often multiple and can be painful or tender
Macro ─ Small (usually <2 cm), well-circumscribed, often encapsulated, yellowish or reddish nodules
Micro

─ Mature adipocytes comprising at least 50% of the tumor
─ Branching network of thin-walled, capillary-sized blood vessels
─ Characteristic fibrin microthrombi within vascular lumina
─ Mast cells are frequently present in the stroma
─ Non-infiltrating (pushing borders) vs infiltrating types (rare)
Ancillary studies ─
─ IHC: S100 positive in adipocytes; CD31, CD34 positive in endothelial cells
─ Molecular: No specific recurrent alterations consistently identified; generally lacks HMGA2 rearrangements of conventional lipomas
DDx

─ Lipoma (lacks prominent vascular component and fibrin thrombi)
─ Kaposi sarcoma (spindle cell proliferation, slit-like vessels, HHV8 positive)
─ Spindle cell hemangioma (cavernous spaces, epithelioid cells, lacks fibrin thrombi)
─ Intramuscular hemangioma (more variable vessel size, infiltrative, lacks prominent thrombi)
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Myolipoma

Benign mesenchymal tumor composed of an admixture of mature adipose tissue and bland smooth muscle
Clinical ─ Adults, typically middle-aged to older (peak 40s-60s); F>M; deep soft tissues, commonly retroperitoneum, abdominal cavity, inguinal region
Macro ─ Well-circumscribed, often large mass; cut surface is yellowish with gray-white firm areas corresponding to smooth muscle
Micro

─ Intimate admixture of mature adipocytes and interlacing fascicles of bland smooth muscle cells
─ Smooth muscle component shows elongated spindle cells with eosinophilic cytoplasm and cigar-shaped nuclei
─ No significant atypia, pleomorphism, or mitotic activity in either component
─ Blood vessels are generally inconspicuous within the smooth muscle component
Ancillary studies ─
─ IHC: Adipocytes S100 positive; Smooth muscle cells positive for SMA, desmin, and h-caldesmon
─ Molecular: HMGA2 (12q15) rearrangements may occur, similar to conventional lipomas
DDx

─ Lipoleiomyosarcoma (extremely rare; requires malignant features in smooth muscle component)
─ Well-differentiated liposarcoma/Atypical lipomatous tumor (shows atypia in adipocytic/stromal cells, MDM2/CDK4 amplified)
─ Angiomyolipoma (prominent thick-walled vessels, HMB45 positive perivascular epithelioid cells)
─ Leiomyoma with fatty change (predominantly smooth muscle with secondary fat)
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Hibernoma

Benign tumor composed of brown adipocytes (brown fat)
Clinical ─ Typically young to middle-aged adults (peak 20s-40s); common sites include interscapular area, neck, axilla, mediastinum, thigh (areas where brown fat persists)
Macro ─ Well-circumscribed, lobulated, encapsulated, soft mass; tan to reddish-brown cut surface due to rich vascularity and mitochondria
Micro

─ Lobular architecture with fibrous septa
─ Cells are polygonal with granular eosinophilic cytoplasm (due to abundant mitochondria) and central nuclei
─ Variable lipid vacuolization:
─ Univacuolated cells (resembling mature white fat but with more eosinophilic cytoplasm)
─ Multivacuolated cells (characteristic "hibernoma cells" with multiple small lipid droplets)
─ Cells with scant lipid
─ Rich capillary network throughout the lobules
─ No significant atypia or mitotic activity
─ Variants: Typical (most common), myxoid, spindle cell, lipoma-like
Ancillary studies ─
─ IHC: S100 positive (cytoplasmic and nuclear); UCP1 (uncoupling protein 1, specific for brown fat) positive
─ Molecular: Deletions or rearrangements involving 11q13 (locus of MEN1 gene) are common
DDx

─ Lipoma (composed of white fat, lacks granular eosinophilic cells and UCP1)
─ Liposarcoma (especially myxoid or pleomorphic variants, show atypia/lipoblasts and specific molecular alterations)
─ Granular cell tumor (S100 positive, but granular cytoplasm is lysosomal, lacks lipid, UCP1 negative)
─ Adult rhabdomyoma (eosinophilic cytoplasm, but myogenic markers positive, lacks lipid vacuoles and UCP1)
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Spindle Cell / Pleomorphic Lipoma

Benign adipocytic neoplasm composed of a variable admixture of mature adipocytes, bland spindle cells, pleomorphic multinucleated floret-like giant cells, and thick ropey collagen bundles, often set in a myxoid stroma

Clinical ─ Typically older adults (peak 45-70s), strong male predominance (M>>F); common in subcutaneous tissue of posterior neck, upper back, and shoulders ("buffalo hump")

Macro ─ Well-circumscribed, encapsulated nodule; cut surface is yellow to gray-white depending on the relative proportions of fat, spindle cells, and stroma

Micro

─ Spectrum of findings with variable components:

─ Mature adipocytes, often smaller than in conventional lipoma

─ Bland, uniform spindle cells with scant cytoplasm, elongated nuclei, often arranged in short fascicles or clusters

─ Pleomorphic, multinucleated floret-like giant cells (characteristic of pleomorphic lipoma component) with hyperchromatic, peripherally arranged nuclei

─ Thick, eosinophilic, "ropey" collagen bundles

─ Myxoid stroma is common and can be abundant

─ Mast cells are frequently numerous

─ Low to absent mitotic activity; lipoblasts are absent

Ancillary studies ─

─ IHC: Spindle cells are CD34 positive (strong and diffuse); Adipocytes and floret cells are S100 positive; MDM2 and CDK4 negative (distinguishes from atypical lipomatous tumor)

─ Molecular: Deletions or loss of chromosome 13q (including RB1 gene) and 16q are characteristic; lacks MDM2/CDK4 amplification

DDx

─ Atypical lipomatous tumor / Well-differentiated liposarcoma (shows adipocytic atypia, MDM2/CDK4 positive/amplified)

─ Lipoma (conventional) (lacks spindle cells, floret cells, and ropey collagen)

─ Neurofibroma (wavy nuclei, S100 positive spindle cells, may contain fat but different morphology)

─ Myxoid liposarcoma (contains lipoblasts, plexiform vascular pattern, DDIT3 rearranged)

─ Nodular fasciitis (if myxoid and cellular, but USP6 rearranged, lacks ropey collagen/floret cells)

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Dermal Spindle Cell / Pleomorphic Lipoma

A variant of spindle cell/pleomorphic lipoma occurring primarily in the dermis
Clinical ─ Similar to conventional spindle cell/pleomorphic lipoma but situated more superficially; older adults, male predominance; typically neck, back, shoulders
Macro ─ Small, well-circumscribed dermal or dermo-subcutaneous nodule

Micro

─ Features similar to conventional spindle cell/pleomorphic lipoma (mature fat, bland spindle cells, +/- floret cells, ropey collagen, myxoid stroma) but centered in the dermis

─ May be less well-encapsulated than deeper counterparts, intermingling with dermal collagen

─ Spindle cells often arranged in fascicles parallel to the epidermis

Ancillary studies ─

─ IHC: Spindle cells CD34 positive; S100 positive in adipocytes and floret cells; MDM2 negative

─ Molecular: Similar 13q and/or 16q deletions as conventional spindle cell/pleomorphic lipoma

DDx

─ Dermatofibroma (Cellular or atypical) (Factor XIIIa positive, CD34 negative or focal)

─ Dermal neurofibroma (S100 positive wavy spindle cells, embedded axons, lacks ropey collagen/floret cells)

─ Atypical fibroxanthoma (Marked pleomorphism, atypical mitoses, diagnosis of exclusion with negative S100, keratin)

─ Superficial atypical lipomatous tumor (rare, shows adipocytic atypia, MDM2 positive)

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Hemosiderotic Fibrolipomatous Tumor (HFLT)

A rare, low-grade mesenchymal neoplasm characterized by an admixture of mature adipose tissue, bland spindle cells, fibrous stroma, and prominent hemosiderin deposition, often with features overlapping PHAT and MIFS
Clinical ─ Typically adults (peak 40-60 years), slight female predominance; commonly involves the distal lower extremities, especially the foot and ankle; presents as a slow-growing, often painful or tender subcutaneous mass or plaque
Macro ─ Poorly circumscribed, firm, infiltrative mass or plaque; cut surface is typically yellowish-brown due to fat and hemosiderin
Micro
─ Infiltrative growth pattern in subcutaneous tissue, extending into dermis or deeper structures
─ Admixture of mature adipose tissue and a fibrous component
─ Fibrous areas contain bland spindle cells, often with a storiform or haphazard arrangement
─ Prominent hemosiderin pigment within stromal cells and macrophages is a key feature
─ Chronic inflammatory infiltrate, including lymphocytes and plasma cells, is common
─ May show scattered mildly pleomorphic cells or pseudolipoblasts
─ Blood vessels can be inconspicuous or ectatic with hyalinization (overlapping PHAT)
─ Low mitotic activity generally observed
Ancillary studies ─
─ IHC: Spindle cells often CD34 positive; CD68 highlights hemosiderin-laden macrophages; S100 positive in adipocytes; Negative for keratins, SMA (usually), desmin
─ Molecular: Characteristically harbors TGFBR3::MGEA5 fusion resulting from t(1;10)(p22;q24), shared with PHAT and some MIFS
DDx
─ Pleomorphic hyalinizing angiectatic tumor (PHAT) (More prominent vascular changes, striking pleomorphism, less prominent organized fat)
─ Myxoinflammatory fibroblastic sarcoma (MIFS) (More prominent myxoid stroma, inflammatory infiltrate, characteristic virocyte-like or Reed-Sternberg-like cells)
─ Dermatofibroma (hemosiderotic variant) (Typically dermal, Factor XIIIa positive, lacks prominent fat and specific fusion)
─ Tenosynovial giant cell tumor, diffuse type (More prominent mononuclear and osteoclast-like giant cells, lacks TGFBR3::MGEA5 fusion)
─ Chronic panniculitis (Inflammation centered in fat, lacks distinct spindle cell proliferation of HFLT)
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Lipoblastoma/Lipoblastomatosis

Benign tumor of immature adipocytes (lipoblasts) occurring almost exclusively in infants and young children; Lipoblastoma is localized and well-circumscribed, while lipoblastomatosis is diffuse and infiltrative
Clinical ─ Primarily infants and children under 3 years of age (most <1 year); slight male predominance; extremities and trunk are common sites; usually presents as a rapidly growing, painless mass
Macro ─ Lipoblastoma: Well-circumscribed, encapsulated, soft, lobulated, gray-white to yellow mass; Lipoblastomatosis: Diffuse, ill-defined, infiltrative growth with similar cut surface
Micro
─ Lobular architecture separated by fibrous septa containing a prominent capillary and venular network
─ Admixture of immature adipocytes at various stages of differentiation:
─ Primitive stellate and spindle mesenchymal cells
─ Univacuolated and multivacuolated lipoblasts (scalloped nuclei)
─ Mature-appearing adipocytes
─ Stroma is often myxoid and can be abundant
─ A zonal maturation pattern may be seen, with more primitive cells peripherally and mature fat centrally within lobules
─ No significant cytologic atypia or hyperchromasia; mitoses are rare
Ancillary studies ─
─ IHC: S100 positive in lipoblasts and mature adipocytes; CD34 can highlight spindle cells and vasculature
─ Molecular: PLAG1 gene (8q12) rearrangements are characteristic, often through fusion with HAS2 or COL1A2
DDx
─ Myxoid liposarcoma (Extremely rare in this age group; characterized by DDIT3 fusion, different morphology with plexiform capillaries and typical lipoblasts)
─ Lipoma (Composed entirely of mature adipocytes, lacks lipoblasts)
─ Infantile fibromatosis/myofibromatosis (Predominantly spindle cells, lacks lipoblasts)
─ Hibernoma (Contains brown fat cells, UCP1 positive, lacks PLAG1 rearrangement)
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Chondroid Lipoma

Benign adipocytic neoplasm characterized by an admixture of mature adipocytes, embryonal fat-like cells (lipoblast-like cells), and a prominent myxochondroid or hyaline chondroid matrix
Clinical ─ Predominantly adult women (F>M, ~5:1); peak age 20-50 years; typically involves proximal extremities (especially thigh) and limb girdles, less commonly trunk or head/neck; usually presents as a slow-growing, deep-seated, painless mass
Macro ─ Well-circumscribed, often encapsulated, firm, lobulated mass; cut surface is typically yellow-tan with glistening grayish-white myxochondroid areas; usually <5 cm
Micro
─ Nests, cords, or strands of eosinophilic epithelioid or spindle cells embedded within an abundant myxochondroid or hyaline cartilaginous matrix
─ Cells often contain small lipid vacuoles (lipoblast-like cells or "hibernoma-like" cells)
─ Mature adipocytes are present, often at the periphery of lobules or admixed
─ Fibrous pseudocapsule is common
─ Lacks significant cytologic atypia, pleomorphism, or high mitotic activity; true lipoblasts of liposarcoma are absent
─ Vascular pattern is not typically plexiform (unlike myxoid liposarcoma)
Ancillary studies ─
─ IHC: S100 positive in mature adipocytes and often in the lipoblast-like cells; EMA and keratins can be positive in the epithelioid cells; Vimentin positive
─ Molecular: Characteristic C11orf95::MKL2 fusion resulting from t(11;16)(q13;p13) is a defining feature
DDx
─ Myxoid liposarcoma (True lipoblasts, plexiform capillaries, DDIT3 fusion, lacks chondroid matrix)
─ Extraskeletal myxoid chondrosarcoma (More uniformly myxoid, cords of eosinophilic cells, NR4A3 fusion, lacks fat)
─ Lipoma with chondroid metaplasia (Rare, true cartilage present, lacks C11orf95::MKL2 fusion)
─ Hibernoma (Brown fat cells, UCP1 positive, lacks prominent chondroid matrix)
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Synovial Lipomatosis / Lipoma Arborescens

Benign condition characterized by diffuse replacement of subsynovial tissue by mature adipose cells, leading to a villous, frond-like proliferation of the synovium
Clinical ─ Typically older adults, M=F; most commonly affects the knee joint; often associated with osteoarthritis, trauma, or chronic irritation; presents with joint swelling, pain, decreased range of motion, or locking
Macro ─ Affected synovium shows a striking papillary or villous architecture with yellow, fatty fronds, resembling a branching tree ("arborescens")
Micro
─ Villous projections of synovial membrane with extensive replacement of the subsynovial connective tissue by lobules of mature adipocytes
─ Overlying synovial lining may be hyperplastic or attenuated, but without atypia
─ Chronic inflammatory infiltrate (lymphocytes, plasma cells) may be present in the stroma
─ Fibrin deposition on the surface or within the stroma can occur
─ No lipoblasts or significant cytologic atypia
Ancillary studies ─
─ IHC: Adipocytes are S100 positive; Synovial lining cells are positive for vimentin and may show CD68
─ Molecular: No specific recurrent genetic alterations are typically associated
DDx
─ Conventional lipoma involving joint (more discrete mass, less diffuse villous synovial involvement)
─ Pigmented villonodular synovitis (TGCT, diffuse type) (lacks prominent adipose tissue, characterized by mononuclear cells, hemosiderin, and foam cells)
─ Synovial hemangioma (prominent vascular channels, lacks diffuse fatty infiltration)
─ Rheumatoid arthritis with rice bodies (different inflammatory pattern, fibrin-rich rice bodies)
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Neural fibrolipoma (Lipomatosis of Nerve)

Benign hamartomatous lesion characterized by excessive fibro-adipose tissue infiltration within the epineurium and perineurium of peripheral nerves, leading to nerve enlargement
Clinical ─ Typically presents in infants, children, or young adults (often congenital or by age 30); M=F; most commonly affects the median nerve, followed by ulnar and radial nerves, and nerves of the feet; associated with macrodactyly (digital gigantism) in up to one-third of cases; presents as a slow-growing, soft, painless mass, may cause nerve compression symptoms (pain, paresthesia, weakness)
Macro ─ Fusiform enlargement of the involved nerve; cut surface shows yellowish fatty tissue interspersed with white fibrous strands and visible nerve fascicles
Micro
─ Mature adipose tissue and dense fibrous connective tissue infiltrating the epineurium and perineurium, separating and surrounding nerve fascicles
─ Nerve fascicles themselves are usually normal in appearance but may show secondary changes like axonal loss or demyelination if compressed
─ Concentric perineurial fibrosis around nerve bundles is often prominent
─ No significant cytologic atypia in adipocytes or fibroblasts
Ancillary studies ─
─ IHC: Adipocytes S100 positive; Axons highlighted by neurofilament; Schwann cells S100 positive; Perineurial cells EMA positive
─ Molecular: No consistent specific genetic abnormalities identified
DDx
─ Conventional lipoma involving nerve (compresses nerve externally rather than infiltrating it)
─ Traumatic neuroma (disorganized nerve bundles, scar tissue, history of injury)
─ Plexiform neurofibroma (associated with NF1, composed of Schwann cells, fibroblasts, perineurial-like cells, axons within tumor, myxoid stroma, S100 positive wavy cells)
─ Intraneural perineurioma (concentric proliferation of EMA positive perineurial cells around axons, lacks adipose tissue)
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Massive Tumorous Lymphedema

A reactive condition characterized by massive, localized accumulation of interstitial fluid and subsequent fibrosis, typically occurring in morbidly obese individuals and mimicking a soft tissue neoplasm
Clinical ─ Primarily affects morbidly obese adults; common sites include the proximal lower extremities (especially thighs), abdominal wall, and scrotum; presents as a very large, slowly enlarging, non-tender, doughy or firm mass (elephantiasis-like); skin overlying may show hyperkeratosis, acanthosis, and papillomatosis
Macro ─ Large, poorly defined, edematous mass of subcutaneous tissue; cut surface is wet, glistening, and grayish-white with thickened fibrous septa and leaking serous fluid; true encapsulation is absent
Micro
─ Marked expansion of the dermis and subcutaneous tissue by edema fluid
─ Dermal fibrosis with thickened collagen bundles and an increase in bland spindle cells (fibroblasts and myofibroblasts)
─ Dilated lymphatic channels are a key feature, often prominent and irregular
─ Chronic inflammatory infiltrate, mainly lymphocytes and plasma cells, is common
─ Adipose tissue may be present but is often diminished or replaced by fibrosis and edema
─ Fat necrosis and hemosiderin deposition can be seen
─ Overlying epidermis frequently shows acanthosis, hyperkeratosis, and papillomatosis
─ No significant cytologic atypia or increased mitotic activity in the spindle cells
Ancillary studies ─
─ IHC: Spindle cells are vimentin positive, may show focal SMA; Lymphatic channels are D2-40 (podoplanin) positive; Factor VIII/CD31/CD34 highlight blood vessels; MDM2 negative
─ Molecular: No specific genetic alterations; importantly, MDM2 amplification is absent (rules out WDLPS)
DDx
─ Well-differentiated liposarcoma (ALT/WDLS) (especially sclerosing or inflammatory variants; shows atypical cells, MDM2 amplification)
─ Low-grade fibromyxoid sarcoma (MUC4 positive, different morphology)
─ Myxofibrosarcoma (more pleomorphism, curvilinear vessels)
─ Angiosarcoma (secondary to chronic lymphedema - Stewart-Treves syndrome; malignant endothelial cells, atypia, mitoses)
─ Aggressive angiomyxoma (pelvic/perineal location, prominent vessels, HMGA2 rearranged)
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Atypical Spindle Cell Tumor / Pleomorphic Lipomatous Tumor

Low-grade adipocytic neoplasm characterized by a predominance of mildly atypical spindle cells, mature adipocytes, and variably pleomorphic (often floret-like) multinucleated cells, with a molecular profile similar to spindle cell/pleomorphic lipoma (13q/RB1 loss) but lacking MDM2 amplification
Clinical ─ Typically adults (wide age range); common in limbs, trunk, and head/neck region; usually subcutaneous but can be deep (intramuscular)
Macro ─ Well-circumscribed, lobulated, yellow-gray to white mass, often firm; size varies
Micro
─ Variable admixture of mature adipocytes, mildly atypical spindle cells, and pleomorphic multinucleated cells
─ Spindle cells: Mildly enlarged, hyperchromatic, slightly irregular nuclei; arranged in fascicles or haphazardly within a fibrous or myxoid stroma
─ Pleomorphic cells: Often floret-like multinucleated giant cells, similar to those in pleomorphic lipoma
─ Lipoblasts are generally absent or very rare and not a defining feature
─ Low mitotic activity, necrosis is absent
─ Ropey collagen, as seen in spindle cell/pleomorphic lipoma, may be present
Ancillary studies ─
─ IHC: Spindle cells are often CD34 positive; S100 positive in adipocytes and sometimes pleomorphic cells; MDM2 and CDK4 negative (crucial for distinction from WDLPS/ALT)
─ Molecular: Characterized by loss or deletion of chromosome 13q (including RB1 gene) and/or 16q; Lacks MDM2/CDK4 gene amplification
DDx
─ Spindle cell lipoma / Pleomorphic lipoma (Overlapping features; atypical spindle cell/pleomorphic lipomatous tumor may show slightly more atypia or cellularity but shares molecular basis)
─ Atypical lipomatous tumor / Well-differentiated liposarcoma (Key distinguishing feature is MDM2/CDK4 positivity and amplification)
─ Dedifferentiated liposarcoma (High-grade non-lipogenic sarcoma adjacent to WDLPS)
─ Myxofibrosarcoma (Curvilinear vessels, more significant pleomorphism if high grade, lacks RB1 loss)
─ Solitary fibrous tumor (STAT6 positive, different morphology)
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Well-Differentiated Liposarcoma/Atypical Lipomatous Tumor

Low-grade malignant adipocytic neoplasm composed of mature adipocytes with variation in cell size and scattered atypical hyperchromatic stromal cells and/or lipoblasts; characterized by MDM2 gene amplification; termed Atypical Lipomatous Tumor (ALT) for lesions in extremities/trunk amenable to complete excision, and Well-Differentiated Liposarcoma (WDLPS) for those in retroperitoneum/mediastinum where complete excision is often not possible and dedifferentiation is more common
Clinical ─ Typically older adults (peak 50-70s); deep soft tissues of limbs (especially thigh), retroperitoneum, paratesticular region, and mediastinum are common sites
Macro ─ Often large, lobulated, well-circumscribed mass; typically yellow and fatty, may have firmer white/tan sclerotic areas
Micro
─ Predominantly mature adipocytes with significant variation in cell size and shape
─ Scattered atypical stromal cells with enlarged, hyperchromatic, irregular nuclei; these can be spindle or epithelioid
─ Lipoblasts (immature adipocytes with vacuolated cytoplasm and scalloped nuclei) may be present but are not required for diagnosis if other atypical features and MDM2 amplification are present
─ Fibrous septa are common and may be thickened and hyalinized
─ Variants include:
─ Lipoma-like: Closely resembles lipoma but with scattered atypical cells/lipoblasts
─ Sclerosing: Prominent collagenous stroma with scattered atypical cells and adipocytes
─ Inflammatory: Dense chronic inflammatory infiltrate, often obscuring the adipocytic component (plasma cells, lymphocytes, eosinophils)
─ Low mitotic activity, necrosis is generally absent (unless dedifferentiation occurs)
Ancillary studies ─
─ IHC: MDM2 and CDK4 nuclear positivity in atypical stromal cells and lipoblasts (correlates with amplification); S100 positive in adipocytes and lipoblasts
─ Molecular: Amplification of the 12q13-15 region, including MDM2 and CDK4 genes, is the pathognomonic genetic hallmark
DDx
─ Lipoma (lacks significant adipocytic size variation, atypical stromal cells, lipoblasts, and MDM2/CDK4 amplification)
─ Spindle cell/Pleomorphic lipoma / Atypical spindle cell/pleomorphic lipomatous tumor (CD34 positive spindle cells, floret cells, ropey collagen, 13q/RB1 loss, MDM2/CDK4 negative/unamplified)
─ Dedifferentiated liposarcoma (shows an abrupt transition to a high-grade non-lipogenic sarcoma)
─ Myxoid liposarcoma (characteristic myxoid stroma, plexiform capillaries, DDIT3 rearrangement)
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Well-Differentiated Inflammatory Liposarcoma

A rare variant of well-differentiated liposarcoma/atypical lipomatous tumor (WDLPS/ALT) characterized by a prominent, dense lymphoplasmacytic inflammatory infiltrate that may obscure the underlying adipocytic neoplasm
Clinical ─ Similar to conventional WDLPS/ALT, typically older adults; often arises in the retroperitoneum or deep soft tissues of the extremities
Macro ─ May appear as a fleshy, firm, or yellowish mass, potentially with areas suggestive of inflammation rather than a typical fatty tumor
Micro
─ Underlying features of WDLPS/ALT, including mature adipocytes with size variation and scattered atypical hyperchromatic stromal cells and/or lipoblasts
─ Diagnostic hallmark is a dense and diffuse chronic inflammatory infiltrate composed predominantly of lymphocytes and plasma cells, often with lymphoid follicles
─ Eosinophils and histiocytes can also be present
─ The inflammatory component can be so extensive as to obscure the neoplastic adipocytic elements, making diagnosis challenging
─ Atypical stromal cells and lipoblasts may be focal and require careful search
Ancillary studies ─
─ IHC: MDM2 and CDK4 nuclear positivity in atypical stromal cells and lipoblasts (confirms diagnosis of WDLPS/ALT spectrum); S100 positive in adipocytes; CD45/LCA, CD20, CD3, CD138 highlight inflammatory components
─ Molecular: Amplification of MDM2 and CDK4 genes (12q13-15 region) is definitional for WDLPS/ALT spectrum
DDx
─ Inflammatory myofibroblastic tumor (IMT) (ALK positive in a subset, lacks MDM2 amplification and atypical adipocytic component)
─ Castleman disease (hyaline vascular or plasma cell types; characteristic nodal architecture, lacks adipocytic atypia and MDM2 amplification)
─ Hodgkin lymphoma or non-Hodgkin lymphoma involving adipose tissue (specific lymphoma markers positive, lacks adipocytic atypia and MDM2 amplification)
─ IgG4-related disease (storiform fibrosis, obliterative phlebitis, increased IgG4+ plasma cells, lacks adipocytic atypia and MDM2 amplification)
─ Massive tumorous lymphedema (lacks atypical cells and MDM2 amplification)
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Dedifferentiated Liposarcoma (DDLPS)

A high-grade non-lipogenic sarcoma that arises in association with, or as a recurrence of, a well-differentiated liposarcoma/atypical lipomatous tumor (WDLPS/ALT)
Clinical ─ Typically older adults (peak 60-70s); most common in the retroperitoneum, also occurs in deep soft tissues of extremities and spermatic cord; often presents as a large, rapidly growing or recurrent mass
Macro ─ Large, often multinodular mass; typically shows a biphasic appearance with yellowish fatty areas of WDLPS/ALT juxtaposed with firm, fleshy, gray-white areas of dedifferentiated sarcoma; hemorrhage and necrosis are common in the dedifferentiated component
Micro
─ Abrupt transition from an area of WDLPS/ALT to a non-lipogenic sarcoma (the dedifferentiated component)
─ Dedifferentiated component most commonly resembles undifferentiated pleomorphic sarcoma (UPS) or high-grade myxofibrosarcoma, but can also show fibrosarcoma-like, rhabdomyosarcomatous, osteosarcomatous, or chondrosarcomatous differentiation (heterologous differentiation)
─ The dedifferentiated component is typically high grade, showing marked cellularity, pleomorphism, high mitotic activity (often >5-10/10 HPF), and necrosis
─ Low-grade dedifferentiation is rare but recognized, often fibromatosis-like or resembling low-grade myofibroblastic sarcoma
─ The WDLPS/ALT component must be identifiable, though it may be focal
Ancillary studies ─
─ IHC: Both WDLPS/ALT and dedifferentiated components often show nuclear positivity for MDM2 and CDK4 (though expression can be lost or heterogeneous in the dedifferentiated part); S100 highlights adipocytes in WDLPS component; markers for heterologous elements (eg, desmin for rhabdomyoblastic differentiation) may be positive in the dedifferentiated component
─ Molecular: Amplification of MDM2 and CDK4 (12q13-15) is present in both components, confirming the link; additional complex genetic alterations are acquired in the dedifferentiated component
DDx
─ Other high-grade sarcomas (eg, UPS, myxofibrosarcoma, leiomyosarcoma) without an associated WDLPS/ALT component (MDM2/CDK4 amplification is key for DDLPS)
─ Malignant peripheral nerve sheath tumor (MPNST) (especially with heterologous elements; S100/SOX10 often positive, H3K27me3 loss common)
─ Sarcomatoid carcinoma (keratin positive)
─ Melanoma (S100, SOX10, melanocytic markers positive)
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DDLPS - Mixed Pattern Context

Dedifferentiated liposarcoma (DDLPS) where the dedifferentiated component displays multiple distinct high-grade sarcoma morphologies or an admixture of low-grade and high-grade non-lipogenic sarcoma patterns
Clinical ─ Similar to DDLPS overall; arises in association with WDLPS/ALT, common in retroperitoneum and deep soft tissues
Macro ─ Large, heterogeneous mass with areas of fat (WDLPS/ALT) and variegated non-fatty sarcomatous areas reflecting different morphologies
Micro
─ Juxtaposition of WDLPS/ALT with a dedifferentiated component showing more than one histological pattern of non-lipogenic sarcoma
─ Examples of mixed patterns:
─ Undifferentiated pleomorphic sarcoma-like areas admixed with fibrosarcoma-like areas
─ Myxofibrosarcoma-like areas transitioning to rhabdomyosarcomatous differentiation
─ A low-grade dedifferentiated component (eg, fibromatosis-like) coexisting with a high-grade dedifferentiated component (eg, UPS-like)
─ Each component exhibits features typical for its respective sarcoma type regarding cellularity, atypia, and mitotic activity
─ The WDLPS/ALT component must be present
Ancillary studies ─
─ IHC: MDM2 and CDK4 generally positive in both WDLPS/ALT and the various dedifferentiated components (may be heterogeneous); other markers depend on the lines of differentiation present (eg, desmin for rhabdomyoblastic areas, SATB2 for osteosarcomatous areas)
─ Molecular: MDM2/CDK4 amplification is the unifying feature; different dedifferentiated areas may show clonal evolution with additional specific mutations
DDx
─ Malignant mesenchymoma (historical term for sarcoma with two or more distinct heterologous mesenchymal differentiations, not arising from WDLPS/ALT)
─ Other high-grade sarcomas showing diverse morphologies (distinguished by presence of WDLPS/ALT and MDM2 amplification in DDLPS)
─ Collision tumors (rare, distinct neoplasms intermingling)
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Inflammatory Malignant Fibrous Histiocytoma - as DDLPS variant

A historical term, "Inflammatory Malignant Fibrous Histiocytoma (MFH)," is now largely reclassified; many cases, particularly in the retroperitoneum, represent the inflammatory variant of dedifferentiated liposarcoma (DDLPS) when associated with MDM2 amplification and a WDLPS component
Clinical ─ Predominantly older adults; deep soft tissues, especially retroperitoneum; presents as a large, often symptomatic mass
Macro ─ Large, fleshy, often ill-defined mass; may have yellowish (fatty) areas and grayish-white inflammatory or necrotic areas
Micro
─ Features of a high-grade sarcoma, often resembling undifferentiated pleomorphic sarcoma or a high-grade fibrosarcoma, but with a striking and dense inflammatory infiltrate
─ Inflammatory cells are typically neutrophils, eosinophils, lymphocytes, plasma cells, and foamy histiocytes (xanthoma cells)
─ The tumor cells themselves are large, pleomorphic, with atypical nuclei and frequent mitoses
─ If it's a DDLPS variant, an associated WDLPS/ALT component must be present (may be focal)
─ Necrosis is common
Ancillary studies ─
─ IHC: If DDLPS variant, tumor cells are positive for MDM2 and CDK4; inflammatory cells show expected markers (eg, CD68 for histiocytes, CD45 for leukocytes); tumor cells are typically negative for specific lineage markers unless heterologous differentiation is present
─ Molecular: If DDLPS variant, MDM2/CDK4 amplification is present
DDx
─ True inflammatory myofibroblastic tumor (IMT) (less atypia, ALK positive in a subset, lacks MDM2 amplification)
─ Other sarcomas with prominent inflammation (eg, myxofibrosarcoma with inflammation; leiomyosarcoma with inflammation - specific markers and molecular features differ)
─ Lymphoma (eg, anaplastic large cell lymphoma, Hodgkin lymphoma - specific lymphoma markers positive)
─ Carcinoma with sarcomatoid change and inflammation (keratin positive)
─ Xanthogranulomatous inflammation (reactive process, lacks true malignant cells)
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Myxoid Liposarcoma (MLS)

Malignant adipocytic neoplasm characterized by a proliferation of uniform, primitive non-lipogenic round to oval mesenchymal cells and variable numbers of univacuolated lipoblasts within an abundant myxoid stroma containing a distinctive plexiform ("chicken-wire") capillary network
Clinical ─ Typically young to middle-aged adults (peak 30-50s); most common in deep soft tissues of the extremities, especially the thigh; less common in retroperitoneum or other sites
Macro ─ Well-circumscribed, lobulated, gelatinous, glistening mass; often large; cut surface is typically gray-white to pale yellow and overtly myxoid
Micro
─ Lobular architecture with abundant myxoid stroma (Alcian blue positive)
─ Proliferation of relatively uniform, small, round to oval or spindle-shaped primitive mesenchymal cells
─ Variable numbers of univacuolated or multivacuolated lipoblasts (signet-ring like cells with eccentric, scalloped nuclei) are characteristic
─ Pathognomonic feature: A rich, branching, plexiform ("chicken-wire") capillary vascular network
─ "Round cell" component: Hypercellular areas composed of primitive round cells with high nuclear-to-cytoplasmic ratios, increased mitotic activity, and reduced myxoid stroma; presence of >5% round cell component indicates high-grade myxoid liposarcoma (historically "round cell liposarcoma")
─ Transition from myxoid to round cell areas can be abrupt or gradual
Ancillary studies ─
─ IHC: Lipoblasts are S100 positive; primitive mesenchymal cells are often S100 negative or weakly positive; CD34 may highlight vasculature but is negative in tumor cells
─ Molecular: Characterized by specific chromosomal translocations:
─ t(12;16)(q13;p11) resulting in FUS::DDIT3 fusion (most common, ~95%)
─ t(12;22)(q13;q12) resulting in EWSR1::DDIT3 fusion (less common)
DDx
─ Intramuscular myxoma / Juxta-articular myxoma (lacks lipoblasts, plexiform capillaries, and DDIT3 fusion; GNAS mutations in intramuscular myxoma)
─ Myxofibrosarcoma (more pleomorphism, curvilinear vessels, lacks true lipoblasts and DDIT3 fusion)
─ Extraskeletal myxoid chondrosarcoma (cords and nests of eosinophilic cells, NR4A3 fusion, lacks lipoblasts)
─ Lipoblastoma (infants/children, PLAG1 rearranged, different morphology)
─ Low-grade fibromyxoid sarcoma (alternating fibrous/myxoid areas, MUC4 positive, FUS/EWSR1 fusions but different partners)
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“Round Cell” Liposarcoma / High-Grade Myxoid Liposarcoma

A higher-grade component of myxoid liposarcoma, characterized by increased cellularity, predominantly primitive round cells, reduced myxoid stroma, and associated with more aggressive behavior and higher metastatic risk compared to purely myxoid areas
Clinical ─ Similar to myxoid liposarcoma (MLS), typically young to middle-aged adults; deep soft tissues of extremities (especially thigh); presence of round cell component signifies higher grade
Macro ─ Often part of a larger myxoid liposarcoma mass; round cell areas may appear more solid, fleshy, and less gelatinous than purely myxoid areas, potentially with hemorrhage or necrosis
Micro
─ Hypercellular areas composed predominantly of primitive, undifferentiated round cells with scant cytoplasm, high nuclear-to-cytoplasmic ratios, and hyperchromatic nuclei
─ Significant reduction in myxoid stroma compared to conventional MLS areas
─ Plexiform "chicken-wire" capillary network may still be identifiable but can be compressed and less obvious
─ Lipoblasts may be present but can be sparse or difficult to identify in densely cellular areas
─ Mitotic activity is generally increased, and necrosis may be present
─ Defined by >5% of the tumor composed of these round cell areas
─ Often coexists with areas of conventional myxoid liposarcoma, showing a transition
Ancillary studies ─
─ IHC: Similar to MLS, S100 may highlight lipoblasts; primitive round cells usually S100 negative
─ Molecular: Same FUS::DDIT3 or EWSR1::DDIT3 fusions as conventional myxoid liposarcoma; the round cell component is considered a form of progression
DDx
─ Other small round blue cell tumors (eg, Ewing sarcoma, lymphoma, embryonal rhabdomyosarcoma - distinguished by specific IHC markers and molecular genetics)
─ Poorly differentiated synovial sarcoma (TLE1 positive, SS18 rearranged, keratin/EMA positive)
─ Mesenchymal chondrosarcoma (biphasic with cartilage, HEY1::NCOA2 fusion)
─ Dedifferentiated liposarcoma (arises from WDLPS/ALT, MDM2 amplified, lacks DDIT3 fusion)
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Pleomorphic Liposarcoma (PLS)

A high-grade, aggressive adipocytic sarcoma characterized by marked cellular pleomorphism and the presence of pleomorphic lipoblasts, lacking the specific molecular alterations of other liposarcoma subtypes (ie, MDM2 amplification or DDIT3/FUS fusions)
Clinical ─ Typically older adults (peak 50-70s); deep soft tissues of extremities (especially thigh), trunk, and less commonly retroperitoneum; often presents as a rapidly enlarging, painful mass
Macro ─ Large, fleshy, often poorly circumscribed mass; cut surface is typically variegated with yellowish fatty areas, white-gray sarcomatous tissue, hemorrhage, and necrosis
Micro
─ High-grade sarcoma displaying marked cytologic pleomorphism, with bizarre, multinucleated tumor cells
─ Definitive feature is the presence of pleomorphic lipoblasts: large, atypical cells with hyperchromatic, scalloped nuclei and multivacuolated eosinophilic or clear cytoplasm
─ Background of pleomorphic spindle cells and epithelioid cells is common
─ High mitotic activity, including atypical mitoses, is characteristic
─ Necrosis and hemorrhage are frequently observed
─ Does not show areas of well-differentiated liposarcoma or other specific liposarcoma subtypes (diagnosis of exclusion among high-grade liposarcomas)
Ancillary studies ─
─ IHC: S100 is variably positive in lipoblasts and some tumor cells; MDM2 and CDK4 are negative or only weakly/focally positive (no amplification); Desmin, keratins usually negative
─ Molecular: Characterized by complex, unbalanced karyotypes with no specific recurrent translocations; Importantly, lacks MDM2/CDK4 amplification and FUS/EWSR1::DDIT3 fusions
DDx
─ Dedifferentiated liposarcoma (arises from WDLPS/ALT, shows MDM2/CDK4 amplification)
─ Undifferentiated pleomorphic sarcoma (UPS) (lacks definitive pleomorphic lipoblasts)
─ Myxofibrosarcoma (high-grade) (myxoid stroma, curvilinear vessels, may have pseudolipoblasts but lacks true pleomorphic lipoblasts)
─ Malignant peripheral nerve sheath tumor (MPNST) with heterologous liposarcomatous differentiation (rare, background of MPNST, S100/SOX10 positivity in spindle cells)
─ Leiomyosarcoma or rhabdomyosarcoma with pleomorphism (specific myogenic markers positive)
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Pleomorphic Liposarcoma, Epithelioid Variant

A rare variant of pleomorphic liposarcoma in which a significant portion of the tumor is composed of large, pleomorphic cells with epithelioid morphology (abundant eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli) and identifiable pleomorphic lipoblasts
Clinical ─ Similar to conventional pleomorphic liposarcoma; older adults, deep soft tissues
Macro ─ Similar to conventional PLS, often large, fleshy, with necrosis and hemorrhage
Micro
─ Sheets or nests of large, polygonal (epithelioid) cells with abundant eosinophilic cytoplasm, prominent nucleoli, and marked nuclear pleomorphism
─ Presence of unequivocal pleomorphic lipoblasts is required for diagnosis within the epithelioid component or admixed conventional PLS areas
─ High mitotic rate and necrosis are common
─ May merge with areas of classic pleomorphic liposarcoma (spindle and bizarre multinucleated cells)
Ancillary studies ─
─ IHC: S100 variably positive in lipoblasts and epithelioid tumor cells; Cytokeratins may be focally positive in the epithelioid cells, creating a potential pitfall with carcinoma; MDM2/CDK4 negative (no amplification)
─ Molecular: Complex karyotypes; lacks MDM2 amplification and specific translocations of other liposarcomas
DDx
─ Metastatic carcinoma with pleomorphism (more diffuse keratin positivity, lacks true lipoblasts, clinical history)
─ Melanoma (S100/SOX10/melanocytic markers positive, lacks true lipoblasts)
─ Epithelioid angiosarcoma (vascular markers CD31/ERG positive, may have intracytoplasmic lumina)
─ Rhabdoid tumor (INI1 loss, characteristic rhabdoid cells)
─ Conventional pleomorphic liposarcoma (predominantly spindle/pleomorphic cells rather than epithelioid sheets)
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Myxoid Pleomorphic Liposarcoma (MPLS)

A very rare, controversial category of high-grade liposarcoma exhibiting features of both myxoid liposarcoma (myxoid stroma, some arborizing vessels) and pleomorphic liposarcoma (significant cytologic pleomorphism, pleomorphic lipoblasts), but lacking the specific DDIT3 fusions of MLS and MDM2 amplification of DDLPS
Clinical ─ Adults; deep soft tissues; behavior is generally aggressive
Macro ─ Often large, multinodular, with both gelatinous (myxoid) and fleshy (solid/pleomorphic) areas
Micro
─ Admixture of areas resembling myxoid liposarcoma (myxoid matrix, primitive cells, possibly some delicate vasculature) and areas with marked cytologic pleomorphism characteristic of pleomorphic liposarcoma, including pleomorphic lipoblasts
─ The pleomorphism is more pronounced than expected for typical high-grade (round cell) myxoid liposarcoma
─ Lacks the classic uniform cellularity and plexiform capillaries of pure MLS throughout
─ Fails to meet criteria for dedifferentiated liposarcoma (ie, no clear WDLPS component)
Ancillary studies ─
─ IHC: S100 variably positive in lipoblasts and some tumor cells; Negative for MDM2/CDK4 amplification markers; Negative or equivocal for specific markers of other sarcomas
─ Molecular: Complex karyotypes; lacks FUS::DDIT3 or EWSR1::DDIT3 fusions; lacks MDM2/CDK4 amplification
DDx
─ Myxoid liposarcoma with round cell transformation (DDIT3 fusion positive)
─ Pleomorphic liposarcoma with myxoid change (predominantly PLS features)
─ Dedifferentiated liposarcoma with myxoid stroma (arises from WDLPS, MDM2 amplified)
─ High-grade myxofibrosarcoma (curvilinear vessels, significant pleomorphism, but typically lacks true pleomorphic lipoblasts)
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Soft Tissue, Fibroblastic

Nodular Fasciitis

A benign, self-limited, reactive myofibroblastic proliferation characterized by rapid growth and often a history of local trauma, which can be mistaken for sarcoma due to its cellularity and mitotic activity
Clinical ─ Typically young adults (peak 20-40s); common in subcutaneous tissue of upper extremities (especially forearm), trunk, and head/neck; less commonly intramuscular or fascial; presents as a solitary, rapidly growing (often over weeks), sometimes tender nodule, usually <3 cm
Macro ─ Poorly circumscribed, firm or rubbery, gray-white to tan nodule; cut surface may appear fleshy or gelatinous (myxoid variant)
Micro
─ Highly cellular proliferation of plump, immature-appearing spindle to stellate myofibroblasts
─ Cells arranged in short, irregular fascicles, a storiform pattern, or haphazardly within a loose, myxoid, or edematous stroma ("tissue culture-like" or "feathery" appearance)
─ Nuclei are vesicular with small nucleoli; significant pleomorphism is usually absent, but some atypia can be seen
─ Mitotic figures are often frequent and easily found, but atypical mitoses are rare
─ Extravasated red blood cells and a sparse chronic inflammatory infiltrate (lymphocytes) are common
─ Characteristic delicate, branching capillaries
─ Variants include myxoid, cellular, and fibrous types; cranial fasciitis (infants, skull), intravascular fasciitis are related entities
Ancillary studies ─
─ IHC: Tumor cells are positive for SMA (smooth muscle actin) and MSA (muscle-specific actin), often in a "tram-track" pattern; Negative for desmin, S100, keratins, CD34 (usually)
─ Molecular: Characterized by USP6 gene rearrangements (most commonly MYH9::USP6 fusion), leading to overexpression of USP6 protease
DDx
─ Fibrosarcoma / Spindle cell sarcoma (more pronounced atypia, infiltrative growth pattern, lacks USP6 rearrangement)
─ Myxofibrosarcoma (more pleomorphism, curvilinear vessels, typically older adults)
─ Leiomyosarcoma (more distinct fascicles, cigar-shaped nuclei, desmin positive)
─ Dermatofibrosarcoma protuberans (storiform pattern, CD34 positive, COL1A1::PDGFB fusion)
─ Inflammatory myofibroblastic tumor (often ALK positive, more organized fascicles, prominent plasma cells)
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Myxoid Nodular Fasciitis

A variant of nodular fasciitis characterized by a particularly abundant myxoid stroma, which can sometimes make it appear less cellular and potentially mistaken for other myxoid lesions
Clinical ─ Similar to conventional nodular fasciitis; typically young adults, rapid growth, often subcutaneous in upper extremities, trunk, head/neck
Macro ─ Usually a small, poorly circumscribed nodule; cut surface is distinctly gelatinous or mucoid and grayish-white
Micro
─ Overall architecture and cell morphology similar to conventional nodular fasciitis, with plump spindle to stellate myofibroblasts
─ Predominant feature is an exceptionally abundant, loose, myxoid, or edematous stroma (Alcian blue positive)
─ Cells may appear more separated due to the myxoid matrix, leading to a less cellular appearance in some areas
─ Characteristic "tissue culture-like" or "feathery" appearance of cells is retained
─ Mitotic figures, extravasated red blood cells, and inflammatory cells are present, similar to conventional nodular fasciitis
Ancillary studies ─
─ IHC: Positive for SMA and MSA; Negative for desmin, S100, keratins
─ Molecular: USP6 gene rearrangements (eg, MYH9::USP6) are present, confirming its relation to nodular fasciitis
DDx
─ Intramuscular myxoma / Juxta-articular myxoma (less cellular, lacks tissue culture appearance, GNAS mutations in intramuscular type, lacks USP6 rearrangement)
─ Myxoid liposarcoma (contains lipoblasts, plexiform capillaries, DDIT3 fusion)
─ Low-grade myxofibrosarcoma (older adults, more pleomorphism, curvilinear vessels, lacks USP6 rearrangement)
─ Aggressive angiomyxoma (deep pelvic/perineal, prominent vessels, HMGA2 rearranged)
─ Myxoid neurofibroma (S100 positive wavy cells, embedded axons)
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Cranial Fasciitis

A specific subtype of nodular fasciitis occurring in infants and young children, typically involving the soft tissues overlying the skull, and may erode the outer table of the calvarium
Clinical ─ Infants and young children (usually < 2 years, often < 6 months); presents as a rapidly growing, firm, non-tender scalp mass; may be fixed to underlying bone
Macro ─ Well-circumscribed or ill-defined subcutaneous nodule, often attached to the galea or periosteum; may show areas of bony erosion if involving skull
Micro
─ Histologically similar to conventional nodular fasciitis, composed of plump spindle and stellate myofibroblasts in a loose, often myxoid stroma
─ "Tissue culture-like" or "feathery" appearance
─ Mitotic figures are common but typically not atypical
─ May involve underlying periosteum and cause superficial erosion of the skull bone, sometimes with reactive bone formation
─ Cellularity can be variable, often highly cellular
Ancillary studies ─
─ IHC: Positive for SMA and MSA; Negative for desmin, S100, keratins
─ Molecular: USP6 gene rearrangements are characteristic, similar to other forms of nodular fasciitis
DDx
─ Infantile fibrosarcoma (more uniformly cellular, herringbone pattern, ETV6::NTRK3 fusion)
─ Langerhans cell histiocytosis (S100, CD1a, Langerin positive eosinophilic infiltrate)
─ Dermoid or epidermoid cyst (epithelial lining)
─ Cephalohematoma (resolving) (history of birth trauma, blood products)
─ Infantile myofibromatosis (biphasic pattern, hemangiopericytoma-like vessels)
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Pseudosarcomatous Myofibroblastic Proliferation

A reactive, benign proliferation of myofibroblasts that can be mistaken for a sarcoma due to its cellularity and mitotic activity, often occurring in the genitourinary tract (especially bladder), gastrointestinal tract, or at sites of prior surgery or trauma
Clinical ─ Wide age range, can occur in children and adults; bladder (post-operative spindle cell nodule/POSCN), prostate, and other genitourinary sites are notable; also reported in soft tissue following surgery or trauma; may present as a rapidly growing polypoid or nodular mass
Macro ─ Often ill-defined or polypoid, firm, grayish-white to tan lesion; may appear infiltrative or exophytic
Micro
─ Spindle to stellate myofibroblasts arranged in loose fascicles or a haphazard pattern within an edematous, myxoid, or collagenous stroma, often highly vascular ("granulation tissue-like")
─ Cells can have enlarged, vesicular nuclei and prominent nucleoli ("ganglion-like" appearance), but typically lack significant hyperchromasia or overt malignant cytologic features
─ Mitotic activity can be brisk, but atypical mitoses are rare or absent
─ Inflammatory infiltrate, including lymphocytes, plasma cells, and often eosinophils or neutrophils, is common
─ "Tissue culture-like" appearance similar to nodular fasciitis is often described
Ancillary studies ─
─ IHC: Positive for SMA, MSA, vimentin; Desmin is variably positive; Cytokeratins (AE1/AE3, CAM5.2) can be focally positive, especially in bladder lesions (potential pitfall for sarcomatoid carcinoma)
─ IHC: ALK1 is typically negative (important for distinction from inflammatory myofibroblastic tumor, though some IMTs are ALK-negative)
─ IHC: Negative for S100, SOX10, myogenin
─ Molecular: USP6 rearrangements have been reported in some cases, linking them to the nodular fasciitis spectrum
DDx
─ Inflammatory myofibroblastic tumor (IMT) (often ALK positive, more organized fascicular growth, less "tissue culture-like," prominent plasma cells)
─ Sarcomatoid carcinoma (especially in bladder; more pronounced epithelial atypia, cohesive malignant epithelial component, GATA3/p63/Uroplakin positivity)
─ Leiomyosarcoma / Rhabdomyosarcoma (more distinct myogenic differentiation, significant atypia, specific myogenic markers more diffuse)
─ Nodular fasciitis (similar reactive appearance but often more feathery fascicles, extravasated RBCs; USP6 rearranged)
─ Other spindle cell sarcomas (distinguished by specific morphology, IHC, and molecular findings)
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Mycobacterial Spindle Cell Pseudotumor

A rare, non-neoplastic reactive proliferation of histiocytic spindle cells filled with mycobacteria, typically occurring in immunocompromised individuals, especially those with HIV/AIDS or other forms of immunosuppression
Clinical ─ Primarily affects immunocompromised individuals; common sites include lymph nodes, skin, spleen, liver, and lung; presents as single or multiple nodules or masses
Macro ─ Ill-defined or circumscribed nodules or masses; cut surface is often tan-yellow, fleshy, or caseous
Micro
─ Diffuse proliferation of plump spindle cells, often with a storiform or fascicular arrangement, resembling a sarcoma
─ Spindle cells are histiocytes (macrophages) with abundant eosinophilic or pale foamy cytoplasm, containing numerous acid-fast bacilli
─ Nuclei are typically bland, oval to elongated, with minimal atypia; mitoses are infrequent
─ Background inflammatory infiltrate is variable, often sparse, consisting of lymphocytes and plasma cells; granuloma formation is usually poor or absent
─ Necrosis may be present
─ Special stains (Ziehl-Neelsen, Fite-Faraco) highlight abundant intracellular acid-fast bacilli
Ancillary studies ─
─ IHC: Spindle cells are positive for CD68, CD163 (histiocytic markers); Negative for S100, SMA, desmin, keratins
─ Molecular: PCR or culture can identify the specific mycobacterial species (often Mycobacterium avium-intracellulare complex or Mycobacterium tuberculosis)
DDx
─ Kaposi sarcoma (HHV8 positive, vascular proliferation, different IHC profile)
─ Spindle cell melanoma (S100/SOX10/melanocytic markers positive, lacks mycobacteria)
─ Leiomyosarcoma (SMA/desmin positive, lacks mycobacteria)
─ Fibrous histiocytoma (Factor XIIIa positive, lacks mycobacteria)
─ Other spindle cell sarcomas (specific features and IHC, lack mycobacteria)
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Proliferative Fasciitis & Myositis

Reactive, rapidly growing pseudosarcomatous proliferations of myofibroblasts, closely related to nodular fasciitis, but characterized by the additional presence of large, ganglion-like cells; Proliferative fasciitis involves fascia and subcutaneous tissue, while proliferative myositis involves skeletal muscle
Clinical ─ Typically adults (peak 40-60s, older than typical nodular fasciitis); common in extremities (especially forearm, thigh); presents as a rapidly growing, sometimes painful, firm nodule or mass, often <5 cm
Macro ─ Poorly defined, firm, gray-white mass; infiltrative into surrounding tissues
Micro
─ Background similar to nodular fasciitis: cellular proliferation of plump spindle to stellate myofibroblasts in a loose, myxoid, or collagenous stroma ("tissue culture-like")
─ Characteristic feature: Presence of large, polygonal "ganglion-like" cells, which have abundant basophilic or amphophilic cytoplasm, large vesicular nuclei, and prominent nucleoli (resembling ganglion cells or rhabdomyoblasts, but are reactive myofibroblasts)
─ These ganglion-like cells are often scattered individually or in small clusters
─ Mitotic activity can be brisk in the spindle cell component, but atypical mitoses are rare
─ Inflammatory infiltrate (lymphocytes, plasma cells) and extravasated RBCs are common
─ Proliferative myositis shows infiltration and separation of skeletal muscle fibers by the proliferation; muscle fibers may show reactive changes or degeneration
Ancillary studies ─
─ IHC: Spindle cells and ganglion-like cells are positive for SMA and MSA; Negative for desmin (except entrapped muscle in myositis), S100, keratins
─ Molecular: FOS or FOSB gene rearrangements have been reported in a subset of cases, particularly in proliferative myositis
DDx
─ Nodular fasciitis (lacks the prominent ganglion-like cells, though some overlap exists)
─ Rhabdomyosarcoma (especially embryonal or pleomorphic; true rhabdomyoblasts show more definitive myogenic differentiation, MyoD1/myogenin positive)
─ Ganglioneuroma / Ganglioneuroblastoma (true ganglion cells are S100/neurofilament positive, different clinical context)
─ High-grade sarcomas (eg, UPS, myxofibrosarcoma - more significant atypia, pleomorphism, atypical mitoses)
─ Ischemic fasciitis (zonal pattern, fibrinoid necrosis, different clinical setting)
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Myositis Ossificans & Fibro-Osseous Pseudotumor of Digits (includes Heterotopic Ossification)

A benign, self-limited, reactive fibroblastic and osteoblastic proliferation characterized by zonal maturation leading to heterotopic ossification, often following trauma; Fibro-osseous pseudotumor of digits is a similar process in fingers and toes
Clinical ─ Myositis Ossificans (MO): Typically adolescents and young adults (peak teens-30s), M>F; often history of trauma (~50-60%); common in large muscles of extremities (thigh, arm, buttocks), trunk; presents as a rapidly enlarging, often painful, firm mass that later becomes hard and well-demarcated
Clinical ─ Fibro-Osseous Pseudotumor of Digits (FOPD): Affects digits (fingers/toes); similar age group or slightly older; may also follow trauma
Macro ─ MO: Initially soft and fleshy, later well-circumscribed, firm to hard, gritty mass with a shelled-out appearance; FOPD: Smaller, firm nodule in digits
Micro
─ Characteristic zonal pattern (most evident in mature lesions of MO):
─ Central zone: Highly cellular, immature, plump spindle to stellate cells (myofibroblasts) resembling nodular fasciitis or granulation tissue, set in a loose, myxoid stroma; mitoses can be frequent here
─ Intermediate zone: Lace-like or trabecular osteoid production by plump, reactive osteoblasts; primitive woven bone formation
─ Peripheral zone: Mature, well-formed lamellar bone trabeculae, may resemble cortical bone; often surrounded by a fibrous pseudocapsule
─ FOPD: Similar zonal pattern but often less distinct, may be more uniformly cellular with osteoid production throughout, or predominantly fibrous with focal bone; cartilage may be more common
─ Heterotopic Ossification (general term): Bone formation in soft tissues where bone normally does not exist; MO is a specific type
Ancillary studies ─
─ IHC: Spindle cells are positive for SMA and MSA; Osteoblasts are positive for SATB2 and alkaline phosphatase
─ Molecular: USP6 gene rearrangements reported in a subset of MO, similar to nodular fasciitis, especially in early cellular phases
DDx
─ Osteosarcoma (especially extraskeletal or parosteal): Malignant cytologic atypia throughout, infiltrative growth, atypical mitoses, lacks clear zonation (reverse zonation may occur in some osteosarcomas); crucial to assess early, cellular biopsies of MO carefully
─ Nodular fasciitis (lacks ossification, though early MO can resemble it)
─ Proliferative myositis/fasciitis (contains ganglion-like cells, lacks ossification)
─ Tumoral calcinosis (avascular calcified deposits, lacks viable cells/osteoid)
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Keloid

An exuberant scar formation characterized by excessive deposition of dense, hyalinized collagen that extends beyond the boundaries of the original wound, failing to regress spontaneously
Clinical ─ Any age, but more common in individuals aged 10-30 years; increased incidence in individuals with darker skin pigmentation (African, Asian, Hispanic descent); commonly occurs at sites of prior skin trauma (lacerations, surgery, burns, vaccinations, ear piercings, acne); typical sites include earlobes, anterior chest, shoulders, upper back; presents as a raised, firm, often pruritic or painful nodule or plaque that grows beyond the original injury site
Macro ─ Irregularly shaped, raised, firm, smooth-surfaced lesion; color may be erythematous initially, later skin-colored or hyperpigmented; extends beyond the margins of the original wound
Micro
─ Dermal proliferation characterized by thick, brightly eosinophilic, glassy, hyalinized collagen bundles ("keloidal collagen")
─ Collagen bundles are haphazardly arranged, broad, and often parallel to the epidermis in the central portion
─ Relatively hypocellular with scattered bland fibroblasts and myofibroblasts embedded within the dense collagen
─ Overlying epidermis is typically atrophic with loss of rete ridges
─ Adnexal structures are usually absent within the keloid body
─ Early lesions may be more cellular and vascular before extensive hyalinization occurs
─ Importantly, the abnormal collagenous proliferation extends into the adjacent normal dermis beyond the original injury site
Ancillary studies ─
─ IHC: Not typically required for diagnosis; special stains like Masson trichrome can highlight the dense collagen (blue-green)
─ Molecular: Not applicable for routine diagnosis
DDx
─ Hypertrophic scar (raised scar confined to the boundaries of the original wound, finer collagen bundles arranged parallel to epidermis, tends to regress over time)
─ Dermatofibroma (dermal spindle cell proliferation, Factor XIIIa positive, collagen trapping at periphery)
─ Dermatofibrosarcoma protuberans (storiform pattern, CD34 positive, infiltrates subcutis)
─ Scarred basal cell carcinoma or squamous cell carcinoma (will show atypical epithelial cells)
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Hypertrophic Scar

A raised scar resulting from excessive collagen deposition during wound healing, but critically, it remains confined to the boundaries of the original wound and often regresses partially over time
Clinical ─ Develops within weeks to months after skin injury (surgery, trauma, burns, inflammation); presents as a raised, often erythematous, firm scar that may be pruritic or tender; common in areas of skin tension
Macro ─ Raised, firm scar tissue that mirrors the site of the original injury and does not extend beyond its borders; may be linear or widespread depending on the initial trauma
Micro
─ Increased cellularity compared to a mature normotrophic scar, with numerous fibroblasts and myofibroblasts
─ Collagen bundles are finer and more wavy than in keloids, typically arranged parallel to the overlying epidermis and in nodules
─ Increased number of small blood vessels, often oriented perpendicular to the epidermis in the papillary dermis
─ Lacks the thick, brightly eosinophilic, glassy collagen bundles characteristic of keloid
─ Confined to the area of the original wound, without extension into surrounding normal dermis
─ Overlying epidermis may be flattened or slightly acanthotic
Ancillary studies ─
─ IHC: Not typically required for diagnosis; myofibroblasts are SMA positive
─ Molecular: Not applicable for routine diagnosis
DDx
─ Keloid (extends beyond original wound boundaries, thick hyalinized collagen bundles)
─ Mature scar (flatter, less cellular, less vascular)
─ Dermatofibroma (dermal spindle cell proliferation, Factor XIIIa positive)
─ Incisional biopsy site with granulation tissue (more inflammation, edema, prominent neovascularization)
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Elastofibroma

A benign, slow-growing fibroelastic proliferation, almost exclusively occurring in the subscapular region of elderly individuals, characterized by an abundance of abnormal elastic fibers
Clinical ─ Typically affects elderly individuals (peak 60-70s), with a female predominance (F>M up to 5:1); most common location is the subscapular area, between the scapula and the chest wall, deep to the serratus anterior or latissimus dorsi muscles; often bilateral (~10-60%); may present as an asymptomatic mass or cause pain, stiffness, or a clicking sensation with shoulder movement ("elastofibroma dorsi")
Macro ─ Poorly circumscribed, rubbery to firm, unencapsulated mass; cut surface is typically gray-white and fibrous, often with intermingled yellowish fatty streaks; size ranges from a few centimeters to over 10 cm
Micro
─ Admixture of dense, hypocellular collagenous tissue and mature adipose tissue in variable proportions
─ Characteristic feature: Abundance of enlarged, fragmented, abnormal elastic fibers
─ Elastic fibers appear as coarse, deeply eosinophilic, serrated, beaded, or globoid structures ("elastic globes" or "amianthoid-like fibers") when stained with H&E; they stain black with elastic stains (eg, Verhoeff-Van Gieson - VVG)
─ Scattered, bland spindle or stellate fibroblasts are present within the fibrous stroma
─ No significant cytologic atypia or mitotic activity
Ancillary studies ─
─ IHC: Not diagnostic; elastic stains (VVG, orcein) are essential to highlight the characteristic abnormal elastic fibers
─ Molecular: No specific recurrent genetic alterations are consistently identified; thought to be a reactive or degenerative process due to repetitive microtrauma
DDx
─ Desmoid fibromatosis (more cellular, infiltrative, lacks abnormal elastic fibers, nuclear beta-catenin positive)
─ Lipoma (predominantly mature fat, lacks fibrous tissue and abnormal elastic fibers)
─ Fibromatosis variants (eg, nuchal-type fibroma; lacks characteristic elastic fibers)
─ Scar tissue (less organized, lacks the specific elastic fiber morphology)
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Ischemic Fasciitis

A reactive, pseudosarcomatous fibroblastic proliferation typically occurring in elderly, debilitated, or immobilized patients over bony prominences, believed to be related to chronic pressure-induced ischemia; also known as atypical decubital fibroplasia
Clinical ─ Elderly, bedridden, or paraplegic patients; occurs over bony prominences subjected to prolonged pressure, such as the sacrum, greater trochanter, ischial tuberosity, heel, and elbow; often presents as an ulcerated nodule or mass, or a deep-seated induration beneath an ulcer
Macro ─ Poorly defined, firm, indurated mass or plaque, often associated with overlying skin ulceration; cut surface is gray-white to yellow, may show areas of necrosis or cystic change
Micro
─ Often shows a zonal architecture, especially in well-developed lesions:
─ Central zone: Fibrinoid necrosis or degeneration, often with central liquefaction leading to pseudocyst formation
─ Peripheral zone: Proliferation of plump, reactive fibroblasts and myofibroblasts, which can exhibit enlarged, hyperchromatic, and sometimes bizarre (ganglion-like) nuclei due to degenerative atypia; these cells are typically arranged in loose fascicles or haphazardly
─ Prominent vascular proliferation, with small blood vessels often lined by plump endothelial cells, sometimes arranged perpendicular to the surface or ulcer base
─ Fibrin thrombi within vessel lumina may be present
─ Chronic inflammatory infiltrate, hemosiderin deposition, and fat necrosis are common in the surrounding tissue
─ Mitotic activity can be present but is usually not atypical
Ancillary studies ─
─ IHC: Spindle cells are positive for vimentin, often SMA; Negative for keratins, S100, desmin (helps exclude carcinoma, melanoma, myogenic sarcomas)
─ Molecular: Not relevant for this reactive process
DDx
─ Decubitus ulcer with granulation tissue (less atypia in fibroblasts, more overt inflammation)
─ Nodular fasciitis (younger patients, different locations, more uniform "tissue culture" appearance, USP6 rearranged)
─ Squamous cell carcinoma (associated with chronic ulcers) (keratin positive, true malignant epithelial atypia)
─ High-grade sarcomas (eg, UPS, angiosarcoma - more diffuse and infiltrative atypia, atypical mitoses, specific markers if differentiated)
─ Proliferative fasciitis/myositis (ganglion-like cells present, but different clinical context and lacks central fibrinoid necrosis typically)
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WSI H&E CD68 S100 SMA

Fibrous hamartoma of infancy

A benign, superficial soft tissue lesion unique to infants and young children, characterized by a distinctive triphasic pattern of fibrous tissue, primitive mesenchyme, and mature adipose tissue
Clinical ─ Typically occurs in infants and young children, usually within the first 2 years of life (many congenital); strong male predominance (M>F ~3:1); common sites include axilla, upper arm, shoulder, inguinal region, and external genitalia; presents as a rapidly growing, painless, firm to rubbery subcutaneous mass, usually solitary
Macro ─ Poorly circumscribed, unencapsulated, firm, gray-white mass often with visible yellowish fatty areas intermingled; size typically 1-5 cm
Micro
─ Characteristic triphasic pattern with variable proportions of three components:
─ Well-defined fascicles of bland spindle cells (fibroblasts and myofibroblasts) resembling fibromatosis, set in a collagenous stroma
─ Nests, clusters, or whorls of small, round to ovoid primitive-appearing mesenchymal cells with scant cytoplasm and dark nuclei, often embedded in a loose, myxoid, or edematous stroma
─ Mature adipose tissue interspersed between the fibrous and mesenchymal components, often in irregular islands or lobules
─ The components are typically arranged in an organoid or haphazard fashion
─ No significant cytologic atypia or mitotic activity in any component
─ Vascularity is generally not prominent
Ancillary studies ─
─ IHC: Spindle cells (fibrous component) are positive for vimentin and may show focal SMA; Primitive mesenchymal cells are often CD34 positive and vimentin positive; Adipose tissue is S100 positive; Negative for desmin, nuclear beta-catenin, and keratins
─ Molecular: EGFR gene rearrangements (often involving exon 1 duplication) have been reported in a subset of cases, but not consistently; other pathways like PI3K/AKT may be involved
DDx
─ Infantile fibromatosis/Myofibromatosis (lacks the triphasic pattern, especially the primitive mesenchymal and distinct adipose components)
─ Lipoblastoma (composed of lipoblasts and immature fat, PLAG1 rearranged, lacks distinct fibrous and primitive mesenchymal components of FHI)
─ Lipofibromatosis (more infiltrative, predominantly fibrous and fatty, lacks primitive mesenchymal nests, often involves digits)
─ Calcifying aponeurotic fibroma (different location - hands/feet, calcification, chondroid areas, different age)
─ Embryonal rhabdomyosarcoma (malignant, shows rhabdomyoblastic differentiation, myogenin/MyoD1 positive)
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WSI & video

Fibromatosis colli

A benign, self-limiting fibroblastic proliferation occurring within the sternocleidomastoid muscle of infants, typically presenting as a firm neck mass (torticollis)
Clinical ─ Presents in neonates or infants, usually within the first 2-4 weeks of life; slight male predominance; associated with birth trauma (eg, breech delivery, forceps delivery) or intrauterine malpositioning in many cases; characterized by a firm, discrete, painless or minimally tender fusiform swelling within the lower to middle portion of the sternocleidomastoid muscle, leading to tilting of the head to the affected side and rotation of the chin to the opposite side (torticollis)
Macro ─ Poorly defined, firm, white-tan fibrous thickening or mass within the substance of the sternocleidomastoid muscle, causing fusiform enlargement of the muscle
Micro
─ Diffuse or nodular proliferation of bland, uniform spindle cells (fibroblasts and myofibroblasts) replacing and entrapping skeletal muscle fibers of the sternocleidomastoid muscle
─ Entrapped skeletal muscle fibers often show atrophy, degeneration, or vacuolization
─ Spindle cells are arranged in short fascicles or haphazardly within a variably collagenous or slightly myxoid stroma
─ No significant cytologic atypia, minimal to absent mitotic activity, and no necrosis
─ Chronic inflammatory cells may be sparsely present
Ancillary studies ─
─ IHC: Spindle cells are positive for vimentin and often SMA and MSA; Desmin highlights the entrapped skeletal muscle fibers but is negative in the spindle cells; Negative for S100 and keratins
─ Molecular: Not typically characterized by specific recurrent genetic alterations; considered a reactive or reparative process
DDx
─ Infantile fibrosarcoma (more cellular, herringbone pattern, ETV6::NTRK3 fusion, much rarer in this site)
─ Rhabdomyoma (fetal type) (composed of immature skeletal muscle cells, myogenic markers positive throughout)
─ Lymphadenopathy (distinct nodal architecture, lymphoid markers positive)
─ Congenital muscular torticollis (may represent the end stage of fibromatosis colli with more fibrosis and less cellularity)
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Juvenile hyaline fibromatosis (Hyaline Fibromatosis Syndrome)

A rare autosomal recessive disorder characterized by widespread deposition of hyaline material in the skin, gingiva, joints, and other tissues, leading to papulonodular skin lesions, gingival hypertrophy, joint contractures, and sometimes visceral involvement; now part of a spectrum with Infantile Systemic Hyalinosis
Clinical ─ Typically presents in infancy or early childhood (often by age 2); consanguinity is a risk factor; cutaneous lesions appear as pearly white or skin-colored papules and nodules, especially on the head/neck (face, scalp, ears), hands, feet, and back; severe gingival hypertrophy is common; joint contractures can lead to significant disability; osteopenia and osteoporosis may occur; failure to thrive and recurrent infections can be seen in severe forms (Infantile Systemic Hyalinosis)
Macro ─ Skin nodules are firm, pearly white, or flesh-colored; gingiva is markedly enlarged, firm, and pale; affected joints are stiff and contracted
Micro
─ Dermal nodules (or involved tissues) composed of abundant, dense, amorphous, eosinophilic hyaline material (composed of glycoproteins and type VI collagen)
─ Sparsely cellular, with bland spindle to stellate fibroblasts and myofibroblasts embedded within the hyaline matrix, often arranged in cords or small clusters
─ Cells have pale cytoplasm and small, inconspicuous nuclei; no atypia or mitoses
─ Overlying epidermis may be atrophic or normal
─ Blood vessels within the lesion are often scarce
Ancillary studies ─
─ IHC: Spindle cells are positive for vimentin; Hyaline material is positive with PAS stain (diastase resistant) and Alcian blue (variable); Type VI collagen is a major component of the hyaline material
─ Molecular: Caused by biallelic mutations in the ANTXR2 gene (also known as CMG2), which encodes capillary morphogenesis protein 2
DDx
─ Lipoid proteinosis (Urbach-Wiethe disease) (different genetic basis - ECM1 mutations, different clinical features like hoarse cry, beaded eyelids)
─ Winchester syndrome (multicentric osteolysis, arthropathy, and cutaneous findings; MMP2 or MMP14 mutations)
─ Nodular amyloidosis (amyloid deposits positive with Congo red showing apple-green birefringence)
─ Infantile digital fibromatosis (inclusion bodies, specific location)
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Inclusion body fibromatosis (Infantile Digital Fibroma)

A benign, distinctive myofibroblastic proliferation occurring almost exclusively on the digits of infants and young children, characterized by pathognomonic intracytoplasmic eosinophilic inclusions within the tumor cells
Clinical ─ Typically presents in infants or young children (most cases within the first year of life, can be congenital); affects the dorsal or lateral aspects of the fingers and toes, characteristically sparing the thumbs and great toes; presents as a firm, painless, dome-shaped, skin-colored or reddish nodule, usually <2 cm; multiple lesions can occur
Macro ─ Well-demarcated but unencapsulated, firm, gray-white nodule in the dermis and subcutis of digits
Micro
─ Dermal and subcutaneous proliferation of bland spindle cells (myofibroblasts) arranged in intersecting fascicles or a storiform pattern
─ Pathognomonic feature: Intracytoplasmic, round to oval, brightly eosinophilic inclusions within many of the spindle cells; these inclusions are typically paranuclear, sometimes indenting the nucleus
─ Inclusions are composed of actin filaments
─ Spindle cells have vesicular nuclei and inconspicuous nucleoli; minimal atypia
─ Low mitotic activity is typical
─ Stroma is variably collagenous
Ancillary studies ─
─ IHC: Spindle cells and the intracytoplasmic inclusions are positive for SMA (smooth muscle actin) and MSA (muscle-specific actin); Desmin is typically negative (or only focally positive); Negative for S100 and keratins
─ Ultrastructure: Inclusions are composed of densely packed thin (actin) filaments
─ Molecular: No specific recurrent genetic alterations identified
DDx
─ Other benign fibrous proliferations of childhood (eg, fibrous hamartoma of infancy, infantile fibromatosis - lack characteristic inclusions and specific location)
─ Scar tissue (lacks inclusions, different architecture)
─ Juvenile aponeurotic fibroma (calcifying aponeurotic fibroma) (different location, calcification, chondroid areas)
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Fibroma of tendon sheath

A benign, typically small, lobulated fibrous nodule that is intimately associated with a tendon or tendon sheath, most commonly in the extremities
Clinical ─ Predominantly affects adults (peak 20-50 years), with a male predominance; common sites include fingers, hand, wrist, less frequently feet, ankle, knee; usually presents as a slow-growing, firm, painless, mobile or fixed nodule attached to a tendon or tendon sheath; typically <3 cm in size
Macro ─ Well-circumscribed, firm, lobulated, gray-white to tan nodule; often appears encapsulated and may be attached to or incorporated within tendon sheath or tendon
Micro
─ Well-demarcated, often encapsulated, lobulated proliferation of bland spindle cells (fibroblasts and myofibroblasts) set in a dense collagenous stroma
─ Cellularity can vary between lobules, ranging from hypocellular and densely sclerotic to moderately cellular
─ Characteristic feature: Prominent, slit-like or cleft-like vascular spaces, often more numerous at the periphery of the lobules
─ Spindle cells have elongated nuclei, scant cytoplasm, and inconspicuous nucleoli; no significant atypia
─ Mitotic activity is rare to absent
─ Myxoid change can be present focally
─ Cellular variant: More uniformly cellular, less collagen, may resemble nodular fasciitis or low-grade fibromyxoid sarcoma, but lacks atypia and specific molecular markers of those entities
Ancillary studies ─
─ IHC: Spindle cells are positive for vimentin; SMA is variably positive (often patchy, more so in cellular areas); Negative for S100, desmin, keratins, CD34 (except in vessels)
─ Molecular: USP6 gene rearrangements have been reported, particularly in the cellular variant, linking it to the nodular fasciitis spectrum
DDx
─ Tenosynovial giant cell tumor, localized type (giant cell tumor of tendon sheath) (contains mononuclear cells, osteoclast-like giant cells, foam cells, hemosiderin)
─ Nodular fasciitis (more myxoid, "tissue culture" appearance, lacks prominent slit-like vessels, USP6 rearranged)
─ Desmoid fibromatosis (more infiltrative, long sweeping fascicles, nuclear beta-catenin often positive)
─ Low-grade fibromyxoid sarcoma (alternating fibrous/myxoid areas, MUC4 positive, FUS fusion)
─ Scar tissue (history of trauma, less lobulated, different vascular pattern)
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Soft Tissue, Fibroblastic

Desmoplastic fibroblastoma (Collagenous Fibroma)

A benign, paucicellular fibroblastic neoplasm characterized by bland spindle and stellate cells embedded in an abundant, dense collagenous or fibromyxoid stroma
Clinical ─ Typically affects adults, with a peak incidence in middle to older age (40-70 years); strong male predominance (M:F ~5:1); commonly arises in subcutaneous tissue or deep soft tissues (skeletal muscle) of the extremities (especially arm and shoulder), neck, back, and trunk; presents as a slow-growing, painless, firm, mobile nodule
Macro ─ Well-circumscribed, often pseudoencapsulated, firm, rubbery mass; cut surface is typically white-gray and fibrous, sometimes with glistening myxoid areas; size usually ranges from 1 to 5 cm, but can be larger
Micro

─ Circumscribed but unencapsulated, often multinodular or lobulated growth pattern
─ Paucicellular proliferation of bland, slender spindle-shaped to stellate fibroblasts with scant, pale cytoplasm and small, dark, or vesicular nuclei
─ Cells are arranged haphazardly or in short fascicles within an abundant, dense collagenous stroma; myxoid or edematous stromal change can be prominent in some areas
─ Minimal vascularity within the tumor nodules is characteristic; larger vessels may be present in septa
─ Peripheral entrapment of mature adipose tissue or skeletal muscle fibers is common
─ No significant cytologic atypia, pleomorphism, or mitotic activity (mitoses are rare to absent)
─ Necrosis is absent
Ancillary studies ─
─ IHC: Tumor cells are positive for vimentin; Variable positivity for SMA (smooth muscle actin) and MSA (muscle-specific actin), particularly in more cellular areas; Negative for S100 protein, desmin, keratins, CD34 (except entrapped vessels), and beta-catenin
─ Molecular: Recurrent rearrangements involving the FOSL1 gene (11q13) have been reported in a subset of cases
DDx

─ Desmoid fibromatosis (more infiltrative, more cellular with long sweeping fascicles, nuclear beta-catenin positive)
─ Low-grade fibromyxoid sarcoma (alternating fibrous/myxoid areas, arcades of blood vessels, MUC4 positive, FUS fusion)
─ Neurofibroma (wavy nuclei, S100 positive spindle cells, myxoid stroma)
─ Nuchal-type fibroma (posterior neck/back, thick collagen bundles, CD34 positive spindle cells)
─ Sclerotic lipoma (mature fat admixed with dense collagen, lacks prominent spindle cells of DF)
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Nuchal-Type Fibroma

A benign, paucicellular fibroblastic proliferation characterized by dense, haphazardly arranged collagen bundles and scattered bland spindle cells, typically occurring in the posterior neck and upper back
Clinical ─ Adults, wide age range (peak 30-60 years), slight male predominance; most common in the posterior neck (nuchal region), upper back, and shoulders; may be associated with diabetes mellitus and Gardner syndrome (familial adenomatous polyposis); presents as a poorly defined, firm, subcutaneous or deep soft tissue mass, often slow-growing and painless
Macro ─ Ill-defined, firm, rubbery, white-gray fibrous mass; may appear infiltrative; size can vary from small nodules to large masses
Micro

─ Poorly circumscribed, infiltrative proliferation of hypocellular fibrous tissue
─ Composed of thick, haphazardly arranged, hyalinized collagen bundles, resembling scar tissue or keloid but without the distinct glassy appearance of keloidal collagen
─ Scattered, bland spindle-shaped fibroblasts with inconspicuous nuclei and scant cytoplasm are embedded within the dense collagen
─ Mature adipose tissue is often entrapped within the lesion
─ Minimal vascularity; inflammatory infiltrate is typically sparse or absent
─ No significant cytologic atypia, mitotic activity is rare to absent, necrosis is not seen
Ancillary studies ─
─ IHC: Spindle cells are positive for vimentin and often CD34; Variable positivity for CD99 and bcl-2; Negative for S100, SMA (except entrapped vessels), desmin, keratins, and nuclear beta-catenin
─ Molecular: No specific recurrent genetic alterations consistently identified; distinct from desmoid fibromatosis
DDx

─ Desmoid fibromatosis (more cellular, more organized sweeping fascicles, nuclear beta-catenin positive, usually CD34 negative)
─ Elastofibroma (contains characteristic abnormal elastic fibers, different location typically subscapular)
─ Keloid / Hypertrophic scar (history of injury, keloidal collagen in keloids, different clinical appearance)
─ Desmoplastic fibroblastoma (more circumscribed, less haphazard collagen, typically CD34 negative or very focal)
─ Solitary fibrous tumor (STAT6 positive, more prominent hemangiopericytoma-like vessels)
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Myofibroblastoma

A benign mesenchymal neoplasm composed of myofibroblasts, typically occurring in the breast of older men and postmenopausal women, but also described in extramammary sites
Clinical ─ Extramammary myofibroblastoma: Adults (wide age range, often middle-aged to older); M=F or slight male predominance for some locations; sites include inguinal region, trunk, extremities, head/neck; usually presents as a solitary, slow-growing, painless, well-circumscribed mass
Macro ─ Well-circumscribed, often pseudoencapsulated, firm, rubbery nodule; cut surface is typically gray-white to tan, may show a whorled or fascicular appearance
Micro

─ Well-circumscribed proliferation of bland spindle cells (myofibroblasts) with eosinophilic cytoplasm and elongated, tapering or blunt-ended nuclei
─ Cells are typically arranged in short, intersecting fascicles or clusters, separated by variable amounts of collagenous stroma, which can be hyalinized
─ Prominent thick collagen bundles are often seen
─ Variable cellularity and stromal collagen content; some areas may be more myxoid
─ Low mitotic activity (usually <1-2/10 HPF), no significant cytologic atypia, necrosis is absent
─ Variants described include cellular, epithelioid, collagenized/fibrous, lipomatous, and myxoid types
Ancillary studies ─
─ IHC: Tumor cells are characteristically positive for desmin (often strong and diffuse) and CD34; SMA and MSA are also usually positive; Estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR) may be positive (especially in mammary type); Negative for S100 protein (except entrapped fat or nerves), keratins, and MDM2
─ Molecular: Characterized by monoallelic or biallelic loss of chromosome 13q14, which includes the RB1 and FOXO1 genes
DDx

─ Solitary fibrous tumor (STAT6 positive, lacks desmin)
─ Spindle cell lipoma (if lipomatous variant; CD34 positive but desmin negative, contains mature fat and often ropey collagen)
─ Leiomyoma (more distinct fascicles of smooth muscle, h-caldesmon positive, typically CD34 negative)
─ Desmoid fibromatosis (infiltrative, nuclear beta-catenin positive, lacks RB1 loss)
─ Low-grade myofibroblastic sarcoma (infiltrative growth, potential for recurrence/metastasis, may show atypia)
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Mammary-Type Myofibroblastoma

Refers to myofibroblastoma arising in the breast, which is the classic and most common site for this tumor, showing the same histopathological and immunophenotypic features as extramammary myofibroblastoma
Clinical ─ Primarily affects older men (peak 60-70s) and postmenopausal women; presents as a solitary, painless, firm, mobile, well-circumscribed breast mass; rare in younger women
Macro ─ Well-circumscribed, often encapsulated or pseudoencapsulated, firm, rubbery nodule; cut surface is gray-white to tan, homogeneous, may appear whorled or lobulated; size typically 1-4 cm
Micro

─ Essentially identical to extramammary myofibroblastoma:
─ Well-circumscribed proliferation of bland spindle cells (myofibroblasts) with eosinophilic cytoplasm
─ Arranged in short, intersecting fascicles separated by hyalinized collagen bundles
─ Low mitotic activity, no atypia or necrosis
─ Adipose tissue may be entrapped at the periphery or within the tumor (lipomatous variant)
Ancillary studies ─
─ IHC: Strong and diffuse positivity for desmin and CD34 is characteristic; SMA and MSA positive; ER, PR, AR often positive; Negative for S100, keratins (except rare focal positivity), p63
─ Molecular: Loss of 13q14 (RB1/FOXO1) region
DDx

─ Spindle cell carcinoma (metaplastic carcinoma) (keratin positive, p63 positive, lacks desmin/CD34 coexpression)
─ Fibromatosis (desmoid-type) of breast (infiltrative, nuclear beta-catenin positive, lacks desmin/CD34 coexpression)
─ Pseudoangiomatous stromal hyperplasia (PASH) (complex anastomosing slit-like spaces, less cellular spindle cells, lacks desmin)
─ Solitary fibrous tumor of breast (STAT6 positive, lacks desmin)
─ Leiomyoma of breast (rare, more distinctly smooth muscle, h-caldesmon positive, CD34 negative)
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Intranodal Palisaded Myofibroblastoma

A rare, benign mesenchymal neoplasm of myofibroblastic origin arising exclusively within lymph nodes, characterized by spindle cells with palisading nuclei and eosinophilic cytoplasmic inclusions (amianthoid fibers)
Clinical ─ Adults (wide age range, peak 40-60s), slight male predominance; most commonly involves inguinal lymph nodes, less frequently axillary or cervical nodes; presents as a slow-growing, painless, firm, enlarged lymph node, often discovered incidentally
Macro ─ Affected lymph node is enlarged, firm, and well-circumscribed; cut surface shows a fleshy, gray-white to tan, whorled, or nodular tumor replacing nodal parenchyma, often with a peripheral rim of compressed lymphoid tissue
Micro

─ Well-demarcated tumor within a lymph node, often replacing most of the nodal architecture but respecting the capsule
─ Composed of bland spindle cells (myofibroblasts) arranged in short fascicles, whorls, and prominent nuclear palisades (resembling Verocay bodies of schwannoma but less well-formed)
─ Characteristic feature: Extracellular, amorphous, eosinophilic material often forming stellate or elongated structures ("amianthoid fibers" or "collagenous crystalloids"), which are aggregates of type I and III collagen; these may be surrounded by tumor cells
─ Hemorrhage and hemosiderin deposition are common
─ Blood vessels may be prominent and hyalinized
─ Minimal cytologic atypia, mitotic activity is very low or absent
Ancillary studies ─
─ IHC: Spindle cells are positive for SMA (smooth muscle actin) and often cyclin D1 (nuclear); Negative for desmin, S100, CD34, keratins, CD21, CD35 (follicular dendritic cell markers), HHV8, and Langerin
─ Molecular: No specific recurrent genetic alterations consistently identified; not associated with RB1 loss like other myofibroblastomas
DDx

─ Schwannoma (intranodal) (S100 positive, true Verocay bodies, lacks amianthoid fibers)
─ Kaposi sarcoma (involving lymph node) (HHV8 positive, slit-like vascular spaces)
─ Inflammatory myofibroblastic tumor (involving lymph node) (ALK positive in a subset, more prominent plasma cells, lacks amianthoid fibers/palisading)
─ Fibromatosis (desmoid-type) involving lymph node (very rare, beta-catenin positive)
─ Metastatic spindle cell sarcoma or carcinoma (evidence of primary, specific markers)
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Calcifying aponeurotic fibroma

A distinctive, benign fibroblastic proliferation of childhood and adolescence characterized by a biphasic pattern of epithelioid to spindle cells with foci of calcification and often chondroid metaplasia, typically involving aponeuroses and tendons of the distal extremities
Clinical ─ Primarily affects children and adolescents (peak age 5-15 years), with a male predominance; most common in the hands (palms, fingers) and feet (soles, toes); presents as a slow-growing, firm, often poorly defined subcutaneous nodule or mass, may be fixed to deep structures and cause functional limitation or deformity
Macro ─ Poorly defined, infiltrative, firm, gray-white mass; cut surface may show gritty areas due to calcification; typically small, <3 cm
Micro
─ Poorly circumscribed, infiltrative growth pattern, often involving tendons and aponeuroses
─ Biphasic appearance:
─ Cellular areas: Plump spindle to epithelioid fibroblasts arranged in fascicles or sheets, often with a palisading arrangement around areas of calcification
─ Calcification: Nodular foci of finely granular or psammomatous calcification are characteristic
─ Chondroid metaplasia: Islands of hyaline cartilage may be present, particularly in older lesions or recurrences
─ Background stroma is fibrous and collagenous
─ Minimal cytologic atypia, low mitotic activity (usually <2/10 HPF)
Ancillary studies ─
─ IHC: Spindle cells are positive for vimentin; SMA may be positive in a subset of spindle cells; S100 protein highlights chondroid areas if present; Negative for CD34, desmin, keratins
─ Molecular: Recurrent gene fusions involving FN1 (fibronectin 1) and EGF (epidermal growth factor), specifically FN1::EGF, have been reported
DDx
─ Infantile digital fibromatosis (specific location on digits, intracytoplasmic inclusions, SMA positive)
─ Fibromatosis (desmoid-type or superficial) (lacks calcification and chondroid metaplasia, beta-catenin often positive in desmoids)
─ Synovial sarcoma (if calcification/chondroid metaplasia present; biphasic pattern with epithelial cells, TLE1 positive, SS18 fusion)
─ Soft tissue chondroma (well-circumscribed, mature cartilage, lacks fibroblastic component and FN1::EGF fusion)
─ Myositis ossificans (zonal pattern, different clinical setting)
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Angiofibroma of Soft Tissue

A benign mesenchymal neoplasm composed of bland spindle cells and a prominent network of small, thin-walled blood vessels, typically occurring in adults
Clinical ─ Adults (wide age range, peak 40-60s); slight female predominance; most common in deep soft tissues of the lower extremities (especially thigh and pararticular regions of the knee), less often in upper extremities, trunk, or head/neck; presents as a slow-growing, usually painless, well-circumscribed mass
Macro ─ Well-circumscribed, often encapsulated, firm, rubbery nodule; cut surface is typically gray-white to tan, sometimes with a vaguely lobulated or whorled appearance; size usually <5 cm
Micro
─ Well-circumscribed, often with a fibrous pseudocapsule
─ Relatively uniform proliferation of bland spindle cells with scant, pale eosinophilic cytoplasm and oval to tapering nuclei
─ Cells are arranged in short fascicles, storiform pattern, or haphazardly
─ Characteristic feature: Abundant, small, thin-walled, branching or ectatic blood vessels evenly distributed throughout the tumor
─ Stroma is variably collagenous, sometimes with myxoid change or hyalinization
─ Mast cells are often present
─ No significant cytologic atypia, pleomorphism, or mitotic activity (mitoses are rare)
Ancillary studies ─
─ IHC: Spindle cells are positive for vimentin; CD34 is often positive in spindle cells (variable extent) as well as endothelial cells; EMA may be focally positive in spindle cells; ER and PR may be expressed; Negative for S100 protein, SMA (except perivascular), desmin, keratins, STAT6
─ Molecular: Rearrangements of AHRR and NCOA2 genes have been reported in a subset of cases; some cases show GTF2I mutations
DDx
─ Solitary fibrous tumor (STAT6 positive, CD34 positive, more prominent hemangiopericytoma-like vessels, different stromal collagen)
─ Low-grade fibromyxoid sarcoma (alternating fibrous/myxoid areas, arcades of vessels, MUC4 positive, FUS fusion)
─ Myofibroblastoma (desmin positive, CD34 positive, lacks prominent vascular network)
─ Spindle cell lipoma (contains mature fat, CD34 positive spindle cells, ropey collagen)
─ Cellular angiofibroma (vulvovaginal/inguinoscrotal, prominent hyalinized vessels, different immunoprofile - desmin usually positive, CD34 often negative in spindle cells)
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EWSR1::SMAD3-positive fibroblastic tumor

A rare, recently described fibroblastic neoplasm characterized by a specific EWSR1::SMAD3 gene fusion, typically presenting as a small, well-circumscribed nodule in acral subcutaneous or deep soft tissues
Clinical ─ Typically affects young to middle-aged adults (median age ~30s); strong predilection for acral sites, especially hands and feet (digits, palm, sole); occurs in subcutaneous tissue or deeper soft tissues; presents as a slow-growing, firm, painless nodule
Macro ─ Small (usually <3 cm), well-circumscribed, firm, gray-white nodule; may appear encapsulated
Micro
─ Well-circumscribed, often multilobulated or pseudo-lobulated growth pattern
─ Composed of relatively uniform, bland spindle cells arranged in sweeping fascicles, sheets, or a vague storiform pattern
─ Characteristic feature (often): Peripheral hypercellularity with a more hypocellular, hyalinized, or myxoid central area within lobules
─ Central areas may show microcystic change, calcification, or even ossification (metaplastic bone)
─ Minimal cytologic atypia, mitotic activity is generally low (0-2/10 HPF)
─ Necrosis is absent
Ancillary studies ─
─ IHC: Tumor cells show diffuse nuclear positivity for ERG (a consistent finding); Variable positivity for CD34, SMA, and desmin (often focal); Negative for S100 protein, keratins, MUC4, STAT6
─ Molecular: Defined by the presence of an EWSR1::SMAD3 gene fusion, resulting from t(1;22)(q22;q12) or related variants
DDx
─ Low-grade fibromyxoid sarcoma (MUC4 positive, FUS::CREB3L2 fusion, lacks ERG positivity, different morphology)
─ Solitary fibrous tumor (STAT6 positive, lacks ERG positivity, different morphology)
─ Fibroma of tendon sheath (lacks ERG positivity, often USP6 rearranged in cellular variant)
─ Ossifying fibromyxoid tumor (S100 positive in many, PHF1 fusion, lacks ERG positivity, peripheral bone shell)
─ Myoepithelioma (S100/keratin/EMA positive, EWSR1 fusions but different partners)
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Angiomyofibroblastoma

A benign mesenchymal neoplasm composed of an admixture of bland spindle to epithelioid myofibroblastic cells and numerous small to medium-sized blood vessels, characteristically occurring in the vulvovaginal region of adult women, but also rarely in men (inguinoscrotal region)
Clinical ─ Predominantly affects adult women, typically in the reproductive age to perimenopausal period (peak 25-50s); most common in the vulva, less frequently vagina or perineum; rare cases reported in men (scrotum, inguinal canal); presents as a slow-growing, painless, well-circumscribed subcutaneous or submucosal mass, usually <5 cm
Macro ─ Well-circumscribed, often pseudoencapsulated, soft to rubbery nodule; cut surface is typically gray-white to tan, often with a glistening, gelatinous, or edematous appearance
Micro
─ Well-circumscribed, often with a thin fibrous pseudocapsule
─ Characterized by alternating hypercellular and hypocellular/edematous areas
─ Composed of relatively bland, plump spindle-shaped to epithelioid cells with eosinophilic cytoplasm and oval nuclei; these cells often cluster around numerous small to medium-sized blood vessels
─ Blood vessels are a prominent feature, often with hyalinized walls
─ Stroma is typically loose, edematous, or myxoid, with delicate collagen fibers
─ No significant cytologic atypia, pleomorphism, or mitotic activity (mitoses are rare)
─ Necrosis is absent
Ancillary studies ─
─ IHC: Tumor cells are characteristically positive for desmin (often strong and diffuse) and vimentin; Estrogen receptor (ER) and progesterone receptor (PR) are frequently positive; SMA is variably positive; CD34 is typically positive in a perivascular distribution but often negative in the main tumor cells; Negative for S100 protein and keratins
─ Molecular: Recurrent translocations involving MTG1 (ETV6) and CYP2E1 (ETV6::CYP2E1) have been reported in some cases, also deletions of 13q14 (RB1) are described, similar to myofibroblastoma. However, other studies find no consistent molecular alterations.
DDx
─ Aggressive angiomyxoma (more infiltrative, larger, less cellular, more prominent large vessels, HMGA2 rearranged)
─ Cellular angiofibroma (more cellular, less stromal edema, prominent hyalinized vessels, RB1 loss, often CD34 negative spindle cells but desmin positive)
─ Superficial angiomyxoma (lobulated, more myxoid, epithelial mucin, lacks desmin)
─ Myofibroblastoma (CD34 positive spindle cells, lacks prominent vascularity of AMF, often desmin positive, RB1 loss)
─ Leiomyoma (more fascicular smooth muscle, h-caldesmon positive, less vascular/edematous)
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─ Pathoutlines WSI WSI & video WSI & video WSI video

Gardner fibroma

A benign, paucicellular fibroblastic proliferation that is a soft tissue manifestation of familial adenomatous polyposis (FAP) or Gardner syndrome, and can be a precursor to desmoid-type fibromatosis in these patients
Clinical ─ Typically occurs in infants, children, and young adults (most often <10 years), but can be seen at any age in individuals with FAP; strong association with germline APC gene mutations; common sites include paraspinal region, trunk (especially back), head/neck, and extremities; presents as a poorly defined, firm, subcutaneous or deep soft tissue nodule or plaque, often asymptomatic
Macro ─ Poorly defined, firm, rubbery, white-gray fibrous mass; may appear infiltrative; size is variable
Micro
─ Poorly circumscribed, infiltrative proliferation of hypocellular fibrous tissue
─ Composed of bland, slender spindle cells (fibroblasts) embedded in a dense, haphazardly arranged collagenous stroma
─ Collagen bundles are often thick and irregular, sometimes described as having a "cracked" or "ropy" appearance
─ Minimal vascularity is characteristic
─ Entrapment of mature adipose tissue and adnexal structures (if superficial) is common
─ No significant cytologic atypia, mitotic activity is rare to absent, necrosis is not seen
─ A mild perivascular lymphocytic infiltrate may be present
Ancillary studies ─
─ IHC: Spindle cells are positive for vimentin; Nuclear beta-catenin expression is variable (may be positive in a subset, reflecting APC pathway dysregulation, but often less consistent or strong than in desmoid fibromatosis); Negative for SMA (or very focal), desmin, S100 protein, and keratins
─ Molecular: Associated with germline mutations in the APC gene; somatic CTNNB1 mutations (seen in sporadic desmoids) are typically absent
DDx
─ Desmoid-type fibromatosis (more cellular, more organized sweeping fascicles, consistently strong nuclear beta-catenin positive, often larger and more aggressive clinically)
─ Nuchal-type fibroma (posterior neck/back, CD34 positive spindle cells, lacks APC association typically)
─ Scar tissue (history of injury, different architecture)
─ Desmoplastic fibroblastoma (more circumscribed, different stromal quality, typically CD34 negative)
─ Infantile fibromatosis (more cellular, different clinical context)
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Palmar fibromatosis and plantar fibromatosis (Superficial Fibromatoses)

Benign, locally infiltrative fibroblastic/myofibroblastic proliferations involving the palmar aponeurosis (Dupuytren contracture) or plantar aponeurosis (Ledderhose disease); Penile fibromatosis (Peyronie disease) is a related entity
Clinical ─ Palmar: Typically older adults (peak 50-70s), M>F; often bilateral; causes nodules and cords in palm leading to flexion contractures of fingers (especially 4th and 5th digits)
Clinical ─ Plantar: Wider age range (often middle-aged adults), M>F; involves plantar aponeurosis, usually medial aspect of sole; presents as firm nodules, may be painful, less likely to cause contractures than palmar type
Macro ─ Nodular or cord-like fibrous thickening of the fascia; gray-white, firm, and rubbery tissue that is poorly demarcated and infiltrates surrounding structures
Micro
─ Nodular and/or fascicular proliferation of bland, uniform spindle cells (fibroblasts and myofibroblasts) with pale eosinophilic cytoplasm and elongated or ovoid nuclei
─ Cells are arranged in short to long sweeping fascicles or nodules within a dense collagenous stroma
─ Cellularity varies with lesion age: early lesions (proliferative phase) are more cellular with plump cells and higher mitotic activity (though still low); older lesions (involutional/residual phase) are more collagenous and hypocellular
─ Minimal cytologic atypia; necrosis is absent
─ Infiltrative growth into adjacent fascia, adipose tissue, and sometimes skin or skeletal muscle
Ancillary studies ─
─ IHC: Spindle cells are positive for vimentin and often SMA (smooth muscle actin) and MSA (muscle-specific actin); Nuclear beta-catenin expression is variable, often weaker or more focal than in desmoid-type fibromatosis, or absent
─ Molecular: Trisomies 7 and/or 8 are common cytogenetic findings, particularly in palmar fibromatosis; distinct from the CTNNB1 or APC mutations typical of desmoid fibromatosis
DDx
─ Desmoid-type fibromatosis (deeper location, larger size, more uniformly cellular long fascicles, consistently strong nuclear beta-catenin, different genetics)
─ Scar tissue / Keloid (history of injury, different collagen morphology in keloid)
─ Fibroma of tendon sheath (more lobulated, prominent slit-like vessels)
─ Epithelioid sarcoma (if acral; atypical epithelioid cells, keratin positive, INI1 loss)
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─ pathoutlines video WSI (plantar) WSI (palmar)

Desmoid fibromatosis (Deep Fibromatosis)

A locally aggressive, non-metastasizing myofibroblastic neoplasm characterized by infiltrative growth and a tendency for local recurrence; also known as aggressive fibromatosis
Clinical ─ Wide age range, but most common in young to middle-aged adults (peak 25-40s); slight female predominance overall; classified by location: extra-abdominal (limb girdles, extremities, head/neck), abdominal wall (often in parous women), and intra-abdominal (mesentery, pelvis, retroperitoneum); associated with familial adenomatous polyposis (FAP)/Gardner syndrome (germline APC mutation) or sporadic (CTNNB1 mutation); presents as a firm, deep-seated, often slow-growing mass, may be painful or asymptomatic
Macro ─ Poorly circumscribed, firm, rubbery, gray-white mass with a whorled or trabeculated cut surface; infiltrates surrounding soft tissues and skeletal muscle
Micro
─ Infiltrative proliferation of relatively uniform, bland spindle cells (myofibroblasts) with pale eosinophilic cytoplasm and elongated, vesicular nuclei with small nucleoli
─ Cells are arranged in long, sweeping, interlacing fascicles and bundles
─ Stroma is typically collagenous, but can be variably myxoid, especially in early or recurrent lesions
─ Characteristic thin-walled, elongated, slightly ectatic blood vessels are often prominent
─ Infiltrates adjacent skeletal muscle (causing atrophy and entrapment of muscle fibers) and adipose tissue
─ Low to moderate cellularity; mitotic activity is generally low (usually <2-5/10 HPF), and atypical mitoses are absent; no significant cytologic atypia or necrosis
Ancillary studies ─
─ IHC: Nuclear beta-catenin positivity is characteristic and present in the majority of cases (>80-90%); SMA is often positive; MSA and calponin may be positive; Desmin is typically negative or only focally positive; Negative for S100 protein, keratins, CD34
─ Molecular: Most sporadic cases harbor mutations in CTNNB1 (beta-catenin gene); FAP-associated cases have germline APC gene mutations
DDx
─ Low-grade fibromyxoid sarcoma (alternating fibrous/myxoid areas, arcades of vessels, MUC4 positive, FUS fusion)
─ Solitary fibrous tumor (STAT6 positive, CD34 positive, hemangiopericytoma-like vessels)
─ Scar tissue / Reactive fibrosis (less cellular, more inflammation, history of injury, lacks nuclear beta-catenin)
─ Fibrosarcoma (more cellularity, atypia, mitoses, lacks nuclear beta-catenin)
─ Myofibroblastoma (well-circumscribed, desmin positive, CD34 positive, RB1 loss, lacks nuclear beta-catenin)
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─ pathoutlines WSI WSI WSI WSI WSI case & WSI WSI of HE β-catenin Desmin SMA CD34

Desmoid-Type Fibromatosis in Childhood

Desmoid-type fibromatosis occurring in the pediatric population (typically defined as <18 years), sharing histopathological and molecular features with adult cases but may exhibit some distinct clinical behaviors or associations
Clinical ─ Rare in children compared to adults, but can occur at any pediatric age, including infancy; may be associated with FAP/Gardner syndrome or arise sporadically; common sites include extremities, head/neck, and trunk; intra-abdominal lesions less common than in adults with FAP; presentation similar to adults (firm, deep-seated mass)
Macro ─ Similar to adult desmoid fibromatosis: poorly circumscribed, firm, gray-white, infiltrative mass
Micro
─ Histologically identical to adult desmoid-type fibromatosis: infiltrative proliferation of uniform spindle cells in long sweeping fascicles, collagenous stroma, thin-walled ectatic vessels
─ Low to moderate cellularity, minimal atypia, low mitotic rate
─ Infiltration of adjacent tissues is characteristic
Ancillary studies ─
─ IHC: Nuclear beta-catenin positivity is characteristic; SMA often positive; Negative for S100, desmin (usually), keratins
─ Molecular: CTNNB1 mutations in sporadic cases; germline APC mutations in FAP-associated cases
DDx
─ Infantile fibrosarcoma (more cellular, herringbone pattern, ETV6::NTRK3 fusion, lacks nuclear beta-catenin)
─ Low-grade myofibroblastic sarcoma (may show more atypia, infiltrative, lacks consistent nuclear beta-catenin)
─ Fibrous hamartoma of infancy (triphasic pattern, specific locations, lacks nuclear beta-catenin)
─ Calcifying aponeurotic fibroma (hands/feet, calcification, chondroid areas)
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Intraabdominal/Mesenteric Desmoid Fibromatosis

Desmoid-type fibromatosis arising within the abdominal cavity, most commonly involving the mesentery, retroperitoneum, or pelvis; strongly associated with Familial Adenomatous Polyposis (FAP) / Gardner syndrome
Clinical ─ Often occurs in patients with FAP (especially post-colectomy), but can be sporadic; typically young to middle-aged adults; presents with abdominal pain, palpable mass, bowel obstruction, or hydronephrosis due to compression of adjacent structures; can be a significant cause of morbidity and mortality in FAP patients
Macro ─ Large, poorly demarcated, firm, gray-white, infiltrative mass involving mesenteric fat, bowel wall, or retroperitoneal structures; may encase vessels and ureters
Micro
─ Histologically identical to other desmoid-type fibromatoses: infiltrative proliferation of bland, uniform spindle cells (myofibroblasts) arranged in long sweeping fascicles within a collagenous or sometimes myxoid stroma
─ Characteristic thin-walled, elongated blood vessels
─ Entrapment of fat, nerves, and smooth muscle of bowel wall is common
─ Minimal cytologic atypia and low mitotic activity
Ancillary studies ─
─ IHC: Nuclear beta-catenin positivity is characteristic; SMA often positive; Negative for S100, desmin, keratins
─ Molecular: Germline APC mutations are common in FAP-associated cases; sporadic intra-abdominal desmoids often have CTNNB1 mutations
DDx
─ Sclerosing mesenteritis / Mesenteric panniculitis (prominent inflammation, fat necrosis, foamy macrophages, lacks distinct spindle cell fascicles and nuclear beta-catenin)
─ Gastrointestinal stromal tumor (GIST) (CD117/DOG1 positive, KIT/PDGFRA mutated, different morphology)
─ Inflammatory myofibroblastic tumor (IMT) (more prominent inflammatory infiltrate, ALK positive in a subset, lacks consistent nuclear beta-catenin)
─ Retroperitoneal sarcoma (eg, WDLPS/DDLPS, leiomyosarcoma - distinguished by specific morphology, IHC, and molecular features)
─ Carcinoid tumor with desmoplasia (neuroendocrine markers positive, keratin positive)
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Lipofibromatosis

A rare, benign fibroblastic and adipocytic tumor of infancy and early childhood characterized by an infiltrative proliferation of bland spindle cells admixed with mature adipose tissue, typically involving the hands and feet
Clinical ─ Primarily affects infants and young children (most cases <2 years old, many congenital); slight male predominance; common sites include hands and feet (digits, palm, sole), less frequently other extremities or trunk; presents as a slow-growing, painless, poorly defined subcutaneous mass or diffuse swelling, may cause digital enlargement
Macro ─ Poorly circumscribed, firm, infiltrative mass; cut surface is typically yellow-gray or white, with intermingled fatty and fibrous areas
Micro
─ Poorly circumscribed, infiltrative proliferation involving dermis, subcutis, and sometimes deeper structures like tendons and fascia
─ Composed of two main components:
─ Bland spindle cells (fibroblasts) arranged in short to long fascicles or a storiform pattern, set in a variably collagenous or myxoid stroma
─ Mature adipose tissue intimately admixed with and often appearing entrapped by the spindle cell proliferation; adipocytes are typically univacuolated and mature-appearing
─ No significant cytologic atypia, pleomorphism, or mitotic activity in either component
─ Small, inconspicuous blood vessels
Ancillary studies ─
─ IHC: Spindle cells are positive for vimentin and often CD34; S100 protein is positive in the mature adipocytes but negative in the spindle cells; Negative for SMA (or only very focal), desmin, keratins, and nuclear beta-catenin
─ Molecular: No specific recurrent genetic alterations are consistently identified; distinct from infantile fibrosarcoma (ETV6::NTRK3) and lipoblastoma (PLAG1)
DDx
─ Infantile fibromatosis/Myofibromatosis (lacks the prominent, intimately admixed mature adipose tissue component; may have biphasic pattern)
─ Fibrous hamartoma of infancy (triphasic pattern including primitive mesenchymal nests, different typical locations like axilla)
─ Lipoblastoma (contains lipoblasts, PLAG1 rearranged, more distinctly lobulated by fibrous septa)
─ Neural fibrolipoma (lipomatosis of nerve) (involves nerve trunks, specific clinical setting)
─ Infantile fibrosarcoma (more cellular, herringbone pattern, ETV6::NTRK3 fusion, lacks mature fat)
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Calcifying fibrous tumor

A rare benign mesenchymal neoplasm characterized by paucicellular hyalinized collagenous stroma, bland spindle cells, psammomatous and/or dystrophic calcifications, and a prominent lymphoplasmacytic infiltrate
Clinical ─ Typically affects children and young adults (wide age range, median ~20-30s), but can occur at any age; M=F; common sites include deep soft tissues of extremities, trunk, neck, mediastinum, pleura, peritoneum, and scrotum; presents as a slow-growing, usually painless, firm nodule or mass
Macro ─ Well-circumscribed, unencapsulated or thinly encapsulated, firm, white-gray to tan nodule; cut surface may feel gritty due to calcifications; size varies, usually <5 cm but can be larger
Micro
─ Well-circumscribed, often multinodular or lobulated growth pattern
─ Paucicellular proliferation of bland, slender spindle cells (fibroblasts) with scant cytoplasm and inconspicuous nuclei
─ Abundant, dense, hyalinized collagenous stroma is a key feature
─ Characteristic psammomatous calcifications (laminated, concentric) and/or dystrophic calcifications are present, often numerous
─ Prominent lymphoplasmacytic infiltrate, frequently forming lymphoid aggregates or follicles, is another hallmark
─ No significant cytologic atypia, mitotic activity is rare to absent, necrosis is not seen
Ancillary studies ─
─ IHC: Spindle cells are positive for vimentin; Factor XIIIa and CD34 are variably positive in spindle cells; Negative for SMA (except perivascular), desmin, S100 protein, keratins, ALK1, and nuclear beta-catenin
─ Molecular: No specific recurrent genetic alterations consistently identified; some reports of ZGRF1::SSR1 and FN1::GFAP fusions, but not uniformly found
DDx
─ Solitary fibrous tumor (STAT6 positive, CD34 positive, lacks prominent inflammation and psammomatous calcification)
─ Inflammatory myofibroblastic tumor (IMT) (more cellular, ALK positive in a subset, lacks dense hyalinization and psammomatous calcification)
─ Desmoid-type fibromatosis (more cellular, long sweeping fascicles, nuclear beta-catenin positive, lacks calcification/inflammation)
─ Low-grade fibromyxoid sarcoma (alternating fibrous/myxoid areas, MUC4 positive, FUS fusion, lacks calcification/inflammation)
─ IgG4-related disease (storiform fibrosis, obliterative phlebitis, increased IgG4+ plasma cells, lacks psammomatous calcification)
─ Calcifying aponeurotic fibroma (hands/feet of children, chondroid areas, FN1::EGF fusion)
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Giant cell fibroblastoma (GCFP)

A low-grade fibroblastic neoplasm of childhood, characterized by a biphasic pattern of bland spindle cells and distinctive angulated or sinusoidal pseudovascular spaces lined by multinucleated giant cells; considered part of the DFSP spectrum due to shared COL1A1::PDGFB fusion
Clinical ─ Primarily affects children (most common <10 years, often <5 years), with a male predominance; common sites include trunk (especially back and chest wall), thigh, and inguinal region; presents as a slow-growing, painless subcutaneous or dermal nodule or plaque
Macro ─ Poorly circumscribed, firm or rubbery, gray-white to tan nodule or plaque; may appear infiltrative; size typically 1-5 cm
Micro
─ Poorly circumscribed dermal and/or subcutaneous tumor with infiltrative margins
─ Biphasic pattern with variable cellularity:
─ Hypocellular areas with abundant myxoid or collagenous stroma
─ More cellular areas composed of bland, slender spindle cells with scant cytoplasm and wavy nuclei
─ Characteristic feature: Irregular, branching, angulated or sinusoidal pseudovascular spaces lined by bland spindle cells and prominent, multinucleated, wreath-like giant cells (tumor giant cells, not osteoclast-like)
─ These spaces may contain proteinaceous fluid or red blood cells
─ Minimal cytologic atypia in spindle and giant cells, mitotic activity is low
─ May coexist with or transition into areas resembling conventional dermatofibrosarcoma protuberans (DFSP)
Ancillary studies ─
─ IHC: Spindle cells and giant cells lining pseudovascular spaces are diffusely positive for CD34; Vimentin positive; Negative for S100 protein, SMA, desmin, keratins, Factor XIIIa
─ Molecular: Characterized by the COL1A1::PDGFB gene fusion resulting from t(17;22)(q22;q13) or supernumerary ring chromosomes derived from t(17;22), identical to DFSP
DDx
─ Dermatofibrosarcoma protuberans (DFSP) (storiform pattern, honeycomb infiltration of fat, may lack prominent pseudovascular spaces/giant cells, but represents a spectrum)
─ Lymphangioma / Vascular malformation (true endothelial lining D2-40 or CD31/CD34 positive, lacks spindle cell component and giant cells lining spaces)
─ Plexiform fibrohistiocytic tumor (different giant cells - osteoclast-like, biphasic with histiocytoid nodules, CD34 negative)
─ Benign fibrous histiocytoma (Factor XIIIa positive, CD34 negative, different morphology)
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Dermatofibrosarcoma protuberans (DFSP)

A low-to-intermediate grade fibroblastic sarcoma of the dermis and subcutis, characterized by a storiform growth pattern, infiltration into subcutaneous fat, and a specific COL1A1::PDGFB gene fusion
Clinical ─ Typically affects young to middle-aged adults (peak 20-50s), but can occur at any age; M=F; common sites include trunk (especially chest wall and back), proximal extremities, and head/neck; presents as a slow-growing, firm, indurated plaque that may later develop raised nodules (protuberans); skin overlying may be atrophic or reddish-brown
Macro ─ Firm, plaque-like or multinodular cutaneous/subcutaneous mass; cut surface is typically gray-white and fibrous; often deceptively circumscribed but microscopically infiltrative
Micro
─ Dermal-based, infiltrative proliferation of relatively uniform, bland spindle cells with scant cytoplasm and elongated, wavy nuclei
─ Characteristic storiform ("cartwheel" or "pinwheel") arrangement of cells, particularly in cellular areas
─ Infiltration into subcutaneous adipose tissue in a characteristic "honeycomb" or "lace-like" pattern, with tumor cells surrounding and entrapping individual adipocytes
─ Low mitotic activity (usually <5/10 HPF), minimal pleomorphism, necrosis is rare in conventional DFSP
─ Variants include:
─ Myxoid DFSP (significant myxoid stroma >50%)
─ Pigmented DFSP (Bednar tumor) (contains melanin-laden dendritic cells)
─ Giant cell fibroblastoma (see separate entry, part of DFSP spectrum)
─ Fibrosarcomatous transformation (DFSP-FS): Development of higher-grade fascicular areas resembling fibrosarcoma, associated with increased cellularity, atypia, mitoses, and sometimes necrosis; confers a higher risk of metastasis
Ancillary studies ─
─ IHC: Tumor cells are diffusely and strongly positive for CD34; Vimentin positive; Negative for Factor XIIIa, S100 protein, SMA, desmin, keratins
─ Molecular: Characterized by the COL1A1::PDGFB gene fusion resulting from translocation t(17;22)(q22;q13) or supernumerary ring chromosomes derived from t(17;22)
DDx
─ Dermatofibroma (benign fibrous histiocytoma) (Factor XIIIa positive, CD34 negative, collagen trapping at periphery, lacks COL1A1::PDGFB fusion)
─ Solitary fibrous tumor (STAT6 positive, CD34 positive but different morphology and NAB2::STAT6 fusion)
─ Spindle cell melanoma (S100/SOX10 positive)
─ Neurofibroma (S100 positive spindle cells, myxoid stroma)
─ Kaposi sarcoma (plaque stage) (HHV8 positive, vascular slits)
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Myxoid Dermatofibrosarcoma Protuberans

A variant of dermatofibrosarcoma protuberans (DFSP) in which a significant portion (>50%) of the tumor exhibits prominent myxoid stromal change, while retaining the characteristic storiform architecture and COL1A1::PDGFB fusion
Clinical ─ Similar to conventional DFSP: young to middle-aged adults, trunk and extremities common; may present as a softer, more ill-defined lesion than typical DFSP due to myxoid component
Macro ─ May appear more gelatinous or less firm than classic DFSP due to the myxoid stroma; otherwise similar (plaque-like or nodular)
Micro
─ Overall architecture and infiltrative pattern similar to conventional DFSP, including storiform arrangement of spindle cells and honeycomb infiltration of subcutaneous fat
─ Defining feature: Abundant myxoid or edematous stroma occupying >50% of the tumor volume (Alcian blue positive)
─ Spindle cells may appear more separated or stellate within the myxoid areas
─ Cellularity is often lower in myxoid areas compared to classic DFSP
─ Cytologic features of spindle cells (bland, wavy nuclei) and mitotic activity are generally similar to conventional DFSP
─ Fibrosarcomatous transformation can also occur in myxoid DFSP
Ancillary studies ─
─ IHC: Tumor cells are diffusely CD34 positive; Vimentin positive; Negative for S100, SMA, desmin
─ Molecular: COL1A1::PDGFB fusion is present, identical to conventional DFSP
DDx
─ Myxofibrosarcoma (low-grade) (older adults, curvilinear vessels, more pleomorphism usually, lacks COL1A1::PDGFB fusion and diffuse CD34)
─ Myxoid neurofibroma (S100 positive spindle cells, embedded axons)
─ Superficial angiomyxoma (lobulated, epithelial mucin, prominent vessels, lacks storiform pattern and COL1A1::PDGFB fusion)
─ Low-grade fibromyxoid sarcoma (MUC4 positive, FUS fusion, alternating fibrous/myxoid zones)
─ Myxoid solitary fibrous tumor (STAT6 positive, NAB2::STAT6 fusion)
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Solitary fibrous tumor (SFT)

A ubiquitous mesenchymal neoplasm, originally described in the pleura but now recognized in virtually any anatomic site, characterized by a "patternless" arrangement of bland spindle cells, prominent "staghorn" or hemangiopericytoma-like vasculature, and a specific NAB2::STAT6 gene fusion
Clinical ─ Typically affects adults (wide age range, peak 40-60s); M=F; can occur anywhere, common sites include pleura, deep soft tissues of extremities and trunk, abdomen/pelvis, head/neck (meninges, orbit, sinonasal); presentation varies by site, often a slow-growing, painless mass; hypoglycemia (Doege-Potter syndrome due to IGF2 production) is rare
Macro ─ Often well-circumscribed, lobulated, firm, rubbery mass; cut surface is typically gray-white and fibrous, sometimes with whorled or myxoid areas; size is highly variable
Micro
─ Highly variable histologic appearance, often showing a "patternless pattern" with alternating hypo- and hypercellular areas
─ Bland, ovoid to spindle cells with indistinct pale eosinophilic cytoplasm and small, uniform nuclei
─ Cells are arranged in short fascicles, storiform pattern, or haphazardly
─ Stroma is variably collagenous (often with thick, "keloidal" collagen bundles) or myxoid
─ Characteristic feature: Prominent, branching, thin-walled, ectatic blood vessels, often with a "staghorn" or hemangiopericytoma-like configuration
─ Mitotic activity is usually low (<4 mitoses/10 HPF in most benign/intermediate risk SFTs)
─ Risk stratification (benign, intermediate, malignant) based on patient age, tumor size, mitotic activity, cellularity, pleomorphism, and necrosis; malignant SFTs show increased mitoses (≥4/10 HPF), hypercellularity, atypia, and/or necrosis
─ Variants include: Giant cell-rich SFT (formerly giant cell angiofibroma), fat-forming SFT (lipomatous hemangiopericytoma), myxoid SFT
Ancillary studies ─
─ IHC: Diffuse, strong nuclear positivity for STAT6 is highly sensitive and specific; CD34 is positive in most cases (but can be lost in malignant SFTs); CD99 and bcl-2 are often positive; Negative for S100 protein, SMA (except perivascular), desmin, keratins
─ Molecular: Defined by an intrachromosomal inversion inv(12)(q13q13) leading to NAB2::STAT6 gene fusion (various fusion variants exist)
DDx
─ Myofibroblastoma (desmin positive, lacks STAT6)
─ Spindle cell lipoma (contains fat, lacks STAT6)
─ Low-grade fibromyxoid sarcoma (MUC4 positive, FUS fusion, lacks STAT6)
─ Dermatofibrosarcoma protuberans (storiform, honeycomb fat infiltration, COL1A1::PDGFB fusion, lacks STAT6)
─ Synovial sarcoma (monophasic) (TLE1 positive, keratin/EMA often positive, SS18 fusion, lacks STAT6)
─ Malignant peripheral nerve sheath tumor (S100/SOX10 variable, H3K27me3 loss, lacks STAT6)
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─ pathoutlines WSI WSI WSI WSI HE CD34 video

Giant Cell–Rich Solitary Fibrous Tumor / Giant Cell Angiofibroma

A variant of solitary fibrous tumor (SFT) characterized by a prominent component of multinucleated giant cells, often osteoclast-like, in addition to the typical features of SFT; Giant Cell Angiofibroma is now considered part of this spectrum
Clinical ─ Similar to conventional SFT, typically adults; common sites include orbit, head/neck, inguinal region, back, and other soft tissue locations; usually presents as a slow-growing, painless mass
Macro ─ Well-circumscribed, lobulated, firm mass; cut surface may be grayish-white and fibrous, sometimes with cystic or hemorrhagic areas
Micro
─ Background features of solitary fibrous tumor: "patternless pattern" of bland spindle cells, hemangiopericytoma-like (staghorn) vessels, and variable collagenous stroma
─ Defining feature: Presence of numerous multinucleated giant cells, often osteoclast-like, scattered throughout the lesion or forming clusters
─ Pseudovascular spaces or cystic areas lined by tumor cells and giant cells may be prominent (features previously emphasized in "giant cell angiofibroma")
─ Spindle cell component is typically bland with low mitotic activity
─ Cellularity can be variable
Ancillary studies ─
─ IHC: Spindle cells show nuclear STAT6 positivity; CD34, CD99, and bcl-2 are often positive in spindle cells; Multinucleated giant cells are typically CD68 positive but STAT6 negative
─ Molecular: NAB2::STAT6 gene fusion is present, confirming its classification as SFT
DDx
─ Conventional solitary fibrous tumor (lacks prominent giant cells)
─ Tenosynovial giant cell tumor (TGCT) (lacks STAT6 positivity, different mononuclear cell morphology, lacks NAB2::STAT6 fusion)
─ Giant cell tumor of soft tissue (lacks STAT6 positivity, lacks SFT architecture, different immunoprofile)
─ Non-ossifying fibroma or benign fibrous histiocytoma with giant cells (lacks STAT6, different overall architecture, typically CD34 negative)
─ Leiomyosarcoma with osteoclast-like giant cells (myogenic markers positive, lacks STAT6)
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Fat-Forming Solitary Fibrous Tumor / Lipomatous Hemangiopericytoma

A rare variant of solitary fibrous tumor (SFT) that contains a significant component of mature adipose tissue admixed with the typical SFT morphology; "Lipomatous hemangiopericytoma" is an older term now encompassed within this SFT variant
Clinical ─ Similar to conventional SFT, typically adults; occurs in deep soft tissues, retroperitoneum, pelvis, and other sites where SFTs arise; presentation is usually a slow-growing mass
Macro ─ Well-circumscribed mass; cut surface shows a mixture of yellowish fatty areas and grayish-white fibrous areas
Micro
─ Coexistence of two distinct components:
─ Typical solitary fibrous tumor areas: "Patternless pattern" of bland spindle cells, hemangiopericytoma-like vessels, variable collagen
─ Mature adipose tissue: Lobules or sheets of univacuolated adipocytes without atypia, comprising a significant portion of the tumor (eg, >10-30%)
─ The two components are intimately admixed or may be more sharply demarcated
─ No lipoblasts or atypical adipocytes are present
Ancillary studies ─
─ IHC: Spindle cell component shows nuclear STAT6 positivity and is often CD34 positive; Adipocytes are S100 positive but STAT6 negative; MDM2/CDK4 negative (to exclude WDLPS/ALT)
─ Molecular: NAB2::STAT6 gene fusion is present in the SFT component
DDx
─ Well-differentiated liposarcoma / Atypical lipomatous tumor (MDM2/CDK4 positive/amplified, atypical stromal cells, lacks STAT6 positivity and typical SFT architecture)
─ Spindle cell lipoma (CD34 positive spindle cells, mature fat, often ropey collagen, 13q/RB1 loss, lacks STAT6 positivity)
─ Myofibroblastoma, lipomatous variant (desmin positive, CD34 positive, RB1 loss, lacks STAT6)
─ Conventional solitary fibrous tumor with entrapped fat (fat is usually peripheral or sparse, not a major component)
─ Dedifferentiated liposarcoma with SFT-like areas (arises from WDLPS, MDM2 amplified)
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Meningeal Solitary Fibrous Tumor

Solitary fibrous tumor (SFT) arising from the meninges, histologically and molecularly identical to SFTs in other locations; previously often misclassified as "hemangiopericytoma" of the meninges
Clinical ─ Adults (wide age range); presents as a dural-based mass, mimicking meningioma; symptoms depend on location and size (headaches, seizures, focal neurological deficits)
Macro ─ Well-circumscribed, firm, dural-based mass; may be highly vascular; often appears attached to the dura
Micro
─ Histologic features are identical to SFTs elsewhere:
─ "Patternless pattern" of bland spindle cells with ovoid nuclei and scant cytoplasm
─ Prominent branching, "staghorn" or hemangiopericytoma-like blood vessels
─ Alternating hypo- and hypercellular areas, variable collagenous (keloidal) or myxoid stroma
─ Risk stratification (WHO Grade I, II, III) based on mitotic activity, cellularity, atypia, and necrosis, similar to soft tissue SFTs
Ancillary studies ─
─ IHC: Strong and diffuse nuclear STAT6 positivity is diagnostic; CD34, CD99, bcl-2 are often positive; Negative for S100 protein, EMA (unlike meningioma), GFAP, keratins
─ Molecular: NAB2::STAT6 gene fusion is the defining molecular alteration
DDx
─ Meningioma (especially fibrous or transitional types) (EMA positive, S100 variably positive, lacks STAT6 positivity and NAB2::STAT6 fusion, characteristic meningothelial whorls/psammoma bodies)
─ Schwannoma (S100 positive, Antoni A/B areas, Verocay bodies, lacks STAT6)
─ Dural metastasis (history of primary, specific markers for carcinoma/melanoma etc)
─ Other spindle cell mesenchymal tumors of the meninges (rare, require specific markers)
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Myxoid Solitary Fibrous Tumor

A variant of solitary fibrous tumor (SFT) characterized by prominent myxoid stromal change comprising a significant portion of the tumor, while retaining other typical SFT features and the NAB2::STAT6 fusion
Clinical ─ Similar to conventional SFT, typically adults; can occur in any SFT location; may present as a softer mass if myxoid change is extensive
Macro ─ May appear more gelatinous or less firm than classic SFT due to the myxoid stroma; otherwise similar (well-circumscribed, lobulated)
Micro
─ Background features of solitary fibrous tumor: "Patternless pattern" of bland spindle cells and hemangiopericytoma-like vessels
─ Defining feature: Abundant myxoid or edematous stroma (Alcian blue positive), which may be diffuse or patchy, occupying a significant portion of the tumor
─ Spindle cells may appear more separated, stellate, or embedded in the myxoid matrix
─ Cellularity can be variable, often lower in extensively myxoid areas
─ Typical SFT collagen patterns (eg, keloidal collagen) may also be present
─ Risk assessment follows general SFT criteria (mitoses, atypia, necrosis)
Ancillary studies ─
─ IHC: Nuclear STAT6 positivity is present; CD34, CD99, bcl-2 often positive; Negative for S100, SMA (except perivascular), desmin
─ Molecular: NAB2::STAT6 gene fusion is present
DDx
─ Low-grade fibromyxoid sarcoma (MUC4 positive, FUS fusion, lacks STAT6, distinct arcades of vessels)
─ Myxofibrosarcoma (more pleomorphism, curvilinear vessels, lacks STAT6)
─ Myxoid neurofibroma (S100 positive wavy cells, embedded axons, lacks STAT6)
─ Aggressive angiomyxoma (deep pelvic/perineal, prominent vessels, HMGA2 rearranged, lacks STAT6)
─ Myxoid liposarcoma (lipoblasts, plexiform capillaries, DDIT3 fusion, lacks STAT6)
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Inflammatory myofibroblastic tumor (IMT)

A mesenchymal neoplasm of intermediate malignant potential, composed of myofibroblastic spindle cells with a characteristic prominent lymphoplasmacytic inflammatory infiltrate; a subset is driven by ALK gene rearrangements
Clinical ─ Primarily children and young adults (median age ~10-30s, but wide range); common sites include lung, mesentery, retroperitoneum, abdomen/pelvis, and soft tissues of extremities; can occur virtually anywhere; presentation varies by site, often a mass, may cause pain, fever, weight loss, or laboratory abnormalities (anemia, thrombocytosis, hypergammaglobulinemia)
Macro ─ Well-circumscribed or infiltrative mass; cut surface is typically fleshy, firm, or gelatinous, gray-white to tan; may show hemorrhage or necrosis, especially in larger lesions
Micro
─ Proliferation of bland to moderately atypical spindle cells (myofibroblasts) with vesicular nuclei and small nucleoli, arranged in fascicles or a loose, edematous, or myxoid stroma ("tissue culture-like," resembling nodular fasciitis in some areas)
─ Defining feature: Prominent inflammatory infiltrate composed mainly of plasma cells and lymphocytes, often with eosinophils and neutrophils; lymphoid follicles may be present
─ Large, atypical "ganglion-like" myofibroblasts with prominent nucleoli can be seen, particularly in ALK-positive cases
─ Vascularity is often prominent
─ Mitotic activity is variable, atypical mitoses are generally rare
─ Epithelioid inflammatory myofibroblastic sarcoma is a rare aggressive variant with epithelioid cells, nuclear atypia, and often RANBP2::ALK fusion
Ancillary studies ─
─ IHC: Spindle cells are positive for SMA (smooth muscle actin) and MSA (muscle-specific actin); Desmin is variably positive (more often in ALK-negative cases); ALK protein expression (cytoplasmic, sometimes nuclear or membranous) is seen in ~50-60% of cases, corresponding to ALK rearrangement; CD68 may highlight histiocytes in the infiltrate; Negative for S100, keratins (usually), MyoD1/myogenin
─ Molecular: ALK gene (2p23) rearrangements with various fusion partners (eg, TPM3, TPM4, CLTC, RANBP2) are found in a significant subset; ROS1, NTRK3, RET, PDGFRB rearrangements occur in ALK-negative cases
DDx
─ Nodular fasciitis / Pseudosarcomatous myofibroblastic proliferation (USP6 rearranged in some, ALK negative, generally less prominent plasma cell infiltrate)
─ IgG4-related disease (storiform fibrosis, obliterative phlebitis, increased IgG4+ plasma cells, ALK negative)
─ Leiomyosarcoma (more significant atypia, more diffuse desmin, lacks ALK rearrangement and prominent inflammatory infiltrate)
─ Desmoid-type fibromatosis (nuclear beta-catenin positive, lacks prominent inflammation and ALK rearrangement)
─ Follicular dendritic cell sarcoma (CD21/CD35 positive, often EBV associated)
─ Lymphoma (especially Hodgkin or anaplastic large cell) (specific lymphoma markers, ALK may be positive in ALCL but different pattern/cells)
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─ Pathoutlines WSI of HE actin CD10 desmin WSI WSI & video WSI & video WSI & video video video

Epithelioid Inflammatory Myofibroblastic Sarcoma

An aggressive variant of inflammatory myofibroblastic tumor (IMT) characterized by epithelioid to round cell morphology, prominent nuclear atypia, and often associated with specific ALK gene fusion partners (eg, RANBP2::ALK, RRBP1::ALK) linked to more aggressive behavior
Clinical ─ Tends to affect children and young adults, similar to conventional IMT, but may have a more aggressive clinical course with higher rates of recurrence and metastasis; often arises in intra-abdominal locations (mesentery, omentum, peritoneum)
Macro ─ Typically larger, more infiltrative masses than conventional IMT; may show areas of hemorrhage or necrosis
Micro
─ Predominantly composed of sheets or clusters of large epithelioid to round cells with abundant eosinophilic or amphophilic cytoplasm
─ Nuclei are often vesicular with prominent, centrally located nucleoli, resembling ganglion cells or rhabdoid cells
─ Significant nuclear pleomorphism and atypia are present
─ Background inflammatory infiltrate, characteristic of conventional IMT, may be present but can be sparse or focal
─ Myxoid or collagenous stroma may be less prominent than in conventional IMT
─ Mitotic activity is often brisk, and atypical mitoses can be seen; necrosis is common
Ancillary studies ─
─ IHC: Tumor cells are positive for ALK (often strong and diffuse cytoplasmic, sometimes with nuclear membrane accentuation, especially with RANBP2::ALK); SMA and desmin may be positive but can be focal or weak; Cytokeratins can be focally positive; Negative for S100, MyoD1/myogenin
─ Molecular: ALK gene rearrangements are present, with fusion partners like RANBP2 or RRBP1 often associated with this aggressive variant and epithelioid morphology
DDx
─ Conventional inflammatory myofibroblastic tumor (IMT) (less atypia, more prominent spindle cell component and inflammation, different ALK fusion partners often)
─ Anaplastic large cell lymphoma (ALCL) (ALK positive in a subset, but CD30 positive, lymphoid markers positive, lacks myofibroblastic features)
─ Rhabdoid tumor (INI1 loss, lacks ALK rearrangement, different immunoprofile)
─ Epithelioid sarcoma (INI1 loss, keratin positive, CD34 often positive, lacks ALK rearrangement)
─ Poorly differentiated carcinoma (more cohesive growth, other carcinoma markers, lacks ALK rearrangement)
─ Melanoma (S100/SOX10/melanocytic markers positive, lacks ALK rearrangement)
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Myxoinflammatory fibroblastic sarcoma (MIFS)

A rare, low-grade sarcoma of uncertain differentiation, typically occurring in the distal extremities of adults, characterized by a striking admixture of bizarre, virus-like (virocyte-like) or ganglion-like cells, bland spindle cells, and a prominent inflammatory infiltrate within a myxoid stroma; considered part of a spectrum with HFLT and PHAT
Clinical ─ Typically affects adults (peak age 30-50s); strong predilection for distal extremities, especially hands and feet (acral sites), often involving subcutaneous tissue, fascia, or tendon sheaths; presents as a slow-growing, often multinodular, painless or tender mass
Macro ─ Poorly circumscribed, multinodular, infiltrative mass; cut surface is typically gelatinous or myxoid, gray-white to tan, sometimes with hemorrhagic areas
Micro
─ Multinodular or lobulated growth pattern, often with infiltrative margins
─ Abundant myxoid to edematous stroma (Alcian blue positive)
─ Characteristic heterogeneous cell population:
─ Large, bizarre, pleomorphic cells with vesicular nuclei and prominent, often multiple, inclusion-like nucleoli, resembling virocytes (virus-infected cells) or Reed-Sternberg-like cells (ganglion-like cells)
─ Vacuolated cells resembling lipoblasts ("pseudolipoblasts") are common
─ Bland spindle to stellate fibroblastic cells in the background
─ Prominent inflammatory infiltrate composed of lymphocytes, plasma cells, neutrophils, and eosinophils
─ Hemosiderin deposition is common
─ Mitotic activity is generally low, atypical mitoses are rare
Ancillary studies ─
─ IHC: Tumor cells (including bizarre cells and pseudolipoblasts) are positive for vimentin; CD34 and CD68 may be variably positive; SMA can be focally positive; Negative for S100 protein, keratins, desmin, HMB45, ALK1
─ Molecular: Characterized by TGFBR3 and/or MGEA5 gene rearrangements (often resulting in a TGFBR3::MGEA5 fusion due to t(1;10)), similar to PHAT and HFLT; some cases show VGLL3 rearrangements
DDx
─ Pleomorphic hyalinizing angiectatic tumor (PHAT) (more prominent ectatic hyalinized vessels, less inflammation usually, but significant overlap)
─ Hemosiderotic fibrolipomatous tumor (HFLT) (prominent adipose tissue, less myxoid stroma, less bizarre cells usually, but significant overlap)
─ Myxofibrosarcoma (lacks the characteristic virocyte-like cells and prominent mixed inflammation, more distinct curvilinear vessels)
─ Inflammatory myofibroblastic tumor (IMT) (ALK positive in a subset, more organized spindle cells, lacks virocyte-like cells)
─ Hodgkin lymphoma or other lymphomas (specific lymphoma markers positive)
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─ pathoutlines WSI WSI WSI WSI WSI WSI with video WSI with video

Infantile fibrosarcoma

A malignant spindle cell neoplasm occurring in infancy and early childhood (typically <2 years, often congenital), characterized by a specific ETV6::NTRK3 gene fusion; also known as congenital fibrosarcoma
Clinical ─ Primarily affects infants (most cases present before 1 year of age, many are congenital); M=F; common in extremities (especially distal), trunk, and head/neck; presents as a rapidly growing, firm, fleshy mass, may be quite large at presentation
Macro ─ Poorly circumscribed or deceptively well-circumscribed, infiltrative mass; cut surface is typically fleshy, gray-white to tan, often with areas of hemorrhage, necrosis, or cystic change
Micro
─ Densely cellular proliferation of relatively uniform, immature-appearing spindle cells arranged in intersecting fascicles, often forming a "herringbone" pattern
─ Cells have scant cytoplasm, ovoid to spindle-shaped nuclei with fine chromatin, and inconspicuous nucleoli
─ Mitotic activity is typically brisk and easily identified, but atypical mitoses are uncommon
─ Minimal to moderate cytologic pleomorphism
─ Stroma is usually sparse, but myxoid or collagenous areas can be seen
─ A primitive round cell component may be present in some cases
─ Infiltrative growth into surrounding tissues is common
Ancillary studies ─
─ IHC: Tumor cells are positive for vimentin; SMA may be focally positive; CD34 is variably positive; Pan-TRK antibody (recognizing TRKA, TRKB, TRKC) shows cytoplasmic staining due to NTRK3 fusion protein expression (useful surrogate marker); Negative for S100 protein, desmin, keratins, MyoD1/myogenin
─ Molecular: Defined by the ETV6::NTRK3 gene fusion resulting from t(12;15)(p13;q25)
DDx
─ Myofibromatosis (infantile) (often biphasic with primitive round cells and more mature spindle cells, hemangiopericytoma-like vessels, lacks ETV6::NTRK3 fusion)
─ Lipofibromatosis (admixed mature fat, CD34 positive spindle cells, lacks ETV6::NTRK3 fusion)
─ Spindle cell rhabdomyosarcoma (infantile type) (myogenic markers MyoD1/myogenin positive, specific fusions like VGLL2::NCOA2)
─ Desmoid-type fibromatosis (rare in infants, less cellular, nuclear beta-catenin positive, lacks ETV6::NTRK3 fusion)
─ Primitive myxoid mesenchymal tumor of infancy (PMMTI) (prominent myxoid stroma, BCOR-ITD or other BCOR alterations)
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─ pathoutlines WSI WSI WSI

Adult fibrosarcoma

A malignant mesenchymal neoplasm composed of spindle cells showing fibroblastic differentiation, characterized by a fascicular (herringbone) growth pattern and variable collagen production; now considered a diagnosis of exclusion after ruling out other specific spindle cell sarcomas with defined molecular or immunophenotypic features
Clinical ─ Primarily affects adults (wide age range, peak 30-60s, but can occur in older individuals); common in deep soft tissues of extremities (especially thigh), trunk, and head/neck; presents as a slow-growing or rapidly enlarging, often painless mass
Macro ─ Appears relatively circumscribed but is unencapsulated and infiltrative; cut surface is typically firm, fleshy, gray-white, and may show a whorled or trabeculated pattern; hemorrhage and necrosis can be present, especially in higher-grade tumors
Micro
─ Cellular proliferation of relatively uniform spindle cells with tapering nuclei and scant cytoplasm, arranged in intersecting fascicles forming a characteristic "herringbone" pattern
─ Variable amounts of stromal collagen produced by tumor cells
─ Cellularity, cytologic atypia, and mitotic activity determine grade (low vs high):
─ Low-grade: Moderate cellularity, minimal atypia, low mitotic rate (<5-10/10 HPF)
─ High-grade: High cellularity, significant atypia/pleomorphism, brisk mitotic activity (often >10-20/10 HPF), necrosis common
─ Lacks specific features of other spindle cell sarcomas (eg, SFT, MPNST, synovial sarcoma, LMS)
Ancillary studies ─
─ IHC: Tumor cells are positive for vimentin; SMA may be focally positive; Diagnosis is largely one of exclusion, so negative for S100 protein, SOX10, desmin, keratins, CD34 (usually), STAT6, TLE1, MUC4, MDM2, specific lineage markers
─ Molecular: No specific recurrent genetic alterations define adult fibrosarcoma; complex karyotypes are common in high-grade lesions; important to exclude sarcomas with specific fusions
DDx
─ Monophasic synovial sarcoma (TLE1 positive, keratin/EMA often positive, SS18 fusion)
─ Malignant peripheral nerve sheath tumor (MPNST) (S100/SOX10 often variably positive, H3K27me3 loss, arises from nerve or in NF1)
─ Solitary fibrous tumor (STAT6 positive, CD34 positive, characteristic vasculature)
─ Low-grade fibromyxoid sarcoma (MUC4 positive, FUS fusion, alternating fibrous/myxoid zones)
─ Leiomyosarcoma (desmin/h-caldesmon positive, more prominent eosinophilic cytoplasm)
─ Undifferentiated pleomorphic sarcoma (UPS) (more pronounced pleomorphism, lacks herringbone pattern)
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─ pathoutlines WSI WSI

Myxofibrosarcoma

A malignant fibroblastic neoplasm characterized by variably cellular areas with spindle cells showing at least focal atypia/pleomorphism, set in a myxoid stroma containing prominent elongated, curvilinear, thin-walled blood vessels; one of the most common sarcomas in older adults
Clinical ─ Typically affects older adults (peak 60-80s); common in extremities (especially lower limb), followed by trunk, head/neck; usually arises in subcutaneous tissue or dermis, can also be intramuscular; presents as a slow-growing, painless or tender, often multinodular mass
Macro ─ Multinodular, infiltrative mass with a gelatinous or myxoid cut surface; may show hemorrhagic or firmer white areas corresponding to higher cellularity or necrosis; size is variable, often large at presentation
Micro
─ Infiltrative growth pattern, often with multiple discrete or coalescing nodules
─ Variable cellularity, often with hypocellular myxoid areas peripherally and more cellular, solid areas centrally or in deeper portions
─ Composed of spindle to stellate fibroblastic cells with at least focal cytologic atypia and pleomorphism, which is a key feature for diagnosis and grading
─ Abundant myxoid stroma (Alcian blue positive) is characteristic
─ Prominent, elongated, curvilinear, thin-walled blood vessels are a hallmark feature, often numerous
─ Pseudolipoblasts (vacuolated fibroblastic cells resembling lipoblasts but S100 negative) are common
─ Grading (low, intermediate, high, or 3-tiered system) based on degree of cellularity, atypia/pleomorphism, mitotic activity, and presence of necrosis:
─ Low-grade: Hypocellular, minimal atypia, few mitoses, abundant myxoid stroma
─ High-grade: Hypercellular, marked pleomorphism, frequent mitoses, +/- necrosis, solid sheets of tumor cells
Ancillary studies ─
─ IHC: Tumor cells are positive for vimentin; SMA may be focally positive; CD34 can be positive in some cases, especially low-grade; Negative for S100 protein (except entrapped cells), desmin, keratins, MUC4, specific sarcoma markers
─ Molecular: Characterized by complex karyotypes with numerous gains and losses, particularly involving chromosome 7 and 17; no specific recurrent translocations are consistently identified
DDx
─ Myxoid liposarcoma (true lipoblasts, S100 positive, plexiform capillaries, DDIT3 fusion)
─ Low-grade fibromyxoid sarcoma (alternating fibrous/myxoid areas, bland cytology, MUC4 positive, FUS fusion)
─ Intramuscular myxoma / Juxta-articular myxoma (lacks atypia/pleomorphism and curvilinear vessels; GNAS mutations in IM myxoma)
─ Myxoid malignant peripheral nerve sheath tumor (S100/SOX10 often positive, H3K27me3 loss)
─ Undifferentiated pleomorphic sarcoma with myxoid change (more extreme pleomorphism, lacks prominent curvilinear vessels consistently)
─ Nodular fasciitis (myxoid variant) (younger patients, rapid growth, "tissue culture" appearance, USP6 rearranged, lacks significant atypia)
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─ pathoutlines WSI WSI WSI WSI with video WSI with video

Epithelioid Myxofibrosarcoma

A rare, aggressive variant of myxofibrosarcoma characterized by a significant component (>50%) of large, pleomorphic epithelioid cells, often with rhabdoid features, in addition to conventional myxofibrosarcoma elements
Clinical ─ Similar to high-grade conventional myxofibrosarcoma, typically older adults; extremities common; may have a more aggressive clinical course with higher metastatic potential
Macro ─ Often a large, fleshy, infiltrative mass with myxoid and solid areas; necrosis and hemorrhage may be prominent
Micro
─ Sheets, nests, or cords of large, polygonal epithelioid cells with abundant eosinophilic or amphophilic cytoplasm, vesicular nuclei, and prominent nucleoli
─ Marked cytologic pleomorphism and atypia are characteristic of the epithelioid component
─ Rhabdoid features (eccentric nuclei, paranuclear eosinophilic inclusions) may be present in epithelioid cells
─ Admixed areas of conventional myxofibrosarcoma (spindle cells, myxoid stroma, curvilinear vessels) are usually identifiable, though can be focal
─ High mitotic activity, including atypical forms, and necrosis are common
Ancillary studies ─
─ IHC: Tumor cells are positive for vimentin; Epithelioid cells may show focal positivity for keratins (AE1/AE3, CAM5.2) or EMA, creating a potential pitfall with carcinoma; SMA may be focally positive; Negative for S100 protein, desmin, MUC4, specific sarcoma markers
─ Molecular: Complex karyotypes, similar to high-grade conventional myxofibrosarcoma; no specific recurrent translocations are consistently identified for this variant
DDx
─ Metastatic carcinoma (especially poorly differentiated or sarcomatoid) (more diffuse keratin positivity, specific carcinoma markers like GATA3, PAX8, etc,, clinical history)
─ Melanoma (S100/SOX10/melanocytic markers positive)
─ Epithelioid sarcoma (INI1 loss, CD34 often positive, different morphology)
─ Extrarenal rhabdoid tumor (INI1 loss, younger age group typically)
─ Epithelioid angiosarcoma (vascular markers CD31/ERG positive)
─ High-grade conventional myxofibrosarcoma (predominantly spindle cell, epithelioid component <50%)
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Low-Grade Fibromyxoid sarcoma (LGFMS)

An indolent but fully malignant fibroblastic neoplasm characterized by a deceptively bland appearance with alternating fibrous and myxoid zones, often with arcades of curvilinear blood vessels, and a specific FUS::CREB3L2 or related fusion; also known as Evans tumor
Clinical ─ Typically affects young to middle-aged adults (peak 20-50s), but can occur at any age, including children; common in deep soft tissues of the trunk (chest wall, abdomen, pelvis) and proximal extremities (especially thigh); presents as a slow-growing, often large, painless mass
Macro ─ Well-circumscribed or lobulated, firm, rubbery mass; cut surface is typically white-tan and fibrous, often with glistening, whorled, or gelatinous myxoid areas; size is variable, can be very large
Micro
─ Characteristic biphasic pattern with alternating zones:
─ Fibrous areas: Composed of bland, uniform spindle cells with scant cytoplasm and elongated, tapering nuclei, arranged in sweeping fascicles or a storiform/whorling pattern; dense collagenous stroma
─ Myxoid areas: Hypocellular, with spindle or stellate cells embedded in an abundant myxoid matrix (Alcian blue positive); often contain prominent, delicate, curvilinear or arcuate thin-walled blood vessels
─ Transition between fibrous and myxoid areas can be gradual or abrupt
─ Minimal cytologic atypia, mitotic activity is very low (usually <1-2/10 HPF), necrosis is typically absent
─ Giant collagen rosettes (hyalinizing spindle cell tumor with giant rosettes - HSCTGR pattern) may be present in a subset of cases, characterized by central amorphous eosinophilic collagen surrounded by palisading tumor cells
Ancillary studies ─
─ IHC: Tumor cells are characteristically positive for MUC4 (diffuse, strong staining, highly sensitive and specific); EMA (epithelial membrane antigen) is often positive (patchy or diffuse); CD99 and bcl-2 may be positive; Negative for S100 protein, SMA, desmin, keratins, CD34 (except vessels), STAT6
─ Molecular: Defined by recurrent gene fusions, most commonly FUS::CREB3L2 (t(7;16)(q33;p11)); less common variants include FUS::CREB3L1 or EWSR1::CREB3L1
DDx
─ Myxofibrosarcoma (low-grade) (more atypia/pleomorphism, prominent curvilinear vessels but different overall pattern, MUC4 negative)
─ Myxoid neurofibroma (S100 positive wavy cells, embedded axons, MUC4 negative)
─ Solitary fibrous tumor (myxoid variant) (STAT6 positive, CD34 positive, NAB2::STAT6 fusion, MUC4 negative)
─ Desmoid-type fibromatosis (nuclear beta-catenin positive, lacks myxoid zones and MUC4 positivity)
─ Myxoid liposarcoma (lipoblasts, plexiform capillaries, DDIT3 fusion, MUC4 negative)
─ Perineurioma (EMA positive, claudin-1 positive, MUC4 negative)
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─ pathoutlines WSI WSI WSI Hyalinizing Spindle Cell Tumor with Giant Rosettes WSI Sclerosing epithelioid fibrosarcoma

Low-Grade Myofibroblastic Sarcoma

A rare, malignant mesenchymal neoplasm composed of spindle cells showing myofibroblastic differentiation, characterized by infiltrative growth and a tendency for local recurrence and late metastasis, but lacking the high-grade features of pleomorphic myofibroblastic sarcoma
Clinical ─ Affects a wide age range, including children and adults; common sites include head/neck (especially oral cavity/tongue), extremities, and trunk; can arise in deep soft tissues or superficial locations; presents as a slow-growing, firm, often painless mass
Macro ─ Poorly circumscribed, infiltrative, firm, gray-white mass; cut surface may be fibrous or fleshy
Micro
─ Infiltrative proliferation of relatively uniform spindle cells with eosinophilic cytoplasm and elongated, tapering or blunt-ended nuclei
─ Cells are typically arranged in long, sweeping fascicles, sometimes with a storiform or herringbone pattern
─ Nuclear atypia is generally mild to moderate; pleomorphism is not prominent
─ Mitotic activity is variable but usually low to moderate (eg, <10/10 HPF); atypical mitoses are uncommon
─ Stroma is variably collagenous, can be myxoid in areas
─ Necrosis is usually absent or minimal
─ Distinction from benign myofibroblastic proliferations (eg, myofibroma, myofibromatosis) relies on infiltrative growth, cellularity, and at least focal atypia/mitotic activity, but can be challenging
Ancillary studies ─
─ IHC: Tumor cells are positive for SMA (smooth muscle actin) and MSA (muscle-specific actin); Desmin is variably positive (often focal or patchy, some cases negative); Calponin may be positive; CD34 is typically negative in tumor cells (may highlight vessels); Negative for S100 protein, keratins, h-caldesmon (unlike leiomyosarcoma), nuclear beta-catenin, ALK1
─ Molecular: No specific recurrent genetic alterations are consistently identified; some cases show alterations in genes like FN1, SRF, or TGFB pathways, but these are not diagnostic
DDx
─ Desmoid-type fibromatosis (nuclear beta-catenin positive, lacks significant atypia)
─ Leiomyosarcoma (more distinct smooth muscle features, h-caldesmon positive, often more atypia)
─ Adult fibrosarcoma (diagnosis of exclusion, lacks consistent myofibroblastic markers)
─ Inflammatory myofibroblastic tumor (prominent inflammatory infiltrate, ALK positive in a subset)
─ Myofibroma/Myofibromatosis (more circumscribed, often biphasic, lacks significant atypia/infiltrative sarcomatous growth)
─ Nodular fasciitis (more reactive appearance, "tissue culture" pattern, USP6 rearranged)
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Infantile fibromatosis

A group of benign, locally infiltrative fibroblastic/myofibroblastic proliferations occurring in infancy and early childhood, encompassing a spectrum of lesions previously known by various names (eg, congenital fibromatosis, diffuse infantile fibromatosis, aggressive infantile fibromatosis); distinct from infantile fibrosarcoma
Clinical ─ Typically presents within the first 2 years of life, many are congenital or noted in the neonatal period; M>F slightly; common sites include extremities (especially distal), head/neck, and trunk; can involve superficial soft tissues, deep soft tissues (muscle), and rarely viscera or bone; presents as a firm, often rapidly growing, solitary or multiple masses
Macro ─ Poorly circumscribed, firm, infiltrative, gray-white to tan mass; cut surface is fibrous and may appear whorled
Micro
─ Variably cellular proliferation of relatively uniform, bland spindle cells (fibroblasts and myofibroblasts) with pale eosinophilic cytoplasm and elongated or ovoid nuclei
─ Cells are arranged in intersecting fascicles, a storiform pattern, or more haphazardly
─ Infiltrative growth into surrounding skeletal muscle and adipose tissue is characteristic
─ Stroma is variably collagenous or myxoid; myxoid change can be prominent, especially in younger lesions
─ Mitotic activity can be brisk, especially in rapidly growing lesions, but atypical mitoses are absent or very rare
─ No significant nuclear atypia or pleomorphism
─ Some lesions (previously "myofibromatosis") show a biphasic pattern with peripheral spindle cells and central, less differentiated, more rounded cells, often with a hemangiopericytoma-like vascular pattern
Ancillary studies ─
─ IHC: Spindle cells are positive for vimentin and often SMA; MSA may be positive; Desmin is typically negative (except entrapped muscle); CD34 may be positive in some areas, especially the less differentiated components; Negative for S100 protein, keratins, nuclear beta-catenin, MyoD1/myogenin
─ Molecular: No single unifying genetic alteration; some myofibromatosis cases show PDGFRB mutations or NOTCH pathway alterations; distinct from ETV6::NTRK3 of infantile fibrosarcoma
DDx
─ Infantile fibrosarcoma (more uniformly cellular, herringbone pattern, ETV6::NTRK3 fusion, Pan-TRK positive)
─ Fibrous hamartoma of infancy (triphasic pattern with fibrous, primitive mesenchymal, and adipose components)
─ Lipofibromatosis (prominent mature adipose tissue admixed with spindle cells, CD34 positive spindle cells)
─ Desmoid-type fibromatosis (rare in this age, more organized fascicles, nuclear beta-catenin positive)
─ Rhabdomyoma (fetal type) / Spindle cell rhabdomyosarcoma (myogenic markers positive)
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Primitive Myxoid Mesenchymal Tumor of Infancy

A rare, distinctive, locally aggressive mesenchymal neoplasm of infancy and early childhood, characterized by primitive spindle to stellate cells in an abundant myxoid stroma, often with BCOR gene alterations (typically internal tandem duplication)
Clinical ─ Primarily affects infants and young children (usually <3 years, many congenital or in first year); slight male predominance; common in deep soft tissues of the trunk (chest wall, back, abdomen/pelvis), extremities, and head/neck; presents as a rapidly growing, often large, poorly defined mass
Macro ─ Poorly circumscribed, infiltrative, soft, gelatinous, gray-white to tan mass due to abundant myxoid stroma; may have cystic areas
Micro
─ Diffuse or vaguely lobular proliferation of relatively uniform, primitive-appearing spindle, stellate, or ovoid cells with scant cytoplasm and round to oval vesicular nuclei
─ Cells are embedded in an abundant, loose, myxoid, or edematous stroma (Alcian blue positive)
─ Delicate, branching ("chicken-wire" or arcuate) capillary network is often prominent, resembling that seen in myxoid liposarcoma or Ewing sarcoma (BCOR-rearranged type)
─ Cellularity is variable, often low to moderate
─ Mitotic activity is usually low, but can be focally increased; cytologic atypia is minimal
─ Infiltrative growth into adjacent tissues is common
Ancillary studies ─
─ IHC: Tumor cells are positive for vimentin; CD99 may be positive (often patchy); BCOR immunohistochemistry can show nuclear positivity in cases with BCOR alterations; SMA may be focally positive; Negative for S100 protein, keratins, desmin, myogenin, FLI1, NKX2.2, MUC4, STAT6
─ Molecular: Characterized by BCOR gene internal tandem duplication (BCOR-ITD) in many cases; other BCOR fusions (eg, BCOR::MAML3) or related genetic alterations may also occur; distinct from ETV6::NTRK3 of infantile fibrosarcoma and DDIT3 fusions of myxoid liposarcoma
DDx
─ Infantile fibrosarcoma (more cellular, herringbone pattern, ETV6::NTRK3 fusion, Pan-TRK positive)
─ Myxoid liposarcoma (extremely rare in infants, true lipoblasts, DDIT3 fusion)
─ Myxofibrosarcoma (infantile cases rare, more pleomorphism, curvilinear vessels, lacks BCOR alterations)
─ Myxoid neurofibroma (S100 positive wavy cells, embedded axons)
─ Ewing sarcoma (BCOR-rearranged type) (older children/adolescents typically, different clinical context, may share BCOR positivity but often different specific alteration and morphology)
─ Lipoblastoma (lobulated, lipoblasts, PLAG1 rearranged)
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Infantile Rhabdomyofibrosarcoma

A proposed rare sarcoma of infancy showing overlapping features of infantile fibrosarcoma and rhabdomyosarcoma, potentially representing a hybrid or composite tumor; its distinctness and classification are still evolving
Clinical ─ Affects infants and very young children; site and presentation are variable, may involve soft tissues of extremities, trunk, or head/neck
Macro ─ Typically a fleshy, infiltrative mass, similar to infantile fibrosarcoma or embryonal rhabdomyosarcoma
Micro
─ Displays a combination of features:
─ Areas resembling infantile fibrosarcoma: Cellular spindle cell proliferation, often with a herringbone pattern, brisk mitoses
─ Areas suggestive of rhabdomyosarcoma: Presence of rhabdomyoblasts (strap cells, tadpole cells, or more primitive round cells with eosinophilic cytoplasm) and/or expression of myogenic markers
─ The proportion and distinctness of each component can vary
─ Overall appearance is that of a malignant spindle and/or round cell tumor with evidence of both fibroblastic and myogenic differentiation
Ancillary studies ─
─ IHC: Spindle cell component may resemble fibrosarcoma (vimentin positive, +/- SMA, Pan-TRK potentially if ETV6::NTRK3 present); Rhabdomyoblastic component shows positivity for desmin, MyoD1, and myogenin
─ Molecular: Molecular findings are crucial; some cases may show ETV6::NTRK3 fusion (typical of infantile fibrosarcoma), while others might have alterations seen in rhabdomyosarcoma or distinct genetic changes; the molecular profile helps clarify lineage and classification
DDx
─ Infantile fibrosarcoma (lacks definitive rhabdomyoblastic differentiation/markers)
─ Embryonal rhabdomyosarcoma (predominantly rhabdomyoblastic, lacks ETV6::NTRK3 fusion)
─ Spindle cell rhabdomyosarcoma (MyoD1/myogenin positive, specific fusions in infantile variant like VGLL2::NCOA2)
─ Malignant peripheral nerve sheath tumor (MPNST) with heterologous rhabdomyosarcomatous differentiation (Triton tumor) (background of MPNST, S100/SOX10 variable)
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Sclerosing Epithelioid Fibrosarcoma

A rare, aggressive fibroblastic sarcoma characterized by nests and cords of epithelioid cells embedded in a dense, hyalinized (sclerotic) stroma, often showing MUC4 expression and FUS or EWSR1 gene rearrangements, with significant overlap with low-grade fibromyxoid sarcoma
Clinical ─ Typically affects adults (wide age range, peak 30-60s); common in deep soft tissues of extremities (especially lower limb), trunk, and head/neck; presents as a slow-growing, firm, often painless mass; can occur in bone
Macro ─ Well-circumscribed or infiltrative, firm, lobulated mass; cut surface is typically white-gray, fibrous, and sclerotic
Micro
─ Nests, cords, strands, or sheets of relatively uniform, small to medium-sized epithelioid cells with clear to eosinophilic cytoplasm and round to oval vesicular nuclei
─ Cells are embedded in an abundant, dense, hyalinized, or sclerotic collagenous stroma, which may resemble osteoid in some areas
─ Peripheral metaplastic bone formation can occur
─ Cytologic atypia is generally mild to moderate; mitotic activity is usually low but can be variable
─ May show transition to or coexistence with areas resembling low-grade fibromyxoid sarcoma (LGFMS) or hyalinizing spindle cell tumor with giant rosettes
Ancillary studies ─
─ IHC: Tumor cells are characteristically positive for MUC4 (strong, diffuse staining, highly sensitive); EMA may be positive (patchy or diffuse); S100 protein is positive in a subset of cases (variable); Negative for keratins (broad-spectrum), CD34, STAT6, desmin, SMA
─ Molecular: Recurrent gene fusions, most commonly FUS::CREB3L2 (similar to LGFMS); EWSR1::CREB3L1 or FUS::CREB3L1 fusions also occur
DDx
─ Low-grade fibromyxoid sarcoma (LGFMS) (often shows alternating fibrous/myxoid zones, may lack prominent epithelioid cells or dense sclerosis throughout, but represents a spectrum with SEF)
─ Ossifying fibromyxoid tumor (OFMT) (peripheral bone shell, PHF1 fusion, S100 often positive, MUC4 negative)
─ Myoepithelial carcinoma (S100/keratin/EMA/GFAP/SMA variably positive, EWSR1 rearrangements but different partners)
─ Metastatic carcinoma (especially scirrhous types) (keratin positive, MUC4 may be positive in some carcinomas but different morphology/context)
─ Sclerosing rhabdomyosarcoma (myogenic markers positive)
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Soft Tissue, Fibrohistiocytic

Tenosynovial giant cell tumor (TGCT)

A group of generally benign neoplasms arising from the synovium of joints, bursae, or tendon sheaths, characterized by a proliferation of mononuclear cells admixed with multinucleated osteoclast-like giant cells, foam cells, and hemosiderin-laden macrophages; includes localized type (formerly giant cell tumor of tendon sheath) and diffuse type (formerly pigmented villonodular synovitis - PVNS)
Clinical ─ Affects adults, typically young to middle-aged (peak 20-50s)
─ Localized type: Most common in fingers and hand, also toes/feet; presents as a slow-growing, firm, painless or mildly tender nodule attached to tendon sheath
─ Diffuse type: Affects large joints (knee mc, also hip, ankle, shoulder, elbow); presents with joint pain, swelling, stiffness, limited motion, and recurrent hemarthrosis
Macro ─
─ Localized type: Well-circumscribed, lobulated, firm nodule; cut surface is variegated yellow, brown, gray due to lipid, hemosiderin, and fibrous tissue; usually <3-4 cm
─ Diffuse type: Poorly defined, extensive, villous, nodular, or plaque-like synovial thickening; color is typically reddish-brown to dark brown due to prominent hemosiderin deposition
Micro
─ Variable admixture of cell types:
─ Mononuclear cells: Round to oval stromal/histiocytoid cells (considered the neoplastic component), with pale eosinophilic cytoplasm and vesicular nuclei
─ Osteoclast-like multinucleated giant cells: Numerous, evenly distributed or clustered
─ Foam cells (lipid-laden macrophages): Often present in clusters
─ Hemosiderin-laden macrophages: Abundant, contributing to pigmentation
─ Background stroma is fibrous, may show hyalinization or myxoid change
─ Chronic inflammatory infiltrate (lymphocytes) is common
─ Localized type: Forms discrete nodules, often with a fibrous pseudocapsule
─ Diffuse type: Shows infiltrative growth into synovium and adjacent soft tissues, often with villous or frond-like projections; can erode underlying bone
─ Mitotic activity is usually low in mononuclear cells; atypia is minimal
─ Malignant TGCT (rare): Shows features of overt sarcoma (increased cellularity, atypia, mitoses, necrosis) arising in association with conventional TGCT
Ancillary studies ─
─ IHC: Mononuclear cells and giant cells are positive for CD68, CD163 (histiocytic markers); A subset of mononuclear cells may express desmin or SMA; Negative for S100 protein, keratins; CSF1 (colony-stimulating factor 1) expression by tumor cells
─ Molecular: Characterized by translocations involving the CSF1 gene (1p13), leading to its overexpression; common fusion partner is COL6A3 (t(1;6))
DDx
─ Hemochromatosis / Hemophilic arthropathy (hemosiderin deposition but lacks neoplastic mononuclear cell proliferation)
─ Fibroma of tendon sheath (lacks giant cells, foam cells, hemosiderin; more uniformly fibrous)
─ Non-ossifying fibroma (if bone erosion by diffuse type; NOF is intraosseous, different histology)
─ Leiomyoma (smooth muscle proliferation, desmin/SMA positive)
─ Malignant sarcomas (eg, UPS, synovial sarcoma - show overt malignant features)
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─ pathoutlines WSI WSI WSI WSI WSI WSI desmin WSI HE trichrome iron

Giant Cell Tumor of Tendon Sheath / Localized-Type TGCT

The localized form of tenosynovial giant cell tumor (TGCT), typically presenting as a well-circumscribed nodule attached to a tendon sheath, most commonly in the fingers or hand
Clinical ─ Most common soft tissue tumor of the hand; typically affects adults aged 30-50 years; F>M slightly; involves fingers (volar or dorsal aspect) most frequently, also hand, wrist, less commonly toes/feet; presents as a slow-growing, firm, usually painless or mildly tender nodule
Macro ─ Well-circumscribed, lobulated, firm nodule, often encapsulated or pseudoencapsulated; cut surface is variegated, with areas of yellow (lipid), brown (hemosiderin), and gray-white (fibrous tissue); usually small (<3-4 cm)
Micro
─ Forms discrete, well-demarcated nodules, often with a fibrous pseudocapsule
─ Composed of an admixture of:
─ Mononuclear stromal/histiocytoid cells with round to oval nuclei and pale cytoplasm
─ Numerous osteoclast-like multinucleated giant cells
─ Clusters of foam cells (lipid-laden macrophages)
─ Hemosiderin-laden macrophages and extracellular hemosiderin deposits
─ Cells are set in a fibrous stroma, which can be hyalinized
─ Mitotic activity in mononuclear cells is generally low (<5/10 HPF), atypia is minimal
─ May show cleft-like spaces or cystic change
Ancillary studies ─
─ IHC: Mononuclear and giant cells positive for CD68, CD163; subset of mononuclear cells may express desmin or SMA; Negative for S100, keratins
─ Molecular: CSF1 gene rearrangements are characteristic
DDx
─ Fibroma of tendon sheath (lacks giant cells, foam cells, hemosiderin; more uniformly fibrous with slit-like vessels)
─ Epidermal inclusion cyst (if on digit; lined by squamous epithelium, contains keratin)
─ Foreign body granuloma (contains foreign material, different inflammatory pattern)
─ Non-ossifying fibroma (if bone erosion; intraosseous lesion)
─ Diffuse-type TGCT (more infiltrative, involves entire synovium of larger joints)
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Diffuse-Type TGCT

The diffuse form of tenosynovial giant cell tumor (TGCT), characterized by widespread involvement of the synovium of a large joint, leading to synovial thickening, villous proliferation, and often bone erosion; formerly known as pigmented villonodular synovitis (PVNS)
Clinical ─ Typically affects adults aged 20-50 years; M=F; most commonly involves large joints, especially the knee (>75% of cases), followed by hip, ankle, shoulder, and elbow; presents with insidious onset of joint pain, swelling, stiffness, limited range of motion, and recurrent non-traumatic hemarthrosis
Macro ─ Poorly defined, extensive synovial proliferation that can be villous, nodular, or a combination; synovium is thickened, boggy, and typically reddish-brown to dark brown due to heavy hemosiderin deposition; may infiltrate adjacent soft tissues and erode underlying bone
Micro
─ Diffuse infiltration of the synovial membrane by a proliferation similar to localized-type TGCT:
─ Mononuclear stromal/histiocytoid cells
─ Osteoclast-like multinucleated giant cells
─ Foam cells
─ Abundant hemosiderin pigment within macrophages and stroma
─ Often forms prominent villous or frond-like projections into the joint space
─ Infiltrative growth into subsynovial tissues, tendons, ligaments, and articular cartilage/bone is common
─ Mitotic activity is generally low; cytologic atypia is minimal
─ Can be intra-articular or extra-articular (involving bursae or tendon sheaths diffusely)
Ancillary studies ─
─ IHC: Similar to localized-type TGCT (mononuclear and giant cells CD68/CD163 positive)
─ Molecular: CSF1 gene rearrangements are characteristic
DDx
─ Hemophilic arthropathy / Chronic hemarthrosis (prominent hemosiderin but lacks the specific neoplastic mononuclear cell proliferation and giant cells of TGCT)
─ Synovial chondromatosis (cartilaginous nodules, lacks TGCT cell types)
─ Rheumatoid arthritis or other chronic synovitis (different inflammatory pattern, pannus formation, lacks characteristic TGCT cell mix)
─ Synovial sarcoma (malignant spindle cell tumor, biphasic pattern or monophasic, SS18 fusion, TLE1 positive)
─ Localized-type TGCT (forms a discrete nodule, less extensive synovial involvement)
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Malignant Diffuse-Type TGCT

A rare sarcoma arising in the setting of diffuse-type tenosynovial giant cell tumor (TGCT), characterized by areas of overt malignancy juxtaposed with or replacing conventional diffuse-type TGCT
Clinical ─ Rare complication of diffuse-type TGCT; typically affects adults with long-standing diffuse TGCT, often after multiple recurrences; large joints (knee, hip) are most common sites; presents with accelerated growth, increased pain, or destructive features beyond typical TGCT
Macro ─ Similar to diffuse-type TGCT but with areas that are more fleshy, solid, and overtly sarcomatous, often with hemorrhage and necrosis; invasion of adjacent bone and soft tissues is usually more pronounced
Micro
─ Coexistence of areas typical of diffuse-type TGCT (mononuclear cells, osteoclast-like giant cells, foam cells, hemosiderin) and areas of frank sarcoma
─ Sarcomatous component most commonly resembles undifferentiated pleomorphic sarcoma (UPS) or fibrosarcoma, with high cellularity, marked cytologic atypia, pleomorphism, high mitotic activity (often >10-20/10 HPF), and necrosis
─ Less commonly, the malignant component may show other lines of differentiation (eg, rhabdomyosarcoma)
─ The transition between conventional TGCT and sarcoma can be abrupt or gradual
─ The malignant component lacks the typical osteoclast-like giant cells and foam cells of conventional TGCT, or they are markedly reduced
Ancillary studies ─
─ IHC: Mononuclear cells in the conventional TGCT component are CD68/CD163 positive; the sarcomatous component is often negative or only focally positive for these markers, and typically negative for S100 and keratins (unless specific heterologous differentiation); CSF1 expression may persist
─ Molecular: CSF1 gene rearrangements characteristic of TGCT may be present, along with additional complex genetic alterations in the sarcomatous component (eg, TP53 mutations, CDKN2A deletion) indicative of malignant progression
DDx
─ Diffuse-type TGCT with reactive atypia (lacks overt sarcomatous areas, lower mitotic rate, less extreme atypia)
─ Other primary soft tissue sarcomas arising near a joint (eg, synovial sarcoma, UPS - distinction relies on identifying a pre-existing or coexisting TGCT component and potentially CSF1 rearrangement)
─ Metastatic sarcoma or carcinoma (clinical history, specific markers for primary)
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Fibrous histiocytoma (Dermatofibroma and Variants)

A common benign dermal mesenchymal neoplasm composed of a mixture of fibroblastic and histiocytoid cells, often with a storiform pattern and overlying epidermal hyperplasia; Dermatofibroma is the most common cutaneous form
Clinical ─ Typically affects adults (any age, peak 20-50s), F>M slightly; common on extremities (especially lower legs), also trunk and arms; presents as a firm, often pigmented (tan to brown, sometimes reddish or yellowish) papule or nodule, usually <1-2 cm; may be pruritic or tender; often shows a "dimple sign" (central depression upon lateral compression)
Macro ─ Small, firm, dermal nodule; color varies (tan, brown, red, yellow); usually well-demarcated but unencapsulated
Micro
─ Dermal-based, poorly circumscribed proliferation of spindle cells (fibroblasts/myofibroblasts) and plump histiocytoid cells, often with admixed foam cells, multinucleated giant cells (Touton or osteoclast-like), and hemosiderin-laden macrophages
─ Spindle cells are typically arranged in short fascicles with a characteristic storiform (cartwheel) pattern, particularly in cellular areas
─ Trapping of collagen bundles at the periphery of the lesion ("collagen trapping") is a common feature
─ Overlying epidermis frequently shows acanthosis, hyperkeratosis, and basal layer hyperpigmentation; adnexal structures may be entrapped
─ Vascularity is variable, can be prominent
─ Mitotic activity is generally low; atypia is minimal in classic forms
─ Variants include: Cellular, aneurysmal (blood-filled spaces), epithelioid, atypical, deep, lipidized ("ankle-type"), palisading, atrophic
Ancillary studies ─
─ IHC: Tumor cells are positive for Factor XIIIa (dermal dendrocytes, variable); Vimentin positive; SMA may be positive in a subset of spindle cells; CD68 highlights histiocytoid cells and giant cells; Negative for CD34 (important for DDx with DFSP), S100 protein (except scattered dendritic cells), keratins
─ Molecular: No specific recurrent genetic alterations define most common fibrous histiocytomas; some variants (eg, cellular, atypical) can show clonal changes but are still considered benign or of very low malignant potential
DDx
─ Dermatofibrosarcoma protuberans (DFSP) (diffusely CD34 positive, storiform pattern with honeycomb infiltration of fat, COL1A1::PDGFB fusion)
─ Melanocytic nevus (especially desmoplastic or combined) (S100/SOX10/melanocytic markers positive)
─ Spindle cell squamous cell carcinoma (keratin positive, p63/p40 positive)
─ Scar tissue (history of injury, less cellular, different architecture)
─ Xanthogranuloma (more prominent foamy histiocytes and Touton giant cells, lacks storiform pattern)
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─ pathoutlines WSI WSI WSI WSI WSI

Aneurysmal Benign Fibrous Histiocytoma

A distinctive variant of benign fibrous histiocytoma (dermatofibroma) characterized by prominent, large, blood-filled cystic or cavernous spaces within the lesion, often accompanied by abundant hemosiderin deposition
Clinical ─ Similar to classic fibrous histiocytoma, typically adults; extremities are common sites; may present as a bluish, brown, or black papule or nodule, sometimes mistaken for a vascular lesion or melanoma due to its color and potential for rapid change or bleeding
Macro ─ Well-demarcated dermal nodule, often dark red, blue, or black due to hemorrhage; cystic spaces filled with blood may be apparent
Micro
─ Background features of fibrous histiocytoma: dermal proliferation of spindle cells (fibroblasts/myofibroblasts) and histiocytoid cells, often with a storiform pattern and collagen trapping at the periphery
─ Defining feature: Presence of large, irregular, blood-filled cystic or cavernous spaces that lack a true endothelial lining; these spaces are thought to result from hemorrhage and stromal degeneration within the tumor
─ Abundant hemosiderin pigment within macrophages and stroma is characteristic, often extensive
─ Foam cells and multinucleated giant cells may also be present
─ Overlying epidermal changes (acanthosis, hyperpigmentation) are common
Ancillary studies ─
─ IHC: Similar to classic fibrous histiocytoma: Factor XIIIa positive (variable), CD68 positive (histiocytes/giant cells); Negative for CD34, S100 (except scattered cells), keratins; Vascular markers (CD31, ERG) will highlight true vessels but not the lining of the aneurysmal spaces
─ Molecular: Generally lacks specific recurrent genetic alterations
DDx
─ Hemangioma / Vascular malformation (true endothelial lining of vascular spaces, CD31/ERG positive lining)
─ Angiosarcoma (malignant endothelial cells, atypia, mitoses, infiltrative growth)
─ Melanoma (especially nodular or bleeding) (S100/SOX10/melanocytic markers positive)
─ Kaposi sarcoma (slit-like vascular spaces, spindle cells, HHV8 positive)
─ Classic fibrous histiocytoma (lacks prominent aneurysmal spaces)
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Atypical / Pseudosarcomatous Fibrous Histiocytoma

A rare variant of benign fibrous histiocytoma (dermatofibroma) characterized by increased cellularity, some degree of cytologic atypia (pleomorphism, large hyperchromatic nuclei), and potentially increased mitotic activity, but lacking features of frank malignancy and following a benign clinical course; also known as atypical benign fibrous histiocytoma or dermatofibroma with monster cells
Clinical ─ Similar to classic fibrous histiocytoma, typically adults; extremities common; may be larger or grow more rapidly than typical dermatofibromas, raising clinical concern for malignancy
Macro ─ Firm dermal nodule, may be larger or more irregular than classic fibrous histiocytoma
Micro
─ Dermal-based, often well-circumscribed but unencapsulated proliferation
─ Background architecture often resembles cellular fibrous histiocytoma with storiform or fascicular growth of spindle cells
─ Defining feature: Presence of scattered or clustered large, bizarre, pleomorphic, multinucleated, or mononuclear cells with hyperchromatic, smudged, or vesicular nuclei ("monster cells"); these atypical cells may resemble those seen in pleomorphic sarcomas
─ Mitotic activity can be variable, occasionally brisk (eg, >5/10 HPF), but atypical mitoses are rare or absent
─ Despite the atypia, the overall growth pattern is usually organized and lacks widespread infiltrative destruction or necrosis seen in true sarcomas
─ Overlying epidermal hyperplasia is common
Ancillary studies ─
─ IHC: Similar to classic fibrous histiocytoma: Factor XIIIa positive (variable), CD68 positive (histiocytes/atypical cells); Negative for CD34, S100 (except scattered cells), keratins, desmin; p53 may be expressed in atypical cells but is not indicative of malignancy in this context
─ Molecular: Clonal chromosomal abnormalities have been reported, but no consistent translocations or mutations defining malignancy are present
DDx
─ Dermatofibrosarcoma protuberans (DFSP) (diffusely CD34 positive, honeycomb infiltration, COL1A1::PDGFB fusion)
─ Atypical fibroxanthoma (AFX) (sun-damaged skin of elderly, more diffuse pleomorphism, diagnosis of exclusion after ruling out SCC/melanoma)
─ Undifferentiated pleomorphic sarcoma (UPS) (typically larger, deeper, more diffuse extreme pleomorphism, necrosis, infiltrative borders)
─ Pleomorphic melanoma (S100/SOX10/melanocytic markers positive)
─ Leiomyosarcoma or other pleomorphic sarcomas (specific lineage markers positive)
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Deep Fibrous Histiocytoma

A benign fibrohistiocytic neoplasm identical in histology to cutaneous benign fibrous histiocytoma (dermatofibroma) but arising in deep soft tissues (subcutis, skeletal muscle, or deeper locations) rather than being primarily dermal
Clinical ─ Typically affects adults (wide age range); common in extremities (especially lower limb), head/neck, and trunk; presents as a slow-growing, usually painless, firm, deep-seated mass
Macro ─ Well-circumscribed, often pseudoencapsulated, firm, lobulated nodule; cut surface is typically gray-white to tan, fibrous; size can be larger than typical dermal fibrous histiocytomas (often 2-5 cm or more)
Micro
─ Histologically similar to cutaneous fibrous histiocytoma:
─ Well-circumscribed proliferation of bland spindle cells (fibroblasts/myofibroblasts) and histiocytoid cells
─ Storiform or fascicular growth pattern is common
─ Admixture of foam cells, multinucleated giant cells (Touton or osteoclast-like), and hemosiderin-laden macrophages can be seen
─ Stroma is variably collagenous
─ Lacks the epidermal changes (acanthosis, hyperpigmentation) often seen in dermal counterparts
─ Mitotic activity is generally low, cytologic atypia is minimal
─ May show infiltrative margins into surrounding fat or muscle at the periphery
Ancillary studies ─
─ IHC: Tumor cells are positive for Factor XIIIa (variable), vimentin; CD68 highlights histiocytoid cells and giant cells; SMA may be focally positive in spindle cells; Negative for CD34 (important for DDx with SFT and DFSP), S100 protein (except scattered dendritic cells), keratins, desmin
─ Molecular: Generally lacks specific recurrent genetic alterations, similar to cutaneous fibrous histiocytoma
DDx
─ Solitary fibrous tumor (STAT6 positive, CD34 positive, characteristic vasculature)
─ Dermatofibrosarcoma protuberans (if extending deep; diffusely CD34 positive, COL1A1::PDGFB fusion)
─ Low-grade fibromyxoid sarcoma (alternating fibrous/myxoid areas, MUC4 positive, FUS fusion)
─ Myofibroblastoma (desmin positive, CD34 positive, RB1 loss)
─ Undifferentiated pleomorphic sarcoma (if deep FH shows some atypia; UPS has more diffuse, significant atypia and pleomorphism, higher mitoses, necrosis)
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─ pathoutlines WSI WSI HE FXIIIa CD34

Epithelioid fibrous histiocytoma

A benign variant of fibrous histiocytoma (dermatofibroma) characterized by a prominent component of epithelioid cells, often with ALK expression and ALK gene rearrangements
Clinical ─ Typically affects children and young adults (median age ~20-30s), but can occur at any age; common on extremities, also trunk; presents as a solitary, firm, reddish-brown or skin-colored papule or nodule, usually <1 cm
Macro ─ Small, well-circumscribed dermal nodule; often reddish or brown due to vascularity
Micro

─ Dermal-based, well-circumscribed, often dome-shaped proliferation, may have an epidermal collarette
─ Predominantly composed of plump epithelioid cells with abundant eosinophilic or amphophilic cytoplasm, round to oval vesicular nuclei, and often small, distinct nucleoli
─ Cells are arranged in sheets, nests, or cords; conventional spindle cell areas of fibrous histiocytoma are often present, especially at the periphery
─ Admixed inflammatory cells, including lymphocytes and eosinophils, are common
─ Hemosiderin deposition, foam cells, and multinucleated giant cells may be present
─ Low mitotic activity, minimal to mild atypia in most cases
Ancillary studies ─
─ IHC: Epithelioid cells are characteristically positive for ALK (anaplastic lymphoma kinase) with a cytoplasmic and/or nuclear staining pattern in a majority of cases; Vimentin positive; Factor XIIIa is often negative or only weakly positive in epithelioid areas (unlike classic FH); CD68 may highlight some cells; Negative for S100 protein, keratins, CD34, desmin, melanocytic markers
─ Molecular: ALK gene rearrangements (2p23) with various fusion partners (eg, TPM3, CLTC, EML4) are common and characteristic, especially in ALK-positive cases
DDx

─ Spitz nevus / Epithelioid melanocytic nevus (S100/SOX10/melanocytic markers positive, lacks ALK rearrangement)
─ Reticulohistiocytoma (larger cells with glassy cytoplasm, S100 positive in some, lacks ALK rearrangement)
─ Juvenile xanthogranuloma (more prominent foamy histiocytes and Touton giant cells, Factor XIIIa positive, lacks ALK rearrangement)
─ Epithelioid sarcoma (INI1 loss, keratin positive, more aggressive, lacks ALK rearrangement)
─ Langerhans cell histiocytosis (S100/CD1a/Langerin positive, characteristic grooved nuclei, eosinophils)
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─ Pathoutlines WSI of EMA & HE WSI WSI video & WSI

Cellular Fibrous Histiocytoma

A variant of benign fibrous histiocytoma (dermatofibroma) characterized by increased cellularity, a more prominent fascicular or storiform growth pattern, and potential extension into the superficial subcutis, which may lead to a slightly higher recurrence rate than classic fibrous histiocytoma
Clinical ─ Similar to classic fibrous histiocytoma, typically adults; common on extremities, trunk; may be larger and deeper than conventional fibrous histiocytoma, sometimes >2 cm
Macro ─ Firm, dermal or dermo-subcutaneous nodule; often appears less pigmented than classic fibrous histiocytoma
Micro

─ Dermal-based proliferation, often extending into the superficial subcutaneous tissue in broad, pushing tongues
─ Highly cellular proliferation of predominantly spindle cells with scant cytoplasm and ovoid to fusiform nuclei
─ Spindle cells are typically arranged in prominent, intersecting fascicles or a distinct storiform (cartwheel) pattern
─ Mitotic activity is generally higher than in conventional fibrous histiocytoma (eg, 1-5 mitoses/10 HPF is common), but atypical mitoses are absent or very rare
─ Cytologic atypia is usually minimal; pleomorphic or "monster" cells are generally not a feature (unlike atypical fibrous histiocytoma)
─ Foamy histiocytes, multinucleated giant cells, and hemosiderin may be present but are often less conspicuous than in classic fibrous histiocytoma
─ Collagen trapping at the periphery is common; overlying epidermal hyperplasia may be present
Ancillary studies ─
─ IHC: Tumor cells are positive for Factor XIIIa (often patchy), vimentin; SMA may be more prominent and diffuse than in conventional fibrous histiocytoma; CD68 highlights scattered histiocytoid cells; Negative for CD34 (important for DDx with DFSP), S100 protein, keratins
─ Molecular: Some cases may show clonal chromosomal abnormalities, but no specific recurrent translocations are characteristic; generally benign despite increased cellularity
DDx

─ Dermatofibrosarcoma protuberans (DFSP) (diffusely CD34 positive, honeycomb infiltration of fat, COL1A1::PDGFB fusion, typically less SMA positivity)
─ Leiomyoma (cutaneous) (more prominent eosinophilic cytoplasm, desmin positive, h-caldesmon positive)
─ Spindle cell melanoma (S100/SOX10/melanocytic markers positive)
─ Atypical fibroxanthoma (AFX) (sun-damaged skin of elderly, more pleomorphism, diagnosis of exclusion, usually CD34/S100/keratin negative)
─ Leiomyosarcoma (superficial) (more significant atypia, necrosis, desmin/h-caldesmon positive)
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─ atypical WSI WSI

Plexiform fibrohistiocytic tumor

An uncommon mesenchymal neoplasm of intermediate malignant potential (rarely metastasizing), typically occurring in children and young adults, characterized by a biphasic pattern of histiocytoid/osteoclast-rich nodules and fibroblastic spindle cell fascicles, often with a plexiform or multinodular growth
Clinical ─ Primarily affects children, adolescents, and young adults (median age ~15 years), with a female predominance; common in upper extremities (especially hand, wrist, forearm), less often lower extremities or trunk; presents as a slow-growing, firm, painless or mildly tender subcutaneous or dermal nodule or plaque, often present for months to years
Macro ─ Poorly circumscribed, firm, multinodular or plaque-like mass; cut surface is gray-white to tan; size typically 1-3 cm, can be larger
Micro

─ Dermal and/or subcutaneous tumor with an infiltrative, often plexiform or multinodular growth pattern
─ Characteristic biphasic components:
─ Cellular nodules: Composed predominantly of mononuclear histiocytoid cells (with round vesicular nuclei and eosinophilic cytoplasm) and numerous osteoclast-like multinucleated giant cells; scattered lymphocytes and eosinophils may be present
─ Spindle cell fascicles: Interspersed between or surrounding the cellular nodules, composed of bland fibroblast/myofibroblast-like spindle cells with scant cytoplasm, arranged in short fascicles or a storiform pattern
─ Low to moderate overall cellularity; mitotic activity is generally low (usually <5/10 HPF), atypical mitoses are rare
─ Minimal to mild cytologic atypia in both components
Ancillary studies ─
─ IHC: Mononuclear histiocytoid cells and osteoclast-like giant cells are positive for CD68 and CD163; Spindle cells are positive for vimentin and may show focal SMA positivity; Negative for S100 protein, keratins, CD34, Factor XIIIa (usually), desmin, ALK1
─ Molecular: No specific recurrent genetic alterations are consistently identified for diagnostic purposes
DDx

─ Tenosynovial giant cell tumor (TGCT), localized or diffuse (more prominent synovial differentiation, different mononuclear cell morphology, CSF1 rearrangement)
─ Fibrous histiocytoma (dermatofibroma) with giant cells (lacks distinct plexiform/biphasic pattern, Factor XIIIa positive)
─ Giant cell tumor of soft tissue (lacks biphasic pattern, different clinical context, lacks H3F3A mutations of bone GCT)
─ Langerhans cell histiocytosis (S100/CD1a/Langerin positive, characteristic grooved nuclei, eosinophils)
─ Rosai-Dorfman disease (extranodal) (S100/CD68 positive large histiocytes with emperipolesis)
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Giant cell tumor of soft tissue

A rare mesenchymal neoplasm histologically resembling giant cell tumor of bone (GCTB), but arising in soft tissue without any connection to bone or periosteum, and genetically distinct from GCTB (lacking H3F3A mutations)
Clinical ─ Typically affects adults (wide age range, peak 40-60s), M=F; most common in superficial soft tissues (dermis/subcutis) of the extremities (especially lower limb), followed by trunk; less commonly in deep soft tissues; usually presents as a solitary, slow-growing, painless or mildly tender nodule
Macro ─ Well-circumscribed, often lobulated, firm nodule; cut surface is typically reddish-brown, tan, or gray, sometimes with cystic or hemorrhagic areas; usually small (<3-5 cm)
Micro

─ Well-circumscribed, often lobulated, but usually unencapsulated proliferation
─ Composed of two main cell types, intimately admixed:
─ Mononuclear stromal cells: Round, oval, or slightly spindled cells with vesicular nuclei, indistinct cytoplasm, and small nucleoli (considered the neoplastic component)
─ Osteoclast-like multinucleated giant cells: Numerous, large, and evenly distributed throughout the tumor, containing many bland nuclei similar to those of the mononuclear cells
─ Mitotic activity is usually present in the mononuclear cells (can be up to 5-10/10 HPF), but atypical mitoses are rare
─ Hemosiderin deposition, foam cells, and secondary aneurysmal bone cyst-like changes (blood-filled spaces) may be present focally
─ Reactive woven bone formation can occur at the periphery but is not a dominant feature
─ Malignant variant (Giant Cell Tumor of Soft Tissue, Malignant) is exceedingly rare, showing overt sarcomatous features in the mononuclear component
Ancillary studies ─
─ IHC: Mononuclear stromal cells and giant cells are positive for CD68; Mononuclear cells may show focal SMA positivity; Negative for S100 protein (except entrapped nerves), keratins, desmin, HMB45; Importantly, negative for H3.3 G34W/V/R/L (unlike GCT of bone)
─ Molecular: Lacks the H3F3A gene mutations characteristic of GCT of bone; no other specific recurrent genetic alterations are consistently identified
DDx

─ Tenosynovial giant cell tumor (TGCT) (similar cell types but often more prominent foam cells/hemosiderin, synovial context, CSF1 rearrangement)
─ Plexiform fibrohistiocytic tumor (biphasic pattern with spindle cell fascicles, plexiform growth)
─ Leiomyosarcoma with osteoclast-like giant cells (myogenic markers positive, more atypia)
─ Non-ossifying fibroma (if in soft tissue near bone; storiform pattern, more prominent foam cells)
─ Malignant fibrous histiocytoma / Undifferentiated pleomorphic sarcoma with giant cells (more pleomorphism, atypia, higher mitoses)
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Vascular Ectasias

A general term for localized dilations of pre-existing blood vessels (capillaries, venules, or arterioles) without true endothelial proliferation, encompassing various conditions based on morphology and clinical context
Clinical ─ Extremely common, can occur at any age and any site, particularly skin and mucous membranes; presentation varies widely from asymptomatic flat red macules to raised angiomatous papules or nodules; includes conditions like telangiectasias, spider angiomas, venous lakes, angiokeratomas (if associated epidermal hyperplasia)
Macro ─ Appearance depends on the specific type of ectasia; may be small red macules (telangiectasia), central red papule with radiating vessels (spider angioma), soft blue compressible papule (venous lake)
Micro

─ Characterized by dilation of existing small blood vessels within the dermis or submucosa
─ Endothelial lining is typically flattened and inconspicuous, without atypia, multilayering, or significant proliferation
─ Vessel walls may be thin or slightly thickened/hyalinized depending on the type and duration
─ Surrounding stroma is usually unremarkable or may show solar elastosis, edema, or mild fibrosis
─ Specific types:
─ Telangiectasia: Simple dilation of capillaries and venules in the superficial dermis
─ Spider angioma (nevus araneus): Central dilated arteriole with radiating capillaries
─ Venous lake: Dilated, thin-walled venule in dermis, often with organizing thrombi
─ Angiokeratoma: Vascular ectasia in papillary dermis with overlying epidermal acanthosis and hyperkeratosis
Ancillary studies ─
─ IHC: Endothelial cells lining ectatic vessels are positive for CD31, CD34, ERG, FLI1; Negative for GLUT1 (helps distinguish from infantile hemangioma in some contexts)
─ Molecular: Not applicable for most vascular ectasias, as they are non-neoplastic or developmental anomalies; some syndromic ectasias (eg, HHT) have specific genetic bases
DDx

─ Early Kaposi sarcoma (patch stage) (more spindle cells, promontory sign, HHV8 positive)
─ Capillary hemangioma (true endothelial proliferation, increased cellularity)
─ Angiosarcoma (low-grade) (infiltrative growth, atypia, multilayering of endothelium)
─ Lymphatic malformation / Lymphangiectasia (dilated channels with pale fluid, D2-40 positive lining)
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“Round Cell” Liposarcoma / High-Grade Myxoid Liposarcoma

Pleomorphic Liposarcoma (PLS)

Pleomorphic Liposarcoma, Epithelioid Variant

Myxoid Pleomorphic Liposarcoma (MPLS)

Nodular Fasciitis

Soft Tissue, Vascular

Papillary endothelial hyperplasia (Masson Tumor)

An intravascular reactive process characterized by papillary proliferation of endothelial cells within a thrombosed blood vessel or organizing hematoma, mimicking angiosarcoma
Clinical ─ Can occur at any age and in various locations, most commonly skin, subcutaneous tissue (especially fingers, head/neck, trunk), and oral mucosa; presents as a small, firm, often tender, reddish-blue nodule; may arise within pre-existing vascular lesions (eg, hemangioma, vascular malformation) or in areas of venous stasis
Macro ─ Small (<2 cm), well-demarcated, reddish-blue nodule, often appearing as a blood clot or varix; the papillary structures may be visible within a dilated vessel lumen or hematoma cavity
Micro

─ Intravascular location (within a dilated vessel or lumen of an organizing thrombus) is key for diagnosis
─ Multiple delicate papillary structures composed of hyalinized collagenous or fibrinous cores
─ Papillae are lined by a single layer of bland, plump, cuboidal, or hobnail endothelial cells without significant atypia or multilayering
─ Associated organizing thrombus (fibrin, hemosiderin, inflammatory cells) is frequently present and surrounds the papillary proliferation
─ No significant cytologic atypia, pleomorphism, necrosis, or increased/atypical mitotic activity in the endothelial cells (distinguishes from angiosarcoma)
─ The overall architecture is contained within a vessel or vascular space
Ancillary studies ─
─ IHC: Endothelial cells lining papillae are positive for CD31, CD34, ERG, and FLI1; Negative for keratins and other markers that would suggest angiosarcoma or carcinoma
─ Molecular: Not applicable as it is a reactive process
DDx

─ Angiosarcoma (infiltrative growth, anastomosing vascular channels, significant endothelial atypia, multilayering, mitoses, necrosis)
─ Intravascular pyogenic granuloma (more lobular capillary proliferation, solid areas, lacks extensive papillary structures with hyaline cores)
─ Glomeruloid hemangioma (glomerulus-like capillary tufts, associated with POEMS syndrome, lacks papillary cores)
─ Papillary intralymphatic angioendothelioma (Dabska tumor) (involves lymphatics, different morphology of papillae and endothelial cells)
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Bacillary Angiomatosis

A reactive vascular proliferation caused by infection with Bartonella henselae or Bartonella quintana, typically occurring in immunocompromised individuals, especially those with HIV/AIDS
Clinical ─ Primarily affects immunocompromised patients (HIV/AIDS, organ transplant recipients, patients on immunosuppressive therapy); can involve skin (most common), lymph nodes, liver (peliosis hepatis), spleen, bone, and other organs; skin lesions present as friable, red to purple papules, nodules, or plaques, resembling Kaposi sarcoma or pyogenic granuloma
Macro ─ Skin lesions are typically vascular-appearing, reddish-purple, and may be solitary or multiple, ranging from small papules to large exophytic nodules; visceral lesions cause organomegaly or focal defects
Micro

─ Lobular proliferation of small, capillary-sized blood vessels lined by plump, somewhat epithelioid endothelial cells
─ Endothelial cells may show mild atypia and mitotic activity, but frank malignancy is absent
─ Characteristic feature: Presence of stromal clusters of granular, amorphous, eosinophilic to purplish material representing aggregates of Bartonella bacilli, often best seen with Warthin-Starry or Steiner silver stains, or Giemsa stain
─ Stroma is often edematous and contains a mixed inflammatory infiltrate, characteristically rich in neutrophils and leukocytoclastic debris (neutrophil "dust")
─ Epidermal collarette may be present at the periphery of skin lesions
Ancillary studies ─
─ IHC: Endothelial cells positive for CD31, CD34, ERG; Antibodies against Bartonella species can confirm the organisms, but sensitivity is variable
─ Special Stains: Warthin-Starry or Steiner silver stains, and Giemsa stain can highlight the granular bacterial aggregates
─ Molecular: PCR for Bartonella DNA on tissue samples is a sensitive and specific diagnostic method
DDx

─ Pyogenic granuloma (lobular capillary hemangioma) (lacks bacterial aggregates and prominent neutrophilic infiltrate with debris)
─ Kaposi sarcoma (more spindle cell proliferation, slit-like vascular spaces, HHV8 positive, lacks bacterial aggregates)
─ Angiosarcoma (more significant atypia, infiltrative growth, necrosis, lacks bacterial aggregates)
─ Epithelioid hemangioma (more prominent epithelioid endothelial cells, often eosinophilic infiltrate, lacks bacterial aggregates)
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Reactive Angioendotheliomatosis

A rare, benign reactive intravascular proliferation of endothelial cells that typically presents as cutaneous plaques or nodules, often associated with systemic diseases or conditions causing vascular occlusion or cryoglobulinemia
Clinical ─ Affects adults; presents with erythematous to violaceous plaques, patches, or nodules, sometimes ulcerated, typically on the extremities, trunk, or face; may be localized or diffuse; often associated with underlying conditions such as cryoglobulinemia, monoclonal gammopathy, autoimmune diseases (eg, lupus), bacterial endocarditis, or vascular disease (atherosclerosis, thrombosis)
Macro ─ Erythematous, purpuric, or indurated plaques, patches, or nodules on the skin; lesions can be tender or painful
Micro

─ Diffuse proliferation of small capillary-sized blood vessels within the dermis, sometimes extending into the subcutis
─ Vessels are often dilated and appear to fill and distend pre-existing vascular lumina or proliferate around them
─ Endothelial cells are plump but generally bland, without significant atypia, multilayering, or mitoses (though reactive mitoses can be seen)
─ Fibrin thrombi or evidence of vascular occlusion (eg, cryoglobulin deposits) may be present within vessels
─ Perivascular inflammatory infiltrate, usually lymphocytic, is common
─ Extravasated red blood cells and hemosiderin deposition can be seen
─ Must be distinguished from malignant angioendotheliomatosis (intravascular lymphoma)
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FLI1; Important to perform stains for lymphoid markers (eg, CD20, CD3, CD45/LCA) to exclude intravascular lymphoma, which would show atypical lymphoid cells within vessel lumina
─ Molecular: Not applicable for this reactive process
DDx

─ Intravascular lymphoma (malignant angioendotheliomatosis) (atypical lymphoid cells within vessel lumina, positive for lymphoid markers)
─ Kaposi sarcoma (spindle cells, slit-like spaces, HHV8 positive)
─ Angiosarcoma (infiltrative growth, endothelial atypia, mitoses, necrosis)
─ Vasculitis (inflammatory destruction of vessel walls, fibrinoid necrosis)
─ Glomeruloid hemangioma (glomerulus-like capillary tufts, POEMS syndrome association)
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Glomeruloid Hemangioma

A distinctive benign vascular proliferation characterized by capillary tufts resembling renal glomeruli, typically occurring as multiple cutaneous lesions in patients with POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes)
Clinical ─ Strongly associated with POEMS syndrome, but can rarely occur without it; presents as multiple, small (usually <1 cm), firm, reddish-purple to violaceous papules or nodules, primarily on the trunk and extremities
Macro ─ Small, reddish-purple papules or nodules on the skin
Micro

─ Well-circumscribed proliferation of capillary-sized blood vessels within the dermis
─ Characteristic feature: Formation of tightly coiled capillary tufts that resemble renal glomeruli ("glomeruloid bodies")
─ These glomeruloid tufts are often located within dilated, thin-walled vascular spaces (sinusoids)
─ Capillaries within tufts are lined by plump but bland endothelial cells
─ Eosinophilic, PAS-positive hyaline globules (thought to be immunoglobulin deposits or basement membrane material) may be present within the lumina of the glomeruloid structures or in the surrounding stroma
─ No significant cytologic atypia or mitotic activity
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FLI1; PAS stain highlights hyaline globules and basement membranes; VEGF (vascular endothelial growth factor) is often strongly expressed
─ Molecular: Not characterized by specific somatic mutations; related to systemic cytokine effects in POEMS syndrome
DDx

─ Cherry angioma (senile hemangioma) (simple dilated capillaries in papillary dermis, lacks glomeruloid tufts)
─ Tufted angioma (lobules of packed capillaries forming "cannonball" structures, lacks distinct glomeruloid tufts with hyaline globules)
─ Papillary endothelial hyperplasia (Masson tumor) (intravascular papillary proliferation with fibrin cores, different morphology)
─ Kaposi sarcoma (spindle cells, slit-like spaces, HHV8 positive)
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Acroangiodermatitis (Pseudo-Kaposi Sarcoma)

A reactive angiodermatitis occurring on the lower extremities, typically in the setting of chronic venous insufficiency, arteriovenous malformations, or paralyzed limbs, clinically and histologically mimicking Kaposi sarcoma
Clinical ─ Typically affects adults, especially elderly individuals with chronic venous stasis (stasis dermatitis) or patients with congenital/acquired arteriovenous shunts or paralyzed limbs; presents as purplish-red to brownish plaques or nodules on the ankles and dorsal feet (acral sites)
Macro ─ Violaceous or brownish, indurated plaques or nodules on the distal lower extremities; may be associated with edema, varicose veins, skin pigmentation, and ulceration (stasis changes)
Micro

─ Proliferation of small capillary-sized blood vessels in the dermis, often arranged in lobules or vertically oriented
─ Endothelial cells are plump but generally bland, without significant atypia or mitoses
─ Perivascular fibrosis and stromal hemosiderin deposition are prominent features
─ Extravasated red blood cells are common
─ Epidermis may show acanthosis, hyperkeratosis, and spongiosis, consistent with stasis dermatitis
─ A chronic inflammatory infiltrate (lymphocytes, plasma cells) is often present
─ Importantly, lacks the characteristic spindle cell proliferation and slit-like vascular spaces of true Kaposi sarcoma
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FLI1; Smooth muscle actin (SMA) may highlight pericytes; HHV8 (LANA-1) immunostain is negative (crucial for distinguishing from Kaposi sarcoma)
─ Molecular: Not applicable for this reactive process
DDx

─ Kaposi sarcoma (true spindle cell proliferation, slit-like vascular spaces, "promontory sign," HHV8 positive)
─ Stasis dermatitis without significant vascular proliferation (predominantly dermal fibrosis, hemosiderin, epidermal changes)
─ Angiosarcoma (infiltrative growth, endothelial atypia, mitoses, necrosis)
─ Tufted angioma / Kaposiform hemangioendothelioma (different architectural patterns, occur in different clinical settings)
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Cavernous Hemangioma

A benign vascular lesion composed of large, dilated, thin-walled vascular channels resembling cavernous erectile tissue; now often considered a type of venous malformation, especially when deep-seated
Clinical ─ Can occur at any age, often congenital or noted in childhood; common sites include skin, subcutaneous tissue, liver, spleen, and deep soft tissues (eg, muscle); presents as a soft, compressible, often bluish mass; may be associated with pain or thrombosis; size is variable
Macro ─ Poorly circumscribed or well-demarcated, spongy, reddish-blue to purple mass; cut surface reveals blood-filled cystic spaces; phleboliths (calcified thrombi) may be present
Micro

─ Composed of large, dilated, irregularly shaped vascular channels lined by a single layer of flattened, bland endothelial cells
─ Vessel walls are typically thin, composed mainly of fibrous connective tissue with variable amounts of smooth muscle, often less organized than normal veins
─ Channels are often closely packed with minimal intervening stroma, which may be fibrotic or contain adipose tissue
─ Organizing thrombi, phleboliths (calcified thrombi), and hemosiderin deposition are common findings within the vascular spaces
─ No significant cytologic atypia, endothelial proliferation, or increased mitotic activity
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, and FLI1; Smooth muscle cells in vessel walls are SMA positive; D2-40 is negative (distinguishes from lymphatic malformations)
─ Molecular: Often considered part of the spectrum of venous malformations, some of which may harbor TIE2/TEK mutations, though not routinely tested for cavernous hemangiomas
DDx

─ Venous malformation (VM) (largely overlapping/synonymous term, especially for larger, deeper lesions; VM emphasizes developmental anomaly)
─ Lymphatic malformation (macrocystic) (lined by D2-40 positive endothelium, contains lymph not blood)
─ Angiosarcoma (infiltrative growth, endothelial atypia, multilayering, mitoses, necrosis)
─ Sinusoidal hemangioma (distinctive sinusoidal pattern with "sievelike" spaces, often in breast or subcutaneous tissue)
─ Arteriovenous malformation (AVM) (contains abnormal arterial structures and arteriovenous shunting)
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Synovial hemangioma

A benign vascular lesion, usually considered a type of vascular malformation (often venous or mixed), arising within the synovial membrane of a joint, bursa, or tendon sheath
Clinical ─ Typically presents in children and young adults (most before age 30); knee is the most common site, followed by elbow, wrist, and ankle; symptoms include recurrent joint pain, swelling, hemarthrosis (bleeding into the joint), and limited range of motion; can be localized or diffuse within the synovium
Macro ─ Appears as a lobulated, spongy, reddish-brown or purplish mass involving the synovial lining; may be well-circumscribed (localized) or diffusely infiltrate the synovium (diffuse)
Micro

─ Proliferation of variably sized vascular channels within the synovial tissue, which may be hyperplastic
─ Vessel types can be cavernous (most common, resembling venous malformation), capillary, or mixed arteriovenous
─ Vessels are lined by bland, flattened endothelial cells
─ Intervening stroma often shows fibrosis, hemosiderin deposition (due to recurrent hemorrhage), and chronic inflammation
─ Organizing thrombi and phleboliths may be present
─ Overlying synovial lining may show reactive hyperplasia or villous change
─ No significant cytologic atypia or increased mitotic activity
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FLI1; SMA highlights smooth muscle in vessel walls
─ Molecular: Generally considered a malformation, specific genetic alterations are not well-defined for most sporadic cases, but may align with those of other vascular malformations if specific subtypes are present
DDx

─ Tenosynovial giant cell tumor, diffuse type (PVNS) (lacks prominent vascular channels, characterized by mononuclear cells, osteoclast-like giant cells, and foam cells; CSF1 rearranged)
─ Lipoma arborescens (synovial lipomatosis) (synovial villi replaced by mature adipose tissue, lacks prominent vascular proliferation)
─ Angiosarcoma involving synovium (extremely rare; shows malignant endothelial atypia, mitoses, infiltrative growth)
─ Hemophilic arthropathy (history of bleeding disorder, prominent hemosiderin, synovial hypertrophy, but lacks primary vascular proliferation)
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Intramuscular hemangioma

A benign vascular lesion, usually considered a type of vascular malformation (venous, capillary, arteriovenous, or mixed), that arises within skeletal muscle and often shows an infiltrative growth pattern
Clinical ─ Typically presents in children and young adults (most common in first three decades); common in extremities (especially lower limb - thigh, calf), trunk (paraspinal muscles), and head/neck (masseter muscle); presents as a poorly defined, deep-seated mass that may be painful, especially with activity or palpation; size is variable
Macro ─ Poorly circumscribed, infiltrative mass within skeletal muscle; cut surface is spongy, reddish-brown to purple, and may contain visible fatty areas if adipose tissue is prominent; often unencapsulated
Micro

─ Infiltrative proliferation of variably sized vascular channels within and between skeletal muscle fibers, often causing muscle fiber atrophy or entrapment
─ Vessel type determines classification:
─ Capillary type (small vessel): Proliferation of small, capillary-sized vessels
─ Cavernous type (large vessel): Dominated by large, dilated, vein-like channels (most common type)
─ Arteriovenous type (mixed vessel): Contains thick-walled arterial structures and venous channels, suggesting shunting
─ Often admixed with mature adipose tissue, which can be extensive (historically, some were called "infiltrating angiolipoma" - this is a misnomer and unrelated to true angiolipoma)
─ Intervening stroma may be fibrous or myxoid
─ Organizing thrombi, phleboliths, and hemosiderin deposition can be seen
─ No significant cytologic atypia or increased mitotic activity in endothelial cells
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FLI1; Adipocytes are S100 positive if present; SMA highlights smooth muscle in vessel walls and entrapped muscle
─ Molecular: May show genetic alterations consistent with specific types of vascular malformations (eg, TIE2/TEK mutations in venous components, PIK3CA mutations in some mixed malformations)
DDx

─ Angiosarcoma (malignant endothelial atypia, mitoses, necrosis, prominent endothelial tufting, infiltrative destruction)
─ Kaposiform hemangioendothelioma (more cellular, spindle cell component, glomeruloid tufts, typically in infants/young children)
─ Arteriovenous malformation (AVM) (if predominantly AVM features, see separate entry)
─ Rhabdomyosarcoma (malignant skeletal muscle tumor, myogenic markers positive)
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Arteriovenous malformation (AVM) / Arteriovenous hemangioma

A developmental vascular anomaly characterized by abnormal direct connections (shunts) between arteries and veins, bypassing the normal intervening capillary bed; Arteriovenous hemangioma is an older term often used for smaller, more localized AVMs
Clinical ─ Can be congenital or develop later in life (often becoming apparent in childhood or young adulthood); common sites include head/neck (especially brain - intracranial AVMs), extremities, trunk, and viscera; presentation varies from asymptomatic to pulsatile mass, pain, warmth, overlying skin changes (ulceration, bleeding), bruits, or high-output cardiac failure if shunting is significant
Macro ─ Typically a tangled mass of abnormally formed, thick-walled and thin-walled blood vessels; may be poorly defined and infiltrative, or more localized; color is reddish-purple
Micro

─ Composed of a mixture of abnormally formed arterial and venous channels, with direct arteriovenous communications
─ Arterial component: Vessels with thickened muscular walls, often with irregular intimal thickening, elastic lamina fragmentation, or duplication
─ Venous component: Dilated, thin-walled veins, which may show "arterialization" (thickened walls with increased smooth muscle and elastic fibers) due to increased blood flow and pressure
─ Intervening stroma may show fibrosis, chronic inflammation, hemosiderin deposition, and dystrophic calcification
─ A capillary component (nidus) may be present between feeding arteries and draining veins in some AVMs
─ No significant endothelial atypia or neoplastic proliferation
Ancillary studies ─
─ IHC: Endothelial cells positive for CD31, CD34, ERG, FLI1; SMA highlights smooth muscle in vessel walls; Elastic stains (eg, Verhoeff-Van Gieson) can highlight arterial structures and abnormalities in elastic laminae
─ Molecular: Most are sporadic; some AVMs are associated with genetic syndromes (eg, HHT/Osler-Weber-Rendu - ENG, ACVRL1 mutations; Parkes Weber syndrome - RASA1 mutations; Capillary Malformation-AVM syndrome - RASA1, EPHB4 mutations)
DDx

─ Other vascular malformations (Venous, Capillary, Lymphatic - lack direct AV shunting and distinct arterial components)
─ Angiosarcoma (malignant endothelial features, atypia, mitoses)
─ Intramuscular hemangioma (may have an AVM component but often mixed with other vessel types and adipose tissue)
─ Hemangioendothelioma (various types, show neoplastic endothelial proliferation)
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Venous hemangioma / Venous malformation (VM)

A common type of slow-flow vascular malformation composed of abnormally dilated, thin-walled vein-like channels; "Venous hemangioma" is an older term, with "venous malformation" now preferred to emphasize its developmental, non-neoplastic nature
Clinical ─ Often present at birth or becomes apparent in childhood/early adulthood, may enlarge slowly over time; can occur anywhere in the body, including skin, subcutaneous tissue, muscle, bone, and viscera; presents as a soft, compressible, often bluish or violaceous mass; may be associated with pain (especially with thrombosis or phlebolith formation), swelling, or cosmetic disfigurement
Macro ─ Poorly circumscribed or well-demarcated, spongy, compressible mass; color is typically blue, purple, or reddish-brown; cut surface reveals blood-filled, dilated vascular spaces; phleboliths (calcified thrombi) are common
Micro

─ Composed of irregularly shaped, dilated vascular channels resembling veins or venules
─ Channels are lined by a single layer of flattened, bland endothelial cells
─ Vessel walls are typically thin and composed of fibrous connective tissue with variable amounts of smooth muscle, which is often attenuated or irregularly distributed (unlike normal veins)
─ Lumina often contain blood and may show organizing thrombi or phleboliths (lamellated calcifications)
─ Intervening stroma is usually minimal and may be fibrous or contain adipose tissue
─ No significant cytologic atypia, endothelial proliferation, or increased mitotic activity
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FLI1; SMA highlights smooth muscle in vessel walls (often sparse or irregular); D2-40 is negative (distinguishes from lymphatic malformations)
─ Molecular: Sporadic VMs are commonly associated with somatic activating mutations in TEK (encoding TIE2 receptor) or PIK3CA genes
DDx

─ Cavernous hemangioma (largely overlapping or synonymous term, especially for more organized lesions with larger spaces)
─ Lymphatic malformation (lined by D2-40 positive endothelium, contains lymph not blood, lacks phleboliths)
─ Arteriovenous malformation (contains arterial structures and evidence of AV shunting)
─ Angiosarcoma (malignant endothelial features, atypia, mitoses, infiltrative destruction)
─ Glomuvenous malformation (contains glomus cells in vessel walls, distinct genetics)
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Sinusoidal Hemangioma

A benign vascular lesion characterized by a distinctive pattern of interconnecting, thin-walled, dilated sinusoidal vascular channels, often with a "pseudopapillary" or "sievelike" appearance
Clinical ─ Typically affects middle-aged to older adults, with a female predominance; most common in the subcutaneous tissue of the extremities, breast, and trunk; presents as a solitary, slow-growing, often painless, firm nodule
Macro ─ Well-circumscribed, firm, bluish or reddish nodule; cut surface is often spongy and hemorrhagic
Micro

─ Well-circumscribed, often lobulated proliferation of back-to-back, thin-walled, dilated sinusoidal vascular channels
─ Channels are often congested with blood and may show focal organizing thrombi
─ Characteristic "sievelike" or "pseudopapillary" pattern due to interanastomosing channels and scant intervening stroma
─ Endothelial cells are typically flattened and bland, without atypia or significant mitotic activity
─ Extravasated red blood cells and hemosiderin deposition may be present in the stroma
─ Mitotic figures are rare; necrosis is absent
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, and FLI1
─ Molecular: No specific recurrent genetic alterations are consistently identified
DDx

─ Cavernous hemangioma / Venous malformation (larger, more irregularly dilated vessels, often thicker walls, less prominent sinusoidal pattern)
─ Anastomosing hemangioma (more distinctly anastomosing pattern with hobnail endothelial cells, often occurs in deeper locations like kidney/retroperitoneum, may have extramedullary hematopoiesis)
─ Angiosarcoma (infiltrative growth, endothelial atypia, multilayering, mitoses, necrosis)
─ Spindle cell hemangioma (admixture of cavernous spaces and spindle cell areas)
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Anastomosing hemangioma

A benign vascular neoplasm characterized by an anastomosing pattern of sinusoidal capillary-sized vessels, often with hobnail endothelial cells and intraluminal fibrin, typically occurring in deeper soft tissues or visceral locations
Clinical ─ Primarily affects adults (wide age range, median ~50s); common sites include kidney (especially perirenal or renal hilar soft tissue), liver, ovary, adrenal gland, testis, and deep soft tissues of the retroperitoneum, paraspinal region, or extremities; often an incidental finding on imaging, but can present with symptoms related to mass effect or hemorrhage
Macro ─ Typically a poorly defined or circumscribed, hemorrhagic, spongy mass; color varies from red-brown to tan; size is variable, can be large
Micro

─ Lobular or diffuse proliferation of irregularly anastomosing, thin-walled, sinusoidal-like vascular channels
─ Endothelial cells are often mildly plump or hobnail-shaped, with minimal to no cytologic atypia
─ Intraluminal fibrin deposits or organizing thrombi are common
─ Extramedullary hematopoiesis (especially in renal/retroperitoneal lesions) is a characteristic but not constant finding
─ Small, eosinophilic, PAS-positive hyaline globules may be present within the cytoplasm of endothelial cells or in the stroma
─ Minimal intervening stroma, which may be edematous or hyalinized
─ Mitotic activity is very low or absent; necrosis is not a feature
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, and FLI1; Negative for GLUT1 and D2-40 (usually)
─ Molecular: Recurrent activating mutations in GNAQ, GNA11, or GNA14 genes have been reported in a subset of cases
DDx

─ Angiosarcoma (especially low-grade) (more significant endothelial atypia, multilayering, infiltrative growth, mitoses, necrosis; lacks GNA-family mutations)
─ Sinusoidal hemangioma (different architectural pattern - more "sievelike," less hobnailing, typically subcutaneous)
─ Kaposi sarcoma (spindle cell proliferation, slit-like spaces, HHV8 positive)
─ Papillary endothelial hyperplasia (Masson tumor) (intravascular location, distinct papillary structures with hyaline cores)
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Epithelioid hemangioma (Including Angiolymphoid Hyperplasia With Eosinophilia)

A benign vascular neoplasm composed of epithelioid endothelial cells forming small vessels, often associated with a larger parent vessel and a prominent inflammatory infiltrate rich in eosinophils; Angiolymphoid Hyperplasia With Eosinophilia (ALHE) is largely considered synonymous or a closely related reactive process
Clinical ─ Typically affects young to middle-aged adults (peak 20-40s), F>M slightly; most common in the head/neck region (especially preauricular area, scalp, forehead), also extremities and trunk; usually presents as solitary or multiple, small (<2 cm), firm, reddish-brown or skin-colored papules or nodules in the dermis or subcutaneous tissue; may be pruritic or tender; peripheral blood eosinophilia can occur
Macro ─ Small, well-circumscribed, reddish-brown or violaceous papules or nodules
Micro

─ Well-circumscribed, often lobular proliferation of small to medium-sized blood vessels, frequently centered around a larger, often thick-walled, parent blood vessel (artery or vein)
─ Vessels are lined by characteristic plump, epithelioid ("histiocytoid") endothelial cells with abundant eosinophilic cytoplasm, round to oval vesicular nuclei, and sometimes small, distinct nucleoli; intracytoplasmic vacuoles (primitive lumina) may be present
─ Endothelial cells may protrude into the lumen in a "hobnail" or "tombstone" fashion
─ Prominent background inflammatory infiltrate is a key feature, composed of lymphocytes, plasma cells, and numerous eosinophils; lymphoid follicles with germinal centers may be present
─ Stroma is often edematous or fibrotic
─ Minimal to no cytologic atypia, mitotic activity is rare
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FLI1, and often Factor VIII-related antigen; Negative for keratins (important for DDx with epithelioid carcinoma), S100 protein, melanocytic markers
─ Molecular: Recurrent FOS or FOSB gene rearrangements (eg, ZFP36::FOSB, WWTR1::FOSB) have been identified in a significant subset of epithelioid hemangiomas, particularly those arising in soft tissue and bone, suggesting a neoplastic basis for many cases; ALHE without these fusions may represent a reactive process
DDx

─ Epithelioid hemangioendothelioma (more infiltrative, myxohyaline stroma, WWTR1::CAMTA1 or YAP1::TFE3 fusions, generally lacks prominent eosinophilic infiltrate)
─ Epithelioid angiosarcoma (marked cytologic atypia, mitoses, necrosis, infiltrative growth)
─ Kimura disease (similar eosinophilic infiltrate and lymphoid follicles, but lacks the characteristic epithelioid endothelial proliferation; typically deeper, often involves salivary glands/lymph nodes, associated with IgE elevation)
─ Insect bite reaction / Arthropod assault (wedge-shaped dermal inflammation with eosinophils, but lacks distinct epithelioid vascular proliferation)
─ Bacillary angiomatosis (neutrophilic infiltrate, granular bacterial aggregates)
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Epithelioid Angiomatous Nodule

A benign cutaneous vascular lesion characterized by a solitary, small, well-circumscribed nodule composed of epithelioid endothelial cells and a variable inflammatory infiltrate; considered by some to be a solitary or early form of epithelioid hemangioma/ALHE
Clinical ─ Typically presents as a small, solitary, reddish papule or nodule on the skin, often on the extremities or trunk of adults
Macro ─ Small (<1 cm), well-demarcated, reddish or violaceous papule or nodule
Micro

─ Well-circumscribed, dermal proliferation of small blood vessels lined by plump epithelioid endothelial cells with abundant eosinophilic cytoplasm and vesicular nuclei
─ Vessels are often capillary-sized or slightly larger, sometimes forming small lobules
─ A variable inflammatory infiltrate, which may include lymphocytes, plasma cells, and eosinophils, is typically present but may be less intense than in classic ALHE
─ The lesion is generally smaller and more discrete than typical multifocal ALHE
─ No significant cytologic atypia or mitotic activity
Ancillary studies ─
─ IHC: Endothelial cells positive for CD31, CD34, ERG, FLI1; Negative for keratins, S100
─ Molecular: FOS or FOSB rearrangements may be present, similar to epithelioid hemangioma
DDx

─ Epithelioid hemangioma / ALHE (larger, often multiple lesions, more prominent inflammation, but significant overlap)
─ Spindle cell hemangioma (different morphology with cavernous spaces and spindle cells)
─ Pyogenic granuloma (lobular capillary proliferation, epidermal collarette, lacks prominent epithelioid cells consistently)
─ Bacillary angiomatosis (neutrophilic infiltrate, bacterial aggregates)
─ Insect bite reaction (wedge-shaped inflammation, lacks distinct epithelioid vascular proliferation)
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Lymphangioma and lymphangiomatosis (Lymphatic Malformation)

Benign malformations of lymphatic channels; Lymphangioma refers to a localized lesion, while lymphangiomatosis implies diffuse or multifocal involvement of tissues or organs; now preferably termed Lymphatic Malformation (LM)
Clinical ─ Often congenital or presents in infancy/early childhood (most by age 2); common sites include head/neck (especially posterior triangle - cystic hygroma), axilla, trunk, extremities, and internal organs; presents as a soft, compressible, often transilluminable mass or collection of vesicles; size and symptoms vary greatly depending on location and extent (eg, cosmetic deformity, airway compromise, chylous effusions)
─ Macrocystic LM (formerly cystic hygroma): Large, fluid-filled cysts (>1-2 cm)
─ Microcystic LM (formerly lymphangioma circumscriptum): Small, vesicle-like channels, often involving skin (clusters of translucent vesicles)
─ Mixed LM: Combination of macro- and microcystic components
Macro ─ Soft, spongy, ill-defined or circumscribed mass composed of single or multiple cysts filled with clear, serous, or chylous fluid; skin lesions appear as clusters of translucent or hemorrhagic vesicles
Micro

─ Network of variably sized, dilated, irregular lymphatic channels lined by a single layer of flattened, bland endothelial cells
─ Vessel walls are typically thin, composed of delicate fibrous tissue, and may contain focal aggregates of smooth muscle (especially in larger channels)
─ Lumina contain proteinaceous, eosinophilic lymph fluid, often with scattered lymphocytes; red blood cells are usually sparse or absent (unless secondary hemorrhage)
─ Intervening stroma is loose connective tissue, may contain lymphoid aggregates (often prominent), adipose tissue, or fibrous tissue
─ No significant cytologic atypia or mitotic activity in endothelial cells
─ Lymphangiomatosis involves diffuse infiltration of tissues by these abnormal lymphatic channels
Ancillary studies ─
─ IHC: Endothelial cells lining lymphatic channels are characteristically positive for D2-40 (podoplanin) and PROX1 (lymphatic endothelial markers); Also positive for general vascular markers like CD31, ERG, FLI1; Negative for GLUT1 (distinguishes from infantile hemangioma)
─ Molecular: Sporadic LMs are commonly associated with somatic activating mutations in PIK3CA; syndromic LMs (eg, Gorham-Stout disease, generalized lymphatic anomaly) may have other genetic bases
DDx

─ Venous malformation / Cavernous hemangioma (contain red blood cells, D2-40 negative endothelial lining, may have TIE2/TEK mutations)
─ Hemangioma (infantile/capillary) (cellular proliferation of endothelial cells, GLUT1 positive in infantile type)
─ Cystic hygroma (macrocystic lymphatic malformation - synonymous)
─ Angiosarcoma (malignant endothelial atypia, mitoses, infiltrative destruction)
─ Mesothelioma (cystic variant, if pleural/peritoneal) (keratin positive, calretinin/WT1 positive)
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Acquired Progressive Lymphangioma / Benign Lymphangioendothelioma

A rare, slowly progressive, benign lymphatic vascular proliferation of the dermis and subcutis, characterized by anastomosing lymphatic-like channels that dissect collagen bundles; Benign Lymphangioendothelioma is a synonym
Clinical ─ Typically affects children and young adults, but can occur at any age; presents as an enlarging, ill-defined, erythematous or violaceous plaque, patch, or occasionally nodule; most common on the extremities, trunk, or head/neck; generally asymptomatic but may be associated with mild tenderness or lymphedema
Macro ─ Ill-defined, flat or slightly raised, indurated plaque or patch; color varies from skin-colored to erythematous or purplish; size can be variable and may gradually expand
Micro

─ Proliferation of irregular, anastomosing, thin-walled vascular channels that dissect through dermal collagen bundles in a "paucicellular" or "empty-appearing" pattern
─ Channels are lined by a single layer of bland, flattened or slightly hobnail endothelial cells with minimal to no atypia
─ Lumina often appear empty or contain scant proteinaceous lymph fluid; red blood cells are typically absent or sparse
─ Minimal intervening stroma; inflammatory infiltrate is usually sparse
─ No significant mitotic activity, necrosis, or features of malignancy
─ May extend into the superficial subcutaneous tissue
Ancillary studies ─
─ IHC: Endothelial cells lining the channels are positive for lymphatic markers such as D2-40 (podoplanin) and PROX1, as well as general vascular markers like CD31 and ERG; Negative for GLUT1
─ Molecular: No specific recurrent genetic alterations are consistently identified; some cases have shown GNA14 mutations
DDx

─ Low-grade angiosarcoma (especially "well-differentiated lymphangiosarcoma-like") (more infiltrative, endothelial atypia, multilayering, mitoses, often arises in lymphedema or post-radiation)
─ Lymphatic malformation (often congenital, larger cystic spaces, less dissecting pattern through collagen)
─ Kaposi sarcoma (patch/plaque stage) (spindle cell proliferation, slit-like spaces, promontory sign, HHV8 positive)
─ Hobnail hemangioma (targetoid appearance clinically, more superficial, often hemosiderin)
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Angiomatosis and Lymphangiomatosis

Angiomatosis refers to a diffuse, often extensive proliferation of benign blood vessels (hemangiomatosis) or lymphatic vessels (lymphangiomatosis) involving a large segment of the body, such as an extremity, trunk, or internal organs, often with infiltration of multiple tissue planes (skin, subcutis, muscle, bone)
Clinical ─ Usually congenital or presents in infancy/childhood; can be associated with syndromes (eg, Klippel-Trenaunay syndrome, Parkes Weber syndrome for hemangiomatosis; Gorham-Stout disease for lymphangiomatosis); presentation varies widely depending on the extent and location of involvement, may include limb hypertrophy, cutaneous vascular stains, pain, functional impairment, coagulopathy (Kasabach-Merritt phenomenon in some hemangiomatosis types), or chylous effusions (lymphangiomatosis)
Macro ─ Diffuse enlargement and infiltration of affected tissues by spongy, vascular, or cystic tissue; boundaries are typically ill-defined
Micro

─ Hemangiomatosis: Diffuse proliferation of benign blood vessels, which can be capillary, venous, cavernous, or mixed types, infiltrating multiple tissue planes; vessels are lined by bland endothelial cells; no atypia or malignancy
─ Lymphangiomatosis: Diffuse proliferation of abnormal lymphatic channels, ranging from microcystic to macrocystic, infiltrating multiple tissue planes; channels lined by D2-40/PROX1 positive endothelial cells, contain lymph; no atypia or malignancy
─ Both conditions are characterized by their extensiveness and infiltrative nature into surrounding normal tissues, often without forming a discrete mass
─ Stroma is variable, may be fibrous or contain adipose tissue; inflammation can be present
Ancillary studies ─
─ IHC: Hemangiomatosis: Endothelial cells CD31/CD34/ERG positive; Lymphangiomatosis: Endothelial cells D2-40/PROX1 positive, also CD31/ERG positive
─ Molecular: Genetic alterations depend on the specific syndrome or subtype; PIK3CA mutations are common in CLOVES syndrome and some other overgrowth syndromes with vascular malformations; TIE2/TEK mutations in some venous malformations; lymphatic anomalies can also have PIK3CA or other pathway mutations
DDx

─ Large localized vascular malformations (eg, extensive venous malformation vs hemangiomatosis; extensive lymphatic malformation vs lymphangiomatosis - distinction is based on extent and involvement of multiple tissue types)
─ Angiosarcoma / Lymphangiosarcoma (malignant endothelial atypia, mitoses, necrosis; rare in this age group but can arise in chronic lymphedema)
─ Kaposiform hemangioendothelioma (KHE) (specific morphology with glomeruloid tufts and spindle cells, often associated with Kasabach-Merritt phenomenon)
─ Diffuse infantile hemangioma (GLUT1 positive, often involves liver)
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Capillary Hemangioma Variants

Capillary hemangioma is a broad term for benign vascular tumors composed of capillary-sized vessels; modern classification often distinguishes between infantile hemangiomas (true neoplasms that proliferate and involute) and various capillary malformations (developmental anomalies that persist); this entry focuses on general features and some non-infantile variants often historically grouped under "capillary hemangioma"
Clinical ─ Presentation varies widely based on subtype; common in skin, mucous membranes, and internal organs; includes entities like cherry angiomas, some pyogenic granulomas (lobular capillary hemangioma), and other localized capillary proliferations not fitting into infantile hemangioma or specific malformation syndromes
Macro ─ Typically small, red to purple papules, nodules, or macules; can be solitary or multiple
Micro

─ Composed of a proliferation of small, capillary-sized blood vessels lined by bland endothelial cells
─ Vessels are often closely packed and may form lobules or diffuse infiltrates in the dermis or other tissues
─ Endothelial cells are typically flattened or slightly plump, without atypia or significant mitoses
─ Stroma is usually scant and fibrous or edematous
─ Specific variants:
─ Cherry angioma (senile hemangioma): Common in adults; dilated capillaries in papillary dermis, often with epidermal atrophy or collarette
─ Tufted angioma (see separate entry): Distinct "cannonball" tufts of capillaries
─ Microvenular hemangioma (see separate entry): Infiltrative proliferation of small venule-like vessels
─ Verrucous hemangioma (see separate entry): Combined vascular malformation with overlying verrucous epidermal hyperplasia
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FLI1; GLUT1 is typically negative (except in infantile hemangioma)
─ Molecular: Generally sporadic with no consistent genetic alterations for most non-infantile variants; specific syndromes with capillary malformations have defined genetic bases (eg, RASA1, GNAQ mutations)
DDx

─ Infantile hemangioma (specific clinical course, GLUT1 positive)
─ Kaposi sarcoma (spindle cells, slit-like spaces, HHV8 positive)
─ Angiosarcoma (malignant endothelial features, atypia, mitoses)
─ Bacillary angiomatosis (neutrophilic infiltrate, bacterial aggregates)
─ Vascular ectasias (dilation of pre-existing vessels, no endothelial proliferation)
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Juvenile Capillary Hemangioma (Infantile Hemangioma)

A common benign vascular neoplasm of infancy, characterized by a unique biologic course of rapid proliferation in early life followed by slow, spontaneous involution; it is GLUT1 positive
Clinical ─ Most common tumor of infancy, affecting ~5-10% of infants, F>M; more common in premature, low birth weight infants, and Caucasians; typically appears within the first few weeks of life (may be preceded by a pale patch or telangiectasia); undergoes a rapid proliferative phase (first 6-12 months), followed by a plateau and then slow, spontaneous involution over several years (usually by age 5-10); common sites include head/neck (scalp, face), trunk, extremities; can be superficial ("strawberry" mark), deep (subcutaneous bluish mass), or mixed; most are solitary and uncomplicated, but large, segmental, or visceral lesions can cause complications (ulceration, bleeding, airway obstruction, cardiac failure, ophthalmologic issues, skeletal distortion)
Macro ─ Superficial lesions are bright red, raised, lobulated ("strawberry" appearance); deep lesions are bluish, rubbery masses; size varies from small papules to large plaques or tumors
Micro

─ Proliferative phase: Highly cellular, well-circumscribed, lobular proliferation of plump endothelial cells forming poorly canalized or solid capillary-sized vascular channels; pericytes are prominent around vessels; mitoses can be frequent but are not atypical
─ Involuting phase: Gradual replacement of vascular lobules by fibrofatty tissue; endothelial cells become flattened, lumina become more apparent; apoptosis of endothelial cells occurs; inflammation (macrophages) may be present
─ Involuted (residual) phase: Largely replaced by fibrofatty tissue with scattered, inconspicuous, ectatic residual vessels
Ancillary studies ─
─ IHC: Endothelial cells are characteristically positive for GLUT1 (glucose transporter 1) throughout all phases (highly specific for infantile hemangioma among vascular tumors of infancy); Also positive for CD31, CD34, ERG, FLI1; Pericytes are SMA positive
─ Molecular: Not characterized by specific recurrent somatic mutations for diagnostic use; thought to arise from placental-derived or endothelial progenitor cells
DDx

─ Other vascular tumors of infancy (eg, tufted angioma, kaposiform hemangioendothelioma - GLUT1 negative, different morphology and clinical associations)
─ Vascular malformations (eg, capillary, venous, lymphatic, AVM - present at birth, grow commensurately with child, GLUT1 negative, different histology)
─ Pyogenic granuloma (lobular capillary hemangioma) (often occurs later, exophytic, history of trauma, GLUT1 negative)
─ Congenital hemangioma (RICH/NICH) (fully formed at birth, GLUT1 negative)
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Congenital Nonprogressive Hemangioma

A type of benign vascular tumor that is fully formed at birth and does not exhibit the postnatal proliferation and involution characteristic of infantile hemangiomas; includes two main subtypes: Rapidly Involuting Congenital Hemangioma (RICH) and Non-Involuting Congenital Hemangioma (NICH)
Clinical ─ Present at birth as fully developed lesions; occur less frequently than infantile hemangiomas; sites include skin (head/neck, trunk, extremities), liver, and other locations
─ RICH: Undergoes rapid regression, often completing involution within the first 1-2 years of life; may leave residual atrophic skin or fibrofatty tissue
─ NICH: Persists indefinitely without significant growth or involution; may enlarge proportionately with the child
Macro ─ Variable appearance: often violaceous or bluish plaques or nodules, sometimes with central pallor, telangiectasias, or ulceration (especially RICH); NICH may be warmer than surrounding skin
Micro

─ Both RICH and NICH share some features: lobular architecture with variably sized vascular channels (capillary to cavernous), often with prominent pericytes and fibrous stroma; endothelial cells are generally bland
─ RICH (early phase): May show features similar to involuting infantile hemangioma, with prominent, often ectatic vessels, thrombosis, hemosiderin, and beginning fibrofatty replacement; endothelial cells may be somewhat plump but involuting
─ NICH: Characterized by lobules of capillary to venule-sized vessels with thickened, hyalinized walls and prominent smooth muscle/pericytes; stroma is often more fibrous; may show features resembling arteriovenous malformation focally
─ Importantly, neither RICH nor NICH shows the intense endothelial proliferation of early infantile hemangioma
Ancillary studies ─
─ IHC: Endothelial cells are GLUT1 negative (key feature distinguishing from infantile hemangioma); Positive for CD31, CD34, ERG, FLI1
─ Molecular: Some NICH cases have been associated with GNAQ or GNA11 mutations, similar to capillary malformations and some other vascular anomalies
DDx

─ Infantile hemangioma (appears postnatally or as precursor lesion, proliferative phase, GLUT1 positive)
─ Vascular malformations (eg, capillary, venous, AVM - GLUT1 negative, but NICH can have overlapping features with some malformations, especially AVM-like channels)
─ Tufted angioma / Kaposiform hemangioendothelioma (GLUT1 negative, different morphology - "cannonball" tufts or spindle cells/glomeruloid structures respectively)
─ Pyogenic granuloma (lobular capillary hemangioma) (acquired, exophytic, often history of trauma, GLUT1 negative)
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Lobular Capillary Hemangioma (Pyogenic Granuloma)

A common benign, rapidly growing, acquired vascular proliferation of capillaries arranged in lobules, often occurring at sites of prior trauma or irritation; Pyogenic Granuloma is the traditional and widely used term
Clinical ─ Affects all ages, common in children and young adults; also occurs in pregnant women (granuloma gravidarum or pregnancy tumor), typically on gingiva; common sites include skin (fingers, head, neck, trunk) and mucous membranes (oral cavity - lips, gingiva; nasal cavity); presents as a bright red to violaceous, soft, often pedunculated or sessile papule or nodule that bleeds easily; rapid growth over weeks is characteristic
Macro ─ Friable, erythematous, often ulcerated, pedunculated or sessile polypoid lesion; typically <2 cm; surface may be crusted
Micro

─ Well-circumscribed, exophytic, polypoid lesion, often with an epidermal collarette at the base and overlying epidermal ulceration or erosion
─ Characterized by a striking lobular architecture: aggregates of closely packed, capillary-sized blood vessels lined by plump endothelial cells, separated by fibrous septa
─ Stroma within lobules is often edematous and may contain a mixed inflammatory infiltrate (neutrophils, lymphocytes, plasma cells)
─ Endothelial cells are bland, though mitotic figures can be numerous, especially in early or traumatized lesions, but are not atypical
─ Older lesions may show more fibrosis within the stroma ("sclerosing pyogenic granuloma")
─ Intravascular variant (intravascular pyogenic granuloma) arises within a vessel lumen
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FLI1; Pericytes surrounding capillaries are SMA positive; GLUT1 is negative (distinguishes from infantile hemangioma)
─ Molecular: BRAF or RAS mutations have been reported in a subset of cases, particularly those unresponsive to simple excision or occurring in unusual locations, suggesting a neoplastic basis for some
DDx

─ Granulation tissue (more inflammation, less lobular architecture, occurs in healing wounds)
─ Kaposi sarcoma (spindle cell proliferation, slit-like spaces, HHV8 positive)
─ Bacillary angiomatosis (neutrophilic infiltrate with granular bacterial aggregates, occurs in immunocompromised)
─ Angiosarcoma (malignant endothelial atypia, infiltrative growth, necrosis)
─ Cherry angioma (dilated capillaries in papillary dermis, lacks lobular architecture)
─ Infantile hemangioma (GLUT1 positive, different clinical course)
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Cherry Angioma

A very common benign cutaneous vascular proliferation characterized by dilated capillaries in the papillary dermis, typically appearing as small, bright red papules in adults; also known as senile hemangioma or Campbell de Morgan spot
Clinical ─ Extremely common, increases in prevalence with age (most adults have at least a few); typically appear from the third decade onwards; common on the trunk and proximal extremities; present as small (usually 1-5 mm), bright cherry-red, dome-shaped papules or macules; usually asymptomatic and of cosmetic concern only
Macro ─ Small, bright red, well-demarcated papules or macules on the skin surface
Micro

─ Well-circumscribed proliferation of dilated, thin-walled capillary-sized blood vessels located primarily within the papillary dermis
─ Vessels are lined by a single layer of flattened, bland endothelial cells
─ Lumina are often congested with red blood cells
─ Intervening stroma is often edematous or slightly fibrotic
─ Overlying epidermis may be normal or slightly atrophic, sometimes with an epidermal collarette at the periphery
─ No significant endothelial atypia, proliferation, or mitotic activity
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FLI1; GLUT1 is negative
─ Molecular: Not typically characterized by specific recurrent genetic alterations; thought to be a degenerative or age-related phenomenon rather than a true neoplasm by some
DDx

─ Angiokeratoma (vascular ectasia with overlying epidermal hyperkeratosis and acanthosis)
─ Telangiectasia (simple dilation of pre-existing vessels, less clustered)
─ Glomeruloid hemangioma (glomerulus-like capillary tufts, associated with POEMS syndrome)
─ Bacillary angiomatosis (lobular proliferation with neutrophils and bacteria, in immunocompromised)
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Acquired Elastotic Hemangioma

A rare, benign cutaneous vascular proliferation characterized by dilated capillaries within a distinctive sclerotic, elastotic dermis, typically occurring on sun-exposed skin of older individuals
Clinical ─ Primarily affects older adults (typically >60 years); strong association with chronic sun exposure; most common on the extensor surfaces of the forearms and hands, also neck and face; presents as a solitary, slowly enlarging, asymptomatic, erythematous to violaceous, annular or arcuate patch or thin plaque, often with central clearing or slight atrophy
Macro ─ Annular or arcuate, flat or slightly raised, erythematous patch or plaque with a distinct border and often central clearing; typically 1-5 cm in diameter
Micro

─ Diffuse proliferation of small, dilated, thin-walled capillary-sized blood vessels throughout the upper and mid-dermis
─ Vessels are lined by bland, flattened endothelial cells, without atypia or mitoses
─ Characteristic feature: The dermal stroma surrounding the vessels is markedly sclerotic (hyalinized collagen) and shows prominent solar elastosis (clumps and tangles of abnormal elastic fibers)
─ Vessels often appear to be "floating" within this altered stroma
─ Perivascular lymphocytic infiltrate is usually sparse or absent
─ Overlying epidermis may be atrophic
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FLI1; Elastic stains (eg, Verhoeff-Van Gieson) highlight the solar elastosis
─ Molecular: No specific recurrent genetic alterations are known
DDx

─ Granuloma annulare (palisading granulomas around altered collagen/mucin, lacks prominent vascular proliferation and marked solar elastosis)
─ Erythema annulare centrifugum (trailing scale, perivascular lymphocytic infiltrate, lacks prominent vascular proliferation and elastosis)
─ Disseminated superficial actinic porokeratosis (DSAP) (cornoid lamella histologically, different clinical appearance)
─ Cutaneous lupus erythematosus (interface dermatitis, follicular plugging, specific autoimmune serology)
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Verrucous Hemangioma

A rare, congenital or early childhood vascular malformation characterized by combined capillary and venous components extending from the dermis into the subcutis, with characteristic overlying verrucous epidermal hyperplasia
Clinical ─ Usually present at birth or appears in early childhood, persists and may slowly enlarge; most common on the lower extremities (especially legs and feet), but can occur elsewhere; presents as a solitary or grouped bluish-red to violaceous, hyperkeratotic, warty (verrucous) plaque or nodule; may bleed or become crusted
Macro ─ Irregular, warty, hyperkeratotic plaque or nodule; color is often dark red, blue, or purple; surface may be papillomatous
Micro

─ Combination of vascular malformation and reactive epidermal changes:
─ Vascular component: Composed of dilated, thin-walled vascular channels of varying sizes (capillary to cavernous/venous) involving the dermis and extending into the subcutaneous adipose tissue; vessels are lined by bland endothelial cells
─ Epidermal component: Marked hyperkeratosis, parakeratosis, acanthosis, and papillomatosis of the overlying epidermis, giving a verrucous appearance
─ Dermal papillae are often elongated and edematous
─ No significant endothelial atypia or mitotic activity
─ Chronic inflammatory infiltrate may be present in the dermis
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FLI1; D2-40 may be positive if lymphatic component present; GLUT1 is negative
─ Molecular: Generally considered a malformation; some cases may have somatic mutations in genes associated with vascular anomalies (eg, PIK3CA)
DDx

─ Angiokeratoma (more superficial vascular ectasia with overlying epidermal hyperplasia, does not typically extend deeply into subcutis with large channels)
─ Lymphatic malformation with verrucous hyperplasia (lymphatic channels D2-40 positive, lacks prominent blood-filled spaces)
─ Verruca vulgaris (viral wart) (koilocytic atypia in epidermis, lacks underlying vascular malformation)
─ Squamous cell carcinoma (verrucous carcinoma) (malignant epithelial atypia, infiltrative growth)
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Symplastic Hemangioma

A benign vascular lesion, often a variant of cherry angioma or other capillary hemangiomas, characterized by focal degenerative nuclear atypia (symplastic change) within endothelial cells, but lacking other features of malignancy; also known as atypical senile hemangioma or hemangioma with symplastic endothelial cells
Clinical ─ Typically occurs in older adults, similar sites to cherry angiomas (trunk, extremities); presents as a small, red to violaceous papule, often indistinguishable clinically from a typical cherry angioma or other benign vascular lesion
Macro ─ Small, red or violaceous papule, usually <5 mm
Micro

─ Underlying architecture of a benign vascular lesion, most commonly a cherry angioma (dilated capillaries in papillary dermis) or a simple capillary hemangioma
─ Defining feature: Presence of scattered, focal, large, hyperchromatic, pleomorphic endothelial cell nuclei ("symplastic" atypia)
─ These atypical nuclei are degenerative and are not associated with increased mitotic activity, atypical mitoses, necrosis, or infiltrative growth
─ The overall cellularity and architecture remain those of a benign vascular lesion
─ Endothelial cells with symplastic atypia still line well-formed vascular channels
Ancillary studies ─
─ IHC: Endothelial cells (including atypical ones) are positive for CD31, CD34, ERG, FLI1; Ki-67 proliferation index is low; p53 may be focally positive in atypical cells but is not indicative of malignancy in this context
─ Molecular: No specific recurrent genetic alterations associated with malignancy are present
DDx

─ Angiosarcoma (diffuse endothelial atypia, increased mitoses, atypical mitoses, infiltrative growth, necrosis; symplastic hemangioma lacks these aggressive features)
─ Radiation-associated atypical vascular lesion (AVL) (history of radiation, different clinical context, MYC often negative unlike post-radiation angiosarcoma)
─ Epithelioid hemangioma (different epithelioid cell morphology, often eosinophilic infiltrate)
─ Kaposi sarcoma (spindle cells, slit-like spaces, HHV8 positive)
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Microvenular Hemangioma

A benign, acquired cutaneous vascular proliferation characterized by an infiltrative growth of small, thin-walled venule-like vessels in the dermis
Clinical ─ Typically affects young to middle-aged adults, but can occur at any age; presents as a solitary, slowly enlarging, asymptomatic, erythematous to violaceous macule, patch, or thin plaque; common sites include extremities (especially arms), trunk, and head/neck
Macro ─ Small (usually <2 cm), ill-defined, reddish-purple or violaceous macule or thin plaque
Micro

─ Poorly circumscribed, infiltrative proliferation of small, branching, thin-walled blood vessels resembling venules within the dermis, often dissecting collagen bundles
─ Vessels are lined by a single layer of bland, flattened endothelial cells without atypia or significant mitotic activity
─ Lumina are often narrow or collapsed, may contain scattered red blood cells
─ Stroma is typically unremarkable dermal collagen; inflammatory infiltrate is usually sparse or absent
─ No significant endothelial proliferation, atypia, or features of malignancy
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, and FLI1; GLUT1 is negative
─ Molecular: No specific recurrent genetic alterations are consistently identified
DDx

─ Early Kaposi sarcoma (patch stage) (more prominent spindle cells, promontory sign, HHV8 positive)
─ Acquired progressive lymphangioma / Benign lymphangioendothelioma (lymphatic channels D2-40 positive, lacks red blood cells)
─ Targetoid hemosiderotic hemangioma (hobnail hemangioma) (more superficial, targetoid appearance, hobnail cells, hemosiderin)
─ Telangiectasia (simple dilation of pre-existing vessels, less infiltrative proliferation)
─ Low-grade angiosarcoma (more infiltrative, endothelial atypia, mitoses)
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Hobnail Hemangioma (“Targetoid Hemosiderotic Hemangioma”)

A benign, small, superficial vascular lesion characterized by dilated superficial vessels lined by prominent "hobnail" endothelial cells and deeper, dissecting capillary-like channels, often with a distinctive clinical targetoid appearance due to central hemosiderin deposition; "Targetoid Hemosiderotic Hemangioma" is a common synonym
Clinical ─ Typically affects young to middle-aged adults; common on the trunk and extremities; presents as a solitary, small (usually <1 cm) papule with a characteristic targetoid appearance: a central reddish-brown or violaceous papule surrounded by a pale halo and an outer ecchymotic or pigmented ring
Macro ─ Small, target-like lesion with a central dark papule and peripheral rings of varying color (pale, ecchymotic)
Micro

─ Biphasic pattern often observed:
─ Superficial dermis: Dilated, thin-walled vascular spaces in the papillary dermis, lined by prominent, cuboidal to hobnail endothelial cells (nuclei protrude into the lumen)
─ Deeper dermis: Narrow, slit-like, or angulated vascular channels dissecting collagen bundles, lined by flattened endothelial cells; these deeper vessels may resemble those of benign lymphangioendothelioma or microvenular hemangioma
─ Hemosiderin deposition is common, especially in the superficial dermis, contributing to the clinical pigmentation
─ Chronic inflammatory infiltrate (lymphocytes) is often present in the stroma
─ No significant cytologic atypia or mitotic activity
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FLI1; D2-40 (podoplanin) may be positive in the deeper, slit-like channels, suggesting some lymphatic differentiation or origin in some cases
─ Molecular: No specific recurrent genetic alterations are consistently identified
DDx

─ Kaposi sarcoma (patch/plaque stage) (spindle cell proliferation, promontory sign, HHV8 positive)
─ Microvenular hemangioma (more diffuse infiltrative pattern of venule-like vessels, lacks prominent hobnail cells and targetoid appearance)
─ Insect bite reaction (wedge-shaped inflammation, eosinophils, lacks consistent hobnail cells)
─ Tufted angioma (distinct "cannonball" tufts of capillaries)
─ Dermatofibroma (hemosiderotic variant) (Factor XIIIa positive, different spindle cell proliferation)
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Tufted angioma

A benign, localized vascular neoplasm of childhood or early adulthood, characterized by discrete lobules ("tufts") of tightly packed capillaries scattered in the dermis and subcutis; considered part of a spectrum with kaposiform hemangioendothelioma (KHE) but lacks the aggressive features and significant thrombocytopenia of KHE
Clinical ─ Typically presents in infancy, childhood, or early adulthood (most before age 5); common on the neck, upper trunk, shoulders, and proximal extremities; presents as a slowly enlarging, firm, indurated, dull red, violaceous, or brownish plaque or nodule, often ill-defined; may be associated with hypertrichosis or hyperhidrosis over the lesion; Kasabach-Merritt phenomenon is rare and mild if present (unlike KHE)
Macro ─ Ill-defined, indurated plaque or nodule, often several centimeters in diameter; color varies from erythematous to violaceous or tan-brown
Micro

─ Characteristic feature: Multiple discrete, rounded lobules ("tufts" or "cannonballs") of densely packed, capillary-sized blood vessels scattered throughout the dermis and sometimes extending into the subcutaneous tissue
─ Capillaries within tufts are lined by plump, relatively bland endothelial cells, and lumina are often inconspicuous or slit-like
─ Crescent-shaped, dilated lymphatic-like vascular channels are often present at the periphery of the tufts or in the intervening stroma
─ Intervening stroma is usually unremarkable dermal collagen or fibrous tissue
─ Minimal cytologic atypia, rare mitotic figures
─ Lacks the infiltrative sheets of spindle cells and significant atypia seen in KHE
Ancillary studies ─
─ IHC: Endothelial cells of capillaries are positive for CD31, CD34, ERG, FLI1; Lymphatic-like channels at periphery of tufts are often D2-40 (podoplanin) positive; GLUT1 is negative
─ Molecular: Somatic activating mutations in GNA14 have been reported in some cases, similar to KHE, supporting a pathogenetic link
DDx

─ Kaposiform hemangioendothelioma (KHE) (more infiltrative, confluent lobules, often prominent spindle cell component, more frequently associated with significant Kasabach-Merritt phenomenon)
─ Infantile hemangioma (GLUT1 positive, different proliferative and involutional phases, different morphology)
─ Capillary hemangioma (other types) (lacks distinct "cannonball" tufts and peripheral lymphatic-like channels)
─ Glomeruloid hemangioma (glomerulus-like capillary tufts, associated with POEMS syndrome)
─ Angiosarcoma (malignant endothelial atypia, mitoses, necrosis)
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WSI HE CD31 D2-40 SMA video for WSI

Kaposiform Hemangioendothelioma (KHE)

A locally aggressive vascular neoplasm of intermediate malignancy, typically occurring in infants and young children, characterized by infiltrating nodules and sheets of spindle cells mixed with poorly formed vascular channels, often associated with Kasabach-Merritt phenomenon (profound thrombocytopenia and consumptive coagulopathy)
Clinical ─ Primarily affects infants and young children (most cases present in the first year of life, can be congenital); common in deep soft tissues of the trunk (retroperitoneum, mediastinum), extremities, and head/neck; presents as a large, firm, poorly defined, infiltrative mass, often with a violaceous or ecchymotic hue; Kasabach-Merritt phenomenon (KMP) is a frequent and life-threatening complication due to platelet trapping within the tumor
Macro ─ Ill-defined, firm, infiltrative mass; cut surface is often hemorrhagic, violaceous, or reddish-brown; may show areas of fibrosis
Micro

─ Infiltrating nodules, lobules, and sheets of neoplastic cells, often with a poorly defined interface with surrounding tissues
─ Two main components:
─ Spindle cells: Plump spindle cells arranged in fascicles or sheets, often forming slit-like vascular spaces resembling Kaposi sarcoma or poorly formed capillaries
─ Glomeruloid or tufted areas: Clusters of capillaries resembling tufted angioma or renal glomeruli, often with hyaline globules within microthrombi
─ Endothelial cells lining channels and within tufts may be plump or hobnail-like
─ Extravasated red blood cells, hemosiderin deposition, and fibrin thrombi are common
─ Lymphatic-like channels may be present at the periphery of lobules
─ Cytologic atypia is generally mild, mitotic activity is low, but infiltrative growth is characteristic
Ancillary studies ─
─ IHC: Spindle and endothelial cells are positive for CD31, CD34, ERG, FLI1; Lymphatic markers like D2-40 (podoplanin) and PROX1 are often positive, particularly in spindle cells and lining some channels; GLUT1 is negative; HHV8 (LANA-1) is negative (distinguishes from Kaposi sarcoma)
─ Molecular: Somatic activating mutations in GNA14 have been identified in a significant proportion of cases, linking it pathogenetically to tufted angioma
DDx

─ Tufted angioma (more discrete "cannonball" lobules, less infiltrative, less prominent spindle cell component, KMP rare and mild)
─ Infantile hemangioma (GLUT1 positive, different morphology and clinical course)
─ Kaposi sarcoma (HHV8 positive, different clinical setting - typically immunocompromised or elderly)
─ Spindle cell hemangioma (admixture of cavernous spaces and spindle cells, lacks glomeruloid tufts and KMP)
─ Angiosarcoma (more significant atypia, mitoses, necrosis, older age group typically)
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Retiform hemangioendothelioma

A rare, low-grade angiosarcoma characterized by an distinctive arborizing network of vascular channels resembling the architecture of normal rete testis, often with prominent lymphocytic inflammation
Clinical ─ Typically affects young to middle-aged adults (peak 20-40s), but can occur at any age; common on distal extremities (especially lower legs and feet), less often trunk or head/neck; presents as a slow-growing, solitary, indurated plaque or nodule, often violaceous or reddish-brown; may ulcerate
Macro ─ Ill-defined, firm plaque or nodule; color varies from violaceous to reddish-brown or tan; size typically 1-5 cm
Micro

─ Dermal and/or subcutaneous proliferation of elongated, arborizing, anastomosing vascular channels that strikingly resemble the rete testis ("long rete ridges")
─ Channels are lined by prominent, often monomorphic, cuboidal or hobnail endothelial cells ("matchstick" or "hobnail" appearance) with scant cytoplasm and minimal atypia
─ Lumina are often narrow and may appear empty or contain scant blood
─ A prominent lymphocytic infiltrate, sometimes forming lymphoid follicles, is a characteristic feature within the stroma surrounding the vascular channels
─ Mitotic activity is generally low; necrosis is absent
─ Infiltrative growth into surrounding dermis and subcutis is typical
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FLI1; D2-40 (podoplanin) is often positive, suggesting at least partial lymphatic differentiation or origin; Negative for GLUT1, HHV8, keratins
─ Molecular: No specific recurrent genetic alterations are consistently identified, though some cases may show NFATC1 rearrangements
DDx

─ Dabska tumor (papillary intralymphatic angioendothelioma) (prominent intraluminal papillary tufts with hyaline cores, occurs in children, also D2-40 positive)
─ Angiosarcoma (conventional) (greater endothelial atypia, multilayering, mitoses, necrosis, lacks consistent rete testis-like pattern and prominent lymphocytic infiltrate)
─ Hobnail hemangioma (targetoid hemosiderotic hemangioma) (more superficial, targetoid clinical appearance, biphasic pattern with superficial dilated vessels)
─ Acquired progressive lymphangioma / Benign lymphangioendothelioma (more dissecting pattern of lymphatic-like channels, lacks hobnail cells and rete testis architecture)
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Papillary intralymphatic angioendothelioma (Dabska Tumor)

A rare, low-grade angiosarcoma of lymphatic differentiation, typically occurring in infants and children, characterized by intralymphatic papillary endothelial proliferations; also known as Dabska tumor or endovascular papillary angioendothelioma
Clinical ─ Primarily affects infants and children, but can occur in adults; most common in the skin and subcutaneous tissue of the extremities, trunk, head/neck, and testis/paratestis; presents as a slow-growing, painless, violaceous or erythematous plaque, nodule, or mass
Macro ─ Ill-defined or circumscribed, violaceous or reddish plaque or nodule; cut surface may appear cystic or spongy
Micro

─ Dermal or subcutaneous tumor composed of dilated, thin-walled lymphatic-like vascular spaces
─ Characteristic feature: Intraluminal papillary projections or tufts lined by prominent, cuboidal or hobnail endothelial cells, often with scant cytoplasm and hyperchromatic nuclei (low-grade atypia)
─ Papillary cores are typically hyalinized and acellular, or may contain lymphocytes
─ Lymphocytic infiltrate is common in the stroma surrounding the vascular channels
─ Mitotic activity is generally low; necrosis is absent
─ Infiltrative growth pattern may be present
Ancillary studies ─
─ IHC: Endothelial cells (including those lining papillae) are positive for general vascular markers (CD31, ERG, FLI1) and lymphatic markers (D2-40/podoplanin, PROX1); Negative for GLUT1, HHV8, keratins
─ Molecular: Some cases show GATA6 mutations or fusions (eg, KDR::GATA6); some pediatric cases have shown ETV6 or PTBP1 fusions with KDR
DDx

─ Retiform hemangioendothelioma (rete testis-like arborizing channels, also D2-40 positive, lacks prominent intraluminal hyaline papillae, different clinical setting usually)
─ Angiosarcoma (conventional) (greater endothelial atypia, multilayering, mitoses, necrosis, more aggressive features)
─ Papillary endothelial hyperplasia (Masson tumor) (intravascular organizing thrombus, lacks lymphatic differentiation, different papillary structure)
─ Lymphatic malformation (lacks papillary endothelial proliferation and hobnail cells)
─ Kaposiform hemangioendothelioma (different morphology with spindle cells and glomeruloid tufts, often Kasabach-Merritt)
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Composite hemangioendothelioma

A rare, low-grade malignant vascular neoplasm characterized by an admixture of different benign, intermediate, and/or low-grade malignant vascular patterns within the same lesion, often including components resembling epithelioid hemangioma, retiform hemangioendothelioma, and spindle cell hemangioma
Clinical ─ Affects a wide age range, often young to middle-aged adults; common in distal extremities (hands, feet), less often trunk or head/neck; presents as a slow-growing, solitary or multiple, firm, reddish-brown or violaceous nodule or plaque; may be locally aggressive and recur, but metastatic potential is generally low
Macro ─ Ill-defined or circumscribed, firm nodule or plaque; color varies from tan to reddish-brown or violaceous
Micro

─ Admixture of two or more distinct vascular patterns within the same lesion, often in a zonal or intermingled fashion
─ Commonly observed components include:
─ Areas resembling epithelioid hemangioma (epithelioid endothelial cells, eosinophilic infiltrate)
─ Areas resembling retiform hemangioendothelioma (arborizing rete testis-like channels, hobnail cells, lymphocytic infiltrate)
─ Areas resembling spindle cell hemangioma (cavernous spaces with spindle cells, epithelioid cells, phleboliths)
─ Areas resembling lymphangioma or well-differentiated angiosarcoma may also be present
─ Cytology within each component is generally bland to low-grade atypical; mitotic activity is usually low
─ Overall architecture is often infiltrative
Ancillary studies ─
─ IHC: Expression is variable depending on the components present; Endothelial cells positive for CD31, ERG, FLI1; D2-40 may highlight lymphatic components or retiform areas; S100 may be positive in areas resembling spindle cell hemangioma (some cells); ALK negative
─ Molecular: Heterogeneous; some cases show WWTR1::CAMTA1 or YAP1::TFE3 fusions (characteristic of epithelioid hemangioendothelioma); other specific alterations related to individual components are generally absent
DDx

─ Specific individual vascular neoplasms (eg, pure epithelioid hemangioma, pure retiform hemangioendothelioma - diagnosis of composite HE requires distinct mixed patterns)
─ Angiosarcoma (conventional) (more diffuse high-grade atypia, mitoses, necrosis, lacks well-defined mixed patterns of low-grade components)
─ Kaposi sarcoma (HHV8 positive, characteristic spindle cells and slit-like spaces)
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Kaposi sarcoma (KS)

A low-grade vascular neoplasm caused by Human Herpesvirus 8 (HHV8), also known as Kaposi Sarcoma-Associated Herpesvirus (KSHV); occurs in distinct clinical-epidemiological forms: Classic, Endemic (African), Iatrogenic (transplant-related), and AIDS-related (epidemic)
Clinical ─ Presentation varies by type:
─ Classic KS: Older men of Mediterranean, Eastern European, or Jewish descent; indolent, violaceous macules/plaques/nodules on distal lower extremities, may involve GI tract or lymph nodes slowly
─ Endemic African KS: Variable course; lymphadenopathic form in children is aggressive; nodular cutaneous form in adults is more indolent
─ Iatrogenic KS: Organ transplant recipients or patients on chronic immunosuppression; skin lesions common, may regress with reduced immunosuppression
─ AIDS-related KS: HIV-infected individuals (especially with low CD4 counts); often multifocal and aggressive, involving skin, mucous membranes, lymph nodes, and viscera (lungs, GI tract)
Macro ─ Red, purple, violaceous, or brownish macules, papules, plaques, or nodules on skin or mucosal surfaces; visceral lesions are often hemorrhagic nodules
Micro

─ Progression through patch, plaque, and nodular stages:
─ Patch stage: Subtle proliferation of irregular, thin-walled, jagged vascular channels around pre-existing vessels and adnexa ("promontory sign"); sparse spindle cells and lymphoplasmacytic infiltrate; hemosiderin common
─ Plaque stage: More prominent vascular proliferation with increased spindle cells forming short fascicles; extravasated red blood cells, hemosiderin, and plasma cells are characteristic; slit-like vascular spaces begin to form
─ Nodule stage: Densely cellular proliferation of intersecting fascicles of spindle cells forming slit-like vascular spaces containing red blood cells; numerous extravasated RBCs and hemosiderin; characteristic eosinophilic, PAS-positive hyaline globules (thought to be degenerated RBCs or plasma proteins) are often present within spindle cells or stroma; mitotic activity is variable
Ancillary studies ─
─ IHC: Spindle cells and endothelial cells are positive for HHV8 (LANA-1 nuclear stain - highly specific and sensitive); Positive for general vascular markers (CD31, CD34, ERG, FLI1); D2-40 (podoplanin) is often positive (reflecting lymphatic differentiation of spindle cells)
─ Molecular: Detection of HHV8 DNA by PCR can also confirm diagnosis
DDx

─ Acroangiodermatitis (Pseudo-Kaposi sarcoma) (reactive vascular proliferation in stasis, HHV8 negative)
─ Dermatofibroma (hemosiderotic) (Factor XIIIa positive, HHV8 negative)
─ Spindle cell hemangioma (cavernous spaces, lacks HHV8)
─ Angiosarcoma (more significant atypia, mitoses, necrosis, HHV8 negative)
─ Bacillary angiomatosis (neutrophilic infiltrate, granular bacterial aggregates, HHV8 negative)
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Pseudomyogenic hemangioendothelioma (Vascular Context)

An uncommon vascular neoplasm of intermediate malignancy, characterized by plump spindle and epithelioid cells with eosinophilic cytoplasm resembling muscle cells (hence "pseudomyogenic"), often involving multiple tissue planes (skin, subcutis, muscle, bone) typically within a single anatomical region, and frequently harboring SERPINE1::FOSB or ACTB::FOSB fusions
Clinical ─ Typically affects young adults (peak age 20-40s), with a strong male predominance; common in distal extremities (especially lower limb - foot, ankle, leg), also trunk; often presents as multiple, painful or tender, firm nodules or plaques that may be erythematous or violaceous; lesions can be synchronous or metachronous within the same region; systemic metastasis is rare, but nodal involvement can occur
Macro ─ Ill-defined, firm nodules or indurated plaques, often involving multiple tissue layers; cut surface is typically gray-white to tan, fleshy
Micro

─ Infiltrative proliferation of plump spindle and epithelioid cells arranged in loose fascicles, sheets, or a haphazard pattern
─ Cells have abundant, deeply eosinophilic, somewhat fibrillar cytoplasm, giving a "pseudomyogenic" or "rhabdoid-like" appearance
─ Nuclei are round to oval, often vesicular with distinct nucleoli; cytologic atypia is usually mild to moderate
─ Background stroma is often loose, edematous, or fibrous, characteristically with a prominent neutrophilic inflammatory infiltrate (neutrophils may be scattered or form aggregates)
─ Vasoformative areas (small capillaries or slit-like spaces) may be inconspicuous or focal
─ Mitotic activity is generally low to moderate
Ancillary studies ─
─ IHC: Tumor cells are characteristically positive for ERG and FLI1 (nuclear endothelial markers); Cytokeratins (AE1/AE3, CAM5.2) are frequently positive (a key diagnostic feature and potential pitfall); INI1/SMARCB1 expression is retained; Negative or only focally positive for CD31 and CD34 (unlike most vascular tumors); Negative for desmin, myogenin, S100 protein, HMB45, HHV8
─ Molecular: Defined by recurrent gene fusions, most commonly SERPINE1::FOSB; less frequently ACTB::FOSB
DDx

─ Epithelioid sarcoma (INI1 loss, CD34 often positive, more cohesive epithelioid sheets, lacks FOSB fusion)
─ Rhabdomyosarcoma (MyoD1/myogenin positive, lacks FOSB fusion and keratin positivity)
─ Epithelioid hemangioma / ALHE (lacks spindle cells, FOS/FOSB rearranged but different partners/morphology, keratin negative)
─ Epithelioid angiosarcoma (more significant atypia, mitoses, necrosis, CD31/CD34 often positive, lacks FOSB fusion)
─ Spindle cell melanoma (S100/SOX10/melanocytic markers positive)
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Epithelioid hemangioendothelioma (EHE)

A vascular neoplasm of intermediate malignancy composed of epithelioid endothelial cells arranged in cords, nests, or strands within a characteristic myxohyaline or chondroid-like stroma; a subset is defined by WWTR1::CAMTA1 or YAP1::TFE3 fusions
Clinical ─ Typically affects adults (wide age range, peak 30-60s); can arise in soft tissue (extremities, trunk, head/neck), liver, lung, bone, and other visceral sites; presentation is variable depending on site, may be an incidental finding or cause pain, mass effect, or organ dysfunction; can be solitary or multifocal; clinical course is variable and unpredictable, ranging from indolent to aggressive with metastatic potential
Macro ─ Firm, gray-white to tan, often multinodular or infiltrative mass; cut surface may appear fibrous, chondroid, or gelatinous; size is variable
Micro

─ Cords, nests, strands, or small clusters of epithelioid endothelial cells embedded in an abundant myxohyaline, chondroid-like, or densely sclerotic stroma
─ Tumor cells are polygonal with abundant eosinophilic or clear cytoplasm, round to oval vesicular nuclei, and often small, distinct nucleoli; some cells may show intracytoplasmic vacuoles or lumina (so-called "blister cells"), which may contain red blood cells
─ Cytologic atypia is generally mild to moderate; mitotic activity is usually low, but can be higher in more aggressive cases
─ Necrosis may be present, particularly in larger or higher-grade tumors
─ The YAP1::TFE3 variant often shows more solid, vasoformative areas with less stroma and more prominent epithelioid cells with clear cytoplasm
Ancillary studies ─
─ IHC: Tumor cells are positive for endothelial markers CD31, ERG, and FLI1; CD34 is variably positive (often lost in epithelioid areas); Cytokeratins (AE1/AE3, CAM5.2) are positive in a significant subset (potential pitfall for carcinoma); CAMTA1 or TFE3 nuclear positivity may be seen depending on the fusion type (but antibodies can be unreliable or difficult to interpret); Negative for S100 protein, desmin, SMA (usually), HHV8
─ Molecular: Characteristic gene fusions:
─ WWTR1(TAZ)::CAMTA1 (t(1;3)(p36;q25)) is most common
─ YAP1::TFE3 (t(X;11)(p11;q13)) is less common, often associated with more epithelioid/clear cell morphology
DDx

─ Metastatic carcinoma (especially adenocarcinoma with mucinous or signet ring features, or clear cell carcinoma) (keratin positive but different profile, lacks vascular markers and specific fusions)
─ Epithelioid angiosarcoma (more significant atypia, mitoses, necrosis, infiltrative sheets, lacks specific EHE fusions)
─ Epithelioid hemangioma / ALHE (lacks significant myxohyaline stroma, FOS/FOSB rearranged, prominent eosinophilic infiltrate)
─ Myoepithelial carcinoma (S100/GFAP/SMA variably positive, different EWSR1 fusions if present)
─ Extraskeletal myxoid chondrosarcoma (NR4A3 fusion, lacks vascular markers and EHE fusions)
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Angiosarcoma

A malignant neoplasm of endothelial differentiation, characterized by infiltrative growth and the formation of anastomosing vascular channels lined by atypical endothelial cells
Clinical ─ Typically affects older adults (peak 60-70s), but can occur at any age; common sites include skin (especially scalp and face of elderly - "cutaneous angiosarcoma of head and neck"), deep soft tissue, breast (often post-radiation or related to lymphedema), liver, spleen, and bone; presentation is variable, ranging from bruise-like lesions or plaques to nodules or large, infiltrative masses; often aggressive with a high rate of local recurrence and distant metastasis
Macro ─ Ill-defined, hemorrhagic, spongy, or fleshy mass or lesion; may appear as multifocal nodules or diffuse induration; infiltrative margins are characteristic
Micro

─ Highly variable histologic appearance, ranging from well-differentiated (resembling benign vascular lesions but with atypia) to poorly differentiated (appearing as epithelioid or spindle cell sarcoma with minimal vasoformation)
─ Characteristic feature (when present): Anastomosing, irregular vascular channels lined by atypical endothelial cells that dissect through tissue planes (eg, dermal collagen, adipose tissue, muscle)
─ Endothelial cells exhibit cytologic atypia, including hyperchromasia, pleomorphism, enlarged nuclei, prominent nucleoli, and increased mitotic activity (including atypical forms)
─ Endothelial tufting, multilayering, and intraluminal "hobnail" cells are common
─ Solid epithelioid or spindle cell areas may be present, particularly in higher-grade tumors
─ Necrosis and hemorrhage are frequently observed
─ Grading is often based on differentiation, atypia, mitotic rate, and necrosis (eg, Grade 1, 2, 3)
Ancillary studies ─
─ IHC: Endothelial cells are positive for vascular markers CD31, CD34 (can be lost in high-grade/epithelioid areas), ERG (nuclear, highly sensitive), and FLI1 (nuclear); Cytokeratins may be positive in epithelioid angiosarcoma (potential pitfall); Negative for S100 protein (except entrapped cells), desmin, SMA (except pericytes/reactive myofibroblasts), HMB45, HHV8
─ Molecular: Complex karyotypes are common; MYC gene amplification is characteristic of radiation-induced and lymphedema-associated angiosarcomas; KDR, PLCG1, and TP53 mutations may occur in sporadic angiosarcomas
DDx

─ Hemangioma / Vascular malformation (lack atypia, mitoses, infiltrative destructive growth)
─ Epithelioid hemangioendothelioma (myxohyaline stroma, specific fusions WWTR1::CAMTA1 or YAP1::TFE3)
─ Kaposi sarcoma (HHV8 positive, characteristic spindle cells and slit-like spaces)
─ Spindle cell/pleomorphic sarcomas (eg, UPS, melanoma, carcinoma - lack consistent vascular marker expression, specific markers for other lineages)
─ Papillary endothelial hyperplasia (Masson tumor) (intravascular, organizing thrombus, lacks atypia)
─ Atypical vascular lesion (post-radiation) (less atypia, lacks frank invasion, MYC negative)
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Spindle Cell Angiosarcoma

A variant of angiosarcoma in which the neoplastic endothelial cells are predominantly spindle-shaped, often forming fascicles and resembling other spindle cell sarcomas, but retaining evidence of vascular differentiation
Clinical ─ Similar to conventional angiosarcoma; can occur in various locations, including skin, soft tissue, and viscera
Macro ─ Often fleshy, firm, or hemorrhagic infiltrative mass
Micro

─ Predominantly composed of atypical spindle cells arranged in intersecting fascicles, sometimes with a herringbone pattern
─ Vasoformative areas with irregular, anastomosing vascular channels lined by atypical spindle endothelial cells must be identifiable, at least focally, to confirm vascular lineage
─ Spindle cells show hyperchromatic, pleomorphic nuclei and increased mitotic activity
─ Necrosis may be present
─ May merge with areas of more classic (vasoformative) or epithelioid angiosarcoma
Ancillary studies ─
─ IHC: Spindle cells are positive for vascular markers ERG and FLI1 (nuclear); CD31 and CD34 may be positive but can be focal or lost, especially in poorly differentiated areas; Negative for S100, desmin, SMA (except reactive cells), keratins (usually)
─ Molecular: Similar to conventional angiosarcoma; MYC amplification if radiation/lymphedema-associated
DDx

─ Other spindle cell sarcomas (eg, fibrosarcoma, leiomyosarcoma, MPNST, synovial sarcoma, spindle cell melanoma - distinguished by specific IHC markers and lack of consistent vascular marker expression throughout the spindle cells)
─ Kaposi sarcoma (HHV8 positive, characteristic slit-like spaces and hyaline globules)
─ Conventional angiosarcoma (more prominent vasoformative areas with epithelioid or hobnail cells)
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Epithelioid Angiosarcoma

An aggressive variant of angiosarcoma composed predominantly (>50-75%) of large, polygonal epithelioid endothelial cells with abundant eosinophilic cytoplasm, often mimicking carcinoma or melanoma
Clinical ─ Typically affects adults; common in deep soft tissues, but can also occur in skin, bone, and viscera (eg, thyroid, adrenal gland); often presents as a rapidly growing, painful mass; tends to be high grade and metastasize early
Macro ─ Fleshy, gray-white to tan, often hemorrhagic and necrotic mass; usually infiltrative
Micro

─ Sheets, nests, or cords of large, polygonal (epithelioid) cells with abundant eosinophilic or amphophilic cytoplasm
─ Nuclei are typically large, vesicular, with prominent, often centrally located nucleoli; marked nuclear pleomorphism and atypia are characteristic
─ Intracytoplasmic vacuoles or lumina (primitive vascular differentiation), sometimes containing red blood cells, may be present in some cells ("blister cells")
─ Focal vasoformation with irregular, anastomosing channels lined by atypical epithelioid cells is usually identifiable, but can be subtle or absent in predominantly solid areas
─ High mitotic rate, including atypical forms, and extensive necrosis are common
Ancillary studies ─
─ IHC: Tumor cells are positive for vascular markers ERG (nuclear, most sensitive) and FLI1 (nuclear); CD31 is often positive; CD34 is frequently negative or only focally positive in epithelioid areas; Cytokeratins (AE1/AE3, CAM5.2) are positive in a significant subset (~30-50%), creating a major diagnostic pitfall with carcinoma; Vimentin is usually positive; Negative for S100 protein, HMB45, Melan-A, desmin, SMA (usually), HHV8
─ Molecular: Complex karyotypes are typical; MYC amplification is generally absent unless it is a post-radiation or lymphedema-associated epithelioid angiosarcoma
DDx

─ Metastatic carcinoma (especially poorly differentiated or sarcomatoid carcinoma) (more diffuse and strong keratin positivity, specific carcinoma markers like GATA3, PAX8, TTF1 positive depending on origin; ERG/FLI1/CD31 negative)
─ Melanoma (S100/SOX10/melanocytic markers positive; ERG/FLI1/CD31 negative)
─ Epithelioid hemangioendothelioma (EHE) (less cytologic atypia/mitoses, characteristic myxohyaline stroma, specific fusions WWTR1::CAMTA1 or YAP1::TFE3)
─ Epithelioid sarcoma (INI1 loss, CD34 often positive, different morphology)
─ Extrarenal rhabdoid tumor (INI1 loss, younger age group typically, different morphology)
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Post-radiation & Lymphedema-associated angiosarcoma

Angiosarcoma arising in the context of prior therapeutic radiation or chronic lymphedema (eg, Stewart-Treves syndrome following mastectomy with axillary lymph node dissection); these are often characterized by MYC amplification
Clinical ─ Radiation-associated: Occurs years (latency usually >5-10 years, median ~7-10 years) after radiation therapy for various cancers (eg, breast, cervix, Hodgkin lymphoma); arises within or at the edge of the radiation field
Clinical ─ Lymphedema-associated (Stewart-Treves syndrome): Develops in longstanding chronic lymphedema, classically in the upper extremity after radical mastectomy and axillary dissection for breast cancer, but can occur in other settings of chronic lymphedema (congenital, post-traumatic, filarial)
Clinical ─ Both types typically present as multifocal violaceous or erythematous papules, plaques, nodules, or diffuse induration; often aggressive with poor prognosis
Macro ─ Bruise-like patches, purplish papules, nodules, or areas of brawny induration; lesions are often multifocal and may ulcerate or bleed
Micro

─ Often starts as a subtle proliferation of anastomosing, irregular vascular channels lined by mildly atypical endothelial cells within the dermis and subcutis, resembling atypical vascular lesion (AVL) in early stages, especially post-radiation
─ Progresses to more obvious angiosarcoma with increasing cellularity, endothelial atypia (hyperchromasia, pleomorphism, prominent nucleoli), multilayering, tufting, and infiltrative growth dissecting collagen and fat
─ Frank vasoformation with anastomosing channels is typical, but epithelioid or spindle cell areas can occur
─ Lymphatic differentiation (dilated, D2-40 positive channels) may be prominent, especially in lymphedema-associated cases
─ Mitotic activity becomes more evident with progression; necrosis may be present
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34 (can be variable), ERG, FLI1; MYC protein overexpression (nuclear staining) is a characteristic and diagnostically useful feature in a high percentage of these angiosarcomas (correlates with MYC amplification); D2-40 may be positive if lymphatic differentiation
─ Molecular: MYC gene amplification (chromosome 8q24) is a key molecular hallmark, particularly in radiation-associated angiosarcoma and Stewart-Treves syndrome
DDx

─ Atypical vascular lesion (AVL) (post-radiation) (less cellularity, minimal atypia, lacks frank invasion or multilayering, MYC negative or only very focal/weak protein expression, no MYC amplification)
─ Kaposi sarcoma (HHV8 positive, MYC negative)
─ Cutaneous metastasis from other cancers (specific markers for primary)
─ Other types of angiosarcoma (sporadic) (MYC amplification usually absent unless occult radiation/lymphedema)
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Postradiation Atypical Vascular Lesion

A benign or low-grade vascular proliferation occurring in previously irradiated skin, characterized by small, anastomosing lymphatic-like or capillary-like channels with minimal atypia; important to distinguish from postradiation angiosarcoma
Clinical ─ Develops months to years after radiation therapy (latency often 3-6 years); typically arises in the skin within the radiation field (eg, breast, chest wall); presents as solitary or multiple, small, reddish, violaceous, or skin-colored papules, vesicles, or plaques; generally stable or slowly progressive
Macro ─ Small (<1-2 cm), discrete papules, vesicles, or flat plaques; color varies from pink/red to violaceous or brownish
Micro

─ Well-demarcated (usually) proliferation of thin-walled, irregular, anastomosing vascular channels primarily in the superficial dermis, sometimes extending deeper
─ Channels are often dilated and may appear empty or contain scant lymph or blood, resembling lymphatic vessels (lymphatic-type AVL) or small capillaries (capillary-type AVL)
─ Endothelial cells are generally flattened or slightly plump, with minimal to mild cytologic atypia (some nuclear hyperchromasia or enlargement may be seen, but no significant pleomorphism, prominent nucleoli, or multilayering)
─ Mitotic activity is very low or absent
─ Lacks frank infiltrative growth into surrounding structures, significant endothelial multilayering, tufting, or necrosis seen in angiosarcoma
─ Background dermis often shows radiation-induced changes (fibrosis, elastosis, telangiectasias)
Ancillary studies ─
─ IHC: Endothelial cells are positive for CD31, CD34, ERG, FLI1; D2-40 (podoplanin) is often positive in lymphatic-type AVL; MYC protein expression is typically negative or only very focally weak (in contrast to strong, diffuse MYC in postradiation angiosarcoma)
─ Molecular: MYC gene amplification is absent (a key feature distinguishing from postradiation angiosarcoma)
DDx

─ Postradiation angiosarcoma (shows infiltrative growth, significant endothelial atypia, multilayering, mitoses, necrosis, and typically MYC overexpression/amplification)
─ Lymphatic malformation / Lymphangioma circumscriptum (if lymphatic-type; AVL is acquired post-radiation, malformations often congenital/earlier onset)
─ Telangiectasias (simple dilation of pre-existing vessels, no endothelial proliferation)
─ Kaposi sarcoma (HHV8 positive, spindle cells)
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Perivascular Epithelioid Cell Tumor (PEComa) (Vascular Context)

A mesenchymal neoplasm composed of histologically and immunohistochemically distinctive perivascular epithelioid cells (PECs), which show features of both smooth muscle and melanocytic differentiation; this entry focuses on its occurrence in soft tissue, where it often presents as a mass with prominent vasculature, although PEComas can arise in virtually any anatomic site
Clinical ─ Affects a wide age range, more common in females; sites include uterus, retroperitoneum, kidney (angiomyolipoma), liver, lung, and soft tissues; may be associated with Tuberous Sclerosis Complex (TSC), especially angiomyolipomas and lymphangioleiomyomatosis (LAM); presentation varies from incidental finding to symptomatic mass; behavior ranges from benign to malignant, with criteria for malignancy including large size (>5 cm), infiltrative growth, high nuclear grade, necrosis, and high mitotic activity (>1/50 HPF)
Macro ─ Variable; often well-circumscribed, fleshy or firm, tan-white to brown mass; may show hemorrhage or necrosis in malignant cases; angiomyolipomas are characterized by fat, muscle, and vessels
Micro

─ Composed of epithelioid cells with clear to granular eosinophilic cytoplasm, arranged in nests, sheets, or fascicles, often intimately associated with blood vessel walls ("perivascular")
─ Nuclei are typically round to oval, centrally located, with vesicular chromatin and small nucleoli; atypia varies from bland to markedly pleomorphic in malignant cases
─ Spindle cell component may be present
─ Stroma is often scant, but can be hyalinized or myxoid
─ Vasculature can be prominent, sometimes with thick hyalinized walls
─ Specific PEComa family members include angiomyolipoma (AML), lymphangioleiomyomatosis (LAM), clear cell "sugar" tumor of lung, and a group of rare miscellaneous PEComas in other sites
Ancillary studies ─
─ IHC: Characteristically co-expresses melanocytic markers (HMB45, Melan-A/MART-1, MITF) and smooth muscle markers (SMA, calponin, desmin - desmin often weaker or focal); TFE3 nuclear positivity in a subset of PEComas, especially those with TFE3 gene fusions (often HMB45/Melan-A negative); S100 protein is variably positive (often weak/focal); Negative for keratins, ERG, FLI1 (usually)
─ Molecular: Many sporadic PEComas and TSC-associated PEComas show inactivating mutations in TSC1 or TSC2 genes (leading to mTOR pathway activation); A subset of PEComas (often uterine, HMB45/Melan-A negative) harbor TFE3 gene fusions (eg, SFPQ::TFE3, ASPSCR1::TFE3)
DDx

─ Melanoma (especially clear cell or spindle cell) (lacks consistent smooth muscle marker expression; specific melanoma mutations like BRAF may be present)
─ Clear cell sarcoma of soft tissue (EWSR1::ATF1/CREB1 fusion, lacks smooth muscle markers)
─ Epithelioid smooth muscle tumors (eg, epithelioid leiomyoma/leiomyosarcoma) (lack melanocytic markers)
─ Epithelioid GIST (CD117/DOG1 positive, lacks melanocytic markers, arises in GI tract)
─ Clear cell renal cell carcinoma (metastatic) (PAX8/CAIX positive, lacks melanocytic/smooth muscle markers)
─ Alveolar soft part sarcoma (ASPSCR1::TFE3 fusion but different morphology with nests/crystals, TFE3 IHC positive)
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Skin video WSI HEHMB45MelanA video video

Glomus tumor

A benign neoplasm composed of modified smooth muscle cells resembling those of the normal glomus body, an arteriovenous anastomosis involved in thermoregulation
Clinical ─ Affects adults (wide age range, peak 20-50s); common in distal extremities, especially subungual region of fingers and toes, also occurs in deep soft tissues, viscera, and bone; often presents as a small (<1 cm), solitary, intensely painful (especially with cold or pressure), bluish-red papule or nodule; multiple lesions can occur (glomangiomatosis)
Macro ─ Small, well-circumscribed, firm, reddish-blue to purple nodule; may appear encapsulated
Micro

─ Solid sheets, nests, or cords of uniform, round to polygonal cells (glomus cells) with scant eosinophilic or clear cytoplasm and sharply defined cell borders
─ Nuclei are round, centrally located, with fine chromatin and inconspicuous nucleoli ("punched-out" appearance)
─ Cells are typically arranged around capillary-sized blood vessels, which may be prominent or inconspicuous
─ Minimal intervening stroma
─ No significant cytologic atypia or mitotic activity (malignant glomus tumor is rare and defined by specific criteria)
─ Variants:
─ Solid glomus tumor (most common): Predominantly sheets of glomus cells with sparse vasculature
─ Glomangioma: Prominent, dilated, cavernous-like vascular component admixed with glomus cells
─ Glomangiomyoma: Features of glomangioma with additional well-developed smooth muscle fascicles
─ Symplastic glomus tumor: Contains bizarre, pleomorphic nuclei but lacks other features of malignancy (rare mitoses, no necrosis)
Ancillary studies ─
─ IHC: Glomus cells are positive for SMA (smooth muscle actin) and MSA (muscle-specific actin); Type IV collagen highlights cell nests (chicken-wire pattern); Vimentin positive; Negative for desmin (usually), S100 protein, keratins, CD34 (except vessels), endothelial markers
─ Molecular: Recurrent NOTCH gene fusions (eg, MIR143::NOTCH2, NOTCH1/2/3 rearrangements) are characteristic of glomus tumors and related lesions; BRAF V600E mutations in a subset of symplastic glomus tumors
DDx

─ Myopericytoma (more prominent concentric perivascular proliferation of spindle cells, often desmin negative, PDGFRB mutated)
─ Eccrine spiradenoma / Poroma (if cutaneous; keratin/EMA positive, show ductal differentiation)
─ Epithelioid vascular tumors (eg, epithelioid hemangioma - CD31/ERG positive)
─ Paraganglioma (S100 positive sustentacular cells, neuroendocrine markers positive)
─ Melanocytic nevus (intradermal) (S100/melanocytic markers positive)
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Myopericytoma

A benign perivascular neoplasm composed of oval to spindle cells (myopericytes) showing a characteristic concentric perivascular proliferation around blood vessels; considered part of a spectrum with myofibroma and glomus tumor
Clinical ─ Typically affects adults (wide age range, peak 30-50s); common in skin and subcutaneous tissue of the extremities (especially distal), less often head/neck or trunk; presents as a solitary, slow-growing, usually painless, firm nodule, typically <2 cm
Macro ─ Well-circumscribed, often pseudoencapsulated, firm, gray-white to tan nodule
Micro

─ Well-demarcated, often lobulated proliferation of relatively bland, oval to spindle-shaped myoid-appearing cells (myopericytes) with eosinophilic cytoplasm and indistinct cell borders
─ Characteristic feature: Concentric, multilayered proliferation of tumor cells around small to medium-sized blood vessels, often with hyalinized vessel walls
─ Cells may also form solid sheets or fascicles in areas away from vessels
─ Stroma is variably collagenous or myxoid
─ Minimal cytologic atypia, mitotic activity is low (usually <1/10 HPF), necrosis is absent
─ Malignant myopericytoma is rare, defined by increased size, infiltrative growth, atypia, mitoses, and necrosis
Ancillary studies ─
─ IHC: Tumor cells are consistently positive for SMA (smooth muscle actin) and often MSA (muscle-specific actin); Calponin may be positive; Desmin is typically negative or only very focally positive (helps distinguish from angioleiomyoma); Negative for S100 protein, keratins, CD34 (except vessels), endothelial markers
─ Molecular: Recurrent PDGFRB gene rearrangements or mutations have been identified in many cases, linking them to myofibroma/myofibromatosis and some glomus tumors
DDx

─ Glomus tumor (more uniform round cells with distinct borders, less concentric perivascular growth usually, NOTCH fusions, often desmin negative but SMA+)
─ Angioleiomyoma (more prominent thick-walled muscular vessels, interlocking smooth muscle fascicles, desmin positive, lacks concentric myopericytic proliferation)
─ Solitary fibrous tumor (STAT6 positive, CD34 positive, hemangiopericytoma-like vessels but different cell type)
─ Myofibroma (often biphasic with primitive round cells and more mature spindle cells, hemangiopericytoma-like vessels, PDGFRB altered - part of spectrum)
─ Eccrine spiradenoma (if cutaneous; shows ductal differentiation, keratin positive)
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Myofibroma / Myofibromatosis

Benign mesenchymal neoplasms composed of myofibroblasts, often showing a characteristic biphasic pattern with primitive round cells and more differentiated spindle cells, typically with a hemangiopericytoma-like vascular pattern; Myofibroma refers to a solitary lesion, while myofibromatosis indicates multiple lesions (often congenital/infantile) which can involve skin, soft tissue, bone, and viscera
Clinical ─ Myofibroma (solitary): Affects all ages, common in adults as well as children; often skin/subcutis of head/neck or trunk
Clinical ─ Myofibromatosis (multiple): Primarily infants and young children (most <2 years, many congenital - "congenital generalized myofibromatosis"); can be multicentric cutaneous/soft tissue, or involve bone and internal organs (visceral involvement carries poorer prognosis)
Clinical ─ Both present as firm, painless or tender nodules
Macro ─ Well-circumscribed, firm, rubbery nodule(s); cut surface is gray-white to tan, often with a whorled or vaguely lobulated appearance; size varies from <1 cm to several centimeters
Micro

─ Well-demarcated, often lobulated or multinodular proliferation
─ Characteristic biphasic pattern is common, especially in infantile/multiple lesions:
─ Peripheral areas: Composed of fascicles of bland spindle cells (myofibroblasts) with eosinophilic cytoplasm and elongated nuclei, resembling smooth muscle or fibromatosis
─ Central areas: Less differentiated, more cellular zones of small, primitive-appearing round to oval cells with scant cytoplasm and dark nuclei, often with a prominent hemangiopericytoma-like (staghorn) vascular pattern
─ Adult solitary myofibromas may be more uniformly spindle-celled and collagenous, resembling leiomyoma or fibroma
─ Mitotic activity is usually low, cytologic atypia is minimal, necrosis is typically absent (though central ischemic necrosis can occur in larger lesions)
Ancillary studies ─
─ IHC: Spindle cells and primitive round cells are positive for vimentin and SMA (smooth muscle actin); MSA (muscle-specific actin) is often positive; Desmin is variably positive (often focal, patchy, or negative, distinguishing from leiomyoma which is diffusely desmin positive); CD34 may highlight vasculature or be focally positive in tumor cells; Negative for S100 protein, keratins, nuclear beta-catenin
─ Molecular: Recurrent activating mutations or rearrangements in PDGFRB gene are common, particularly in infantile myofibromatosis; NOTCH3 mutations also reported; some adult myofibromas may show SRF-RELA fusions
DDx

─ Leiomyoma (more distinctly smooth muscle, diffusely desmin and h-caldesmon positive, usually lacks biphasic pattern/HP-like vessels)
─ Infantile fibromatosis (spectrum, may lack biphasic pattern and HP-like vessels, often more infiltrative)
─ Myopericytoma (more prominent concentric perivascular proliferation of myopericytes, usually desmin negative, PDGFRB altered - part of spectrum)
─ Solitary fibrous tumor (STAT6 positive, CD34 diffusely positive in spindle cells, NAB2::STAT6 fusion)
─ Nodular fasciitis (more myxoid, "tissue culture" appearance, USP6 rearranged)
─ Glomus tumor (different cell morphology, NOTCH fusions, desmin negative)
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Angioleiomyoma

A benign smooth muscle tumor arising from the tunica Media ─ placeholderof small veins or arteries, characterized by an admixture of mature smooth muscle fascicles and numerous thick-walled blood vessels; also known as vascular leiomyoma
Clinical ─ Typically affects adults (peak age 30-60s), with a female predominance; most common in the subcutaneous tissue of the lower extremities (especially legs and feet), also upper extremities and head/neck; usually presents as a solitary, small (<2 cm), firm, well-circumscribed nodule that is often painful or tender, particularly with pressure or temperature changes
Macro ─ Well-circumscribed, often encapsulated, firm, rubbery nodule; cut surface is typically gray-white to tan or reddish-brown, may appear whorled or vascular
Micro

─ Well-demarcated, often encapsulated proliferation of mature smooth muscle cells intimately admixed with numerous small to medium-sized, thick-walled blood vessels
─ Smooth muscle cells are arranged in intersecting fascicles and bundles that often appear to merge with or radiate from the muscular walls of the vessels
─ Cells have eosinophilic fibrillar cytoplasm and elongated, blunt-ended ("cigar-shaped") nuclei without significant atypia or pleomorphism
─ Blood vessel walls are typically thick and muscular, sometimes with hyalinization
─ Mitotic activity is rare to absent; necrosis is not seen
─ Variants based on predominant vessel type: Solid (compact smooth muscle, inconspicuous vessels), Cavernous (dilated vessels, less smooth muscle), Venous (thick-walled veins, prominent smooth muscle)
─ Adipose tissue, myxoid change, or calcification can be present focally
Ancillary studies ─
─ IHC: Smooth muscle cells are diffusely and strongly positive for SMA (smooth muscle actin), MSA (muscle-specific actin), desmin, and h-caldesmon; Endothelial cells lining vessels are CD31/CD34/ERG positive
─ Molecular: No specific recurrent genetic alterations are consistently identified
DDx

─ Leiomyoma (conventional) (less prominent vascular component, may occur in different sites like uterus/skin - pilar)
─ Myopericytoma (concentric perivascular proliferation of myopericytes, typically desmin negative or very focal, PDGFRB altered)
─ Glomus tumor (different round cell morphology, NOTCH fusions, desmin negative)
─ Angiosarcoma (malignant endothelial atypia, infiltrative growth)
─ PEComa (co-expresses melanocytic markers like HMB45/Melan-A)
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Soft Tissue, Muscular

Leiomyoma

A benign neoplasm composed of mature smooth muscle cells, characterized by intersecting fascicles of spindle cells with eosinophilic cytoplasm and blunt-ended, "cigar-shaped" nuclei
Clinical ─ Common, can occur at any age but most frequent in adults; arises in various locations:
─ Cutaneous leiomyomas: Arise from arrector pili muscles (pilar leiomyoma - often multiple and painful) or dartos muscle of genital skin (genital leiomyoma)
─ Deep soft tissue leiomyomas: Less common, occur in extremities, retroperitoneum, abdominal cavity
─ Vascular leiomyomas (angioleiomyomas): Arise from vessel walls (see separate entry)
─ Uterine leiomyomas ("fibroids"): Extremely common in women of reproductive age
Clinical ─ Presentation varies by site; cutaneous lesions are firm papules/nodules; deep lesions are often slow-growing masses
Macro ─ Typically well-circumscribed, firm, gray-white to tan masses; cut surface often shows a whorled or fascicular pattern; size is variable
Micro

─ Composed of intersecting fascicles of relatively uniform spindle cells with abundant eosinophilic, fibrillar cytoplasm and elongated, blunt-ended ("cigar-shaped") nuclei
─ Nuclei have fine chromatin and inconspicuous nucleoli
─ Minimal to no cytologic atypia, pleomorphism is absent or very focal (eg, symplastic change in some uterine leiomyomas)
─ Mitotic activity is rare to absent (typically <1-2/10 HPF in soft tissue leiomyomas, criteria vary by site, eg, uterine leiomyomas have specific criteria)
─ Necrosis is generally absent (coagulative tumor cell necrosis is a feature of leiomyosarcoma, though hyaline necrosis can be seen in benign lesions)
─ Stroma is variably collagenous, may show myxoid change or hyalinization
─ Variants include: Cellular, epithelioid, myxoid, hydropic, symplastic (bizarre nuclei but low mitoses, benign in uterus)
Ancillary studies ─
─ IHC: Tumor cells are diffusely and strongly positive for SMA (smooth muscle actin), MSA (muscle-specific actin), desmin, and h-caldesmon; Estrogen receptor (ER) and progesterone receptor (PR) are often positive, especially in genital tract and some deep soft tissue leiomyomas; Negative for S100 protein, keratins, CD34 (except vessels)
─ Molecular: Uterine leiomyomas frequently have MED12 mutations, HMGA2 rearrangements, or FH inactivation; soft tissue leiomyomas less well characterized genetically, but some deep lesions show 1p deletions or ALK rearrangements (inflammatory leiomyoma phenotype)
DDx

─ Leiomyosarcoma (distinguished by presence of significant cytologic atypia, tumor cell necrosis, and/or increased mitotic activity beyond site-specific thresholds)
─ Myofibroma/Myofibromatosis (often biphasic, hemangiopericytoma-like vessels, desmin may be patchy or negative, CD34 often positive)
─ Schwannoma (wavy nuclei, Verocay bodies, Antoni A/B pattern, S100 positive, desmin negative)
─ Solitary fibrous tumor (STAT6 positive, CD34 positive, characteristic vasculature)
─ Fibromatosis (desmoid-type) (infiltrative, nuclear beta-catenin positive, lacks strong desmin/h-caldesmon)
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Disseminated Peritoneal Leiomyomatosis, Intravenous Leiomyomatosis, and Benign Metastasizing Leiomyoma

A group of rare, unusual smooth muscle proliferative conditions, typically occurring in women of reproductive age with a history of uterine leiomyomas, characterized by histologically benign smooth muscle lesions in extrapulmonary sites (DPL, IVL) or lungs (BML)
Clinical ─ DPL: Multiple benign smooth muscle nodules studding peritoneal surfaces, often an incidental finding during surgery or imaging in women with uterine leiomyomas or hormonal exposure (pregnancy, oral contraceptives)
Clinical ─ IVL: Grossly visible, worm-like plugs of benign smooth muscle tissue extending from uterine or pelvic veins into larger veins (eg, iliac veins, inferior vena cava, rarely right heart); can cause venous obstruction or cardiac symptoms
Clinical ─ BML: Multiple, bilateral, well-circumscribed benign smooth muscle nodules in the lungs, typically asymptomatic and found incidentally on imaging in women with a history of uterine leiomyomas (often years after hysterectomy)
Macro ─ DPL: Numerous small, firm, gray-white nodules on peritoneum; IVL: Rubbery, tan-white, cord-like masses within veins; BML: Multiple, discrete, firm, gray-white nodules in lung parenchyma
Micro

─ All three conditions are characterized by histologically bland smooth muscle proliferation identical to uterine leiomyoma:
─ Intersecting fascicles of uniform spindle cells with eosinophilic cytoplasm and cigar-shaped nuclei
─ Minimal to no cytologic atypia, rare mitotic figures (usually <5/10 HPF), no tumor cell necrosis
─ DPL: Nodules are submesothelial, may show hydropic change or decidualization if hormonally stimulated
─ IVL: Smooth muscle nodules are within vessel lumina, often attached to vessel wall; may show hyalinization or hydropic change
─ BML: Well-circumscribed nodules in lung parenchyma, may compress adjacent alveoli; can show hydropic change, hyalinization, or focal calcification
Ancillary studies ─
─ IHC: Smooth muscle cells are positive for SMA, MSA, desmin, h-caldesmon; ER and PR are typically strongly positive; Negative for S100, keratins
─ Molecular: Clonality has been demonstrated, suggesting a metastatic or disseminated neoplastic process rather than metaplasia; some cases show genetic alterations similar to uterine leiomyomas (eg, MED12 mutations, HMGA2 rearrangements)
DDx

─ Leiomyosarcoma (metastatic or primary) (shows cytologic atypia, necrosis, significant mitoses; crucial to distinguish, especially for BML and IVL)
─ Endometriosis (if peritoneal) (contains endometrial glands and stroma, CD10 positive stroma)
─ Peritoneal mesothelioma (keratin positive, calretinin/WT1 positive)
─ Multiple pulmonary hamartomas (if BML) (contain cartilage, fat, entrapped epithelium)
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Leiomyosarcoma

A malignant mesenchymal neoplasm showing smooth muscle differentiation, characterized by intersecting fascicles of atypical spindle cells with eosinophilic cytoplasm and blunt-ended nuclei
Clinical ─ Typically affects adults (peak 50-70s); common sites include deep soft tissues of extremities (especially thigh), retroperitoneum, uterus, large blood vessels (eg, inferior vena cava - "vascular leiomyosarcoma"), and skin (cutaneous/subcutaneous - "superficial leiomyosarcoma"); presentation varies by site, often a growing, sometimes painful mass; retroperitoneal lesions can be very large at diagnosis
Macro ─ Often appears well-circumscribed but is infiltrative; cut surface is typically fleshy, firm, gray-white to tan, with a whorled or fascicular appearance; hemorrhage and necrosis are common, especially in larger or higher-grade tumors
Micro

─ Cellular proliferation of spindle cells with eosinophilic, fibrillar cytoplasm and elongated, blunt-ended ("cigar-shaped") nuclei, arranged in intersecting fascicles (often at right angles)
─ Diagnosis requires presence of smooth muscle differentiation (usually by IHC) and malignant features:
─ Significant cytologic atypia (pleomorphism, hyperchromasia, irregular nuclear contours, prominent nucleoli)
─ Tumor cell necrosis (coagulative type)
─ Increased mitotic activity (thresholds vary by site and tumor type, eg, >5-10/10 HPF in soft tissue; criteria for uterine LMS are more complex)
─ At least two of these three features are generally required for malignancy in soft tissue (atypia + mitoses, or atypia + necrosis, or mitoses + necrosis if atypia is borderline); some advocate any one if marked
─ Grading (Grade 1, 2, 3) based on differentiation, atypia, mitotic rate, and extent of necrosis
─ Variants include: Epithelioid, myxoid, inflammatory, dedifferentiated leiomyosarcoma
Ancillary studies ─
─ IHC: Tumor cells are positive for SMA (smooth muscle actin), MSA (muscle-specific actin), desmin, and h-caldesmon (most specific smooth muscle marker); ER/PR may be positive, especially in uterine/retroperitoneal tumors in females; Negative for S100 protein, keratins (except rare focal positivity), CD34, STAT6
─ Molecular: Complex karyotypes with numerous gains and losses are common; TP53 and RB1 pathway alterations are frequent; no specific recurrent translocations define most leiomyosarcomas (unlike some other sarcomas)
DDx

─ Leiomyoma (cellular or atypical variants) (lacks sufficient atypia, necrosis, or high mitoses according to site-specific criteria)
─ Other spindle cell sarcomas (eg, fibrosarcoma, MPNST, synovial sarcoma, UPS - distinguished by specific IHC markers, molecular genetics, and morphology)
─ Gastrointestinal stromal tumor (GIST) (if GI tract; CD117/DOG1 positive, KIT/PDGFRA mutated)
─ Myofibroblastic sarcoma (desmin often weaker/patchier, h-caldesmon usually negative)
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EBV-associated smooth muscle tumor

A rare smooth muscle neoplasm occurring almost exclusively in the setting of immunodeficiency (congenital, acquired e.g., HIV/AIDS, or iatrogenic e.g., post-transplant), characterized by Epstein-Barr virus (EBV) infection of the tumor cells
Clinical ─ Affects immunocompromised individuals of any age; common sites include central nervous system (CNS - brain, spinal cord), viscera (liver, GI tract, lung), and less commonly soft tissues; lesions are often multifocal and may behave aggressively if immunosuppression cannot be reversed
Macro ─ Variable; often well-circumscribed nodules or masses, but can be infiltrative; cut surface is typically gray-white to tan, fleshy
Micro

─ Proliferation of spindle cells resembling conventional smooth muscle, arranged in intersecting fascicles or sheets
─ Cytologic atypia can range from bland (leiomyoma-like) to moderate or marked (leiomyosarcoma-like)
─ Mitotic activity is variable
─ A prominent intratumoral lymphocytic infiltrate (often T-cells) is a characteristic feature, sometimes obscuring the spindle cells
─ Necrosis may be present, especially in higher-grade lesions
─ Primitive round cell or epithelioid morphology can occur
Ancillary studies ─
─ IHC: Spindle cells are positive for smooth muscle markers (SMA, MSA, desmin); EBV infection is demonstrated by EBER (EBV-encoded RNA) in situ hybridization (nuclear signal in tumor cells - diagnostic); LMP1 (latent membrane protein 1) may also be positive; Lymphoid infiltrate is CD3/CD8 positive T-cells typically, with scattered CD20 positive B-cells; CD21 may highlight follicular dendritic cells if lymphoid follicles are present
─ Molecular: Clonal EBV infection within tumor cells
DDx

─ Conventional leiomyoma or leiomyosarcoma (EBER negative, typically occurs in immunocompetent individuals, lymphocytic infiltrate usually less prominent or different character)
─ Inflammatory myofibroblastic tumor (IMT) (ALK positive in a subset, different inflammatory pattern, EBER negative)
─ Kaposi sarcoma (HHV8 positive, different morphology and IHC)
─ Lymphoma with spindle cell features (lymphoid markers positive throughout spindle cells, EBER may be positive in some lymphoma types but smooth muscle markers negative)
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Inflammatory leiomyosarcoma

A rare variant of leiomyosarcoma characterized by a significant inflammatory infiltrate intimately admixed with malignant smooth muscle cells; its distinctness from leiomyosarcoma with reactive inflammation is debated, and it may overlap with ALK-rearranged inflammatory leiomyomas/leiomyosarcomas when ALK is positive
Clinical ─ Typically affects adults; sites are variable, including retroperitoneum, uterus, deep soft tissues, and GI tract; may present with systemic symptoms (fever, weight loss) in addition to mass effect
Macro ─ Fleshy, often large and infiltrative mass; may have areas of hemorrhage, necrosis, and a yellowish or tan inflammatory appearance
Micro

─ Features of leiomyosarcoma: Intersecting fascicles of atypical spindle cells with eosinophilic cytoplasm and cigar-shaped nuclei, exhibiting cytologic atypia, tumor cell necrosis, and/or significant mitotic activity
─ Defining feature: A prominent and diffuse inflammatory infiltrate intimately admixed with the tumor cells, which can sometimes obscure the underlying sarcoma
─ Inflammatory cells typically include lymphocytes, plasma cells, neutrophils, eosinophils, and histiocytes (including foamy macrophages)
─ Vasculature can be prominent
Ancillary studies ─
─ IHC: Malignant spindle cells are positive for smooth muscle markers (SMA, MSA, desmin, h-caldesmon); Inflammatory cells show expected markers (eg, CD45, CD68, CD3, CD20, CD138); ALK protein expression should be assessed, as some ALK-rearranged smooth muscle tumors can have prominent inflammation and aggressive behavior (these may be better classified as ALK-rearranged leiomyoma/leiomyosarcoma)
─ Molecular: If ALK positive, ALK gene rearrangements may be present; otherwise, complex karyotypes similar to conventional leiomyosarcoma are expected
DDx

─ Inflammatory myofibroblastic tumor (IMT) (usually less cytologic atypia in spindle cells, ALK positive in a subset, often lacks diffuse desmin/h-caldesmon)
─ Xanthogranulomatous inflammation / Inflammatory pseudotumor (reactive process, lacks true malignant spindle cells with smooth muscle differentiation)
─ Dedifferentiated liposarcoma with inflammatory component (MDM2/CDK4 positive, arises from WDLPS/ALT)
─ Leiomyosarcoma with reactive inflammation (distinction may be subjective and difficult; inflammatory LMS implies inflammation is an integral part of the tumor)
─ Gastrointestinal stromal tumor (GIST) with inflammation (if GI tract; CD117/DOG1 positive)
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Adult Rhabdomyoma

A benign neoplasm composed of large, polygonal cells showing mature skeletal muscle differentiation, typically occurring in the head and neck region of older adults
Clinical ─ Typically affects adults (median age ~60s), with a male predominance; most common in the head/neck region, particularly larynx, pharynx, oral cavity (tongue, floor of mouth), and soft tissues of the neck; less commonly in other sites like heart (cardiac rhabdomyoma - often associated with tuberous sclerosis, distinct entity); presents as a slow-growing, painless, solitary or multinodular mass, may cause obstructive symptoms (eg, hoarseness, dysphagia) depending on location
Macro ─ Well-circumscribed, often lobulated or polypoid, firm, tan-pink to red-brown mass; cut surface may appear fleshy or granular; size varies, usually 1-5 cm
Micro

─ Composed of sheets, nests, or lobules of large, polygonal to round cells with abundant, deeply eosinophilic, granular cytoplasm (due to numerous mitochondria)
─ Cells often contain intracytoplasmic vacuoles (glycogen accumulation), which can indent the nucleus, sometimes creating a "spider cell" appearance (more typical of cardiac rhabdomyoma)
─ Nuclei are typically round, centrally or eccentrically located, with vesicular chromatin and often prominent nucleoli
─ Intracytoplasmic crystalline inclusions (rod-like or needle-like, "jackstraw" pattern) composed of actin/myosin filaments may be seen and are characteristic when present
─ Cross-striations may be identifiable but can be focal or difficult to discern without special stains
─ Minimal to no cytologic atypia, mitotic activity is rare to absent
─ Stroma is usually scant, with a rich capillary network
Ancillary studies ─
─ IHC: Tumor cells are strongly positive for myogenic markers: desmin, MSA (muscle-specific actin), myoglobin; MyoD1 and myogenin are often positive but can be patchy or weak (unlike rhabdomyosarcoma which usually shows strong nuclear staining); Phosphotungstic acid-hematoxylin (PTAH) stain can highlight cross-striations and crystalline inclusions
─ IHC: Negative for S100 protein (except entrapped nerves), keratins
─ Molecular: Some cases have shown mutations in PTCH1 or other genes in the hedgehog signaling pathway, but no consistent defining genetic alteration for sporadic adult rhabdomyoma
DDx

─ Granular cell tumor (S100 positive, SOX10 positive, lacks cross-striations and myogenic markers like desmin/myoglobin)
─ Hibernoma (composed of brown fat, UCP1 positive, lacks cross-striations/myogenic markers)
─ Oncocytoma (if in glandular sites; composed of oncocytes, lacks cross-striations/myogenic markers, keratin positive)
─ Rhabdomyosarcoma (especially pleomorphic or embryonal variants) (shows malignant cytologic features, atypia, high mitoses, more diffuse MyoD1/myogenin)
─ Paraganglioma (neuroendocrine markers positive, S100 positive sustentacular cells)
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Fetal Rhabdomyoma, Classic -Type

A benign neoplasm composed of immature skeletal muscle cells resembling fetal muscle at various stages of development (typically 7-12 weeks gestation), most commonly occurring in the head and neck of male infants and young children
Clinical ─ Primarily affects male infants and young children (most cases <3 years old); most common in the head/neck region, particularly preauricular or postauricular soft tissues, also face, orbit, and upper respiratory tract; presents as a solitary, slow-growing, painless, subcutaneous or deep soft tissue mass
Macro ─ Poorly defined or circumscribed, firm, rubbery, gray-white to tan mass; cut surface may appear fleshy or myxoid
Micro

─ Composed of relatively uniform, immature spindle cells mixed with differentiating rhabdomyoblasts at various stages of maturation, set in a loose, often myxoid or edematous stroma
─ Spindle cells have scant cytoplasm and elongated, hyperchromatic nuclei
─ Differentiating rhabdomyoblasts may be strap-shaped, tadpole-shaped, or round, with more abundant eosinophilic cytoplasm; cross-striations are often identifiable but can be focal
─ Cells resemble developing fetal skeletal muscle of the first trimester
─ Minimal to mild cytologic atypia; mitotic activity is generally low but can be present, not atypical
─ No cambium layer (unlike botryoid embryonal rhabdomyosarcoma)
Ancillary studies ─
─ IHC: Tumor cells are positive for desmin, MSA (muscle-specific actin); Myogenin and MyoD1 are usually positive and often more diffusely expressed than in adult rhabdomyoma, highlighting the immature skeletal muscle differentiation; Vimentin positive
─ IHC: Negative for S100 protein, keratins
─ Molecular: No specific recurrent genetic alterations are consistently identified for diagnostic purposes; distinct from embryonal rhabdomyosarcoma which may have RAS pathway mutations
DDx

─ Embryonal rhabdomyosarcoma (more cellular, greater cytologic atypia, pleomorphism, higher mitotic rate, cambium layer in botryoid variant, more aggressive clinical behavior)
─ Spindle cell rhabdomyosarcoma (infantile type) (often congenital, specific fusions like VGLL2::NCOA2, may be more uniformly spindle cell)
─ Infantile fibromatosis/myofibromatosis (lacks definitive rhabdomyoblastic differentiation and myogenic marker expression like MyoD1/myogenin)
─ Fibrous hamartoma of infancy (triphasic pattern, different locations typically)
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Fetal Rhabdomyoma, Intermediate-Type

A rare variant of fetal rhabdomyoma showing features intermediate between the classic fetal type and adult rhabdomyoma, often occurring in older children or young adults and involving head and neck sites; also known as juvenile rhabdomyoma
Clinical ─ Tends to occur in older children and young adults compared to classic fetal rhabdomyoma, but younger than typical adult rhabdomyoma; head/neck region is the most common location
Macro ─ Similar to classic fetal or adult rhabdomyoma: circumscribed or poorly defined, firm mass
Micro

─ Shows a spectrum of features overlapping between classic fetal rhabdomyoma and adult rhabdomyoma
─ More cellular and less myxoid than classic fetal rhabdomyoma
─ Contains a mixture of immature spindle cells and larger, more polygonal cells with more abundant eosinophilic cytoplasm than classic fetal type, but generally lacking the prominent granular cytoplasm or crystalline inclusions of adult rhabdomyoma
─ Cross-striations are usually present and may be more easily found than in some classic fetal types
─ Cytologic atypia is minimal, mitotic activity is low
Ancillary studies ─
─ IHC: Positive for desmin, MSA, MyoD1, and myogenin; the expression of MyoD1/myogenin may be more consistent than in adult rhabdomyoma but less diffuse than in some classic fetal types
─ Molecular: Not well characterized, no specific defining genetic alterations known
DDx

─ Classic fetal rhabdomyoma (more myxoid, more immature spindle cells)
─ Adult rhabdomyoma (larger polygonal cells with granular cytoplasm, +/- crystalline inclusions, typically older patients)
─ Embryonal rhabdomyosarcoma (malignant features, atypia, higher mitoses)
─ Leiomyoma (if spindle cell areas predominate; lacks cross-striations, strong desmin/h-caldesmon but MyoD1/myogenin negative)
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Rhabdomyoma, Genital-Type

A benign neoplasm composed of relatively bland spindle and stellate cells showing focal skeletal muscle differentiation, occurring almost exclusively in the vulvovaginal region of adult women
Clinical ─ Primarily affects adult women of reproductive age (peak 20-40s); most common in the vulva, less frequently vagina or cervix; presents as a solitary, slow-growing, polypoid or nodular, painless or mildly tender mass; usually small (<5 cm)
Macro ─ Polypoid, fleshy, or rubbery mass; cut surface is typically gray-white to tan, may appear edematous or myxoid
Micro

─ Hypocellular to moderately cellular proliferation of bland spindle, stellate, or oval cells set in a loose, abundant, edematous or myxoid stroma
─ Cells have scant pale eosinophilic cytoplasm and elongated or ovoid vesicular nuclei; cytologic atypia is minimal or absent
─ Scattered larger cells with more abundant eosinophilic cytoplasm and occasionally identifiable cross-striations (rhabdomyoblasts) may be present, but can be very focal and require careful search
─ Blood vessels are often prominent, thin-walled, and ectatic
─ Low mitotic activity, necrosis is absent
─ Often covered by squamous epithelium if polypoid and superficial
Ancillary studies ─
─ IHC: Tumor cells (especially larger, more differentiated ones) are positive for desmin and MSA; MyoD1 and myogenin are often positive but typically focal and restricted to the more differentiated rhabdomyoblastic cells (not diffuse); Vimentin positive; ER and PR may be positive; Negative for S100 protein, keratins
─ Molecular: No specific recurrent genetic alterations are consistently identified
DDx

─ Aggressive angiomyxoma (deep pelvic/perineal, more infiltrative, prominent large vessels, HMGA2 rearranged, lacks rhabdomyoblastic differentiation)
─ Angiomyofibroblastoma (well-circumscribed, alternating cellular/edematous areas, prominent vessels, desmin positive but lacks rhabdomyoblastic differentiation)
─ Embryonal rhabdomyosarcoma, botryoid variant (if vaginal in child; cambium layer, hypercellular, atypia, diffuse MyoD1/myogenin)
─ Fibroepithelial stromal polyp (vaginal) (lacks rhabdomyoblastic differentiation, often atypical stromal cells)
─ Superficial angiomyxoma (lobulated, epithelial mucin, lacks rhabdomyoblastic differentiation)
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Embryonal Rhabdomyosarcoma (ERMS)

A malignant neoplasm composed of primitive mesenchymal cells showing varying degrees of skeletal muscle differentiation, resembling embryonic skeletal muscle at different developmental stages; it is the most common type of rhabdomyosarcoma overall, particularly in children
Clinical ─ Primarily affects infants and young children (peak age <10 years, most <5 years); common sites include head/neck (orbit, parameningeal sites), genitourinary tract (vagina, bladder, prostate, paratestis), and retroperitoneum; less common in extremities
Clinical ─ Botryoid variant: Polypoid, grape-like masses in mucosa-lined hollow organs (eg, vagina, bladder, nasopharynx)
Clinical ─ Spindle cell variant: Better prognosis, often paratesticular in boys or head/neck (see also Spindle cell / Sclerosing RMS)
Macro ─ Variable; often a gray-white to tan, fleshy, infiltrative mass; botryoid variant is polypoid and gelatinous ("bunch of grapes")
Micro

─ Highly variable histology, reflecting different stages of embryonal muscle development:
─ Primitive small round to oval cells with hyperchromatic nuclei and scant cytoplasm, often alternating with hypocellular myxoid areas ("marbled" appearance)
─ Rhabdomyoblasts: Key diagnostic cells, show evidence of skeletal muscle differentiation; include strap cells (elongated with eosinophilic cytoplasm, tandem nuclei), tadpole cells (rounded head, tapering tail), racquet cells, and large round cells with abundant eosinophilic cytoplasm; cross-striations may be visible but are not always present
─ Cambium layer: A subepithelial condensation of primitive tumor cells is characteristic of the botryoid variant
─ Spindle cell variant: Predominantly fascicles of spindle cells with varying degrees of rhabdomyoblastic differentiation
─ Mitotic activity is variable but often easily found; necrosis can be present
Ancillary studies ─
─ IHC: Tumor cells (especially rhabdomyoblasts and more differentiated cells) are positive for desmin, MSA (muscle-specific actin); Nuclear positivity for MyoD1 and myogenin (skeletal muscle-specific transcription factors) is crucial for diagnosis, though expression can be patchy or focal in less differentiated areas compared to ARMS; Vimentin positive; Negative for S100 protein, keratins (usually), LCA (CD45)
─ Molecular: Lacks the PAX-FOXO1 fusions characteristic of alveolar rhabdomyosarcoma; common genetic alterations include mutations in RAS pathway genes (HRAS, KRAS, NRAS), TP53, FGFR4, PIK3CA, and CTNNB1, as well as chromosomal gains/losses
DDx

─ Other small round blue cell tumors of childhood (eg, Ewing sarcoma, neuroblastoma, lymphoma, Wilms tumor - distinguished by specific IHC and molecular features)
─ Alveolar rhabdomyosarcoma (alveolar pattern, more uniform round cells, strong/diffuse MyoD1/myogenin, PAX-FOXO1 fusion)
─ Spindle cell / Sclerosing rhabdomyosarcoma (distinct morphology, different molecular in some infantile cases - may overlap with ERMS spindle cell variant)
─ Fetal rhabdomyoma (benign, less cellularity/atypia, more differentiated overall)
─ Inflammatory myofibroblastic tumor (prominent inflammatory infiltrate, ALK positive in a subset)
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Alveolar Rhabdomyosarcoma (ARMS)

An aggressive malignant neoplasm composed of primitive round cells often arranged in nests resembling pulmonary alveoli, typically characterized by specific gene fusions involving PAX3 or PAX7 with FOXO1
Clinical ─ Primarily affects adolescents and young adults (peak age 10-25s), but can occur in younger children and older adults; common in deep soft tissues of the extremities (especially lower limb), trunk (paraspinal, perineum), and head/neck; less common in genitourinary tract compared to ERMS; tends to be more aggressive than ERMS with a higher propensity for early lymph node and distant metastasis
Macro ─ Fleshy, gray-tan to pink, often large and deeply situated infiltrative mass; hemorrhage and necrosis are common
Micro

─ Characteristic alveolar pattern (classic ARMS): Nests or aggregates of primitive, relatively uniform round cells separated by dense fibrovascular septa; tumor cells often show discohesion centrally within nests, with peripheral cells clinging to the septa ("alveolar" spaces)
─ Solid variant: Lacks distinct alveolar spaces but is composed of diffuse sheets of similar primitive round cells; must be distinguished from other small round blue cell tumors and often requires molecular confirmation
─ Tumor cells: Monotonous, round nuclei with coarsely stippled chromatin, inconspicuous or small nucleoli, and scant eosinophilic or clear cytoplasm
─ Multinucleated tumor giant cells, often with wreath-like peripheral nuclei ("rhabdomyoblast-like giant cells"), may be present but are not true differentiating rhabdomyoblasts
─ Mitotic activity is usually high, necrosis is common
─ Rhabdomyoblastic differentiation (strap cells, tadpole cells) is typically sparse or absent, unlike ERMS
Ancillary studies ─
─ IHC: Tumor cells are positive for desmin, MSA (muscle-specific actin); Nuclear positivity for MyoD1 and myogenin is characteristic and typically strong and diffuse (more so than in ERMS); Vimentin positive; Negative for S100 protein, keratins, LCA (CD45), CD99 (usually)
─ Molecular: Defined by specific chromosomal translocations:
─ t(2;13)(q35;q14) resulting in PAX3::FOXO1 fusion (most common, ~70-80%, associated with poorer prognosis)
─ t(1;13)(p36;q14) resulting in PAX7::FOXO1 fusion (less common, ~10-20%, may have slightly better prognosis than PAX3 fusion)
─ Fusion-negative ARMS (histologically alveolar but lacking PAX-FOXO1 fusion) exists, behavior may be more like ERMS or spindle cell/sclerosing RMS depending on other features/genetics
DDx

─ Embryonal rhabdomyosarcoma (more pleomorphic cells, rhabdomyoblasts common, lacks alveolar pattern and PAX-FOXO1 fusion)
─ Other small round blue cell tumors (eg, Ewing sarcoma - CD99/NKX2.2 positive, EWSR1 fusion; lymphoma - LCA/lymphoid markers positive; neuroblastoma - synaptophysin/PHOX2B positive)
─ Poorly differentiated synovial sarcoma (TLE1 positive, keratin/EMA often positive, SS18 fusion)
─ Desmoplastic small round cell tumor (DSRCT) (keratin/desmin/WT1 positive, EWSR1::WT1 fusion)
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Pleomorphic Rhabdomyosarcoma

A high-grade sarcoma composed of bizarre, pleomorphic cells with definitive evidence of skeletal muscle differentiation (identifiable rhabdomyoblasts), occurring almost exclusively in adults; it is a diagnosis of exclusion among rhabdomyosarcoma subtypes, lacking features of ERMS, ARMS, or spindle cell/sclerosing RMS
Clinical ─ Primarily affects adults (usually >40-50 years), rare in children; common in deep soft tissues of the extremities (especially thigh), trunk, and less commonly retroperitoneum or head/neck; presents as a rapidly enlarging, often painful, deep-seated mass
Macro ─ Large, fleshy, often poorly circumscribed mass; cut surface is typically variegated, with white-gray sarcomatous tissue, yellowish fatty areas (if entrapped fat), and common hemorrhage and necrosis
Micro

─ High-grade pleomorphic sarcoma resembling undifferentiated pleomorphic sarcoma (UPS) or other high-grade sarcomas, but with the crucial diagnostic feature of unequivocal rhabdomyoblasts
─ Rhabdomyoblasts are typically large, bizarre, pleomorphic cells with abundant, deeply eosinophilic cytoplasm; may be strap-shaped, tadpole-shaped, racquet-shaped, or large round cells; cross-striations may be identifiable but are often focal and difficult to find
─ Background cells are highly pleomorphic spindle cells, epithelioid cells, or bizarre multinucleated tumor cells with marked nuclear atypia, hyperchromasia, and irregular contours
─ High mitotic activity, including atypical mitoses, is characteristic
─ Extensive necrosis and hemorrhage are frequently observed
─ Lacks the primitive round cell component of ERMS/ARMS and the specific fascicular/sclerotic patterns of spindle cell/sclerosing RMS; also lacks PAX-FOXO1 fusions
Ancillary studies ─
─ IHC: Definitive rhabdomyoblastic differentiation is confirmed by positivity for desmin, MSA (muscle-specific actin), and robust nuclear staining for MyoD1 and/or myogenin in at least some tumor cells (especially the rhabdomyoblasts); Myoglobin may also be positive
─ IHC: Negative for S100 protein (except entrapped nerves), keratins, CD34, STAT6, ALK, PAX-FOXO1 fusion protein surrogates
─ Molecular: Characterized by complex, unbalanced karyotypes with numerous chromosomal gains and losses; no specific recurrent translocations define this subtype; important to exclude specific fusion-associated sarcomas with rhabdomyoblastic differentiation
DDx

─ Undifferentiated pleomorphic sarcoma (UPS) (lacks definitive rhabdomyoblasts and myogenic marker expression)
─ Dedifferentiated liposarcoma with heterologous rhabdomyosarcomatous differentiation (must identify an associated WDLPS/ALT component and MDM2 amplification)
─ Malignant peripheral nerve sheath tumor (MPNST) with heterologous rhabdomyosarcomatous differentiation (Triton tumor) (arises from nerve or in NF1 patient, S100/SOX10 positivity in spindle cell MPNST component, H3K27me3 loss common)
─ Leiomyosarcoma (pleomorphic variant) (smooth muscle markers like h-caldesmon positive, MyoD1/myogenin negative)
─ Melanoma (pleomorphic/spindle cell) (S100/SOX10/melanocytic markers positive)
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Spindle cell / Sclerosing Rhabdomyosarcoma

A subtype of rhabdomyosarcoma characterized by a predominant population of spindle cells arranged in fascicles, often with a herringbone pattern, and/or prominent stromal sclerosis; encompasses distinct molecular and clinical subgroups, including infantile/congenital (often with good prognosis and specific fusions) and adult types (some with MYOD1 mutations and aggressive behavior)
Clinical ─ Bimodal age distribution:
─ Infantile/Congenital type: Often presents in testis/paratestis of male infants (excellent prognosis), or less commonly in head/neck or other sites
─ Adult type: Affects older children, adolescents, and adults; common in head/neck, extremities, and trunk; often more aggressive, especially MYOD1-mutant cases
Macro ─ Firm, gray-white to tan, often infiltrative mass; may appear circumscribed; sclerosing variant can be very hard
Micro

─ Spindle cell component: Predominantly composed of relatively uniform to moderately atypical spindle cells arranged in long, intersecting fascicles, often forming a "herringbone" pattern similar to fibrosarcoma or leiomyosarcoma; cells have scant to moderate eosinophilic cytoplasm and elongated nuclei
─ Sclerosing component: Characterized by prominent hyalinized or sclerotic collagenous stroma separating individual tumor cells, nests, or small fascicles; tumor cells may appear epithelioid or embedded in a pseudovascular or pseudoalveolar pattern within the dense stroma; osteoid-like matrix may be present
─ Rhabdomyoblastic differentiation (strap cells, tadpole cells, cross-striations) may be present but can be focal or subtle, requiring careful search or IHC confirmation
─ Cytologic atypia and mitotic activity are variable, generally lower in infantile type and higher in adult/MYOD1-mutant types
Ancillary studies ─
─ IHC: Tumor cells (spindle and/or epithelioid) are positive for desmin, MSA; Nuclear positivity for MyoD1 and myogenin is characteristic and essential for diagnosis, often diffuse even in spindle cells
─ Molecular: Genetically heterogeneous:
─ Infantile/Congenital (paratesticular and some other sites): Often harbor NCOA2 fusions (eg, VGLL2::NCOA2, SRF::NCOA2, TEAD1::NCOA2) or less commonly ETV6::NTRK3 (congenital fibrosarcoma-like RMS); associated with good prognosis
─ Adolescent/Adult (often head/neck, extremities): A subset (especially sclerosing type) has MYOD1 mutations (commonly L122R), associated with poor prognosis; others may have TFCP2 or MEIS1 fusions, or lack known recurrent alterations
DDx

─ Leiomyosarcoma (h-caldesmon positive, MyoD1/myogenin negative)
─ Infantile fibrosarcoma (ETV6::NTRK3 fusion, Pan-TRK positive, MyoD1/myogenin negative)
─ Fibrosarcoma (adult) (diagnosis of exclusion, lacks myogenic markers)
─ Malignant peripheral nerve sheath tumor (MPNST) (S100/SOX10 variable, H3K27me3 loss, lacks myogenic markers)
─ Monophasic synovial sarcoma (TLE1 positive, keratin/EMA often positive, SS18 fusion, lacks myogenic markers)
─ Sclerosing epithelioid fibrosarcoma (MUC4 positive, FUS/EWSR1 fusions, lacks myogenic markers)
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Ectomesenchymoma

A rare malignant neoplasm, typically of infancy or early childhood, characterized by a biphasic pattern showing features of both rhabdomyosarcoma (usually embryonal type) and neuroectodermal elements (such as ganglion cells, Schwann cells, or neuroblasts)
Clinical ─ Primarily affects infants and young children (most <5 years, can be congenital); common sites include head/neck (orbit, nasopharynx), genitourinary tract (paratestis, vagina, bladder), perineum, retroperitoneum, and trunk; presents as a growing mass, symptoms depend on location
Macro ─ Variable appearance; often a fleshy, gray-white to tan, infiltrative mass; may have cystic or myxoid areas
Micro

─ Biphasic tumor composed of two distinct malignant components intimately admixed or in separate areas:
─ Skeletal muscle component: Typically resembles embryonal rhabdomyosarcoma, with primitive small round/spindle cells and identifiable rhabdomyoblasts (strap cells, tadpole cells); less commonly, alveolar or spindle cell RMS patterns
─ Neuroectodermal component: Can include mature or immature ganglion cells (large cells with vesicular nuclei, prominent nucleoli, amphophilic cytoplasm), Schwannian stroma (spindle cells resembling neurofibroma or schwannoma), neuroblasts (small round cells forming rosettes or with neuropil), or rarely pigmented neuroectodermal cells
─ The proportion of each component varies widely
Ancillary studies ─
─ IHC: Skeletal muscle component is positive for desmin, MSA, MyoD1, and myogenin
─ IHC: Neuroectodermal component shows reactivity depending on differentiation: Ganglion cells/neuroblasts are positive for synaptophysin, chromogranin, neurofilament protein (NFP); Schwannian stroma is S100 protein and SOX10 positive; GFAP may be positive in glial elements if present
─ Molecular: Complex karyotypes are common; lacks specific recurrent fusions typically associated with pure RMS subtypes (eg, PAX-FOXO1) or pure neuroblastic tumors (eg, MYCN amplification); some cases may show RAS pathway mutations or other alterations found in ERMS
DDx

─ Embryonal rhabdomyosarcoma (lacks the distinct neuroectodermal component)
─ Malignant peripheral nerve sheath tumor (MPNST) with rhabdomyosarcomatous differentiation (Triton tumor) (neuroectodermal component is malignant Schwann cell proliferation, usually S100/SOX10 positive, lacks mature ganglion cells; often NF1 associated or arises from nerve)
─ Ganglioneuroblastoma (neuroblastic component predominates, lacks definitive RMS component, MYCN amplification may be present)
─ Teratoma with rhabdomyosarcomatous differentiation (contains elements from all three germ layers, eg, mature epithelium, cartilage)
─ Dedifferentiated sarcoma with heterologous differentiation (if in older individuals, context is different)
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Soft Tissue, Nerve Sheath

Schwannoma

A benign peripheral nerve sheath tumor composed entirely of differentiated Schwann cells, typically encapsulated and often showing a biphasic pattern of Antoni A and Antoni B areas
Clinical ─ Most common benign peripheral nerve sheath tumor; typically affects adults (peak age 20-50s), but can occur at any age; common sites include head/neck (especially cranial nerves like VIII - vestibular schwannoma/acoustic neuroma, and sympathetic chain), flexor surfaces of extremities (especially near joints - elbow, wrist, knee), posterior mediastinum, and retroperitoneum; can arise from spinal nerve roots; multiple schwannomas are characteristic of Neurofibromatosis type 2 (NF2) and schwannomatosis (SMARCB1 or LZTR1 mutated)
Clinical ─ Usually presents as a slow-growing, solitary, painless or mildly tender, encapsulated, mobile mass; may cause neurologic symptoms (pain, paresthesia, weakness) if compressing the parent nerve or adjacent structures
Macro ─ Well-circumscribed, encapsulated, fusiform or eccentric mass attached to or arising from a peripheral nerve; nerve fibers are typically splayed over the capsule, not within the tumor; cut surface is often yellow-tan, gray-white, or hemorrhagic, frequently with cystic degeneration, especially in larger ("ancient") lesions
Micro

─ Encapsulated tumor; parent nerve often identifiable in the capsule
─ Characteristic biphasic pattern:
─ Antoni A areas: Cellular, composed of compact spindle cells with indistinct cytoplasm and wavy, tapered nuclei, arranged in short fascicles, whorls, or showing nuclear palisading around acellular eosinophilic fibrillary processes (Verocay bodies - pathognomonic when present)
─ Antoni B areas: Hypocellular, with loosely arranged spindle or oval cells in an abundant myxoid or edematous stroma; microcystic change is common; vessels are often prominent
─ Blood vessels are frequently prominent, often thick-walled, hyalinized, and ectatic, sometimes with thrombosis
─ Degenerative changes ("ancient schwannoma") are common in long-standing lesions and include nuclear atypia (large, hyperchromatic, pleomorphic nuclei without mitoses), hemorrhage, hemosiderin deposition, cystic change, and stromal hyalinization; these changes do not imply malignancy
─ Variants include: Cellular, plexiform, epithelioid, melanotic, microcystic/reticular schwannoma
Ancillary studies ─
─ IHC: Tumor cells (Schwann cells) show strong and diffuse nuclear and cytoplasmic positivity for S100 protein and SOX10; GFAP may be focally positive; CD34 may highlight some spindle cells or vessels; EMA highlights the capsule (perineurial cells) but is negative in tumor cells; Negative for neurofilament protein (axons are excluded from the tumor body, unlike neurofibroma), keratins, desmin, SMA
─ Molecular: Inactivation of the NF2 gene (on chromosome 22q, encoding merlin protein) via mutation or loss of heterozygosity is found in most sporadic schwannomas and is definitional for NF2-associated schwannomas; schwannomatosis-related schwannomas have germline SMARCB1 or LZTR1 mutations with somatic NF2 inactivation in the tumor
DDx

─ Neurofibroma (not truly encapsulated except plexiform type, mixed cell population including axons within tumor, S100 often patchy, different stromal quality)
─ Malignant peripheral nerve sheath tumor (MPNST) (infiltrative growth, cytologic atypia beyond degenerative changes, high mitotic activity, necrosis, S100 often weak/patchy or lost, H3K27me3 loss common)
─ Perineurioma (EMA positive tumor cells, S100 negative, different morphology)
─ Leiomyoma (smooth muscle markers positive, S100 negative)
─ Solitary fibrous tumor (STAT6 positive, CD34 positive, lacks S100)
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ancient WSI cellular WSI

Conventional Schwannoma

The most common type of schwannoma, a benign peripheral nerve sheath tumor composed entirely of differentiated Schwann cells, characterized by a biphasic pattern of Antoni A and Antoni B areas and Verocay bodies
Clinical ─ As per general Schwannoma; adults (20-50s), associated with NF2 or schwannomatosis if multiple; head/neck, extremities, posterior mediastinum, retroperitoneum
Macro ─ Encapsulated, often eccentric to a nerve; yellowish-tan, may have cystic change or hemorrhage, especially if "ancient"
Micro

─ Encapsulated; nerve fibers typically splayed in capsule, not within tumor
─ Antoni A areas: Cellular, compact spindle cells with wavy, tapered nuclei, indistinct cytoplasm; cells arranged in fascicles, whorls, or with nuclear palisading around acellular eosinophilic fibrillary processes (Verocay bodies)
─ Antoni B areas: Hypocellular, loosely arranged spindle/oval cells in abundant myxoid or edematous stroma; microcystic change common
─ Blood vessels: Often prominent, thick-walled, hyalinized, and ectatic
─ Degenerative changes ("ancient schwannoma"): Nuclear atypia (large, hyperchromatic nuclei without mitoses), hemorrhage, hemosiderin, cystic change, stromal hyalinization; these do not imply malignancy
Ancillary studies ─
─ IHC: Strong, diffuse S100 and SOX10 positivity; GFAP focally positive; EMA highlights capsule; Neurofilament negative within tumor
─ Molecular: NF2 gene inactivation in most sporadic and NF2-associated cases
DDx

─ Neurofibroma (axons within tumor, S100 patchy, mixed cell types, not purely Schwann cells)
─ MPNST (infiltrative, significant atypia, mitoses, necrosis, S100 often lost or patchy)
─ Perineurioma (EMA positive tumor cells, S100 negative)
─ Cellular schwannoma (predominantly Antoni A, lacks Antoni B/Verocay bodies, may have mitoses but no significant atypia)
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Cellular Schwannoma

A variant of schwannoma composed predominantly or exclusively of hypercellular Antoni A-like areas, lacking significant Antoni B component and Verocay bodies, which may sometimes be mistaken for a malignant peripheral nerve sheath tumor due to its high cellularity and occasional mitotic activity
Clinical ─ Similar to conventional schwannoma but may be larger and more deeply seated; common in posterior mediastinum, retroperitoneum, pelvis, and deep soft tissues of extremities; less common in cranial nerves
Macro ─ Well-circumscribed, encapsulated, firm, gray-white to tan solid mass; typically lacks the cystic and hemorrhagic changes common in ancient conventional schwannomas
Micro

─ Densely cellular proliferation composed almost entirely of Antoni A-like tissue
─ Spindle cells are arranged in fascicles, whorls, or a herringbone pattern, with minimal intervening stroma
─ Antoni B areas and well-formed Verocay bodies are typically absent or very focal and inconspicuous
─ Nuclei are uniform, wavy, or ovoid; cytologic atypia is usually minimal, but focal mild atypia can be seen
─ Mitotic activity can be present (occasionally up to 5-10/10 HPF), but atypical mitoses are absent
─ Necrosis is generally absent, though small foci of ischemic necrosis can occur in large tumors
─ Foamy histiocytes and lymphoid aggregates may be present, especially subcapsularly
─ Blood vessels are often prominent but may not be as hyalinized as in conventional schwannoma
Ancillary studies ─
─ IHC: Strong and diffuse S100 protein and SOX10 positivity is characteristic and essential for diagnosis; GFAP may be focally positive; EMA highlights capsule
─ Molecular: NF2 gene inactivation is common, similar to conventional schwannoma
DDx

─ Malignant peripheral nerve sheath tumor (MPNST) (more significant cytologic atypia, pleomorphism, higher and often atypical mitotic activity, necrosis, infiltrative growth, S100 often lost or patchy, H3K27me3 loss common)
─ Conventional schwannoma (shows distinct Antoni B areas and Verocay bodies)
─ Monophasic synovial sarcoma (TLE1 positive, keratin/EMA often positive, SS18 fusion, S100 usually negative or weak)
─ Leiomyoma/Leiomyosarcoma (smooth muscle markers positive, S100 negative)
─ Fibrosarcoma (S100 negative, diagnosis of exclusion)
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Plexiform Schwannoma

A rare variant of schwannoma characterized by a multinodular or plexiform growth pattern, where the tumor involves multiple nerve fascicles or forms interconnected nodules along a nerve or within soft tissue
Clinical ─ Can occur at any age, including childhood; may be associated with Neurofibromatosis type 2 (NF2) or schwannomatosis, but most are sporadic; common in skin and subcutaneous tissue, also deeper soft tissues; presents as a solitary or multiple nodules, sometimes forming a palpable cord-like mass
Macro ─ Grossly appears as a multinodular or "bag of worms" mass if involving a large nerve segment, or as discrete but clustered nodules; individual nodules are encapsulated and resemble conventional schwannoma
Micro

─ Composed of multiple, discrete, encapsulated nodules of schwannoma tissue separated by connective tissue or nerve elements
─ Each individual nodule typically shows features of conventional schwannoma, including Antoni A and Antoni B areas, Verocay bodies, and hyalinized vessels
─ Cellular, ancient, or other schwannoma variants can occur within the plexiform nodules
─ The plexiform growth pattern involves multiple fascicles of a nerve or forms a branching network of tumor nodules within soft tissue
─ No significant cytologic atypia beyond that acceptable for schwannoma variants (eg, ancient change)
Ancillary studies ─
─ IHC: Strong and diffuse S100 protein and SOX10 positivity within the tumor nodules; EMA highlights the capsule of individual nodules
─ Molecular: NF2 gene inactivation is common, especially if associated with NF2
DDx

─ Plexiform neurofibroma (pathognomonic for NF1; unencapsulated proliferation of mixed cell types including axons within tumor nodules, S100 patchy, myxoid stroma)
─ Plexiform fibrohistiocytic tumor (different cell types - histiocytoid/osteoclast-rich nodules and spindle cells, CD68 positive, S100 negative)
─ Multinodular conventional schwannoma (distinction is subtle, plexiform implies interconnected or nerve-segment involvement)
─ Malignant peripheral nerve sheath tumor arising in plexiform schwannoma (very rare; would show features of malignancy)
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Epithelioid Schwannoma

A rare variant of schwannoma characterized by a predominance of epithelioid cells rather than spindle cells, which can pose diagnostic challenges due to its resemblance to other epithelioid neoplasms
Clinical ─ Typically affects adults; common in skin and subcutaneous tissue of extremities, trunk, or head/neck; usually presents as a solitary, slow-growing, painless nodule; association with NF2 or schwannomatosis is uncommon
Macro ─ Well-circumscribed, firm, gray-white to tan nodule; usually small (<3 cm)
Micro

─ Composed predominantly or exclusively of sheets, nests, or cords of epithelioid cells with abundant eosinophilic or clear cytoplasm, distinct cell borders, and large, vesicular, often eccentrically placed nuclei with prominent nucleoli
─ Minimal or absent conventional spindle cell schwannoma component (Antoni A/B areas)
─ Stroma is often scant or hyalinized; a myxoid background may be present
─ Lymphoid aggregates or a sparse lymphocytic infiltrate are common
─ Cytologic atypia can be variable, from bland to moderately atypical, but mitoses are usually rare; necrosis is absent
─ Malignant epithelioid schwannoma is a distinct, aggressive entity (see MPNST, epithelioid variant)
Ancillary studies ─
─ IHC: Tumor cells show strong and diffuse S100 protein and SOX10 positivity; EMA may be focally positive within tumor cell clusters (unlike capsule-only staining in conventional schwannoma); GFAP may be positive; Negative for keratins (crucial for DDx with carcinoma), melanocytic markers (HMB45, Melan-A), desmin, SMA
─ Molecular: Some cases show loss of SMARCB1/INI1 expression, particularly if associated with schwannomatosis or in malignant transformation, but benign epithelioid schwannomas typically retain INI1 expression; NF2 status is variable
DDx

─ Epithelioid malignant peripheral nerve sheath tumor (MPNST) (frankly malignant cytologic features, high mitoses, necrosis, often INI1 loss)
─ Melanoma (epithelioid) (HMB45/Melan-A positive, lacks diffuse S100 in some cases)
─ Carcinoma (metastatic or primary adnexal) (keratin positive, specific carcinoma markers)
─ Granular cell tumor (granular cytoplasm, CD68 positive)
─ PEComa (HMB45/Melan-A and smooth muscle markers positive)
─ Rhabdoid tumor (INI1 loss, characteristic rhabdoid cells, aggressive behavior)
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Melanotic Schwannoma

A rare nerve sheath tumor composed of Schwann cells that exhibit melanocytic differentiation, characterized by melanin pigment production; distinct from malignant melanotic nerve sheath tumor and clear cell sarcoma (melanoma of soft parts)
Clinical ─ Affects a wide age range, often adults; common sites include spinal nerve roots (forming "dumbbell" tumors), paraspinal ganglia, and visceral locations (GI tract, heart); may be associated with Carney complex (multiple myxomas, endocrine tumors, pigmented lesions) in ~50% of cases (psammomatous melanotic schwannoma variant)
Clinical ─ Presents with symptoms related to nerve compression or mass effect; skin lesions are rare
Macro ─ Well-circumscribed, often encapsulated, firm mass; cut surface is typically dark brown to black due to melanin pigment; may show cystic change or calcification (psammoma bodies in Carney complex-associated type)
Micro

─ Composed of spindle cells and/or epithelioid cells arranged in fascicles, nests, or sheets
─ Tumor cells contain variable amounts of finely granular, brown melanin pigment within their cytoplasm; melanophages are also common
─ Nuclei are typically oval to spindle-shaped, with vesicular chromatin and often prominent nucleoli; cytologic atypia is usually mild to moderate
─ Psammoma bodies (laminated calcifications) are characteristic of the variant associated with Carney complex
─ Mitotic activity is generally low; necrosis is usually absent in benign forms
─ Distinction from malignant melanotic nerve sheath tumor relies on absence of overt malignant features (high mitoses, significant pleomorphism, necrosis, infiltrative growth)
Ancillary studies ─
─ IHC: Tumor cells show dual differentiation, co-expressing S100 protein and SOX10 (Schwannian markers) as well as melanocytic markers (HMB45, Melan-A, MITF); GFAP may be positive; Negative for keratins, desmin
─ Molecular: Carney complex-associated cases have germline mutations in PRKAR1A gene; sporadic cases lack specific consistent alterations but are distinct from clear cell sarcoma (EWSR1 fusions)
DDx

─ Malignant melanotic nerve sheath tumor (shows overt malignant features, aggressive behavior)
─ Melanoma (malignant) (may lack diffuse S100/SOX10 in some spindle variants, often BRAF/NRAS mutations, lacks PRKAR1A association)
─ Clear cell sarcoma of soft tissue (melanoma of soft parts) (EWSR1::ATF1 or EWSR1::CREB1 fusion, different morphology with nests of clear cells)
─ Pigmented neurofibroma (melanin confined to benign dendritic melanocytes admixed with neurofibroma, lacks dual melanocytic/Schwannian immunophenotype in tumor cells)
─ Schwannoma with incidental melanocytes (melanin only in scattered non-neoplastic cells)
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Microcystic/Reticular Schwannoma

A distinctive but rare variant of schwannoma characterized by a prominent microcystic and reticular growth pattern, often occurring in visceral locations, particularly the gastrointestinal tract
Clinical ─ Affects a wide age range, including adults and children; common in the gastrointestinal tract (stomach, colon, pancreas), also occurs in subcutaneous tissue, deep soft tissues, and other visceral sites; often an incidental finding or presents with non-specific symptoms related to location
Macro ─ Typically a well-circumscribed, solid or partially cystic nodule; cut surface may appear gelatinous or mucoid; usually small (<3 cm)
Micro

─ Well-circumscribed, often encapsulated or partially encapsulated proliferation
─ Characteristic reticular, lace-like, or honeycomb (microcystic) growth pattern: anastomosing strands and cords of bland spindle to ovoid Schwann cells forming small cystic spaces filled with pale eosinophilic or myxoid fluid
─ Cells have scant eosinophilic or clear cytoplasm and small, uniform, ovoid to spindle-shaped nuclei; atypia is minimal or absent
─ Antoni A/B areas and Verocay bodies typical of conventional schwannoma are usually absent or very inconspicuous
─ Hyalinized blood vessels, similar to those in conventional schwannoma, may be present
─ Lymphoid aggregates are often seen at the periphery
─ Mitotic activity is very low or absent
Ancillary studies ─
─ IHC: Tumor cells show strong and diffuse S100 protein and SOX10 positivity; GFAP may be focally positive; EMA highlights capsule if present; Negative for keratins, CD117 (c-kit), DOG1, SMA, desmin
─ Molecular: NF2 gene inactivation is common, similar to conventional schwannoma; some visceral cases, particularly in the GI tract, may lack NF2 alterations and have shown other changes (eg, PRKAR1A inactivation in some Carney complex-associated cases, though these are usually psammomatous melanotic schwannomas)
DDx

─ Reticular perineurioma (EMA positive tumor cells, S100 negative, different morphology)
─ Myxoid neurofibroma (S100 patchy, contains axons, mixed cell types, associated with NF1 if plexiform/diffuse)
─ Aggressive angiomyxoma (if pelvic/perineal; prominent large vessels, HMGA2 rearranged, S100 negative)
─ Low-grade myxofibrosarcoma (infiltrative, curvilinear vessels, more atypia, S100 negative)
─ Signet ring cell carcinoma (metastatic) (keratin positive, specific carcinoma markers, S100 negative)
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Schwannomatosis and Genetic Predisposition

A tumor predisposition syndrome characterized by the development of multiple schwannomas (and sometimes meningiomas), but typically without vestibular schwannomas (acoustic neuromas), distinguishing it from Neurofibromatosis type 2 (NF2); it is the third major form of neurofibromatosis/schwannomatosis syndromes
Clinical ─ Typically presents in adulthood (peak 30-60s); characterized by multiple (two or more) non-intradermal schwannomas; chronic pain is a common and often debilitating symptom, out of proportion to tumor size; vestibular schwannomas are absent by definition (or if present, criteria for NF2 are not fully met); meningiomas can occur in a subset of patients, especially those with SMARCB1 mutations
Clinical ─ Can be familial (autosomal dominant with incomplete penetrance) or sporadic
Genetic Predisposition ─
─ Germline pathogenic variants in SMARCB1 (INI1) gene (22q11.23) are found in a significant proportion of familial and some sporadic cases
─ Germline pathogenic variants in LZTR1 gene (22q11.21) are found in another subset, also associated with increased risk of meningiomas
─ A "four-hit" hypothesis involving somatic inactivation of NF2 in addition to germline and somatic hits in SMARCB1/LZTR1 is proposed for tumor development
─ Some cases remain molecularly uncharacterized
Micro (Schwannomas in Schwannomatosis) ─
─ Histologically, the schwannomas are typically conventional, showing Antoni A and B areas, Verocay bodies, and hyalinized vessels
─ They may also show features of other schwannoma variants (eg, cellular, ancient)
─ Loss of SMARCB1/INI1 protein expression (by IHC) may be seen in some schwannomas from patients with germline SMARCB1 mutations, but is not a universal finding
Ancillary studies (for individual schwannomas) ─
─ IHC: S100 and SOX10 positive; INI1/SMARCB1 IHC may show loss in tumor cells if corresponding germline mutation and somatic second hit
─ Molecular: Genetic testing for germline SMARCB1, LZTR1 mutations, and somatic NF2 mutations in tumors can confirm diagnosis and aid in genetic counseling
DDx (for clinical presentation) ─

─ Neurofibromatosis type 2 (NF2) (bilateral vestibular schwannomas are hallmark; also multiple other schwannomas, meningiomas, ependymomas; germline NF2 mutation)
─ Neurofibromatosis type 1 (NF1) (neurofibromas are hallmark, café-au-lait spots, Lisch nodules, axillary/inguinal freckling; germline NF1 mutation)
─ Multiple sporadic schwannomas (without fulfilling criteria for a defined syndrome)
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Hybrid Schwannoma/Perineurioma

A rare benign peripheral nerve sheath tumor composed of an intimate admixture of cells showing Schwann cell differentiation and cells showing perineurial cell differentiation
Clinical ─ Typically affects adults (wide age range); common in skin and subcutaneous tissue of extremities and trunk; presents as a solitary, slow-growing, painless nodule, usually small (<2 cm)
Macro ─ Well-circumscribed, firm, gray-white to tan nodule; may appear encapsulated
Micro

─ Well-demarcated, often encapsulated or partially encapsulated proliferation
─ Composed of an intermingled population of two cell types:
─ Schwann cells: Spindle cells with wavy nuclei and eosinophilic cytoplasm, often forming small fascicles or Antoni A-like areas; may show Verocay body-like structures focally
─ Perineurial cells: Spindle to epithelioid cells with more elongated, slender, bipolar cytoplasmic processes, often forming delicate whorls or lamellar arrangements around Schwann cell fascicles or individual cells
─ Stroma is variably collagenous or slightly myxoid
─ Cytologic atypia is minimal, mitotic activity is very low or absent
Ancillary studies ─
─ IHC: Shows a biphasic pattern reflecting the dual differentiation:
─ Schwann cell component: Strong and diffuse S100 protein and SOX10 positivity
─ Perineurial cell component: EMA (epithelial membrane antigen) positivity, claudin-1 positivity, GLUT1 positivity; S100 negative
─ CD34 may be positive in some perineurial cells or stromal cells
─ Molecular: Some cases show genetic alterations involving chromosome 22q (NF2 locus), but specific recurrent fusions are not consistently identified; some may show VGLL3 rearrangements
DDx

─ Schwannoma (conventional) (lacks EMA/claudin-1 positive perineurial cells intermingled within tumor body, S100 diffuse)
─ Perineurioma (soft tissue or intraneural) (lacks S100/SOX10 positive Schwann cells, diffusely EMA/claudin-1 positive)
─ Neurofibroma (mixed cell population including axons, S100 patchy, EMA may highlight some perineurial cells but different architecture)
─ Dermatofibrosarcoma protuberans (CD34 positive, S100/EMA negative, COL1A1::PDGFB fusion)
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Neurofibroma

A benign peripheral nerve sheath tumor composed of a heterogeneous mixture of Schwann cells, perineurial-like cells, fibroblasts, mast cells, and embedded axons, all within a variably collagenous or myxoid stroma; it is a hallmark lesion of Neurofibromatosis type 1 (NF1) but also occurs sporadically
Clinical ─ Can occur at any age, common in adults; may be solitary (sporadic) or multiple (NF1-associated); NF1 is an autosomal dominant disorder characterized by multiple neurofibromas (especially plexiform and diffuse types), café-au-lait macules, Lisch nodules (iris hamartomas), axillary/inguinal freckling, optic pathway gliomas, and predisposition to other tumors (eg, MPNST, pheochromocytoma, GIST)
Clinical ─ Types include:
─ Localized cutaneous neurofibroma: Most common type, often sporadic; soft, dome-shaped or pedunculated skin papule/nodule
─ Localized intraneural neurofibroma: Fusiform enlargement of a nerve segment
─ Diffuse neurofibroma: Plaque-like infiltration of dermis and subcutis, often head/neck, associated with NF1
─ Plexiform neurofibroma: Pathognomonic for NF1; diffuse, complex, "bag of worms" enlargement of multiple nerve fascicles and branches, carries risk of MPNST transformation
Macro ─ Variable: Localized cutaneous are soft, fleshy nodules; Diffuse are ill-defined thickenings; Plexiform are tortuous, cord-like masses expanding nerve trunks
Micro

─ Not truly encapsulated (except plexiform type may be surrounded by expanded epineurium), often infiltrative margins in diffuse/plexiform types
─ Hypocellular to moderately cellular proliferation of mixed cell types:
─ Schwann cells: Spindle cells with characteristic wavy, "buckled," or comma-shaped nuclei and indistinct pale cytoplasm
─ Fibroblasts: Spindle cells with more elongated, tapering nuclei
─ Perineurial-like cells: Cells with more flattened or epithelioid appearance, often inconspicuous
─ Mast cells: Numerous, scattered throughout
─ Axons: Presence of small, embedded axons within the tumor is a key diagnostic feature (highlighted by neurofilament stain)
─ Stroma is variably loose and myxoid ("shredded carrot" or "shredded newspaper" collagen is characteristic) or more densely collagenous
─ Diffuse type: Infiltrates dermis and subcutis, often surrounding adnexal structures and vessels; may contain Meissner-like bodies (tactile corpuscle-like structures)
─ Plexiform type: Expands multiple nerve fascicles, retaining a nerve-like architecture but with increased cellularity and myxoid stroma within fascicles
─ Atypical neurofibroma (in NF1): Shows increased cellularity, mild atypia, loss of typical architecture, but lacks definitive features of MPNST; represents a lesion with increased risk of MPNST development
Ancillary studies ─
─ IHC: Schwann cells are S100 protein and SOX10 positive (often patchy or less intense than in schwannoma); CD34 highlights admixed spindle cells (fibroblasts) and endothelial cells; Neurofilament protein (NFP) highlights embedded axons; EMA may stain some perineurial-like cells focally; Mast cells highlighted by CD117 (c-kit) or mast cell tryptase
─ Molecular: Inactivation of the NF1 gene (on chromosome 17q, encoding neurofibromin protein) is found in NF1-associated neurofibromas and a subset of sporadic neurofibromas
DDx

─ Schwannoma (encapsulated, purely Schwann cells, Antoni A/B, Verocay bodies, diffuse S100, lacks axons within tumor)
─ Malignant peripheral nerve sheath tumor (MPNST) (cellular atypia, high mitoses, necrosis, S100 often lost/patchy, H3K27me3 loss common; arises from NF or de novo)
─ Perineurioma (EMA/claudin-1 positive tumor cells, S100 negative, lacks axons)
─ Desmoplastic fibroblastoma / Collagenous fibroma (different stromal quality, CD34 variable, S100 negative)
─ Dermatofibroma (Factor XIIIa positive, lacks S100 positive spindle cells and axons)
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─ pathoutlines localized WSI WSI WSI diffuse WSI WSI

Localized Neurofibroma

A common benign peripheral nerve sheath tumor composed of a mixed proliferation of Schwann cells, perineurial-like cells, fibroblasts, and axons, typically occurring as a solitary lesion in individuals without Neurofibromatosis type 1 (NF1) or as one of the manifestations in NF1
Clinical ─ Can occur at any age, common in adults; may be sporadic or NF1-associated; includes cutaneous neurofibroma (soft, dome-shaped or pedunculated skin papule/nodule, most common type overall) and localized intraneural neurofibroma (fusiform enlargement of a small nerve segment)
Macro ─ Cutaneous: Soft, fleshy, skin-colored or brownish papule/nodule, often <2 cm; Intraneural: Fusiform swelling of a nerve segment, usually small
Micro

─ Unencapsulated (cutaneous) or involving a nerve fascicle (intraneural)
─ Hypocellular to moderately cellular proliferation of:
─ Schwann cells with wavy, "buckled" nuclei and pale cytoplasm
─ Fibroblasts with slender, tapering nuclei
─ Perineurial-like cells (often inconspicuous)
─ Mast cells are numerous
─ Embedded axons (neurofilament positive) are a key feature
─ Stroma is loose and myxoid ("shredded carrot" collagen) or more densely collagenous
─ No significant cytologic atypia or mitotic activity
Ancillary studies ─
─ IHC: Schwann cells S100/SOX10 positive (often patchy); CD34 highlights fibroblasts/stromal cells; Neurofilament highlights axons; EMA may stain some perineurial-like cells
─ Molecular: Sporadic cases may have somatic NF1 mutations; NF1-associated cases have germline NF1 mutation with somatic second hit
DDx

─ Schwannoma (encapsulated, purely Schwann cells, Antoni A/B, diffuse S100, lacks axons)
─ Diffuse neurofibroma / Plexiform neurofibroma (more extensive, infiltrative, associated with NF1)
─ Perineurioma (EMA/claudin-1 positive tumor cells, S100 negative)
─ Dermatofibroma (Factor XIIIa positive, lacks S100 positive spindle cells/axons)
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Diffuse Neurofibroma

A subtype of neurofibroma characterized by a poorly marginated, infiltrative proliferation of neurofibroma elements within the dermis and subcutaneous tissue, often creating a plaque-like or diffuse swelling; strongly associated with Neurofibromatosis type 1 (NF1)
Clinical ─ Typically presents in children or young adults; strong association with NF1 (though can rarely be sporadic); common sites include head/neck region and trunk; presents as a poorly defined, extensive, plaque-like or diffuse subcutaneous swelling, which may be associated with hyperpigmentation or hypertrichosis of the overlying skin
Macro ─ Ill-defined, diffuse thickening of the skin and subcutaneous tissue, often with a firm or rubbery consistency; cut surface is typically grayish-white and fibrous, may appear gelatinous if very myxoid
Micro

─ Poorly circumscribed, infiltrative proliferation of cells typical of neurofibroma (Schwann cells with wavy nuclei, fibroblasts, perineurial-like cells, mast cells) within an expanded dermis and subcutaneous tissue
─ Tumor cells often infiltrate extensively between collagen bundles and around adnexal structures (hair follicles, sweat glands, nerves, vessels) without destroying them
─ Stroma is variably collagenous or myxoid; myxoid change can be prominent
─ Meissner-like bodies (tactile corpuscle-like structures composed of Schwann cells) are a characteristic finding within the superficial portion of some diffuse neurofibromas
─ Embedded axons are present
─ Cytologic atypia is minimal, mitotic activity is low
Ancillary studies ─
─ IHC: Schwann cells S100/SOX10 positive (often patchy); CD34 highlights fibroblasts/stromal cells; Neurofilament highlights axons; EMA may stain some perineurial-like cells
─ Molecular: NF1 gene inactivation if associated with NF1
DDx

─ Localized cutaneous neurofibroma (more circumscribed, less infiltrative)
─ Plexiform neurofibroma (involves multiple nerve fascicles, "bag of worms" appearance, NF1 associated)
─ Dermatofibrosarcoma protuberans (DFSP) (more cellular, storiform pattern, diffuse CD34 positivity in tumor cells, COL1A1::PDGFB fusion, lacks S100 positive cells and axons)
─ Low-grade myxofibrosarcoma (if very myxoid; older adults, curvilinear vessels, more atypia, S100 negative)
─ Lipomatous tumors (if significant fat entrapment; specific features of lipoma/liposarcoma, S100 in fat cells)
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Plexiform Neurofibroma

A pathognomonic lesion of Neurofibromatosis type 1 (NF1), characterized by a diffuse, complex, often extensive proliferation of neurofibroma elements that involves multiple nerve fascicles and branches, leading to a tortuous, "bag of worms" mass
Clinical ─ Almost exclusively occurs in individuals with NF1, often congenital or appearing in early childhood; can arise from major nerve trunks or smaller peripheral nerves; common sites include head/neck, extremities, trunk, and viscera; presents as a slowly enlarging, often irregular, rope-like or nodular mass that follows the course of nerves; may cause significant disfigurement, pain, neurologic deficits, or functional impairment; carries a lifetime risk (~5-15%) of malignant transformation to Malignant Peripheral Nerve Sheath Tumor (MPNST)
Macro ─ Grossly appears as an enlarged, tortuous, thickened nerve trunk or a complex network of interconnected, firm, rubbery, gray-white to tan cords and nodules ("bag of worms"); cut surface is fibrous or myxoid
Micro

─ Characterized by the expansion of multiple nerve fascicles by neurofibromatous tissue, often retaining an overall nerve-like architecture but with markedly increased size and altered internal structure
─ Each involved fascicle is expanded by a proliferation of Schwann cells with wavy nuclei, fibroblasts, perineurial-like cells, and mast cells, set in an abundant myxoid or collagenous stroma
─ Embedded axons are present within the expanded fascicles
─ The epineurium surrounding the involved nerve trunk is often thickened and fibrotic
─ Myxoid change is very common and can be extensive
─ Cytologic atypia is typically minimal, mitotic activity is low in conventional areas
─ Areas of increased cellularity or atypia ("atypical neurofibroma") should be carefully evaluated for possible early MPNST transformation, especially in NF1 patients
Ancillary studies ─
─ IHC: Schwann cells S100/SOX10 positive (often patchy); CD34 highlights fibroblasts/stromal cells; Neurofilament highlights axons; EMA may stain perineurial cells within the expanded epineurium/perineurium of fascicles
─ Molecular: Associated with germline NF1 mutation and somatic "second hit" inactivating the other NF1 allele
DDx

─ Diffuse neurofibroma (more sheet-like infiltration of dermis/subcutis, less distinct involvement of major nerve trunks in a plexiform manner, though overlap can occur)
─ Schwannoma (plexiform variant) (multinodular but each nodule is encapsulated and purely Schwann cells, lacks axons within nodules, S100 diffuse)
─ Malignant peripheral nerve sheath tumor (MPNST) (cellular atypia, high mitoses, necrosis, S100 often lost/patchy, H3K27me3 loss common; may arise from plexiform neurofibroma)
─ Neural fibrolipoma (lipomatosis of nerve) (contains prominent mature adipose tissue infiltrating nerve, different histology)
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Neurofibroma in Neurofibromatosis

Refers to the development of neurofibromas (localized, diffuse, or plexiform) as a cardinal feature of Neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder caused by mutations in the NF1 tumor suppressor gene
Clinical ─ NF1 is characterized by multiple café-au-lait macules, axillary/inguinal freckling, Lisch nodules (iris hamartomas), optic pathway gliomas, specific osseous lesions (eg, sphenoid dysplasia, tibial pseudarthrosis), and a predisposition to various benign and malignant tumors, most notably neurofibromas and MPNSTs
Clinical ─ Neurofibromas in NF1 can be cutaneous (numerous, variable size), diffuse (plaque-like), or plexiform (pathognomonic, risk of MPNST)
Clinical ─ Onset of cutaneous neurofibromas often occurs around puberty and they may increase in size and number with age and hormonal changes (eg, pregnancy)
Micro (Neurofibromas in NF1) ─
─ Histologically similar to sporadic neurofibromas of the corresponding type (localized, diffuse, plexiform)
─ Composed of a mixed population of Schwann cells (S100/SOX10 positive), fibroblasts (CD34 positive), perineurial-like cells, mast cells, and embedded axons (neurofilament positive) within a collagenous or myxoid stroma
─ Plexiform neurofibromas are uniquely associated with NF1 and show expansion of multiple nerve fascicles
─ "Atypical neurofibromas" can occur in NF1, showing features like increased cellularity, mild atypia, or loss of typical architecture, which may indicate a higher risk for MPNST transformation but are not overtly malignant themselves
Ancillary studies ─
─ IHC: As per specific neurofibroma type (S100/SOX10 for Schwann cells, CD34 for fibroblasts, neurofilament for axons)
─ Molecular: Germline NF1 mutation is present in all cells; neurofibromas typically show a somatic "second hit" inactivating the remaining NF1 allele in neoplastic Schwann cells
DDx (for individual lesions) ─

─ Sporadic neurofibroma (if solitary and no other NF1 stigmata, though NF1 mutations can occur in some sporadic cases)
─ Schwannoma (purely Schwann cells, encapsulated, diffuse S100, lacks axons; NF2 association for multiple schwannomas)
─ Malignant peripheral nerve sheath tumor (MPNST) (arises in ~5-15% of NF1 patients, often from plexiform neurofibromas; shows malignant features)
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Malignant Transformation in Neurofibroma

Refers to the development of a Malignant Peripheral Nerve Sheath Tumor (MPNST) from a pre-existing neurofibroma, most commonly a plexiform neurofibroma in the setting of Neurofibromatosis type 1 (NF1)
Clinical ─ Lifetime risk of MPNST in NF1 patients is ~5-15%; rare in sporadic neurofibromas; suspicion raised by rapid enlargement of a known neurofibroma, new onset or worsening pain, or development of neurologic deficits; median age for MPNST development in NF1 is younger (20s-30s) than sporadic MPNST
Macro ─ Area of malignant transformation within a neurofibroma often appears as a firmer, more fleshy, gray-white, infiltrative nodule or mass, frequently with hemorrhage and necrosis, contrasting with the softer, more uniform appearance of the benign neurofibroma component
Micro

─ Abrupt or gradual transition from a recognizable benign neurofibroma (often plexiform or atypical) to a high-grade spindle cell sarcoma (MPNST)
─ MPNST component shows features of malignancy:
─ Increased cellularity, often with fascicular or herringbone pattern
─ Significant cytologic atypia (hyperchromasia, pleomorphism, irregular nuclei)
─ High mitotic activity (often >10/10 HPF), including atypical mitoses
─ Geographic necrosis is common
─ Perivascular hypercellularity and alternating cellularity ("marbling") can be seen
─ Heterologous elements (eg, rhabdomyosarcoma - Triton tumor, cartilage, bone) may be present in the MPNST component
Ancillary studies ─
─ IHC (MPNST component): S100 protein and SOX10 are often lost or become weak and patchy (in ~50% of cases), contrasting with positivity in the benign neurofibroma component; Loss of H3K27me3 (by IHC) is common in MPNSTs (especially NF1-associated/high-grade) and can be a useful marker of malignant transformation if the benign precursor retains expression; Negative for keratins, desmin, SMA (usually)
─ Molecular: Inactivation of NF1 is the initial step; malignant transformation is associated with acquisition of additional genetic alterations, commonly involving CDKN2A/B (p16/p14ARF) deletion, TP53 mutation, and inactivation of PRC2 complex genes (eg, SUZ12, EED) leading to H3K27me3 loss
DDx

─ Atypical neurofibroma (shows some worrisome features like increased cellularity/mild atypia but lacks definitive criteria for MPNST; considered premalignant or low-grade MPNST by some)
─ Benign neurofibroma with reactive changes (eg, post-biopsy; atypia is usually limited, mitoses low)
─ Other high-grade sarcomas arising near a neurofibroma (collision tumor - very rare; distinction based on whether sarcoma arises from the neurofibroma elements)
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Myxoid Neurofibroma

A subtype of neurofibroma characterized by a particularly abundant myxoid stroma, which can sometimes make the lesion appear less cellular and potentially mimic other myxoid soft tissue tumors
Clinical ─ Can occur as localized cutaneous, localized intraneural, diffuse, or plexiform neurofibroma; may be sporadic or associated with Neurofibromatosis type 1 (NF1); presentation similar to non-myxoid counterparts but may feel softer or more gelatinous
Macro ─ Often appears more translucent, gelatinous, or mucoid on cut section compared to more collagenous neurofibromas; otherwise similar to the specific type of neurofibroma (eg, localized, plexiform)
Micro

─ Overall architecture and cellular composition similar to conventional neurofibroma: mixture of Schwann cells (wavy nuclei), fibroblasts, perineurial-like cells, mast cells, and embedded axons
─ Defining feature: Abundant, loose, myxoid, or edematous stroma (Alcian blue positive) separating the cellular elements
─ Cells may appear more stellate or widely spaced due to the myxoid matrix
─ "Shredded carrot" collagen may be less apparent if stroma is predominantly myxoid
─ Blood vessels are often inconspicuous or delicate within the myxoid areas
─ Cytologic atypia is minimal, mitotic activity is low
Ancillary studies ─
─ IHC: Similar to conventional neurofibroma: Schwann cells S100/SOX10 positive (often patchy); CD34 highlights fibroblasts/stromal cells; Neurofilament highlights embedded axons
─ Molecular: NF1 gene inactivation if associated with NF1 or in some sporadic cases
DDx

─ Schwannoma (especially Antoni B areas or microcystic/reticular variant) (lacks axons within tumor, purely Schwann cells, diffuse S100)
─ Perineurioma (myxoid variant) (EMA/claudin-1 positive tumor cells, S100 negative, lacks axons)
─ Dermal nerve sheath myxoma (neurothekeoma, myxoid type) (lobulated, S100 often patchy or negative in some classifications, lacks axons consistently)
─ Low-grade myxofibrosarcoma (older adults, curvilinear vessels, more atypia, S100 negative)
─ Aggressive angiomyxoma (deep pelvic/perineal, prominent vessels, HMGA2 rearranged, S100 negative)
─ Myxoid liposarcoma (lipoblasts, plexiform capillaries, DDIT3 fusion, S100 negative)
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Dendritic Cell Neurofibroma

A rare variant of neurofibroma characterized by a prominent population of plump spindle to epithelioid cells with dendritic cytoplasmic processes, often with a storiform or fascicular pattern, and typically occurring in the skin or subcutis
Clinical ─ Usually affects adults; presents as a solitary, slow-growing, firm, painless papule or nodule; common sites include skin and subcutaneous tissue of the trunk, head/neck, and extremities; not clearly associated with Neurofibromatosis type 1 (NF1)
Macro ─ Well-demarcated, firm, gray-white to tan nodule, typically small (<2 cm)
Micro

─ Dermal or subcutaneous proliferation of relatively uniform spindle to epithelioid cells with ovoid to vesicular nuclei and pale eosinophilic cytoplasm, often with delicate, branching dendritic cytoplasmic processes
─ Cells are typically arranged in a storiform, fascicular, or diffuse pattern
─ Stroma is variably collagenous or myxoid
─ Unlike conventional neurofibroma, mast cells and embedded axons may be less conspicuous or absent; the mixed cell population of typical neurofibroma is often not apparent
─ Cytologic atypia is minimal, mitotic activity is low
Ancillary studies ─
─ IHC: Tumor cells are typically positive for CD34 and Factor XIIIa; S100 protein and SOX10 are usually negative or only very focally positive in scattered cells (distinguishing from conventional neurofibroma); EMA may be focally positive; Neurofilament negative within the main tumor cell population
─ Molecular: Not well characterized; distinct from conventional neurofibroma (NF1 alterations)
DDx

─ Conventional neurofibroma (S100/SOX10 positive Schwann cells, embedded axons, more mixed cell population, often lacks diffuse CD34/Factor XIIIa in tumor cells)
─ Dermatofibroma (benign fibrous histiocytoma) (Factor XIIIa positive, CD34 often negative, storiform pattern, collagen trapping)
─ Dermatofibrosarcoma protuberans (DFSP) (diffusely CD34 positive, storiform pattern, honeycomb infiltration of fat, COL1A1::PDGFB fusion)
─ Perineurioma (EMA/claudin-1 positive, S100 negative)
─ Solitary fibrous tumor (STAT6 positive, CD34 positive, characteristic vasculature)
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Perineurioma

A benign peripheral nerve sheath tumor composed exclusively of perineurial cells, characterized by bland spindle cells with slender, bipolar cytoplasmic processes arranged in whorls, lamellae, or fascicles; occurs in intraneural and extraneural (soft tissue) forms
Clinical ─ Intraneural perineurioma: Affects children and adults; involves peripheral nerves, causing fusiform enlargement and often progressive mononeuropathy (muscle weakness, sensory loss); common in extremities
Clinical ─ Soft tissue perineurioma (extraneural): Typically affects adults (peak 30-50s); common in skin, subcutaneous tissue, and deep soft tissues of extremities and trunk; presents as a slow-growing, painless nodule
Macro ─ Intraneural: Fusiform or segmental thickening of a nerve; Soft tissue: Well-circumscribed, firm, gray-white to tan nodule, often <5 cm
Micro

─ Composed of uniform, bland spindle cells with characteristically elongated, slender, wavy or tapering nuclei and delicate, thin, bipolar cytoplasmic processes
─ Cells are arranged in various patterns:
─ Storiform or whorled pattern (common in soft tissue perineurioma)
─ Lamellar or onion-skin like concentric proliferation around axons (pathognomonic for intraneural perineurioma, forming "pseudo-onion bulbs")
─ Fascicular or diffuse growth
─ Stroma is variably collagenous, sometimes myxoid (myxoid perineurioma) or sclerotic (sclerosing perineurioma)
─ Cytologic atypia is minimal, mitotic activity is very low or absent
─ Axons are present within the tumor in intraneural perineurioma (surrounded by neoplastic perineurial cells), but absent in soft tissue perineurioma
Ancillary studies ─
─ IHC: Tumor cells (perineurial cells) are characteristically positive for EMA (epithelial membrane antigen), claudin-1, and GLUT1; CD34 is positive in a subset of soft tissue perineuriomas; S100 protein and SOX10 are negative (crucial for distinguishing from schwannoma and neurofibroma); Neurofilament protein highlights entrapped axons in intraneural type
─ Molecular: Soft tissue perineuriomas often show deletions or mutations of chromosome 22q (including the NF2 gene locus) or less commonly other chromosomal abnormalities; TRAF7 mutations have been reported in some cases; intraneural perineuriomas less well characterized genetically but some show NF2 alterations
DDx

─ Schwannoma (S100/SOX10 positive, EMA negative in tumor cells, NF2 mutated)
─ Neurofibroma (S100/SOX10 positive Schwann cells, embedded axons throughout, mixed cell types, EMA negative or focal)
─ Fibroblastic tumors (eg, low-grade fibromyxoid sarcoma, solitary fibrous tumor - specific markers and morphology, EMA negative)
─ Meningioma (if intracranial/spinal or ectopic; EMA positive but different morphology, psammoma bodies, lacks claudin-1/GLUT1 typically)
─ Leiomyoma (smooth muscle markers positive, EMA negative)
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Soft Tissue Perineurioma

A benign peripheral nerve sheath tumor composed exclusively of perineurial cells, arising in soft tissues extraneurally (not directly involving a major nerve trunk); also known as extraneural perineurioma
Clinical ─ Typically affects adults (peak age 30-50s); common in skin, subcutaneous tissue, and deep soft tissues of the extremities, trunk, and less often head/neck; presents as a solitary, slow-growing, painless, firm nodule, usually <5 cm
Macro ─ Well-circumscribed, often pseudoencapsulated, firm, gray-white to tan nodule
Micro

─ Composed of uniform, bland spindle cells with characteristic elongated, slender, wavy or tapering nuclei and delicate, thin, bipolar cytoplasmic processes
─ Cells are typically arranged in a storiform, whorled, fascicular, or lamellar pattern
─ Stroma is variably collagenous, sometimes myxoid (myxoid variant) or densely sclerotic (sclerosing variant - see separate entry)
─ Cytologic atypia is minimal, mitotic activity is very low or absent (usually <1-2/10 HPF)
─ Axons are absent within the tumor (distinguishes from intraneural perineurioma and neurofibroma)
─ Blood vessels may be inconspicuous or somewhat prominent
Ancillary studies ─
─ IHC: Tumor cells are characteristically positive for EMA (epithelial membrane antigen), claudin-1, and GLUT1; CD34 is positive in a subset of cases (variable); Negative for S100 protein, SOX10, neurofilament protein, desmin, SMA (except reactive vessels), keratins
─ Molecular: Often show deletions or mutations of chromosome 22q (including the NF2 gene locus); TRAF7 mutations also reported; distinct from fusions seen in some other spindle cell tumors
DDx

─ Schwannoma (S100/SOX10 positive, EMA negative in tumor cells)
─ Neurofibroma (S100/SOX10 positive Schwann cells, embedded axons, mixed cell types)
─ Dermatofibrosarcoma protuberans (CD34 positive but storiform pattern with honeycomb fat infiltration, COL1A1::PDGFB fusion, EMA negative)
─ Solitary fibrous tumor (STAT6 positive, CD34 positive, characteristic vasculature, EMA negative)
─ Low-grade fibromyxoid sarcoma (MUC4 positive, FUS fusion, often alternating pattern, EMA negative)
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Intraneural Perineurioma

A benign peripheral nerve sheath tumor composed exclusively of perineurial cells that proliferate within and expand nerve fascicles, leading to fusiform nerve enlargement and potential neuropathy
Clinical ─ Affects children and adults (wide age range); typically involves peripheral nerves of the extremities (eg, sciatic, median, ulnar nerves), less commonly cranial nerves or spinal roots; presents with progressive mononeuropathy (muscle weakness, atrophy, sensory loss, pain) due to nerve compression and dysfunction; slow-growing
Macro ─ Fusiform or segmental, often multinodular, firm enlargement of the involved nerve trunk; cut surface may show grayish-white, translucent tissue expanding nerve fascicles
Micro

─ Characterized by the proliferation of bland, spindle-shaped perineurial cells arranged in concentric, multilayered lamellae ("pseudo-onion bulbs") around individual or small groups of preserved axons and their associated Schwann cells, all within expanded nerve fascicles
─ Perineurial cells have elongated, slender, wavy nuclei and thin, bipolar cytoplasmic processes
─ The expanded nerve fascicles are separated by perineurial connective tissue and epineurium
─ Cytologic atypia is minimal, mitotic activity is very low or absent
─ The overall nerve architecture is maintained but distorted by the perineurial proliferation
Ancillary studies ─
─ IHC: Neoplastic perineurial cells are positive for EMA, claudin-1, and GLUT1; S100 protein and SOX10 are negative in the perineurial cells but will highlight the entrapped Schwann cells associated with axons; Neurofilament protein highlights the centrally located, preserved axons within the pseudo-onion bulbs
─ Molecular: Some cases show alterations in the NF2 gene or chromosome 22q, but less consistently than soft tissue perineuriomas; TRAF7 mutations have also been described
DDx

─ Schwannoma (intraneural or plexiform) (S100/SOX10 positive tumor cells, lacks EMA/claudin-1 positivity in tumor cells, axons typically excluded from main tumor mass or splayed in capsule)
─ Neurofibroma (plexiform or intraneural) (mixed cell population including S100/SOX10 positive Schwann cells and fibroblasts, axons intermingled throughout tumor, not just centrally in pseudo-onion bulbs)
─ Chronic inflammatory demyelinating polyneuropathy (CIDP) (inflammatory infiltrates, "onion bulb" formation by reactive Schwann cells, not neoplastic perineurial cells)
─ Charcot-Marie-Tooth disease (hereditary neuropathy) (some types show "onion bulbs" due to Schwann cell hypertrophy, genetic basis, not a tumor)
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Sclerosing Perineurioma

A distinctive benign variant of soft tissue perineurioma characterized by bland spindle cells with perineurial differentiation set in a densely sclerotic or hyalinized collagenous stroma, typically occurring in acral locations
Clinical ─ Primarily affects adults (wide age range); strong predilection for acral sites, especially fingers and toes, also palm and sole; presents as a solitary, slow-growing, firm, painless or mildly tender papule or nodule, usually small (<1-2 cm)
Macro ─ Small, well-circumscribed, very firm, white to tan papule or nodule in the dermis or subcutis
Micro

─ Well-demarcated, often pseudoencapsulated, dermal or subcutaneous proliferation
─ Composed of relatively paucicellular, bland spindle cells with elongated, slender nuclei and inconspicuous cytoplasm
─ Cells are arranged in short fascicles, cords, strands, or a storiform pattern, embedded within an abundant, dense, hyalinized, or sclerotic collagenous stroma
─ "Patterned" or "amianthoid-like" collagen may be seen
─ Cytologic atypia is minimal, mitotic activity is very low or absent
─ Vascularity is often inconspicuous
Ancillary studies ─
─ IHC: Tumor cells (perineurial cells) are characteristically positive for EMA (epithelial membrane antigen), claudin-1, and GLUT1; CD34 may be positive in a subset of cases; S100 protein and SOX10 are negative
─ Molecular: Similar to other soft tissue perineuriomas, may show deletions or mutations of chromosome 22q (including NF2 locus) or TRAF7 mutations in some cases
DDx

─ Dermatofibroma (sclerotic variant) (Factor XIIIa positive, EMA negative, different morphology)
─ Acral fibromyxoma (more myxoid, CD34 positive, S100 often positive, EMA negative)
─ Collagenous fibroma (desmoplastic fibroblastoma) (lacks consistent EMA/claudin-1/GLUT1 positivity, different cell morphology)
─ Scar tissue (history of injury, less organized, lacks perineurial marker expression)
─ Cellular digital fibroma (lacks perineurial markers, often more cellular)
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Reticular and Myxoid Soft Tissue Perineurioma

Variants of soft tissue perineurioma characterized by distinctive architectural patterns: reticular perineurioma shows an anastomosing network of slender spindle cells forming a mesh-like or lace-like pattern, while myxoid perineurioma exhibits abundant myxoid stroma
Clinical ─ Similar to conventional soft tissue perineurioma, typically adults; common in skin, subcutaneous tissue of extremities and trunk; presents as slow-growing, painless nodules
Macro ─ Well-circumscribed, firm or gelatinous (if myxoid) nodules, usually small
Micro (Reticular Perineurioma) ─

─ Anastomosing strands and cords of slender spindle cells with delicate, bipolar cytoplasmic processes, forming an intricate reticular or lace-like network
─ Cells are bland with minimal atypia and rare mitoses
─ Stroma is often scant or slightly collagenous within the reticular network
Micro (Myxoid Perineurioma) ─

─ Spindle cells similar to conventional perineurioma (elongated, slender nuclei, bipolar processes) but set in an abundant, loose, myxoid, or edematous stroma (Alcian blue positive)
─ Cells may appear more stellate or widely separated due to the myxoid matrix
─ Growth pattern can be storiform, fascicular, or haphazard within the myxoid stroma
─ Cytologic atypia is minimal, mitotic activity is very low
Ancillary studies (for both variants) ─
─ IHC: Tumor cells are positive for EMA, claudin-1, and GLUT1; CD34 may be positive in a subset; Negative for S100 protein, SOX10, neurofilament
─ Molecular: May show chromosome 22q deletions or TRAF7 mutations, similar to other perineuriomas
DDx (Reticular Perineurioma) ─

─ Microcystic/Reticular schwannoma (S100/SOX10 positive, EMA negative in tumor cells)
─ Retiform hemangioendothelioma (vascular tumor, CD31/ERG positive, D2-40 often positive, different cell type)
DDx (Myxoid Perineurioma) ─

─ Myxoid neurofibroma (S100/SOX10 positive Schwann cells, embedded axons)
─ Low-grade myxofibrosarcoma (more atypia, curvilinear vessels, S100/EMA negative)
─ Aggressive angiomyxoma (deep pelvic/perineal, HMGA2 rearranged, EMA negative)
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Mucosal Perineurioma

A rare benign perineurial neoplasm arising in mucosal sites, most commonly the oral cavity, characterized by bland spindle cells with perineurial differentiation
Clinical ─ Typically affects adults; most common in the oral cavity (lips, tongue, buccal mucosa), also reported in sinonasal tract and larynx; presents as a small, solitary, slow-growing, firm, painless submucosal nodule or polyp
Macro ─ Small (<2 cm), well-circumscribed, firm, gray-white or tan nodule or polyp beneath intact mucosa
Micro

─ Well-demarcated but unencapsulated proliferation of bland spindle cells in the submucosa
─ Cells have elongated, slender, wavy nuclei and delicate, bipolar cytoplasmic processes
─ Arranged in storiform, fascicular, whorled, or lamellar patterns, similar to soft tissue perineurioma
─ Stroma is variably collagenous, can be slightly myxoid
─ Overlying mucosa is typically intact, may show reactive changes
─ Minimal cytologic atypia, mitotic activity is very low or absent
Ancillary studies ─
─ IHC: Tumor cells are characteristically positive for EMA, claudin-1, and GLUT1; CD34 may be positive in a subset; Negative for S100 protein, SOX10, neurofilament, SMA, desmin, keratins
─ Molecular: Genetic alterations are not as well characterized as soft tissue perineuriomas, but may involve chromosome 22q or TRAF7 similarly
DDx

─ Mucosal schwannoma (S100/SOX10 positive)
─ Mucosal neurofibroma (S100/SOX10 positive Schwann cells, embedded axons, mixed cell types)
─ Leiomyoma (if oral; smooth muscle markers desmin/h-caldesmon positive)
─ Solitary fibrous tumor (STAT6 positive, different morphology)
─ Low-grade myofibroblastic sarcoma (if oral; SMA/desmin variable, more infiltrative, potential atypia)
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Malignant Peripheral Nerve Sheath Tumor (MPNST)

An aggressive sarcoma arising from peripheral nerves or showing nerve sheath differentiation, often associated with Neurofibromatosis type 1 (NF1); it is a diagnosis that requires careful correlation of morphology, immunohistochemistry, and clinical context
Clinical ─ Typically affects adults (peak 20-50s); ~50% arise in patients with NF1 (often at a younger age and from pre-existing plexiform neurofibromas); ~10% arise after radiation therapy; remaining are sporadic (de novo); common sites include major nerve trunks (sciatic nerve, brachial plexus, sacral plexus), deep soft tissues of extremities, trunk, and head/neck; presents as a rapidly enlarging, often painful mass, may cause neurologic deficits
Macro ─ Fusiform or eccentric enlargement of a nerve, or a large, infiltrative soft tissue mass; cut surface is typically fleshy, gray-white to tan, often with areas of hemorrhage, necrosis, and cystic change; margins are infiltrative
Micro

─ Cellular spindle cell sarcoma, classically arranged in intersecting fascicles with a "herringbone" or storiform pattern, but can be highly variable
─ Cells typically have wavy, tapered, or buckled nuclei, hyperchromatic chromatin, and indistinct cytoplasm; cytologic atypia and pleomorphism are usually evident and can be marked
─ High mitotic activity (often >10-20/10 HPF), including atypical mitoses, is a key feature
─ Geographic necrosis is common
─ Characteristic (but not always present) features include perivascular hypercellularity ("vascular tropism"), alternating hypercellular and hypocellular areas ("marbling"), and subendothelial accentuation of tumor cells in large vessels
─ Heterologous elements (divergent differentiation) can occur in ~15% of cases, including rhabdomyosarcoma (malignant Triton tumor), angiosarcoma, osteosarcoma, or chondrosarcoma
─ Epithelioid and glandular variants exist (see separate entries)
Ancillary studies ─
─ IHC: Diagnosis is often challenging by IHC as there is no single specific marker; S100 protein and SOX10 are positive in only ~50-70% of cases, often weak and patchy (strong diffuse S100 argues against MPNST); Loss of H3K27me3 (by IHC) is a relatively sensitive and specific marker, especially in NF1-associated and high-grade MPNSTs (correlates with PRC2 complex inactivation); CD34 is usually negative (except vessels); EMA highlights entrapped perineurial cells or capsule if arising in nerve; Negative for keratins (except glandular/epithelioid variants), desmin, SMA (except heterologous elements or reactive cells), STAT6, MUC4
─ Molecular: Complex karyotypes are typical; inactivation of NF1 (neurofibromin) is common in both NF1-associated and sporadic MPNSTs; inactivation of CDKN2A/B (p16/p14ARF) and TP53 tumor suppressor genes is frequent, especially in high-grade tumors; inactivation of PRC2 complex genes (eg, SUZ12, EED) correlates with H3K27me3 loss
DDx

─ Cellular schwannoma (strong/diffuse S100, lacks significant atypia/necrosis, NF2 loss)
─ Atypical neurofibroma (in NF1; less atypia/mitoses, lacks definitive sarcomatous features, but represents a precursor/low-grade MPNST by some definitions)
─ Monophasic synovial sarcoma (TLE1 positive, keratin/EMA often focally positive, SS18 fusion, S100 usually negative)
─ Fibrosarcoma / Undifferentiated spindle cell sarcoma (S100/SOX10 negative, H3K27me3 retained, diagnosis of exclusion)
─ Spindle cell melanoma (S100/SOX10 often strongly positive, other melanocytic markers like HMB45/Melan-A may be positive)
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─ pathoutlines WSI WSI WSI WSI WSI WSI WSI & WSI WSI WSI video

Epithelioid Malignant Peripheral Nerve Sheath Tumor

A rare, aggressive variant of MPNST characterized by a predominant proliferation of epithelioid cells showing Schwann cell differentiation, often with loss of SMARCB1/INI1 expression
Clinical ─ Typically affects adults; may arise de novo or in association with schwannomatosis (SMARCB1 mutated) or rarely NF1; occurs in deep soft tissues of extremities, trunk, head/neck, or as an intradural or visceral mass; aggressive clinical course with high rates of recurrence and metastasis
Macro ─ Firm, infiltrative mass, often with hemorrhage and necrosis; gray-white to tan cut surface
Micro

─ Sheets, nests, or cords of large, polygonal epithelioid cells with abundant eosinophilic or clear cytoplasm, distinct cell borders, and large, vesicular, often eccentrically placed nuclei with prominent nucleoli (rhabdoid-like features may be present)
─ Cytologic atypia is usually marked, pleomorphism can be significant
─ Mitotic activity is typically brisk, atypical mitoses common; necrosis is frequent
─ A minor spindle cell component resembling conventional MPNST may be present focally
─ Stroma is variable, can be myxoid or collagenous
Ancillary studies ─
─ IHC: Tumor cells are characteristically positive for S100 protein and SOX10 (often strong and diffuse, unlike conventional MPNST which is often patchy/lost); Loss of SMARCB1/INI1 nuclear expression is seen in ~50-90% of cases and is a key diagnostic feature (especially in non-NF1 settings); EMA may be focally positive; Negative for keratins (usually), melanocytic markers, desmin, SMA
─ Molecular: Inactivation of SMARCB1/INI1 (on chromosome 22q) is common, either by mutation or deletion; NF2 alterations may also occur, especially in NF2-associated cases (rare for this variant)
DDx

─ Epithelioid schwannoma (benign) (lacks significant atypia, mitoses, necrosis; INI1 retained usually)
─ Melanoma (epithelioid) (HMB45/Melan-A positive, lacks INI1 loss typically)
─ Carcinoma (metastatic or primary adnexal) (keratin positive, S100/SOX10 negative, INI1 retained)
─ Extrarenal rhabdoid tumor (INI1 loss but typically different morphology, younger age, lacks S100/SOX10)
─ Epithelioid sarcoma (INI1 loss but CD34 often positive, keratin positive, different morphology)
─ PEComa (HMB45/Melan-A and smooth muscle markers positive, INI1 retained)
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Glandular Malignant Peripheral Nerve Sheath Tumor

An extremely rare variant of MPNST characterized by the presence of benign-appearing glandular structures (epithelial differentiation) within an otherwise typical MPNST; also known as malignant peripheral nerve sheath tumor with glandular differentiation
Clinical ─ Similar to conventional MPNST; typically adults, often associated with Neurofibromatosis type 1 (NF1); arises from major nerve trunks or in deep soft tissues; highly aggressive with poor prognosis
Macro ─ Large, infiltrative mass, similar to conventional MPNST; glandular areas may not be grossly apparent
Micro

─ Biphasic tumor composed of:
─ Dominant component: High-grade spindle cell sarcoma typical of conventional MPNST (cellular fascicles, atypia, mitoses, necrosis)
─ Glandular component: Benign-appearing (adenocarcinoma-like or enteric-type) glands or cysts lined by cuboidal, columnar, or mucinous epithelium, embedded within or sharply demarcated from the sarcomatous stroma
─ Glands may contain mucin and show goblet cells or Paneth cell-like granules
─ No evidence of direct origin from overlying epithelium or pre-existing glandular structures (ie, not a collision tumor or carcinosarcoma)
─ The epithelial component is considered a form of heterologous metaplastic differentiation within the MPNST
Ancillary studies ─
─ IHC: Spindle cell (MPNST) component: S100/SOX10 variably positive (often patchy/lost), H3K27me3 often lost
─ IHC: Glandular (epithelial) component: Positive for keratins (AE1/AE3, CAM5.2, CK7, CK20 depending on glandular type), EMA, CEA; Negative for S100, SOX10, myogenic markers
─ Molecular: Complex karyotypes and genetic alterations typical of MPNST (NF1, CDKN2A, TP53, PRC2 inactivation) in the spindle cell component; epithelial component is thought to be clonally related
DDx

─ Metastatic adenocarcinoma with sarcomatoid reaction or desmoplasia (glandular component is malignant and primary, clinical history of carcinoma)
─ Synovial sarcoma (biphasic) (glandular component is part of the sarcoma, SS18 fusion, TLE1 positive, keratin positive in both components often)
─ Carcinosarcoma / Sarcomatoid carcinoma (malignant epithelial and mesenchymal components, different clinical context)
─ Teratoma with malignant transformation (contains elements from all three germ layers)
─ MPNST with entrapped benign glands (glands are clearly pre-existing and passively incorporated, not metaplastic)
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Myxoid Malignant Peripheral Nerve Sheath Tumor

A variant of MPNST characterized by a prominent myxoid stroma (typically >50% of the tumor volume), which can sometimes obscure the malignant cytologic features or mimic other myxoid sarcomas
Clinical ─ Similar to conventional MPNST; may occur in NF1 patients or sporadically; affects adults, deep soft tissues are common sites; aggressive behavior similar to conventional MPNST of comparable grade
Macro ─ Infiltrative mass, often large; cut surface is typically gelatinous, translucent, grayish-white due to abundant myxoid matrix; may have firmer, fleshy areas corresponding to higher cellularity
Micro

─ Background features of MPNST: cellular spindle cell proliferation with fascicular or disorganized growth, nuclear atypia (wavy, tapered, hyperchromatic nuclei), and mitotic activity
─ Defining feature: Abundant myxoid or edematous stroma (Alcian blue positive) occupying a significant portion of the tumor
─ Tumor cells may appear more stellate or separated within the myxoid areas
─ Cellularity can be variable, often with alternating hypercellular and hypocellular myxoid zones
─ Perivascular hypercellularity and necrosis can be present, similar to conventional MPNST
─ Cytologic atypia and mitotic rate should be carefully assessed, as they may be less apparent in hypocellular myxoid regions
Ancillary studies ─
─ IHC: Similar to conventional MPNST; S100 protein and SOX10 are positive in only ~50-70% (often weak/patchy); Loss of H3K27me3 is common; Negative for keratins, desmin, SMA (usually), STAT6, MUC4
─ Molecular: Complex karyotypes and genetic alterations typical of MPNST (NF1, CDKN2A, TP53, PRC2 inactivation)
DDx

─ Myxoid neurofibroma (lacks significant atypia and mitoses, S100 more consistently positive, associated with NF1)
─ Low-grade myxofibrosarcoma (curvilinear vessels, more pleomorphism in non-myxoid areas, S100 negative, lacks MPNST genetics)
─ Myxoid liposarcoma (lipoblasts, plexiform capillaries, DDIT3 fusion, S100 negative)
─ Extraskeletal myxoid chondrosarcoma (NR4A3 fusion, different cell morphology, S100 often patchy, lacks MPNST genetics)
─ Myxoid solitary fibrous tumor (STAT6 positive, NAB2::STAT6 fusion, characteristic SFT vasculature)
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Granular cell tumor

A benign neoplasm, usually of Schwann cell origin, characterized by sheets or nests of large polygonal cells with abundant, distinctly granular eosinophilic cytoplasm due to lysosomal accumulation
Clinical ─ Affects a wide age range (peak 30-60s), F>M slightly, more common in individuals of African descent; most common site is the tongue, followed by skin and subcutaneous tissue (especially head/neck, trunk, extremities), breast, larynx, bronchus, and gastrointestinal tract; usually presents as a solitary, slow-growing, firm, painless or mildly tender nodule, typically <3 cm; malignant variant is exceedingly rare
Macro ─ Small, poorly circumscribed or well-demarcated, firm, gray-white to yellowish nodule; cut surface appears solid and granular
Micro

─ Infiltrative or well-demarcated proliferation of nests, cords, or sheets of large, polygonal to round cells with abundant, strikingly granular eosinophilic cytoplasm (granules are PAS-positive, diastase-resistant lysosomes)
─ Nuclei are small, round to oval, often eccentrically located, and typically bland with inconspicuous nucleoli
─ Cell borders are usually distinct
─ Overlying pseudoepitheliomatous hyperplasia (PEH) of squamous epithelium is a common and characteristic feature in cutaneous and mucosal lesions, which can be mistaken for squamous cell carcinoma
─ Tumor cells may infiltrate between collagen bundles or around adnexal structures and nerves
─ Minimal to no cytologic atypia, mitotic activity is very low or absent in benign tumors
─ Malignant granular cell tumor (rare): Defined by features such as necrosis, spindling of tumor cells, vesicular nuclei with large nucleoli, increased mitotic rate (>2/10 HPF at 200x), nuclear pleomorphism, and rapid growth or large size (>4 cm)
Ancillary studies ─
─ IHC: Tumor cells are strongly and diffusely positive for S100 protein and SOX10 (supporting Schwannian differentiation); Also positive for CD68 (PGM1, KP1 - reflecting lysosomal content), inhibin-alpha, calretinin, PGP9.5, and TFE3 (nuclear); Negative for GFAP, SMA, desmin, keratins (except entrapped structures or PEH), melanocytic markers (HMB45, Melan-A)
─ Molecular: Inactivating mutations in ATP6AP1 or ATP6AP2 genes (involved in lysosomal acidification) have been reported in many sporadic benign granular cell tumors
DDx

─ Rhabdomyoma (adult type) (myogenic markers desmin/myoglobin positive, may have cross-striations/crystals, S100 negative)
─ Hibernoma (composed of brown fat, UCP1 positive, S100 positive but lacks granular lysosomal cytoplasm)
─ Alveolar soft part sarcoma (ASPSCR1::TFE3 fusion, characteristic crystals, different granular quality, S100 negative)
─ Xanthoma / Xanthogranuloma (foamy histiocytes, Touton giant cells, S100 negative, CD68 positive)
─ Metastatic carcinoma (eg, renal cell, breast apocrine) (keratin positive, specific carcinoma markers)
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─ pathoutlines WSI WSI WSI WSI

Nonneural Granular Cell Tumor

A rare type of granular cell tumor that lacks convincing evidence of Schwannian differentiation by immunohistochemistry (ie, negative for S100 protein and SOX10), and whose histogenesis is less certain; some may represent true non-neural granular cell proliferations, while others might be schwannian tumors with aberrant immunophenotypes
Clinical ─ Similar presentation and locations as conventional (neural) granular cell tumors, but much less common; may occur in skin, subcutaneous tissue, or visceral sites
Macro ─ Indistinguishable from conventional granular cell tumor: small, firm, whitish-yellow nodule
Micro

─ Histologically identical to conventional granular cell tumor: sheets, nests, or cords of large polygonal cells with abundant, granular eosinophilic cytoplasm and small, eccentric nuclei
─ Pseudoepitheliomatous hyperplasia may occur in overlying epithelium
─ Key difference is the immunophenotypic profile
Ancillary studies ─
─ IHC: Tumor cells are positive for CD68 (PGM1, KP1); Crucially, they are negative for S100 protein and SOX10 (or show only very limited, non-convincing staining); May show positivity for other markers like NKI-C3 or PGP9.5, but neural markers are absent
─ Molecular: Genetic basis is not as well established as S100-positive granular cell tumors; ATP6AP1/ATP6AP2 mutation status in these cases is less clear
DDx

─ Conventional (neural) granular cell tumor (S100/SOX10 positive)
─ Xanthoma / Histiocytic proliferations (composed of foamy histiocytes, lack distinct granular cytoplasm of GCT)
─ Rhabdomyoma (myogenic markers positive)
─ Alveolar soft part sarcoma (characteristic crystals, TFE3 IHC positive due to fusion)
─ Oncocytoma / Oncocytic carcinoma (if visceral; keratin positive, mitochondrial hyperplasia but different granularity)
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Dermal nerve sheath myxoma

A benign cutaneous nerve sheath tumor characterized by lobules of bland spindle and epithelioid cells set in an abundant myxoid stroma, showing Schwann cell differentiation; also known historically as myxoid neurothekeoma or classic neurothekeoma (Note: "Cellular neurothekeoma" is now considered a distinct entity, likely of fibrohistiocytic origin, and is S100 negative)
Clinical ─ Typically affects young adults (peak age 20-40s), F>M slightly; common on the extremities (especially hands, fingers, arms), head/neck (face, scalp), and trunk; presents as a solitary, slow-growing, painless, dome-shaped or polypoid dermal or subcutaneous nodule, usually <3 cm
Macro ─ Well-circumscribed, often encapsulated or pseudoencapsulated, soft, gelatinous or mucoid nodule; cut surface is typically translucent, gray-white, or yellowish
Micro

─ Multinodular or lobulated growth pattern within the dermis and/or subcutis, often with a fibrous pseudocapsule
─ Lobules are composed of relatively bland spindle, stellate, or sometimes epithelioid cells arranged in cords, nests, or a loose reticular pattern
─ Cells have scant pale eosinophilic or clear cytoplasm and ovoid to spindle-shaped vesicular nuclei with inconspicuous nucleoli
─ Abundant myxoid stroma (Alcin blue positive) is a key feature, filling the spaces within and between lobules
─ Minimal cytologic atypia, mitotic activity is very low or absent
─ Vascularity is usually not prominent
Ancillary studies ─
─ IHC: Tumor cells (Schwann cells) are characteristically positive for S100 protein (often diffuse but can be patchy) and SOX10; GFAP and PGP9.5 may also be positive; CD34 may highlight some stromal cells or vessels but is negative in tumor cells; Negative for EMA (except rare focal cells), claudin-1, GLUT1, keratins, SMA, desmin, melanocytic markers
─ Molecular: Some cases show NCOA2 or PLAG1 gene rearrangements, or EWSR1 fusions with non-ETS partners, but not consistently for diagnostic use; distinct from cellular neurothekeoma (often ALK rearranged if epithelioid features)
DDx

─ Cellular neurothekeoma (more cellular, nested growth, lacks S100 positivity, often NKI/C3 positive, may have ALK rearrangement if epithelioid)
─ Myxoid neurofibroma (contains embedded axons, more mixed cell population, S100 positive Schwann cells but different architecture)
─ Superficial angiomyxoma (more prominent vascularity, epithelial mucin, stromal neutrophils, lacks S100 in tumor cells)
─ Low-grade myxofibrosarcoma (older adults, curvilinear vessels, more atypia, S100 negative)
─ Myxoid perineurioma (EMA/claudin-1/GLUT1 positive, S100 negative)
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Solitary Circumscribed Neuroma

A benign cutaneous neural tumor composed of interlacing fascicles of Schwann cells and embedded small axons, typically well-circumscribed and encapsulated; also known as Palisaded Encapsulated Neuroma (PEN)
Clinical ─ Typically affects adults (peak age 40-60s), M=F; most common on the face (especially perioral region, nose, cheeks, forehead - "neuroma belt"), also occurs on oral mucosa and rarely other sites; presents as a solitary, slow-growing, firm, dome-shaped, skin-colored or pinkish papule or nodule, usually <1 cm; typically painless
Macro ─ Small, well-circumscribed, firm, whitish dermal nodule
Micro

─ Well-circumscribed, often encapsulated (thin fibrous capsule, EMA positive) dermal nodule; may appear to "shell out"
─ Composed of interlacing, well-defined fascicles of bland spindle cells (Schwann cells) with wavy or oval nuclei and scant, pale eosinophilic cytoplasm
─ Nuclear palisading may be present within fascicles but true Verocay bodies are typically absent or poorly formed
─ Clefts or artifactual separation often present between fascicles
─ Small, embedded axons (myelinated or unmyelinated) are present within the fascicles and are a key diagnostic feature (may require neurofilament stain to confirm)
─ No Antoni A/B pattern typical of conventional schwannoma
─ Minimal cytologic atypia, mitotic activity is very low or absent
Ancillary studies ─
─ IHC: Spindle cells (Schwann cells) are positive for S100 protein and SOX10 (often strong and diffuse within fascicles); Neurofilament protein (NFP) highlights the embedded axons within fascicles; EMA is positive in the capsule (perineurial cells) and sometimes focally around small fascicles internally; CD34 may be positive in stromal cells between fascicles
─ Molecular: No specific recurrent genetic alterations are consistently identified; distinct from schwannoma (NF2) and neurofibroma (NF1)
DDx

─ Schwannoma (conventional) (lacks axons within tumor body, shows Antoni A/B pattern, Verocay bodies, diffuse S100)
─ Neurofibroma (localized cutaneous) (more mixed cell population including fibroblasts and mast cells, more haphazard arrangement, S100 often patchy, axons more randomly distributed)
─ Traumatic neuroma (disorganized nerve bundles, fibrosis/scar tissue, history of injury)
─ Leiomyoma (pilar) (smooth muscle markers SMA/desmin positive, S100 negative)
─ Dermatofibroma (Factor XIIIa positive, lacks S100 positive spindle cells and axons)
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Ectopic meningioma and meningothelial hamartoma

Benign neoplasms or hamartomatous lesions composed of meningothelial cells occurring outside the cranial or spinal cavities, most commonly in the head and neck region or skin
Clinical ─ Can occur at any age, often congenital or presenting in childhood (Type I - primary/developmental) or adults (Type II - direct extension/metastasis from intracranial, Type III - unclear origin); common sites for primary ectopic lesions include scalp, orbit, paranasal sinuses, ear/temporal bone, parotid gland, and skin of head/neck; presents as a slow-growing, firm, painless nodule or mass
Clinical ─ Meningothelial hamartoma usually refers to congenital cutaneous lesions often on the scalp
Macro ─ Well-circumscribed, firm, gray-white to tan nodule; may be attached to underlying bone or involve skin adnexa
Micro

─ Histologically resembles intracranial meningioma, with various subtypes possible (meningothelial, transitional, psammomatous, fibrous most common)
─ Composed of lobules, nests, whorls, or sheets of meningothelial cells with syncytial appearance, oval nuclei, fine chromatin, inconspicuous nucleoli, and often intranuclear pseudoinclusions
─ Psammoma bodies (laminated calcifications) are frequently present, especially in transitional or psammomatous types
─ Meningothelial hamartoma of skin (cutaneous meningothelial hamartoma) often shows meningothelial cells intimately admixed with dermal collagen and adnexal structures, sometimes appearing infiltrative but bland
─ No significant cytologic atypia or mitotic activity in benign ectopic meningiomas/hamartomas
Ancillary studies ─
─ IHC: Tumor cells are characteristically positive for EMA (epithelial membrane antigen) and vimentin; S100 protein is variably positive (often weak/focal); Progesterone receptor (PR) is often positive; Negative for keratins (usually), CD34, GFAP, melanocytic markers
─ Molecular: May show NF2 gene mutations or chromosome 22q loss, similar to intracranial meningiomas, especially in Type II/III lesions; congenital/hamartomatous lesions less well characterized
DDx

─ Glomus tumor (if cutaneous; SMA positive, EMA negative, different morphology)
─ Epithelioid schwannoma / Perineurioma (S100/SOX10 positive for schwannoma; EMA positive for perineurioma but different morphology and claudin-1/GLUT1 positive)
─ Metastatic carcinoma (keratin positive, specific carcinoma markers)
─ Adnexal tumors of skin (specific adnexal differentiation, different IHC)
─ Nasal glioma / Glial heterotopia (GFAP positive glial tissue, S100 positive)
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Nasal Glioma / Nasal Glial Heterotopia

A rare congenital lesion consisting of heterotopic mature glial tissue found outside the cranial cavity, typically in or around the nose; it is not a true neoplasm but rather a developmental misplacement of glial tissue (choristoma)
Clinical ─ Presents at birth or in early infancy; M>F slightly; most common locations are extranasal (on or near the nasal bridge, often as a firm, non-compressible subcutaneous nodule), intranasal (within the nasal cavity, causing obstruction), or mixed; typically does not have a direct connection to the intracranial space (unlike encephalocele), though a fibrous stalk may connect to the cribriform plate area in some cases
Macro ─ Firm, rubbery, gray-white or reddish, non-pulsatile nodule or polypoid mass; usually <2-3 cm
Micro

─ Composed of disorganized, mature glial tissue resembling normal brain tissue, including astrocytes, oligodendrocytes, and sometimes ependymal cells or neuronal elements
─ Glial fibrillary acidic protein (GFAP)-positive fibrillary background is characteristic, representing astrocytic processes
─ Astrocytes are typically stellate or fibrillary, with bland nuclei
─ Neurons, if present, are mature-appearing ganglion cells
─ Fibrovascular stroma separates glial tissue into lobules or islands
─ Overlying skin or mucosa may be intact or ulcerated; entrapment of adnexal structures can occur
─ No significant cytologic atypia, mitotic activity, or features of malignancy
Ancillary studies ─
─ IHC: Glial cells (astrocytes) are strongly positive for GFAP and S100 protein; Neurons (if present) are positive for neurofilament protein (NFP) and synaptophysin; Negative for keratins, EMA
─ Molecular: Not applicable as it is a developmental lesion
DDx

─ Encephalocele / Meningoencephalocele (true herniation of brain/meninges through a skull defect, often pulsatile, direct connection to CSF spaces demonstrable on imaging)
─ Dermoid cyst / Epidermoid cyst (lined by squamous epithelium, contains keratin/adnexal structures)
─ Hemangioma / Vascular malformation (vascular proliferation, endothelial markers positive)
─ Rhabdomyosarcoma (embryonal) (malignant small round blue cells, myogenic markers positive)
─ Olfactory neuroblastoma (esthesioneuroblastoma) (malignant neuroectodermal tumor, Homer-Wright rosettes, specific IHC)
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Benign triton tumor / Neuromuscular choristoma

A rare benign hamartomatous lesion characterized by an intimate admixture of mature peripheral nerve elements (Schwann cells, axons) and mature skeletal muscle fibers, typically involving large peripheral nerves or arising in soft tissues along their course
Clinical ─ Primarily affects infants, children, and young adults (most cases <20 years, many congenital or in first decade); slight male predominance; most common sites include major peripheral nerves (sciatic nerve, brachial plexus, median nerve), also paraspinal region and extremities; presents as a slow-growing, firm, often fusiform enlargement of the involved nerve, or as a soft tissue mass; may cause pain, neurologic deficits (weakness, sensory loss), or limb hypertrophy
Clinical ─ Strong association with subsequent development of desmoid-type fibromatosis at the site, particularly after biopsy or attempted excision
Macro ─ Diffuse or localized, firm, rubbery enlargement of the involved nerve or a poorly defined soft tissue mass; cut surface is gray-white to tan, may appear fibrous or fleshy
Micro

─ Intimate and haphazard admixture of two mature tissue components:
─ Peripheral nerve elements: Bundles of Schwann cells (S100/SOX10 positive) and embedded axons (neurofilament positive), resembling neurofibroma or normal nerve tissue
─ Skeletal muscle fibers: Mature, well-differentiated rhabdomyocytes with abundant eosinophilic cytoplasm, peripheral nuclei, and often prominent cross-striations (desmin/myoglobin/MyoD1/myogenin positive)
─ The two components are intermingled without clear separation or organization
─ No cytologic atypia, mitotic activity is absent or very rare, no features of malignancy
─ Stroma is variably collagenous
Ancillary studies ─
─ IHC: Schwann cells positive for S100 protein and SOX10; Axons positive for neurofilament protein (NFP); Skeletal muscle fibers positive for desmin, MSA, myoglobin, MyoD1, and myogenin
─ Molecular: CTNNB1 (beta-catenin) gene mutations have been reported in some cases, potentially linking to the increased risk of subsequent desmoid fibromatosis at the site
DDx

─ Malignant Triton tumor (MPNST with rhabdomyosarcomatous differentiation) (malignant spindle cell MPNST component, rhabdomyoblastic component is also malignant, atypia, mitoses, necrosis)
─ Embryonal rhabdomyosarcoma (primitive cells, lacks mature nerve elements)
─ Desmoid-type fibromatosis (lacks skeletal muscle component, nuclear beta-catenin positive, often arises after manipulation of neuromuscular choristoma)
─ Rhabdomyoma (fetal or adult) (purely skeletal muscle tumor, lacks intermingled nerve elements)
─ Fibromatosis colli (infants, sternocleidomastoid muscle, lacks prominent nerve elements)
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Malignant melanotic nerve sheath tumor

A rare, aggressive sarcoma showing dual differentiation with features of both Schwann cells and melanocytes, characterized by melanin pigment production and malignant cytologic features; also known as Malignant Melanotic Schwannoma
Clinical ─ Affects a wide age range, but often adults (median ~30-50s); ~50% of cases are associated with Carney complex (a familial syndrome with multiple myxomas, endocrine tumors, and pigmented lesions due to PRKAR1A mutations); sporadic cases also occur; common sites include spinal nerve roots (often forming "dumbbell" tumors extending through neural foramina), paraspinal ganglia, sympathetic chain, and visceral locations (GI tract, heart, uterus); cutaneous or superficial soft tissue lesions are less common
Clinical ─ Presents with symptoms related to nerve compression (pain, radiculopathy, myelopathy), mass effect, or rarely with manifestations of Carney complex
Macro ─ Well-circumscribed or infiltrative, firm mass; cut surface is typically dark brown to black due to abundant melanin pigment, but can be amelanotic or variegated; may show hemorrhage, necrosis, or cystic change
Micro

─ Cellular proliferation of spindle cells and/or epithelioid cells arranged in fascicles, nests, sheets, or a storiform pattern
─ Tumor cells contain variable amounts of finely granular, brown melanin pigment within their cytoplasm; melanophages (macrophages laden with melanin) are also common
─ Nuclei are typically oval to spindle-shaped or large and vesicular (epithelioid cells), with prominent nucleoli; cytologic atypia is usually moderate to marked, and pleomorphism can be significant
─ Mitotic activity is variable but often easily identified, including atypical mitoses
─ Necrosis may be present
─ Psammoma bodies (laminated calcifications) are a characteristic feature, especially in the psammomatous variant associated with Carney complex, but can be absent
─ Infiltrative growth into surrounding tissues is common
Ancillary studies ─
─ IHC: Tumor cells characteristically co-express S100 protein and SOX10 (Schwannian markers, often strong and diffuse) as well as melanocytic markers such as HMB45, Melan-A/MART-1, and MITF; GFAP may be focally positive; Negative for keratins, desmin, SMA
─ Molecular: Carney complex-associated cases have germline inactivating mutations in the PRKAR1A gene (tumor suppressor); sporadic cases lack consistent PRKAR1A mutations and are genetically distinct from conventional melanoma (eg, usually lack BRAF/NRAS mutations) and clear cell sarcoma (lacks EWSR1 fusions)
DDx

─ Malignant melanoma (conventional or spindle cell/desmoplastic) (may lack diffuse S100/SOX10 in some variants, often BRAF/NRAS mutations, lacks PRKAR1A association or consistent psammoma bodies)
─ Clear cell sarcoma of soft tissue ("melanoma of soft parts") (EWSR1::ATF1 or EWSR1::CREB1 fusion, nests of clear cells, S100/melanocytic markers positive but different genetics/morphology)
─ Pigmented neurofibroma (melanin confined to benign dendritic melanocytes admixed with neurofibroma, lacks atypia/mitoses and dual melanocytic/Schwannian immunophenotype in the main tumor cells)
─ Melanotic schwannoma (benign counterpart) (lacks significant atypia, low mitoses, no necrosis or infiltrative growth; distinction can be difficult in borderline cases)
─ Pigmented MPNST (extremely rare, MPNST with melanin pigment, but lacks diffuse melanocytic marker expression typically)
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Ganglioneuroma

A benign, mature neuroblastic tumor composed of ganglion cells, Schwann cells, and nerve fibers, representing the most differentiated end of the neuroblastic tumor spectrum (which also includes neuroblastoma and ganglioneuroblastoma)
Clinical ─ Typically occurs in older children, adolescents, and young adults (median age ~7-10 years, but wide range); M=F; common sites include posterior mediastinum, retroperitoneum, adrenal medulla (arising from sympathetic ganglia), and paraspinal sympathetic chain; less commonly in head/neck or pelvis; often asymptomatic and discovered incidentally on imaging, or may present with symptoms due to mass effect (eg, pain, respiratory distress, neurologic compression); may produce catecholamines (rarely causing hypertension or diarrhea)
Macro ─ Well-circumscribed, often encapsulated, firm, rubbery mass; cut surface is typically gray-white to tan, homogeneous, and may appear whorled or fascicular; size can be very large, especially in retroperitoneum
Micro

─ Composed of three main components:
─ Mature ganglion cells: Large, polygonal cells with abundant eosinophilic or amphophilic cytoplasm (Nissl substance), large, round, vesicular, eccentrically placed nuclei, and prominent, single, central nucleoli; ganglion cells are scattered individually or in small clusters
─ Schwann cells: Spindle cells with wavy nuclei and pale cytoplasm, forming a dominant stromal component arranged in fascicles or a loose, collagenous, or myxoid matrix (neuropil-like fibrillary material is often present)
─ Nerve fibers (axons): Intermingled with Schwann cells and stroma
─ No significant cytologic atypia in ganglion cells or Schwann cells; mitotic activity is absent or exceptionally rare
─ Neuroblastic elements (immature neuroblasts, Homer-Wright rosettes) are absent by definition (their presence would classify the tumor as ganglioneuroblastoma or neuroblastoma)
─ Lymphocytic infiltrates may be present focally
─ Variants include maturing ganglioneuroma (areas with some residual maturing neuroblasts, borderline with ganglioneuroblastoma, intermixed)
Ancillary studies ─
─ IHC: Ganglion cells are positive for neurofilament protein (NFP), synaptophysin, chromogranin A (variable), and often neuron-specific enolase (NSE); Schwann cells are positive for S100 protein and SOX10; GFAP may be positive in Schwann cells; Negative for keratins, desmin, SMA
─ Molecular: Generally characterized by genomic stability; lacks MYCN amplification and segmental chromosomal aberrations seen in neuroblastoma; some cases may show alterations in genes like ALK or PHOX2B, but these are more typical of less differentiated neuroblastic tumors
DDx

─ Ganglioneuroblastoma (nodular or intermixed) (contains foci of immature neuroblasts and/or Homer-Wright rosettes in addition to mature ganglioneuroma components)
─ Neuroblastoma (predominantly primitive neuroblasts, Homer-Wright rosettes, MYCN amplification common)
─ Schwannoma (lacks ganglion cells and axons within tumor body, purely Schwann cells, Antoni A/B pattern)
─ Neurofibroma (lacks mature ganglion cells as a neoplastic component, mixed cell types, different stromal quality)
─ Pheochromocytoma/Paraganglioma (if adrenal/sympathetic chain; composed of chief cells and sustentacular cells, chromogranin/synaptophysin positive chief cells, S100 positive sustentacular cells, different morphology)
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Polypoid Ganglioneuroma and Ganglioneuromatosis

Polypoid ganglioneuroma refers to a specific presentation of ganglioneuroma as mucosal polyps, typically in the colon, often multiple and associated with syndromes like Cowden syndrome or PTEN hamartoma tumor syndrome; Ganglioneuromatosis describes a more diffuse or extensive proliferation of ganglioneuroma elements, often involving the GI tract wall (transmural ganglioneuromatosis) or plexiform involvement of nerves, and can be associated with NF1, MEN2B, or PTEN syndromes
Clinical (Polypoid Ganglioneuroma) ─ Usually asymptomatic, found incidentally during endoscopy; can occur in children or adults; often multiple polyps in colorectum; strong association with PTEN hamartoma tumor syndrome (Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome), also juvenile polyposis syndrome
Clinical (Ganglioneuromatosis) ─ Diffuse G: Intestinal pseudo-obstruction, motility disorders; Plexiform G: Nerve dysfunction, mass effects; Associations: NF1 (plexiform neurofibroma with ganglion cells), MEN2B (mucosal neuromas, diffuse intestinal ganglioneuromatosis), PTEN syndromes
Macro (Polypoid Ganglioneuroma) ─ Small (<1 cm), sessile or pedunculated mucosal polyps in colorectum
Macro (Ganglioneuromatosis) ─ Diffuse thickening of bowel wall or ill-defined masses; plexiform type shows enlarged nerves
Micro (Polypoid Ganglioneuroma) ─

─ Lamina propria expansion by a proliferation of mature ganglion cells, Schwann cells, and nerve fibers, often with mucosal splaying and edema
─ Ganglion cells may be focal or numerous, often in clusters
─ Overlying epithelium is typically unremarkable or hyperplastic
Micro (Ganglioneuromatosis) ─

─ Diffuse type: Extensive infiltration of bowel wall (mucosa, submucosa, muscularis propria, serosa) by mature ganglion cells, Schwann cells, and nerve fibers, often causing disorganization of muscle layers
─ Plexiform type: Expansion of intrinsic nerve plexuses (eg, Meissner's, Auerbach's) by ganglioneuromatous tissue, or diffuse involvement of larger nerves in a plexiform manner by ganglioneuroma components
Ancillary studies (for both) ─
─ IHC: Ganglion cells positive for NFP, synaptophysin, chromogranin (variable); Schwann cells S100/SOX10 positive
─ Molecular: Genetic testing for associated syndromes (PTEN, NF1, RET for MEN2B) may be indicated based on clinical context
DDx (Polypoid Ganglioneuroma) ─

─ Juvenile polyp (hamartomatous polyp with dilated glands, inflammation, lacks ganglion cells)
─ Hyperplastic polyp (serrated epithelial changes, lacks ganglion cells)
─ Inflammatory polyp (prominent inflammation, granulation tissue, lacks ganglion cells)
DDx (Ganglioneuromatosis) ─

─ Hirschsprung disease (aganglionic segment with hypertrophic nerve trunks lacking ganglion cells proximal to aganglionic segment)
─ Neurofibroma (plexiform, if NF1) (may contain scattered ganglion cells but predominantly neurofibroma elements)
─ Gangliocytic paraganglioma (duodenum, triphasic with epithelioid, spindle, and ganglion cells)
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Mucosal Schwann Cell Hamartoma

A benign, recently described hamartomatous proliferation of bland Schwann cells within the lamina propria of the colorectum, typically presenting as small polyps or found incidentally
Clinical ─ Usually affects adults (median age ~50-60s); most common in the colorectum (especially distal colon and rectum), less commonly in other GI sites; typically asymptomatic and discovered incidentally during screening colonoscopy; presents as small, sessile or diminutive polyps (<5 mm)
Macro ─ Small, pale or flesh-colored, sessile polyps or slightly raised mucosal areas
Micro

─ Well-demarcated but unencapsulated proliferation of bland spindle cells with wavy nuclei and eosinophilic cytoplasm, confined to the lamina propria of the mucosa, often splaying crypts
─ Cells are arranged in loose fascicles or a storiform pattern, sometimes with a neuroid or Wagner-Meissner body-like appearance
─ No significant cytologic atypia, mitotic activity is absent or exceptionally rare
─ Overlying epithelium is unremarkable; no associated ganglion cells or significant inflammation
─ Does not involve submucosa or deeper layers
Ancillary studies ─
─ IHC: Spindle cells (Schwann cells) are strongly and diffusely positive for S100 protein and SOX10; GFAP may be positive; Negative for EMA, claudin-1, GLUT1 (unlike perineurioma), keratins, SMA, desmin, CD34, neurofilament (axons are typically absent or very sparse within the lesion)
─ Molecular: No specific recurrent genetic alterations identified; distinct from NF1/NF2 associated lesions
DDx

─ Mucosal perineurioma (EMA/claudin-1/GLUT1 positive, S100 negative)
─ Mucosal neurofibroma (more mixed cell population including fibroblasts and mast cells, embedded axons, S100 often patchy)
─ Ganglioneuroma (polypoid) (contains mature ganglion cells in addition to Schwann cells/axons)
─ Schwannoma (conventional) (usually encapsulated, Antoni A/B areas, Verocay bodies; very rare as primary mucosal polyp)
─ Leiomyoma of muscularis mucosae (smooth muscle markers desmin/h-caldesmon positive, S100 negative)
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Chondro-osseous tumors

Soft tissue chondroma

A benign cartilaginous neoplasm arising in soft tissues, unattached to bone or joint synovium, composed of mature hyaline cartilage
Clinical ─ Typically affects adults (peak age 30-60s), M=F; most common in the soft tissues of the hands and feet (especially fingers and toes), less frequently in trunk, head/neck, or larger extremities; presents as a slow-growing, firm, usually painless, mobile or fixed nodule; size typically <3 cm
Macro ─ Well-circumscribed, often encapsulated, lobulated, firm, gray-blue to white, translucent cartilaginous mass
Micro

─ Well-demarcated, often encapsulated, lobulated proliferation of mature hyaline cartilage
─ Chondrocytes are situated within lacunae and are typically bland, with small, round, dark nuclei; cellularity is generally low to moderate
─ Binucleated chondrocytes may be present but are usually infrequent
─ Minimal to no cytologic atypia; mitotic activity is absent or exceptionally rare
─ Matrix is hyaline cartilage, may show focal myxoid change, calcification (punctate or ring-like), or endochondral ossification, especially at the periphery
─ No infiltrative growth into surrounding soft tissues
Ancillary studies ─
─ IHC: Chondrocytes are positive for S100 protein; Negative for keratins (to exclude chondroid chordoma or carcinoma)
─ Molecular: FN1 gene rearrangements (eg, FN1::FGFR1, FN1::FGF2) or IDH1/IDH2 mutations have been reported in some cases, but not consistently for diagnostic use in all soft tissue chondromas
DDx

─ Extraskeletal myxoid chondrosarcoma (more myxoid matrix, cords/clusters of eosinophilic cells, NR4A3 fusion, S100 often negative or patchy)
─ Extraskeletal osteosarcoma (malignant osteoid production by tumor cells, more atypia)
─ Synovial chondromatosis (if near joint; multiple nodules, arises from synovium, may show more cellularity/atypia initially)
─ Calcifying aponeurotic fibroma (hands/feet of children, biphasic with fibroblastic component and calcification, FN1::EGF fusion)
─ Tumoral calcinosis (avascular calcified deposits, lacks viable chondrocytes)
─ Myoepithelioma/Mixed tumor of soft tissue with chondroid differentiation (S100/keratin/EMA/GFAP/SMA variably positive, may have EWSR1 fusion)
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Synovial Chondromatosis

A benign, typically monoarticular condition characterized by cartilaginous metaplasia within the synovial membrane of joints, bursae, or tendon sheaths, resulting in the formation of multiple cartilaginous nodules that may detach and become loose bodies within the joint space
Clinical ─ Typically affects adults (peak age 30-50s), with a male predominance; most common in large joints, especially the knee (>50% of cases), followed by hip, elbow, shoulder, and ankle; presents with joint pain, swelling, stiffness, limited range of motion, crepitus, or locking; primary (idiopathic) form is considered neoplastic or reactive metaplasia, while secondary form occurs due to underlying joint disease (eg, osteoarthritis, trauma)
Macro ─ Synovium appears thickened, boggy, and studded with numerous cartilaginous nodules of varying sizes (from millimeters to centimeters); nodules are typically round to oval, firm, glistening, gray-blue or white; nodules may be attached to synovium by a stalk, embedded within it, or free-floating within the joint space (loose bodies); loose bodies can become ossified
Micro

─ Nodules of hyaline cartilage located within the synovial lining, subsynovial tissue, or as free fragments in the joint space
─ Cartilage nodules are often hypercellular, especially in early or active disease, with chondrocytes arranged in clusters or clones within lacunae
─ Chondrocytes may show mild to moderate cytologic atypia, including enlarged nuclei, hyperchromasia, and binucleation; these features are acceptable in synovial chondromatosis and do not necessarily indicate malignancy, but must be interpreted with caution
─ Mitotic activity is usually very low or absent
─ Matrix is hyaline cartilage, may show focal myxoid change, calcification (often peripheral), or endochondral ossification (leading to osteochondral loose bodies)
─ Surrounding synovial membrane often shows reactive hyperplasia, vascularity, and chronic inflammation
Ancillary studies ─
─ IHC: Chondrocytes are positive for S100 protein
─ Molecular: Recurrent rearrangements involving the ACVR2A gene (often FN1::ACVR2A fusion) or IDH1/IDH2 mutations have been reported in primary synovial chondromatosis, supporting a neoplastic basis for some cases
DDx

─ Degenerative joint disease (osteoarthritis) with osteophytes and cartilage fragments (fragments are usually paucicellular, fibrillated cartilage from articular surface, lack prominent chondrocyte clustering/atypia of active synovial chondromatosis)
─ Chondrosarcoma (secondary, arising from synovial chondromatosis - rare) (marked cytologic atypia, high cellularity, infiltrative growth into adjacent bone/soft tissue beyond joint capsule, destructive growth)
─ Pigmented villonodular synovitis (TGCT, diffuse type) (lacks cartilaginous nodules, composed of mononuclear cells, giant cells, foam cells, hemosiderin)
─ Soft tissue chondroma (extra-articular, solitary usually, less cellular atypia typically)
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Soft Tissue Aneurysmal Bone Cyst

A rare, benign cystic lesion histologically identical to primary aneurysmal bone cyst (ABC) of bone, but arising in soft tissues without any connection to bone or periosteum; also known as extraskeletal aneurysmal bone cyst
Clinical ─ Typically affects children and young adults (similar age group to intraosseous ABC, peak 10-20s); common in deep soft tissues of the extremities (especially thigh), trunk, and less commonly head/neck or retroperitoneum; presents as a rapidly growing, often painful, palpable mass; history of trauma may be present in some cases
Macro ─ Well-circumscribed, multiloculated cystic mass filled with blood or serosanguinous fluid; cut surface shows spongy, blood-filled spaces separated by fibrous septa; a thin pseudocapsule may be present; may show areas of gritty calcification or ossification
Micro

─ Multiloculated cystic spaces filled with unclotted blood, lacking a true endothelial lining (spaces are pseudocysts)
─ Cystic spaces are separated by fibrous septa of variable thickness, composed of:
─ Bland spindle cells (fibroblasts and myofibroblasts) with ovoid to spindle nuclei
─ Numerous osteoclast-like multinucleated giant cells, often clustered around areas of hemorrhage or along septal linings
─ Reactive woven bone formation within the septa is a characteristic feature, often appearing as delicate, linear strands ("streamers") or more mature trabeculae; osteoblastic rimming may be present
─ Hemosiderin deposition, chronic inflammation (lymphocytes, plasma cells), and foamy histiocytes are common within the septa
─ Mitotic figures can be present in the spindle cells but are not atypical
─ Solid variant (less common): Shows more solid cellular areas resembling giant cell tumor or non-ossifying fibroma, with less prominent cystic spaces
Ancillary studies ─
─ IHC: Not specific; spindle cells are vimentin positive, may show focal SMA; Giant cells are CD68 positive; Osteoblasts (if present) are SATB2 positive
─ Molecular: Characterized by USP6 gene rearrangements (chromosome 17p13) in a significant proportion of cases, often fused with CDH11 or other partners; this confirms its neoplastic nature and relationship to primary ABC of bone
DDx

─ Hematoma (organizing) (lacks distinct cellular septa with giant cells and reactive bone, usually resolves)
─ Myositis ossificans (zonal pattern of ossification, different clinical setting usually, USP6 rearranged in early phase)
─ Angiomatoid fibrous histiocytoma (AFH) (pseudoangiomatoid spaces, prominent lymphoid cuff, desmin/CD68 positive tumor cells, EWSR1 fusion)
─ Telangiectatic osteosarcoma (malignant spindle cells producing osteoid, significant cytologic atypia, infiltrative growth)
─ Vascular malformations (true endothelial lining of vascular spaces)
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Extraskeletal Myxoid Chondrosarcoma (EMC)

A malignant soft tissue sarcoma of uncertain differentiation (despite its name, typically lacks true hyaline cartilage), characterized by cords, strands, or clusters of relatively uniform eosinophilic cells in an abundant myxoid stroma, and specific NR4A3 gene rearrangements
Clinical ─ Typically affects adults (peak age 40-60s), M>F slightly; most common in deep soft tissues of the proximal extremities (especially thigh) and limb girdles, less often trunk or head/neck; presents as a slow-growing, often large, deep-seated, painless or mildly painful mass
Macro ─ Well-circumscribed, often pseudoencapsulated, multinodular or lobulated, soft, gelatinous mass; cut surface is typically gray-white, translucent, and overtly myxoid, may have hemorrhagic or cystic areas; size can be very large (often >5-10 cm)
Micro

─ Multinodular or lobulated architecture with fibrous septa separating tumor lobules
─ Composed of cords, strands, nests, clusters, or lace-like arrangements of relatively uniform, small to medium-sized round, oval, or spindle-shaped cells with eosinophilic or clear cytoplasm and round to oval vesicular nuclei, often with small nucleoli
─ Abundant myxoid stroma (Alcian blue positive, hyaluronidase sensitive) is a hallmark feature, often appearing edematous or chondromyxoid but typically lacking true hyaline cartilage differentiation
─ Cells may show rhabdoid features (eccentric nuclei, paranuclear eosinophilic inclusions) in some cases
─ Mitotic activity is generally low (usually <2-5/10 HPF); necrosis is uncommon in conventional EMC
─ Cellular variant: Higher cellularity, less myxoid stroma, increased mitotic activity, and potentially more atypia; may behave more aggressively
─ True hyaline cartilage is rare; if present, may represent divergent differentiation or collision
Ancillary studies ─
─ IHC: Tumor cells are positive for vimentin; S100 protein is variably positive (often weak, patchy, or negative, ~30-50% of cases); EMA (epithelial membrane antigen) may be positive in a subset (patchy); NSE (neuron-specific enolase) and synaptophysin have been reported in some cases, suggesting possible neuroectodermal differentiation in a subset; Negative for keratins (broad-spectrum), SMA, desmin, SOX10 (usually), brachyury, MUC4
─ Molecular: Defined by recurrent rearrangements involving the NR4A3 gene (on chromosome 9q22); most common fusion partner is EWSR1 (t(9;22)(q22;q12)), resulting in EWSR1::NR4A3 fusion; other partners include TAF15 (t(9;17)(q22;q11)), TCF12 (t(9;15)(q22;q21)), TFG, and FUS
DDx

─ Myxoid liposarcoma (true lipoblasts, S100 positive in lipoblasts, plexiform capillaries, DDIT3 fusion, NR4A3 negative)
─ Myxofibrosarcoma (curvilinear vessels, more significant pleomorphism, lacks NR4A3 fusion)
─ Chordoma (axial skeleton, physaliphorous cells, brachyury positive, S100 positive, lacks NR4A3 fusion)
─ Myoepithelial carcinoma (myxoid variant) (keratin/EMA/S100/GFAP/SMA variably positive, EWSR1 fusions but different partners, lacks NR4A3 fusion)
─ Ossifying fibromyxoid tumor (peripheral bone shell, S100 often positive, PHF1 fusion, lacks NR4A3 fusion)
─ Low-grade fibromyxoid sarcoma (alternating fibrous/myxoid zones, MUC4 positive, FUS::CREB3L2 fusion, lacks NR4A3 fusion)
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Extraskeletal Mesenchymal Chondrosarcoma

A rare, aggressive sarcoma arising in soft tissues (or bone), characterized by a distinctive biphasic pattern of undifferentiated small round blue cells and islands of well-differentiated hyaline cartilage; the extraskeletal form is less common than its osseous counterpart
Clinical ─ Typically affects adolescents and young adults (peak age 10-30s), but can occur at any age; common extraskeletal sites include head/neck (especially orbit, meninges), lower extremities, and trunk; presents as a slow-growing or rapidly enlarging mass, may be painful
Macro ─ Appears relatively circumscribed but is often infiltrative; firm, gray-white to tan mass; may show gritty calcified areas (cartilage) and softer fleshy areas (small cell component); hemorrhage and necrosis can be present
Micro

─ Characteristic bimorphic pattern:
─ Undifferentiated small round blue cell component: Sheets, lobules, or diffuse proliferation of primitive, small, round to oval cells with scant cytoplasm, hyperchromatic nuclei, and inconspicuous nucleoli; mitotic activity is often brisk in this component
─ Cartilaginous component: Islands or nodules of well-differentiated (usually low-grade) hyaline cartilage, which may show features of enchondroma or low-grade chondrosarcoma; transition between the two components is typically abrupt
─ A prominent hemangiopericytoma-like (staghorn) vascular pattern is often present within the small cell areas
─ Calcification and ossification can occur within the cartilaginous islands
Ancillary studies ─
─ IHC: Small cell component is positive for vimentin; CD99 may be positive (often patchy or weak); NKX2.2 and SOX9 may be positive in small cells; Cartilaginous component is positive for S100 protein and SOX9; Negative for MyoD1/myogenin, FLI1 (usually), ERG, keratins, desmin, SMA (except vessels)
─ Molecular: Defined by a specific HEY1::NCOA2 gene fusion resulting from t(1;5)(q42;q32) or inv(8)(q21.1q24.13) in most cases; less commonly IRF2BP2::CDX1 fusion
DDx

─ Ewing sarcoma (lacks cartilaginous component, CD99/NKX2.2/FLI1 positive, EWSR1-ETS fusion)
─ Synovial sarcoma (poorly differentiated or biphasic) (TLE1 positive, keratin/EMA often positive, SS18 fusion, S100 usually negative)
─ Embryonal rhabdomyosarcoma (myogenic markers positive, lacks distinct cartilage islands and specific fusion)
─ Small cell osteosarcoma (produces malignant osteoid, SATB2 positive, lacks cartilage islands typically)
─ Dedifferentiated chondrosarcoma (arises from conventional low-grade chondrosarcoma, high-grade non-cartilaginous sarcoma component, different genetics)
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Extraskeletal osteosarcoma

A high-grade malignant mesenchymal neoplasm arising in soft tissues without any attachment to bone or periosteum, in which the tumor cells directly produce osteoid (immature bone) or mature bone
Clinical ─ Primarily affects older adults (peak age 50-70s), rare in younger individuals; M>F slightly; common in deep soft tissues of the extremities (especially thigh), retroperitoneum, and trunk; often presents as a rapidly enlarging, painful, deep-seated mass; may occur in previously irradiated soft tissue (post-radiation osteosarcoma)
Macro ─ Poorly circumscribed or deceptively well-circumscribed, firm to hard, infiltrative mass; cut surface is often gritty due to ossification, may show fleshy gray-white sarcomatous areas, hemorrhage, and necrosis; size is typically large (>5 cm)
Micro

─ Malignant spindle cell or pleomorphic sarcoma in which the tumor cells directly produce osteoid matrix; osteoid can be lace-like, trabecular, sheet-like, or in broad islands, and must be clearly associated with atypical tumor cells (not merely metaplastic bone in a reactive stroma)
─ Tumor cells exhibit high-grade cytologic atypia, including hyperchromasia, pleomorphism, irregular nuclear contours, and prominent nucleoli
─ High mitotic activity, including atypical mitoses, is characteristic
─ Necrosis is common
─ In addition to the osteoblastic component, areas of chondroblastic (malignant cartilage) or fibroblastic (high-grade spindle cell sarcoma resembling fibrosarcoma/UPS) differentiation may be present (subtypes: osteoblastic, chondroblastic, fibroblastic, telangiectatic, small cell, giant cell-rich, similar to osseous osteosarcoma)
─ Must exclude origin from underlying bone (eg, surface osteosarcoma with extensive soft tissue involvement)
Ancillary studies ─
─ IHC: Tumor cells are positive for vimentin; SATB2 (nuclear stain, relatively specific for osteoblastic differentiation) is often positive; Alkaline phosphatase (ALP) and osteocalcin may be positive; SMA, S100 protein (in chondroblastic areas), and keratins (rarely, aberrant) may be focally positive; Negative for desmin, HMB45, STAT6, MUC4, specific carcinoma markers
─ Molecular: Characterized by complex, unbalanced karyotypes with numerous chromosomal gains and losses; TP53 and RB1 pathway alterations are common; MDM2/CDK4 amplification may be seen in some secondary or parosteal-like osteosarcomas but is not typical for conventional extraskeletal osteosarcoma
DDx

─ Myositis ossificans / Heterotopic ossification (zonal pattern of maturation, lacks cytologic atypia, self-limited)
─ Other malignant mesenchymal tumors with osseous metaplasia (eg, MPNST, leiomyosarcoma, synovial sarcoma with bone formation - osteoid is reactive/metaplastic, not directly produced by the main tumor cells; primary tumor shows specific lineage markers)
─ Calcifying pseudoneoplasms (eg, tumoral calcinosis - avascular calcified deposits, lacks viable malignant cells)
─ Dedifferentiated chondrosarcoma with osteosarcomatous component (evidence of pre-existing low-grade chondrosarcoma)
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Fibrodysplasia Ossificans Progressiva

A rare, severely disabling autosomal dominant genetic disorder characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) in soft tissues, leading to permanent immobility and a shortened lifespan; also known as Stone Man Syndrome
Clinical ─ Extremely rare (prevalence ~1 in 2 million); presents in early childhood (often by age 5-10) with episodic, painful inflammatory soft tissue swellings ("flare-ups"), often triggered by minor trauma, intramuscular injections, or viral illness; these flare-ups subsequently mature into masses of heterotopic bone, leading to progressive ossification of skeletal muscles, tendons, ligaments, and fascia; characteristic congenital malformation: short, malformed great toes (hallux valgus, monophalangism) is present at birth in nearly all affected individuals; other skeletal anomalies may occur; progressive ossification leads to joint ankylosis, restricted movement, scoliosis, thoracic insufficiency syndrome, and severe disability
Macro ─ Affected soft tissues show firm to hard, irregular masses of bone replacing normal structures; joints become fused by bridges of heterotopic bone
Micro (early flare-up lesions) ─

─ Intense perivascular lymphocytic and mast cell infiltrate in soft tissues, often with associated edema and hemorrhage
─ Proliferation of bland fibroblastic/myofibroblastic cells, resembling aggressive fibromatosis or early myositis ossificans
Micro (later ossified lesions) ─

─ Mature lamellar bone, often with Haversian systems and bone marrow elements, replacing soft tissues; follows a pattern of endochondral ossification (cartilage precursor stage) and intramembranous ossification
─ Early lesions show cartilage formation, followed by well-organized bone that fuses with adjacent normal skeleton or forms ectopic bone masses
─ No cytologic atypia in cellular components
Ancillary studies ─
─ IHC: Not typically used for diagnosis; cellular components would show expected fibroblastic/myofibroblastic markers (vimentin, SMA variable); bone/cartilage show S100 (cartilage), SATB2 (osteoblasts)
─ Molecular: Caused by a recurrent activating mutation (most commonly R206H) in the ACVR1 gene (encoding activin A receptor type I, a bone morphogenetic protein (BMP) type I receptor), leading to dysregulated BMP signaling and excessive bone formation
DDx

─ Progressive osseous heteroplasia (POH) (different genetic basis - GNAS inactivation, primarily dermal ossification without pre-inflammatory phase or great toe malformation)
─ Myositis ossificans (localized, often trauma-related, zonal pattern, self-limited, no ACVR1 mutation)
─ Other forms of heterotopic ossification (eg, post-traumatic, neurogenic - lack progressive nature and specific genetic/clinical features of FOP)
─ Osteosarcoma (malignant tumor, cytologic atypia, destructive growth)
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Tumoral Calcinosis and Tumoral Calcinosis–Like Lesions

Tumoral calcinosis is a rare hereditary disorder characterized by abnormal calcium and phosphate metabolism (often hyperphosphatemia with normal or elevated calcium), leading to the development of large, lobulated, periarticular calcified masses; Tumoral calcinosis-like lesions refer to similar calcified masses occurring sporadically or in association with other conditions (eg, chronic renal failure, hyperparathyroidism, scleroderma) without the specific metabolic defect of hereditary tumoral calcinosis
Clinical ─ Hereditary tumoral calcinosis: Often presents in childhood or adolescence, may be familial (autosomal recessive or dominant forms); common in individuals of African descent; characterized by large, painless or mildly tender, firm to hard, lobulated subcutaneous or deep soft tissue masses, typically located around major joints (hips, elbows, shoulders, feet); skin overlying may ulcerate and discharge chalky white material
Clinical ─ Tumoral calcinosis-like lesions (secondary/dystrophic): Occur in various settings, often older adults; can be solitary or multiple, location variable
Macro ─ Large, multilobulated, encapsulated or pseudoencapsulated mass; cut surface reveals chalky white, granular, or pasty calcified material within cystic or solid fibrous spaces; fluid-filled locules may be present
Micro

─ Multilobulated masses composed of amorphous, granular, basophilic or eosinophilic calcium phosphate deposits (hydroxyapatite and calcium carbonate)
─ Calcified material is largely acellular but is often surrounded by a prominent histiocytic and foreign-body giant cell reaction ("granulomatous inflammation")
─ Fibrous septa divide the calcified deposits into locules or cysts
─ Chronic inflammation (lymphocytes, plasma cells) and areas of hemorrhage or cholesterol clefts may be present
─ No viable neoplastic cells are present within the calcified material itself
Ancillary studies ─
─ IHC: Not specific; histiocytes and giant cells are CD68 positive
─ Special Stains: Von Kossa stain highlights calcium deposits (black)
─ Lab tests (for hereditary tumoral calcinosis): Serum phosphate often elevated, calcium usually normal or mildly elevated, PTH normal; tests for FGF23, GALNT3, KLOTHO gene mutations in hereditary forms
DDx

─ Myositis ossificans / Heterotopic ossification (shows viable osteoid and bone formation with zonal pattern, not just amorphous calcification)
─ Calcifying fibrous tumor (psammomatous/dystrophic calcification within a paucicellular fibrous tumor with lymphoplasmacytic infiltrate)
─ Synovial chondromatosis with calcification/ossification (cartilaginous nodules, intra-articular or juxta-articular)
─ Gout tophi (urate crystals - birefringent, needle-shaped; different morphology of deposits)
─ Calcinosis cutis (dermal calcification, often smaller, associated with various conditions)
─ Osteosarcoma (malignant tumor cells producing osteoid, not amorphous calcium deposits)
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Soft Tissue, Uncertain Differentiation

Intramuscular Myxoma

A benign mesenchymal neoplasm of uncertain histogenesis, composed of bland spindle and stellate cells set in an abundant myxoid matrix, arising within skeletal muscle
Clinical ─ Typically affects adults (peak age 50-70s), with a female predominance; common in large muscles of the thigh, buttock, shoulder, and upper arm; presents as a slow-growing, often large (>5 cm), deep-seated, painless or minimally tender mass; may be associated with fibrous dysplasia of bone (Mazabraud syndrome) if multiple and in proximity to affected bones
Macro ─ Well-circumscribed, often appears encapsulated but lacks a true capsule, with a glistening, gelatinous, mucoid, or translucent cut surface; consistency is soft to firm; color is typically gray-white or pale yellow; may show cystic change or hemorrhage, especially in larger lesions
Micro

─ Hypocellular proliferation of bland, slender spindle-shaped to stellate cells with scant, pale eosinophilic or amphophilic cytoplasm and small, dark, or vesicular nuclei
─ Cells are arranged haphazardly or in loose fascicles within an abundant, loose, myxoid, or edematous stroma (Alcian blue positive, hyaluronidase sensitive)
─ Characteristic feature: Delicate, inconspicuous capillary network, often with slightly thickened hyalinized walls; larger vessels are generally absent within the main tumor mass
─ Infiltrative growth into adjacent skeletal muscle fibers at the periphery is common, with entrapped, often atrophic muscle fibers
─ No significant cytologic atypia or pleomorphism; mitotic activity is very low or absent
─ Necrosis is not a feature
─ Cellular variant: Shows increased cellularity, more collagenous stroma, and more prominent vasculature, but still lacks atypia and significant mitoses; more prone to recurrence
Ancillary studies ─
─ IHC: Tumor cells are positive for vimentin; CD34 is variably positive (often patchy); SMA (smooth muscle actin) may be focally positive in a minority of cells; Negative for S100 protein (except entrapped fat or nerves), desmin, keratins, MUC4, MDM2
─ Molecular: Activating mutations in the GNAS1 gene (encoding the Gs-alpha protein, typically at codon 201) are common and characteristic, especially in solitary intramuscular myxomas and those associated with Mazabraud syndrome
DDx

─ Myxoid liposarcoma (contains lipoblasts, characteristic plexiform "chicken-wire" capillaries, DDIT3 gene fusion)
─ Low-grade myxofibrosarcoma (more cytologic atypia/pleomorphism, prominent curvilinear vessels, infiltrative growth, typically lacks GNAS mutations)
─ Myxoid neurofibroma (S100 protein positive wavy spindle cells, embedded axons, associated with NF1 if plexiform)
─ Aggressive angiomyxoma (deep pelvic/perineal location, prominent thick-walled vessels, HMGA2 rearranged, lacks GNAS mutations)
─ Myxoma of nerve sheath (dermal nerve sheath myxoma) (S100 often positive, different location)
─ Juxta-articular myxoma (similar histology but specific location near large joints, often more cystic, usually GNAS wild-type)
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Juxta Articular Myxoma

A benign myxoid soft tissue lesion histologically similar to intramuscular myxoma, but specifically occurring in the soft tissues adjacent to large joints, often with prominent cystic changes and a slightly more prominent vascularity
Clinical ─ Typically affects adults (wide age range, often middle-aged to older); common in the vicinity of large joints, especially the knee, but also shoulder, elbow, hip, and ankle; may be associated with osteoarthritis, prior trauma, or meniscal cysts; presents as a slow-growing, often deep-seated, palpable mass, may cause pain or limited joint motion
Macro ─ Well-circumscribed or lobulated, soft, gelatinous mass, often containing multiple cystic spaces filled with clear or mucoid fluid; cut surface is typically translucent and myxoid
Micro

─ Histologically similar to intramuscular myxoma: hypocellular proliferation of bland spindle and stellate cells with scant cytoplasm, set in an abundant myxoid or edematous stroma
─ Prominent cystic degeneration (multilocular cysts of varying sizes) is a characteristic feature and often more pronounced than in intramuscular myxoma
─ Cyst walls may be lined by flattened mesenchymal cells or lack a true lining
─ Vasculature may be slightly more prominent or ectatic compared to typical intramuscular myxoma
─ Scattered chronic inflammatory cells (lymphocytes, plasma cells), hemorrhage, and fibrin deposition can be present, especially near cystic areas
─ No significant cytologic atypia or mitotic activity
Ancillary studies ─
─ IHC: Similar to intramuscular myxoma: tumor cells positive for vimentin; CD34 and SMA variably positive (often focal); Negative for S100 protein, desmin, keratins, MUC4
─ Molecular: Generally lacks the GNAS1 gene mutations commonly found in intramuscular myxomas, suggesting a potentially different pathogenesis or that some may represent myxoid degeneration of other periarticular structures rather than true neoplasms
DDx

─ Intramuscular myxoma (often GNAS mutated, typically less cystic, intramuscular location not necessarily juxta-articular)
─ Ganglion cyst / Synovial cyst (true cyst lining may be present or absent, primarily acellular mucin, lacks the cellular myxoid stroma of JAM)
─ Myxoid liposarcoma (lipoblasts, plexiform capillaries, DDIT3 fusion)
─ Low-grade myxofibrosarcoma (more atypia, curvilinear vessels, infiltrative)
─ Aggressive angiomyxoma (different location - pelvis/perineum, prominent thick-walled vessels, HMGA2 rearranged)
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Deep (aggressive) angiomyxoma

A rare, locally aggressive but non-metastasizing myxoid mesenchymal neoplasm that preferentially occurs in the deep soft tissues of the pelvis, perineum, vulva, scrotum, and inguinal region of adults
Clinical ─ Predominantly affects adults (peak age 30-50s), with a strong female predominance (F>>M, ~6:1); common sites include vulva, vagina, perineum, pelvis in females, and inguinoscrotal region in males; presents as a slow-growing, often large (>10 cm), deep-seated, painless or mildly uncomfortable mass; may be mistaken for a cyst or hernia initially
Macro ─ Large, bulky, poorly circumscribed, infiltrative mass with a characteristic gelatinous, mucoid, or edematous consistency; cut surface is typically translucent, grayish-white, pink, or tan, often with prominent blood vessels; lacks true encapsulation
Micro

─ Hypocellular to moderately cellular proliferation of relatively bland, slender spindle-shaped to stellate mesenchymal cells with scant, pale eosinophilic cytoplasm and small, ovoid to spindle nuclei
─ Cells are arranged haphazardly or in loose fascicles within an abundant, loose, myxoid, or edematous stroma (Alcian blue positive)
─ Characteristic feature: Numerous small to medium-sized, thick-walled or thin-walled blood vessels, often with hyalinized walls, scattered throughout the tumor; tumor cells often cluster around these vessels or appear to radiate from them
─ Extravasated red blood cells and stromal edema are common
─ Infiltrative growth pattern into surrounding soft tissues, muscle, and fat is typical, accounting for high recurrence rates
─ Minimal to no cytologic atypia, mitotic activity is very low (usually <1/10 HPF), necrosis is absent
Ancillary studies ─
─ IHC: Tumor cells are positive for vimentin; Desmin and SMA (smooth muscle actin) are variably positive (often patchy or focal); CD34 is variably positive (may highlight stromal cells or vessels); Estrogen receptor (ER) and progesterone receptor (PR) are frequently positive, especially in tumors from females; Negative for S100 protein, keratins, HMB45
─ Molecular: HMGA2 gene (chromosome 12q14-15) rearrangements (often translocations with various partners) are characteristic and found in a majority of cases
DDx

─ Angiomyofibroblastoma (vulvovaginal, more cellular, well-circumscribed, prominent epithelioid cells around vessels, desmin positive, lacks HMGA2 rearrangement typically)
─ Cellular angiofibroma (vulvovaginal/inguinoscrotal, more cellular, less myxoid, prominent hyalinized vessels, RB1 loss, lacks HMGA2 rearrangement)
─ Superficial angiomyxoma (cutaneous, lobulated, epithelial mucin, lacks HMGA2 rearrangement)
─ Myxoid liposarcoma (lipoblasts, plexiform capillaries, DDIT3 fusion, different location usually, lacks HMGA2 rearrangement)
─ Intramuscular myxoma / Juxta-articular myxoma (different location, less vascular, GNAS mutations in IM myxoma or GNAS wild-type in JAM, lacks HMGA2 rearrangement)
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Atypical fibroxanthoma (AFX)

A superficial, low-grade pleomorphic dermal sarcoma occurring predominantly in the sun-damaged skin of elderly individuals, characterized by bizarre, pleomorphic cells but generally indolent behavior if confined to the dermis and completely excised; considered by many to be a superficial variant of undifferentiated pleomorphic sarcoma (UPS)
Clinical ─ Typically affects elderly individuals (usually >70 years), with a male predominance; most common on chronically sun-exposed skin of the head and neck (scalp, face - especially nose and ears, neck); presents as a rapidly growing, often ulcerated or crusted, reddish or flesh-colored papule or nodule, usually <2 cm
Macro ─ Small, firm, often exophytic, reddish, frequently ulcerated or crusted nodule or papule on sun-damaged skin
Micro

─ Dermal-based, often exophytic, unencapsulated proliferation, typically confined to the dermis or extending minimally into the superficial subcutis; usually separated from the epidermis by a narrow Grenz zone (but ulceration is common)
─ Highly pleomorphic spindle, epithelioid, and bizarre multinucleated tumor cells with large, hyperchromatic, irregular nuclei and prominent nucleoli; cytoplasm is variably eosinophilic or foamy
─ Abundant mitotic activity, including atypical mitoses, is characteristic
─ Necrosis may be present focally but is not extensive
─ No evidence of specific lineage differentiation (eg, no squamous, melanocytic, vascular, or muscular differentiation by morphology or IHC)
─ Background of solar elastosis in the adjacent dermis is common
─ Angiolymphatic invasion is rare; perineurial invasion can occur
─ If deep invasion into subcutis, fascia, or muscle is present, it is better classified as undifferentiated pleomorphic sarcoma (UPS)
Ancillary studies ─
─ IHC: Diagnosis is largely one of exclusion of other pleomorphic malignancies; Tumor cells are positive for vimentin, CD10 (often diffuse), CD68 (variable), procollagen 1, and sometimes focal SMA or other non-specific markers; Crucially, they are negative for broad-spectrum keratins (AE1/AE3, CAM5.2, pankeratin - to exclude spindle cell squamous cell carcinoma), S100 protein, SOX10, HMB45, Melan-A (to exclude melanoma), desmin, CD31, ERG (to exclude leiomyosarcoma, angiosarcoma)
─ Molecular: Characterized by complex karyotypes with numerous chromosomal aberrations and a high mutational burden, often with a UV-signature pattern (C>T transitions); TP53 mutations are common; lacks specific translocations of other sarcomas
DDx

─ Spindle cell squamous cell carcinoma (keratin positive, p63/p40 positive)
─ Spindle cell / Desmoplastic melanoma (S100/SOX10/melanocytic markers positive)
─ Leiomyosarcoma (superficial) (desmin/h-caldesmon positive)
─ Angiosarcoma (vascular markers CD31/ERG positive)
─ Undifferentiated pleomorphic sarcoma (UPS) (histologically identical but with deep subcutaneous/fascial/muscular invasion; AFX is considered superficial UPS)
─ Atypical fibrous histiocytoma (less pleomorphism, lacks widespread bizarre cells and high mitotic rate of AFX)
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Pleomorphic Dermal Sarcoma

A term used for sarcomas primary to the skin that exhibit significant pleomorphism and do not show a specific line of differentiation, essentially representing an undifferentiated pleomorphic sarcoma (UPS) that is largely or entirely confined to the dermis and superficial subcutis; it overlaps significantly with, and some consider it synonymous with or a progression of, atypical fibroxanthoma (AFX) when certain high-risk features are present
Clinical ─ Similar to AFX, typically elderly individuals, sun-exposed skin of head/neck; may represent AFX with more worrisome features or deeper invasion, or de novo dermal UPS
Macro ─ Similar to AFX, often a rapidly growing, ulcerated nodule or plaque
Micro

─ Dermal-based proliferation of highly pleomorphic spindle, epithelioid, and bizarre multinucleated cells, identical to AFX or UPS
─ High mitotic activity, including atypical forms, is present
─ Necrosis is often present
─ Key distinguishing features from typical AFX (which has a very low metastatic risk) may include larger size (>2 cm), deep subcutaneous invasion (beyond superficial lobules), lymphovascular invasion, perineurial invasion, or tumor necrosis; presence of these features increases risk and may warrant the term pleomorphic dermal sarcoma or UPS
─ No evidence of specific lineage differentiation by morphology or IHC
Ancillary studies ─
─ IHC: Diagnosis of exclusion; Positive for vimentin, CD10 (variable), CD68 (variable); Negative for keratins, S100 protein, SOX10, melanocytic markers, desmin, CD31, ERG, etc
─ Molecular: Complex karyotypes, UV-signature mutations common, similar to AFX and cutaneous UPS
DDx

─ Atypical fibroxanthoma (AFX) (distinction can be subtle, PDS implies more aggressive features or deeper extent than classic AFX which is confined to dermis/superficial subcutis without high-risk features)
─ Undifferentiated pleomorphic sarcoma (UPS) (if extensive deep subcutaneous, fascial, or muscular invasion)
─ Spindle cell squamous cell carcinoma (keratin positive)
─ Spindle cell / Desmoplastic melanoma (S100/SOX10/melanocytic markers positive)
─ Other high-grade sarcomas with pleomorphism (eg, leiomyosarcoma, angiosarcoma - specific markers)
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Angiomatoid Fibrous Histiocytoma (AFH)

A rare mesenchymal neoplasm of uncertain differentiation and intermediate malignant potential, typically occurring in children and young adults, characterized by nodules of histiocytoid or spindle cells, pseudoangiomatoid (blood-filled cystic) spaces, and a prominent peripheral cuff of lymphocytes and plasma cells, often with germinal center formation
Clinical ─ Primarily affects children, adolescents, and young adults (peak age 10-30s), but can occur at any age; common in superficial soft tissues (dermis, subcutis) of the extremities (especially near joints), less often trunk or head/neck; presents as a slow-growing, usually painless, well-circumscribed mass; systemic symptoms (fever, anemia, hypergammaglobulinemia) may occur in a subset of patients
Macro ─ Well-circumscribed, often pseudoencapsulated, firm or rubbery nodule; cut surface is typically tan-white to gray, frequently with cystic or hemorrhagic areas (pseudoangiomatoid spaces); size usually 1-5 cm, can be larger
Micro

─ Multinodular or lobulated growth pattern is characteristic
─ Surrounded by a thick fibrous pseudocapsule and a prominent peripheral cuff of lymphoplasmacytic cells, often forming lymphoid follicles with germinal centers
─ Composed of sheets, nodules, or short fascicles of relatively uniform ovoid, spindle, or epithelioid (histiocytoid) cells with eosinophilic or clear cytoplasm and round to oval vesicular nuclei, often with inconspicuous nucleoli
─ Characteristic feature: Blood-filled cystic spaces or clefts of varying sizes, resembling dilated vessels or aneurysmal bone cyst-like spaces ("pseudoangiomatoid spaces"), which may lack a true endothelial lining or be lined by tumor cells
─ Hemosiderin deposition within tumor cells and macrophages is common, especially around cystic spaces
─ Mitotic activity is generally low (usually <2-5/10 HPF), cytologic atypia is minimal to mild
─ Stroma can be fibrous or myxoid
Ancillary studies ─
─ IHC: Tumor cells are positive for desmin (often dot-like or paranuclear), CD68 (variable), EMA (epithelial membrane antigen - variable, often focal), and CD99 (membranous); Vimentin positive; Negative for S100 protein, keratins (broad-spectrum), vascular markers (CD31, ERG - except true vessels), ALK1, Factor XIIIa
─ Molecular: Defined by recurrent translocations involving the EWSR1 gene (chromosome 22q12), most commonly with CREB1 (t(2;22)(q33;q12)), leading to EWSR1::CREB1 fusion; less common fusion partners include ATF1 (EWSR1::ATF1) and FUS::ATF1 or FUS::CREB1
DDx

─ Hematoma (organizing) (lacks cellular nodules, prominent lymphoid cuff, and specific IHC/molecular features)
─ Follicular dendritic cell sarcoma (CD21, CD23, CD35 positive, different morphology, lacks EWSR1 fusion of AFH)
─ Lymphoma (especially Hodgkin or peripheral T-cell lymphoma with prominent histiocytes) (specific lymphoid markers positive, lacks desmin/EMA in tumor cells)
─ Aneurysmal bone cyst (soft tissue variant) (USP6 rearranged, lacks desmin/EMA in tumor cells and EWSR1 fusion)
─ Synovial sarcoma (poorly differentiated, if round cell) (TLE1 positive, keratin/EMA often positive, SS18 fusion)
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Ossifying fibromyxoid tumor (OFMT)

A rare mesenchymal neoplasm of uncertain differentiation, characterized by cords, nests, or strands of small, uniform round to oval cells embedded in a variably fibrous and myxoid stroma, often with a characteristic (though not always present) incomplete peripheral shell of lamellar bone
Clinical ─ Typically affects adults (peak age 40-60s), M>F slightly; most common in subcutaneous tissue or deep soft tissues of the extremities (especially lower limb), also trunk, head/neck, and rarely mediastinum or retroperitoneum; presents as a slow-growing, usually painless, firm, well-circumscribed nodule, often present for years
Macro ─ Well-circumscribed, often encapsulated, firm, lobulated nodule; cut surface is typically gray-white to tan, may be fibrous, myxoid, or gritty if calcified/ossified; size usually <5 cm, can be larger
Micro

─ Lobulated or multinodular growth pattern, often with a fibrous pseudocapsule
─ Composed of relatively uniform, small to medium-sized round, oval, or epithelioid cells with scant eosinophilic or clear cytoplasm and round, vesicular nuclei with inconspicuous nucleoli
─ Cells are arranged in cords, nests, strands, or a trabecular pattern within a variably fibrous, hyalinized, or myxoid stroma
─ Characteristic feature (in ~75-80% of cases): An incomplete or fragmented peripheral shell of mature lamellar bone, sometimes with associated osteoblastic rimming
─ Calcification (punctate or dystrophic) and metaplastic cartilage may also be present within the stroma or bony shell
─ Cytologic atypia is usually minimal, mitotic activity is low (typically <2/50 HPF) in conventional OFMT
─ Atypical/Malignant OFMT (rare): Show increased cellularity, nuclear atypia, hyperchromasia, increased mitotic activity (>2/50 HPF), and/or necrosis; associated with higher risk of recurrence and metastasis
Ancillary studies ─
─ IHC: Tumor cells are positive for S100 protein (in ~75-85% of cases, often diffuse but can be patchy); Vimentin positive; Desmin, SMA, EMA, GFAP, and synaptophysin may be focally positive in a subset of cases; Negative for broad-spectrum keratins, SOX10 (usually), MUC4, STAT6, HMB45
─ Molecular: Recurrent rearrangements involving the PHF1 gene (on chromosome 6p21) are characteristic, often fusing with EP400, MEAF6, or other partners; less commonly, fusions involving EPC1 or ZC3H7B may occur
DDx

─ Schwannoma (especially cellular or ancient) (diffuse S100/SOX10 positive, Antoni A/B areas, lacks peripheral bone shell and PHF1 fusion)
─ Myoepithelioma / Myoepithelial carcinoma (keratin/EMA/S100/GFAP/SMA variably positive, EWSR1 fusions common, lacks peripheral bone shell and PHF1 fusion)
─ Extraskeletal myxoid chondrosarcoma (NR4A3 fusion, myxoid matrix, lacks bone shell, S100 often negative/patchy)
─ Low-grade fibromyxoid sarcoma (MUC4 positive, FUS fusion, alternating fibrous/myxoid zones, lacks bone shell)
─ Soft tissue chondroma (if prominent cartilage; S100 positive but different morphology, lacks PHF1 fusion)
─ Parachordoma (similar S100/keratin coexpression possible, but different morphology and location, lacks PHF1 fusion)
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Myoepithelioma / Myoepithelial carcinoma of soft tissue

Neoplasms composed purely or predominantly of myoepithelial cells, occurring primarily in soft tissue and histologically similar to their salivary gland counterparts; Myoepithelioma is benign, while Myoepithelial carcinoma is malignant, defined by cytologic atypia (or rarely by infiltrative growth alone in bland tumors)
Clinical ─ Affects a wide age range, including children and adults; common in deep soft tissues of the extremities (especially lower limb), also limb girdles, trunk, head/neck; presents as a slow-growing, often painless mass; myoepithelial carcinoma can recur and metastasize
Macro ─ Myoepithelioma: Typically well-circumscribed, lobulated, firm or rubbery nodule, gray-white to tan, often with gelatinous, myxoid, or chondroid-like areas; Myoepithelial carcinoma: Often larger, more infiltrative, may show hemorrhage or necrosis
Micro

─ Highly variable histologic appearance, reflecting the diverse morphology of myoepithelial cells:
─ Architectural patterns: Reticular, nested, solid, trabecular, or fascicular
─ Cell types: Epithelioid (most common), spindle, plasmacytoid, clear cell, or a mixture; cells often have eosinophilic or clear cytoplasm
─ Stroma: Frequently myxoid, chondromyxoid, or hyalinized; true cartilage or bone formation can occur (mixed tumor/chondroid syringoma-like areas)
─ Myoepithelioma: Composed of bland cells with minimal to no cytologic atypia, low mitotic activity (usually <2/10 HPF), and lacks necrosis or significant infiltrative growth
─ Myoepithelial carcinoma: Defined by moderate to marked cytologic atypia (pleomorphism, hyperchromasia, prominent nucleoli); mitotic activity is often increased (>2-5/10 HPF), and atypical mitoses or necrosis may be present; infiltrative growth is common
Ancillary studies ─
─ IHC: Myoepithelial cells characteristically show variable co-expression of epithelial and myoepithelial/mesenchymal markers: S100 protein (often strong and diffuse), keratins (AE1/AE3, CAM5.2, CK14, CK5/6 - often patchy or focal), EMA (variable), GFAP (glial fibrillary acidic protein - often positive, especially in chondromyxoid areas), SMA (smooth muscle actin - variable, more common in spindle cells), calponin, p63/p40 (variable, more common in epithelioid cells)
─ IHC: INI1/SMARCB1 expression is lost in a subset of myoepithelial carcinomas (especially pediatric and some high-grade adult cases), associated with more aggressive behavior
─ Molecular: EWSR1 gene rearrangements (with various fusion partners like PBX1, POU5F1, ZNF444, KLF17) are common in both benign and malignant myoepithelial tumors of soft tissue; FUS rearrangements are less common; PLAG1 fusions (seen in salivary gland mixed tumors) can also occur
DDx

─ Extraskeletal myxoid chondrosarcoma (NR4A3 fusion, lacks consistent epithelial marker expression, S100 often weaker/patchier)
─ Chordoma (brachyury positive, arises in axial skeleton, different morphology)
─ Ossifying fibromyxoid tumor (peripheral bone shell, PHF1 fusion, S100 often positive but lacks consistent keratin/EMA/GFAP)
─ Parachordoma (shares some IHC overlap but different morphology, often S100/keratin/EMA positive)
─ Metastatic carcinoma (especially with clear cell or plasmacytoid features; more diffuse/strong keratin, lacks S100/GFAP usually, specific carcinoma markers)
─ Melanoma (S100/SOX10/melanocytic markers positive, lacks keratin/EMA/GFAP)
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Mixed Tumor/Myoepithelioma / Myoepithelial carcinoma of soft tissue

This designation emphasizes the morphologic spectrum of myoepithelial neoplasms in soft tissue, where "Mixed Tumor" (analogous to pleomorphic adenoma of salivary gland) represents a myoepithelioma with prominent ductal/glandular epithelial differentiation in addition to myoepithelial cells, often within a chondromyxoid stroma; Myoepithelioma has predominantly myoepithelial cells with minimal or no ductal structures; Myoepithelial carcinoma is the malignant counterpart
Clinical ─ Similar to pure myoepithelioma/myoepithelial carcinoma: wide age range, deep soft tissues of extremities, trunk, head/neck; behavior depends on benign (mixed tumor/myoepithelioma) vs malignant (myoepithelial carcinoma) classification
Macro ─ Well-circumscribed, lobulated, firm or rubbery mass; cut surface often gray-white, tan, gelatinous, or chondroid-like
Micro

─ Mixed Tumor type: Biphasic pattern with:
─ Epithelial component: Ducts, tubules, or glands lined by cuboidal or columnar epithelial cells (keratin positive, S100 negative)
─ Myoepithelial component: Spindle, epithelioid, plasmacytoid, or clear cells surrounding ducts or forming solid sheets/cords (S100/GFAP/SMA/keratin variably positive)
─ Stromal component: Abundant myxoid, chondromyxoid, or hyaline cartilaginous stroma is characteristic
─ Myoepithelioma type: Predominantly sheets, nests, or cords of myoepithelial cells (various morphologies) with minimal or absent ductal differentiation, often in a myxoid or collagenous stroma
─ Myoepithelial carcinoma type: Shows cytologic atypia, increased mitoses, +/- necrosis, infiltrative growth, arising in a myoepithelioma/mixed tumor or de novo
Ancillary studies ─
─ IHC: Myoepithelial cells: S100, GFAP, SMA, calponin, p63, keratins (variably positive); Ductal epithelial cells (in mixed tumor): Keratins, EMA positive, S100 negative
─ Molecular: PLAG1 gene fusions (eg, with CTNNB1, LIFR, CHCHD7) are common in mixed tumors/myoepitheliomas with ductal differentiation, similar to salivary gland pleomorphic adenoma; EWSR1 rearrangements are more typical of pure myoepitheliomas/myoepithelial carcinomas without prominent ductal elements
DDx

─ Extraskeletal myxoid chondrosarcoma (if chondromyxoid stroma prominent; NR4A3 fusion, lacks true epithelial/myoepithelial differentiation)
─ Chordoma (brachyury positive, axial skeleton)
─ Metastatic pleomorphic adenoma (history of salivary gland primary)
─ Synovial sarcoma (biphasic) (SS18 fusion, TLE1 positive, different epithelial/spindle morphology)
─ Ossifying fibromyxoid tumor (peripheral bone, PHF1 fusion)
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Pleomorphic hyalinizing angiectatic tumor (PHAT)

A rare mesenchymal neoplasm of uncertain differentiation and intermediate malignant potential (locally aggressive, rarely metastasizing), characterized by clusters of thin-walled, hyalinized, ectatic blood vessels surrounded by variably cellular spindle and pleomorphic cells with abundant hemosiderin deposition; considered part of a spectrum with HFLT and MIFS
Clinical ─ Typically affects adults (peak age 40-70s), slight female predominance; most common in subcutaneous tissue of the lower extremities (especially ankle and foot region), less often upper extremities or trunk; presents as a slow-growing, often painful or tender, poorly defined mass or plaque, may have a purplish or brownish discoloration
Macro ─ Poorly circumscribed, infiltrative, firm or rubbery mass; cut surface is typically variegated, with brownish (hemosiderin), yellowish (fat if HFLT overlap), hemorrhagic, or gelatinous (myxoid if MIFS overlap) areas
Micro

─ Poorly circumscribed, infiltrative growth pattern in subcutaneous tissue, often extending into dermis or deeper structures
─ Characteristic feature: Sheets and clusters of thin-walled, ectatic (dilated) blood vessels surrounded by thick, amorphous, eosinophilic, hyalinized material or fibrinoid deposits in their walls
─ Surrounding stroma is variably cellular, often edematous or myxoid, and composed of:
─ Bland spindle cells with pale cytoplasm
─ Scattered large, pleomorphic, bizarre, hyperchromatic tumor cells (multinucleated or mononuclear) with prominent nucleoli and sometimes intranuclear pseudoinclusions
─ Abundant hemosiderin deposition, both intracellular (within tumor cells and macrophages) and extracellular, is a key feature
─ Chronic inflammatory infiltrate (lymphocytes, plasma cells) is common
─ Mitotic activity is typically very low (<1-2/10 HPF), atypical mitoses are rare; necrosis is usually absent
Ancillary studies ─
─ IHC: Tumor cells (spindle and pleomorphic) are positive for vimentin; CD34 is variably positive (often in spindle cells and endothelial cells); CD68 may highlight histiocytes and some tumor cells; Negative for S100 protein, keratins, SMA (except vessels), desmin, HMB45, ALK1
─ Molecular: Characterized by recurrent t(1;10)(p22;q24) resulting in a TGFBR3::MGEA5 gene fusion, which is shared with hemosiderotic fibrolipomatous tumor (HFLT) and a subset of myxoinflammatory fibroblastic sarcomas (MIFS), indicating these entities form a spectrum
DDx

─ Hemosiderotic fibrolipomatous tumor (HFLT) (prominent mature adipose tissue component, less striking vascular changes and pleomorphism usually, but significant overlap and shared genetics)
─ Myxoinflammatory fibroblastic sarcoma (MIFS) (more prominent myxoid stroma, more pronounced inflammatory infiltrate, characteristic virocyte-like or Reed-Sternberg-like cells, but shares genetics and can overlap)
─ Ancient schwannoma (diffuse S100 positive, Verocay bodies, lacks ectatic hyalinized vessels and TGFBR3::MGEA5 fusion)
─ Malignant peripheral nerve sheath tumor (MPNST) (more overt malignant features, higher mitoses, S100 often patchy/lost, H3K27me3 loss common)
─ Myxofibrosarcoma (curvilinear vessels, lacks prominent hyalinization around vessels and extensive hemosiderin, more consistent pleomorphism in higher grades)
─ Kaposi sarcoma (HHV8 positive, different vascular pattern)
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Phosphaturic mesenchymal tumor (PMT)

A rare mesenchymal neoplasm of uncertain differentiation, characterized by bland spindle cells, distinctive "grungy" or flocculent calcified matrix, prominent vasculature, and association with tumor-induced osteomalacia (TIO) due to overproduction of fibroblast growth factor 23 (FGF23)
Clinical ─ Typically affects adults (wide age range, median ~40-50s); can occur in soft tissue (especially extremities, head/neck) or bone; often presents insidiously with symptoms of osteomalacia (bone pain, fractures, muscle weakness, fatigue) due to hypophosphatemia and altered vitamin D metabolism caused by tumor-secreted FGF23; serum phosphate is low, alkaline phosphatase is high, FGF23 is elevated; removal of tumor usually cures osteomalacia
Macro ─ Variable size, often appears circumscribed but may be infiltrative; cut surface is typically yellowish-tan, gritty, hemorrhagic, or fleshy; may show cystic change or more solid areas
Micro

─ Highly variable histologic appearance, often with a mixed pattern:
─ Bland spindle to stellate or epithelioid cells with indistinct, pale eosinophilic or clear cytoplasm and ovoid to round vesicular nuclei
─ Cells may be arranged in sheets, fascicles, or a hemangiopericytoma-like pattern around prominent, branching, thin-walled blood vessels
─ Characteristic feature: Distinctive flocculent, "grungy," smudgy, or amorphous basophilic to eosinophilic calcified matrix, often described as "feathery" or "osteoid-like" but distinct from true osteoid produced by osteosarcoma; this matrix is often intimately associated with tumor cells and vessels
─ Osteoclast-like multinucleated giant cells are commonly present, often near calcified matrix or areas of hemorrhage
─ Hemosiderin deposition, metaplastic bone or cartilage formation (true cartilage/bone distinct from the grungy matrix), and adipose tissue may be present
─ Cytologic atypia is usually minimal, mitotic activity is low (malignant PMT is rare, defined by atypia, increased mitoses, necrosis)
Ancillary studies ─
─ IHC: Tumor cells are positive for vimentin; FGF23 immunohistochemistry can be positive in tumor cells (variable sensitivity/specificity, best confirmed by serum levels); CD56, ERG (nuclear endothelial marker, surprisingly positive in tumor cells of many PMTs), and SATB2 (osteoblastic marker, may be positive in tumor cells even without true osteoid) are variably positive; SMA may highlight perivascular cells; Negative for S100 protein (usually), keratins, desmin, HMB45, MUC4, STAT6
─ Molecular: Recurrent gene fusions involving FGFR1 (fibroblast growth factor receptor 1) are common, most frequently with FN1 (fibronectin 1), resulting in FN1::FGFR1 fusion; less commonly, FGF1 fusions (eg, FIGN::FGF1) or other FGFR1 partners occur
DDx

─ Giant cell tumor of soft tissue / bone (lacks grungy matrix, H3F3A mutation in bone GCT, lacks FGFR1 fusion)
─ Ossifying fibromyxoid tumor (peripheral bone shell, PHF1 fusion, S100 often positive, lacks grungy matrix and FGFR1 fusion)
─ Mesenchymal chondrosarcoma (biphasic with cartilage and small cells, HEY1::NCOA2 fusion, lacks grungy matrix)
─ Calcifying fibrous tumor (psammomatous/dystrophic calcification, lymphoplasmacytic infiltrate, lacks grungy matrix and FGFR1 fusion)
─ Aneurysmal bone cyst (soft tissue) (blood-filled cysts, USP6 rearranged, lacks grungy matrix and FGFR1 fusion)
─ Hemangiopericytoma / Solitary fibrous tumor (STAT6 positive, NAB2::STAT6 fusion, lacks grungy matrix and FGFR1 fusion)
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Synovial Sarcoma

A malignant mesenchymal neoplasm of uncertain differentiation, defined by a characteristic SS18 gene rearrangement, showing variable epithelial differentiation (glandular or solid epithelial structures); despite its name, it does not arise from synovium and is not related to synovial cells
Clinical ─ Typically affects adolescents and young adults (peak age 15-40s), but can occur at any age; M>F slightly; most common in deep soft tissues of the extremities, especially near large joints (knee region is a classic site), followed by trunk, head/neck, and rarely viscera (lung, pleura, kidney); presents as a slow-growing, often deep-seated, sometimes painful mass; may be present for years before diagnosis
Macro ─ Appears deceptively well-circumscribed or pseudoencapsulated, but is infiltrative; cut surface is typically firm, gray-white to tan, fleshy, or lobulated; cystic change (sometimes extensive), hemorrhage, necrosis, and focal calcification (in ~30% of cases, visible on imaging) can be present
Micro

─ Classified into three main histologic types:
─ Monophasic synovial sarcoma: Composed exclusively of relatively uniform spindle cells (most common type, ~70-80%)
─ Spindle cells: Small, ovoid to fusiform cells with scant cytoplasm, dark oval nuclei, and inconspicuous nucleoli, arranged in dense, cellular fascicles, often with a herringbone pattern or storiform areas
─ Biphasic synovial sarcoma: Shows both spindle cell and epithelial components (~20-30%)
─ Epithelial component: Forms glands, tubules, nests, cords, or solid sheets of cuboidal to columnar epithelial cells with eosinophilic cytoplasm and round vesicular nuclei; glands may contain mucin
─ Poorly differentiated synovial sarcoma: High-grade variant with areas resembling small round cell sarcoma, large cell/rhabdoid sarcoma, or high-grade spindle cell sarcoma, often obscuring typical synovial sarcoma features; associated with worse prognosis
─ Characteristic features common to all types (may be focal):
─ Staghorn or hemangiopericytoma-like branching blood vessels
─ Stromal hyalinization or myxoid change
─ Mast cells are often numerous in the stroma
─ Calcification (punctate or larger areas) can occur
─ Mitotic activity is variable but usually identifiable (average 2-10/10 HPF in conventional types, higher in poorly differentiated)
Ancillary studies ─
─ IHC: Tumor cells (both spindle and epithelial) are positive for TLE1 (nuclear stain, sensitive but not highly specific); Cytokeratins (AE1/AE3, CAM5.2, CK7, CK19) and EMA (epithelial membrane antigen) are typically positive in the epithelial component of biphasic SS and often positive (at least focally, may require extensive search) in the spindle cell component of monophasic SS (a key diagnostic feature); S100 protein and CD34 are positive in a subset of cases (variable, ~30-40%); BCL2 and CD99 are often positive (non-specific); Negative for desmin, SMA (except reactive vessels), SOX10, MyoD1/myogenin, STAT6, MUC4
─ Molecular: Defined by a characteristic reciprocal translocation t(X;18)(p11.2;q11.2) resulting in an SS18::SSX gene fusion (SS18::SSX1 is most common, SS18::SSX2 less common, rarely SS18::SSX4); detection of this fusion by FISH, RT-PCR, or NGS is confirmatory
DDx

─ Malignant peripheral nerve sheath tumor (MPNST) (S100/SOX10 variably positive, H3K27me3 loss common, lacks SS18 fusion and consistent keratins)
─ Fibrosarcoma / Undifferentiated spindle cell sarcoma (diagnosis of exclusion, lacks specific IHC/fusion)
─ Solitary fibrous tumor (STAT6 positive, CD34 positive, lacks SS18 fusion and keratins)
─ Ewing sarcoma (if poorly differentiated/round cell variant; CD99/NKX2.2 positive, EWSR1-ETS fusion)
─ Carcinoma (metastatic or primary with sarcomatoid features) (more diffuse/strong keratins, specific carcinoma markers, lacks SS18 fusion)
─ Mesenchymal chondrosarcoma (if calcification/cartilage; biphasic with small cells and cartilage, HEY1::NCOA2 fusion)
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Biphasic Synovial Sarcoma

A subtype of synovial sarcoma characterized by the presence of two distinct morphologic components: a spindle cell component and an epithelial component forming glands or solid nests
Clinical ─ Similar to overall synovial sarcoma; adolescents and young adults, deep soft tissues of extremities near large joints
Macro ─ Appears circumscribed but infiltrative; gray-white/tan, fleshy; glandular areas may appear cystic or mucoid
Micro

─ Clearly identifiable dual differentiation:
─ Spindle cell component: Relatively uniform, small, ovoid to fusiform cells with scant cytoplasm and dark nuclei, arranged in dense, cellular fascicles; may show hemangiopericytoma-like vessels, stromal hyalinization, or calcification
─ Epithelial component: Forms well-defined glands, tubules, nests, cords, or solid sheets of cuboidal to columnar epithelial cells with eosinophilic cytoplasm and round vesicular nuclei; glands may contain eosinophilic or basophilic mucin; squamous metaplasia can occur focally
─ The two components are intimately admixed or may show sharp demarcation
─ Mitotic activity is variable in both components
Ancillary studies ─
─ IHC: Spindle cells: TLE1 positive, often focally keratin/EMA positive, S100/CD34 variable, BCL2/CD99 often positive; Epithelial cells: Strongly positive for keratins (AE1/AE3, CAM5.2, CK7, CK19) and EMA; TLE1 positive
─ Molecular: SS18::SSX fusion is present
DDx

─ Adenocarcinoma with sarcomatoid change (glandular component is overtly malignant, more pleomorphism, different IHC profile for spindle cells, lacks SS18 fusion)
─ Glandular malignant peripheral nerve sheath tumor (MPNST) (arises from nerve/NF1, MPNST spindle component S100/SOX10 variably positive, H3K27me3 loss, lacks SS18 fusion)
─ Carcinosarcoma (true malignant epithelial and mesenchymal components, rare in soft tissue, lacks SS18 fusion)
─ Teratoma with malignant transformation (contains elements from all three germ layers)
─ Mesothelioma (biphasic) (pleural/peritoneal location, calretinin/WT1/D2-40 positive, lacks SS18 fusion)
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Myxoid Synovial Sarcoma

A rare variant of monophasic synovial sarcoma characterized by a predominantly myxoid stroma, which can make it challenging to distinguish from other myxoid mesenchymal neoplasms
Clinical ─ Similar to conventional synovial sarcoma, but may be less common; adolescents and young adults, deep soft tissues
Macro ─ Often gelatinous, mucoid, or cystic in appearance due to abundant myxoid matrix; may be less firm than classic synovial sarcoma
Micro

─ Composed of relatively uniform spindle cells, similar to those in monophasic fibrous synovial sarcoma, but set in an abundant, loose, myxoid, or edematous stroma (Alcian blue positive)
─ Spindle cells may appear more stellate or separated within the myxoid matrix
─ Fascicular or sheet-like growth patterns may be less apparent, with cells often arranged in cords or a reticular pattern
─ Hemangiopericytoma-like vessels are typically present
─ Focal areas of higher cellularity or more typical monophasic spindle cell pattern may be present and aid in diagnosis
─ Epithelial differentiation (glands) is absent by definition in a purely myxoid monophasic variant
─ Mitotic activity is variable
Ancillary studies ─
─ IHC: Tumor cells are TLE1 positive; Keratin (AE1/AE3, CAM5.2) and EMA positivity is crucial for diagnosis but may be very focal and require extensive sampling or multiple markers in purely myxoid forms; S100/CD34 variable; BCL2/CD99 often positive
─ Molecular: SS18::SSX fusion is present and confirmatory
DDx

─ Low-grade fibromyxoid sarcoma (MUC4 positive, FUS fusion, alternating fibrous/myxoid zones, lacks keratin/EMA)
─ Myxofibrosarcoma (curvilinear vessels, more pleomorphism in non-myxoid areas, lacks keratin/EMA and SS18 fusion)
─ Extraskeletal myxoid chondrosarcoma (NR4A3 fusion, different cell morphology, S100 often patchy, lacks keratin/EMA and SS18 fusion)
─ Myxoid liposarcoma (lipoblasts, plexiform capillaries, DDIT3 fusion, lacks keratin/EMA and SS18 fusion)
─ Myxoid malignant peripheral nerve sheath tumor (S100/SOX10 variable, H3K27me3 loss, lacks keratin/EMA and SS18 fusion)
─ Myxoma (intramuscular/juxta-articular) (lacks atypia, mitoses, keratin/EMA, and SS18 fusion)
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Poorly Differentiated Synovial Sarcoma, Round Cell Variant

A high-grade variant of synovial sarcoma characterized by sheets of primitive small round blue cells, often with high mitotic activity and necrosis, which can obscure the typical features of synovial sarcoma and mimic other small round cell tumors; may arise de novo or as a component of otherwise conventional synovial sarcoma
Clinical ─ Similar to conventional synovial sarcoma but often associated with a more aggressive clinical course and poorer prognosis; adolescents and young adults, deep soft tissues
Macro ─ Fleshy, infiltrative mass, often with extensive hemorrhage and necrosis, reflecting its high-grade nature
Micro

─ Predominantly composed of diffuse sheets of densely packed, primitive, small to medium-sized round cells with scant cytoplasm, hyperchromatic nuclei, and inconspicuous nucleoli
─ Cells may show some nuclear molding
─ High mitotic activity (often >10-20/10 HPF) and extensive necrosis (comedo-type or geographic) are common features
─ Focal areas of more conventional spindle cell synovial sarcoma or even biphasic differentiation may be present if carefully sought, aiding in diagnosis
─ Hemangiopericytoma-like vasculature may be present but can be less obvious than in conventional types
─ Rhabdoid features (large cells with eccentric nuclei and eosinophilic cytoplasmic inclusions) can occur in some poorly differentiated cases
Ancillary studies ─
─ IHC: Tumor cells are TLE1 positive; Keratin (AE1/AE3, CAM5.2) and EMA positivity is very important for diagnosis but may be focal, weak, or dot-like in the round cells, requiring careful evaluation; CD99 is often positive (non-specific); BCL2 positive; S100 protein is positive in a subset (~30%), which can be a pitfall; INI1/SMARCB1 expression is retained; Negative for desmin, MyoD1/myogenin, LCA (CD45), NKX2.2, FLI1 (usually)
─ Molecular: SS18::SSX fusion (SS18::SSX1, SS18::SSX2, or SS18::SSX4) is present and is the gold standard for confirming the diagnosis, especially crucial in poorly differentiated forms
DDx

─ Ewing sarcoma (CD99/NKX2.2/FLI1 positive, EWSR1-ETS fusion, lacks keratin/EMA and SS18 fusion)
─ Alveolar rhabdomyosarcoma (MyoD1/myogenin positive, PAX-FOXO1 fusion, lacks keratin/EMA and SS18 fusion)
─ Desmoplastic small round cell tumor (DSRCT) (keratin/desmin/WT1 positive, EWSR1::WT1 fusion)
─ Mesenchymal chondrosarcoma (biphasic with cartilage, HEY1::NCOA2 fusion, SOX9 positive in small cells)
─ Lymphoma (LCA positive, specific lymphoid markers)
─ Small cell carcinoma (metastatic) (more diffuse/strong keratin, neuroendocrine markers if applicable, lacks SS18 fusion)
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Synovial Sarcoma, Epithelial/Glandular Variant

A rare presentation of biphasic synovial sarcoma where the epithelial component predominates significantly, forming prominent glandular, tubular, or solid sheet-like structures, with a relatively minor or inconspicuous spindle cell component
Clinical ─ Similar to conventional synovial sarcoma; adolescents and young adults, deep soft tissues, often near joints
Macro ─ May appear more cystic, papillary, or mucoid than typical synovial sarcoma if glandular differentiation is extensive and produces mucin
Micro

─ Dominated by epithelial differentiation, which can manifest as:
─ Well-formed glands or tubules lined by cuboidal to columnar epithelial cells, often containing eosinophilic or basophilic mucin
─ Solid sheets or nests of polygonal epithelioid cells with eosinophilic cytoplasm
─ Papillary or cribriform architectural patterns may be seen
─ The spindle cell component, characteristic of monophasic or biphasic synovial sarcoma, is present but distinctly subordinate to the epithelial component, sometimes requiring careful search or found only focally
─ Cytologic atypia in epithelial cells is usually mild to moderate; mitotic activity is variable
─ Calcification, stromal hyalinization, and mast cells can be present, as in conventional synovial sarcoma
Ancillary studies ─
─ IHC: Epithelial component is strongly positive for keratins (AE1/AE3, CAM5.2, CK7, CK19) and EMA; Spindle cell component (if identifiable) is TLE1 positive and may show focal keratin/EMA; S100/CD34 variable or negative
─ Molecular: SS18::SSX fusion is present and confirmatory, identical to other synovial sarcoma subtypes
DDx

─ Adenocarcinoma (metastatic or primary soft tissue adenocarcinoma - very rare) (more diffuse glandular atypia, specific carcinoma markers like PAX8, CDX2, TTF1 depending on origin; lacks SS18 fusion and TLE1)
─ Biphasic synovial sarcoma (more balanced or spindle-predominant epithelial and spindle components)
─ Mesothelioma (epithelioid or biphasic, if pleural/peritoneal) (calretinin/WT1/D2-40 positive, lacks SS18 fusion)
─ Glandular malignant peripheral nerve sheath tumor (MPNST) (arises from nerve/NF1, MPNST spindle component S100/SOX10 variably positive, lacks SS18 fusion)
─ Salivary gland-type tumors in soft tissue (eg, mucoepidermoid carcinoma, adenoid cystic carcinoma - specific histology and IHC, different molecular if known)
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Alveolar soft part sarcoma (ASPS)

A rare malignant neoplasm of uncertain histogenesis, characterized by a distinctive organoid or pseudoalveolar architecture, large polygonal cells with granular eosinophilic cytoplasm, and characteristic intracytoplasmic PAS-positive, diastase-resistant rhomboid or rod-shaped crystals; defined by a specific ASPSCR1::TFE3 gene fusion
Clinical ─ Typically affects adolescents and young adults (peak age 15-35s), with a female predominance; common sites include deep soft tissues of the lower extremities (especially thigh and buttock) and trunk; in children, head/neck region (orbit, tongue) is more frequent; presents as a slow-growing, often painless, deep-seated mass; highly prone to late and widespread metastasis (lungs, brain, bone) despite its often indolent initial growth
Macro ─ Appears well-circumscribed but unencapsulated, soft, fleshy, tan-pink to reddish-brown mass; often highly vascular with prominent draining veins; size is variable, can be large
Micro

─ Characteristic organoid or pseudoalveolar pattern: Nests or clusters of tumor cells separated by delicate, thin-walled fibrovascular septa containing sinusoidal blood vessels
─ Central discohesion within nests is common, leading to the "alveolar" appearance
─ Tumor cells are large, polygonal to round, with abundant, finely granular eosinophilic or clear cytoplasm and distinct cell borders
─ Nuclei are round to oval, vesicular, with prominent, centrally located, often cherry-red nucleoli
─ Pathognomonic feature: Intracytoplasmic rhomboid, rod-shaped, or needle-like crystalline structures, which are PAS-positive and diastase-resistant (may not be present in all cells or all cases, requiring careful search)
─ Mitotic activity is usually low, cytologic atypia is often not marked despite its malignant behavior
─ Necrosis is uncommon in primary tumors
Ancillary studies ─
─ IHC: Tumor cells show nuclear positivity for TFE3 (reflects ASPSCR1::TFE3 fusion, highly sensitive and specific); PAS stain with diastase digestion highlights the intracytoplasmic crystals; Vimentin positive; May show focal desmin or MyoD1 positivity (aberrant, not true myogenic differentiation); Negative for keratins, EMA, S100 protein, SOX10, HMB45, Melan-A, SMA, CD31, ERG, synaptophysin, chromogranin
─ Molecular: Defined by a specific unbalanced translocation der(17)t(X;17)(p11.2;q25) resulting in the ASPSCR1::TFE3 gene fusion
DDx

─ Paraganglioma / Pheochromocytoma (neuroendocrine markers synaptophysin/chromogranin positive, S100 positive sustentacular cells, lacks crystals and TFE3 fusion)
─ Granular cell tumor (S100/SOX10 positive, different granular quality - lysosomal, lacks crystals and TFE3 fusion)
─ Rhabdomyoma / Rhabdomyosarcoma (myogenic markers desmin/MyoD1/myogenin positive, lacks crystals and TFE3 fusion)
─ Melanoma (S100/SOX10/melanocytic markers positive, lacks crystals and TFE3 fusion)
─ Renal cell carcinoma (metastatic, especially clear cell or granular cell types) (PAX8/CD10/CAIX positive, lacks crystals and TFE3 fusion)
─ PEComa (HMB45/Melan-A and smooth muscle markers positive, lacks crystals, may have TFE3 IHC if TFE3-rearranged PEComa variant)
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─ pathoutlines WSI HE TFE3 WSI

Clear cell sarcoma of soft tissue

A rare, aggressive malignant neoplasm showing melanocytic differentiation, characterized by nests and fascicles of cells with clear to pale eosinophilic cytoplasm and prominent nucleoli, typically arising in association with tendons and aponeuroses in distal extremities; also known as Malignant Melanoma of Soft Parts (a misnomer, as it is genetically distinct from cutaneous melanoma)
Clinical ─ Typically affects young adults (peak age 20-40s); common in deep soft tissues of the distal extremities, especially foot and ankle, often intimately associated with tendons or aponeuroses; presents as a slow-growing, firm, often painful mass; high propensity for regional lymph node and distant metastasis (lungs, bone)
Macro ─ Well-circumscribed or infiltrative, firm, gray-white to tan mass; cut surface may show focal pigmentation (melanin) in a subset of cases; necrosis can be present
Micro

─ Nests, clusters, and short fascicles of relatively uniform, medium to large polygonal or spindle cells, separated by delicate fibrous septa
─ Tumor cells have clear, pale eosinophilic, or amphophilic cytoplasm and round to oval vesicular nuclei with prominent, often centrally located, eosinophilic or amphophilic nucleoli (a key feature)
─ Wreath-like multinucleated giant cells (osteoclast-like or tumor giant cells) may be present
─ Melanin pigment may be identifiable within tumor cells or melanophages in some cases, but many are amelanotic
─ Mitotic activity is variable, can be low or brisk
─ Infiltrative growth into surrounding tendons, aponeuroses, or soft tissues is common
Ancillary studies ─
─ IHC: Tumor cells are characteristically positive for S100 protein (strong, diffuse), SOX10, and melanocytic markers (HMB45, Melan-A/MART-1, MITF); Vimentin positive; Negative for keratins, desmin, SMA, CD34, STAT6
─ Molecular: Defined by specific chromosomal translocations, most commonly t(12;22)(q13;q12) resulting in EWSR1::ATF1 gene fusion; less commonly, EWSR1::CREB1 fusion (t(2;22)(q33;q12)) or other rare EWSR1/FUS fusions with CREB family members
DDx

─ Malignant melanoma (metastatic or primary desmoplastic/spindle cell) (lacks consistent EWSR1 fusion, often BRAF/NRAS mutations, morphology can overlap but prominent central nucleoli less consistent)
─ Malignant peripheral nerve sheath tumor (MPNST) (S100 often patchy/lost, lacks melanocytic markers and EWSR1-ATF1/CREB1 fusion, H3K27me3 loss common)
─ Synovial sarcoma (monophasic) (TLE1 positive, keratin/EMA often focally positive, SS18 fusion, lacks melanocytic markers)
─ PEComa (co-expresses melanocytic and smooth muscle markers, lacks EWSR1 fusion, often TSC/TFE3 alterations)
─ Epithelioid sarcoma (INI1 loss, keratin/CD34 positive, lacks melanocytic markers and EWSR1 fusion)
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─ pathoutlines in skin WSI WSI WSI

Desmoplastic small round cell tumor (DSRCT)

A rare and highly aggressive malignant neoplasm composed of nests and clusters of small, primitive round cells within a prominent desmoplastic (fibrous) stroma, characteristically showing polyphenotypic differentiation (epithelial, mesenchymal, and often neuroendocrine features) and defined by a specific EWSR1::WT1 gene fusion
Clinical ─ Predominantly affects adolescent and young adult males (peak age 15-30s, M>>F ~4:1); typically arises from abdominal or pelvic serosal surfaces (peritoneum), presenting with multiple tumor implants (carcinomatosis-like spread); less commonly occurs in other sites (eg, pleura, paratesticular region, ovary, intracranial); presents with abdominal pain, distension, palpable mass, ascites, or bowel obstruction; prognosis is very poor despite aggressive multimodality therapy
Macro ─ Multiple firm, gray-white to tan nodules and masses studding peritoneal surfaces; individual nodules may coalesce to form large, bulky tumors; cut surface is fibrous and gritty
Micro

─ Sharply demarcated nests, islands, cords, or clusters of small, primitive, undifferentiated round to oval cells with scant cytoplasm, hyperchromatic nuclei, finely granular chromatin, and inconspicuous nucleoli
─ Tumor cell nests are embedded within an abundant, dense, desmoplastic (fibrous) stroma, which is often paucicellular
─ Mitotic activity is typically brisk, and apoptosis (single cell necrosis) is common within tumor nests
─ Central necrosis within larger tumor nests can occur
─ Rosette formation or rudimentary glandular structures may be seen focally
─ Lymphovascular invasion is common
Ancillary studies ─
─ IHC: Characteristically shows polyphenotypic differentiation with co-expression of:
─ Epithelial markers: Keratins (AE1/AE3, CAM5.2, CK7 - often dot-like or perinuclear), EMA
─ Mesenchymal markers: Desmin (often dot-like paranuclear), vimentin
─ Neuroendocrine markers: NSE (neuron-specific enolase) is often positive; synaptophysin and chromogranin are less consistent
─ WT1 (Wilms tumor 1): Nuclear positivity using an antibody directed against the C-terminus of WT1 protein is highly characteristic (reflects the WT1 portion of the fusion protein); N-terminus WT1 antibodies are usually negative
─ CD99 may be positive (patchy); Negative for MyoD1/myogenin, LCA (CD45), S100 protein, FLI1, NKX2.2 (usually)
─ Molecular: Defined by a specific chromosomal translocation t(11;22)(p13;q12) resulting in the EWSR1::WT1 gene fusion
DDx

─ Ewing sarcoma (CD99/NKX2.2/FLI1 positive, lacks keratin/desmin/WT1-C-term, EWSR1-ETS fusion)
─ Rhabdomyosarcoma (alveolar or embryonal) (myogenic markers MyoD1/myogenin/desmin positive, lacks keratin/WT1-C-term and EWSR1::WT1 fusion)
─ Lymphoma (LCA positive, specific lymphoid markers)
─ Poorly differentiated synovial sarcoma (TLE1 positive, keratin/EMA may be positive, SS18 fusion, lacks desmin/WT1-C-term)
─ Mesothelioma (if pleural/peritoneal; calretinin/WT1-N-term/D2-40 positive, lacks desmin and EWSR1::WT1 fusion)
─ Small cell carcinoma (metastatic) (more diffuse/strong keratin, neuroendocrine markers more prominent, lacks desmin and EWSR1::WT1 fusion)
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─ pathoutlines WSI WSI WSI WSI WSI WSI & WSI case & WSI video

Extrarenal rhabdoid tumor

A highly aggressive and rare malignant neoplasm of uncertain histogenesis, occurring outside the kidney and central nervous system, characterized by sheets of "rhabdoid" cells (large cells with eccentric nuclei, prominent nucleoli, and eosinophilic cytoplasmic inclusions) and typically defined by loss of SMARCB1/INI1 (or rarely SMARCA4/BRG1) protein expression
Clinical ─ Primarily affects infants and young children (most cases <3 years old), but can occur in older children and rarely adults; common sites include deep soft tissues of the neck, paraspinal region, trunk, extremities, retroperitoneum, and viscera (liver, GI tract); presents as a rapidly growing, often large and infiltrative mass; highly aggressive with early metastasis and very poor prognosis
Macro ─ Fleshy, gray-white to tan, often large and poorly demarcated mass; hemorrhage and necrosis are common and often extensive
Micro

─ Diffuse sheets or poorly cohesive aggregates of characteristic "rhabdoid" cells
─ Rhabdoid cells: Large, polygonal to round cells with abundant, deeply eosinophilic cytoplasm, an eccentric, vesicular nucleus, and a single, prominent, centrally located (within the nucleus) eosinophilic or amphophilic nucleolus
─ Intracytoplasmic eosinophilic hyaline inclusions (composed of aggregated intermediate filaments, mainly vimentin and keratin) are often present and are a key feature, though not universally seen in all cells or all cases
─ Minimal intervening stroma; vascularity can be prominent
─ High mitotic activity, including atypical mitoses, and extensive geographic necrosis are characteristic
─ Cytologic atypia and pleomorphism are marked
Ancillary studies ─
─ IHC: Loss of nuclear SMARCB1/INI1 expression (or rarely SMARCA4/BRG1) is the pathognomonic hallmark and essential for diagnosis; Tumor cells are positive for vimentin; EMA (epithelial membrane antigen) and keratins (AE1/AE3, CAM5.2 - often dot-like or paranuclear) are frequently positive; SMA (smooth muscle actin) may be focally positive; Synaptophysin and CD99 can be positive in a subset; Negative for desmin, myogenin, S100 protein, HMB45, LCA (CD45), GFAP, brachyury
─ Molecular: Defined by biallelic inactivation (mutations, deletions) of the SMARCB1 (INI1) gene on chromosome 22q11.2; less commonly, inactivation of SMARCA4 (BRG1) on chromosome 19p13.2
DDx

─ Epithelioid sarcoma (also shows INI1 loss, but typically different morphology with granuloma-like necrosis, often CD34 positive, occurs in older children/adults usually)
─ Rhabdomyosarcoma (especially pleomorphic or embryonal with rhabdoid features) (retains INI1 expression, MyoD1/myogenin positive)
─ Melanoma (S100/SOX10/melanocytic markers positive, retains INI1 expression)
─ Poorly differentiated carcinoma with rhabdoid features (retains INI1 expression usually, specific carcinoma markers)
─ Alveolar soft part sarcoma (ASPSCR1::TFE3 fusion, TFE3 IHC positive, characteristic crystals, retains INI1)
─ Myoepithelial carcinoma with rhabdoid features (S100/keratin/EMA/GFAP/SMA variably positive, may show INI1 loss in some aggressive cases but often EWSR1 rearranged)
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─ pathoutlines WSI

Intimal sarcoma

A rare, aggressive malignant mesenchymal neoplasm arising from the intima of large blood vessels, most commonly the pulmonary artery, followed by the aorta and other large systemic arteries or veins; characterized by intraluminal growth and often mimicking thromboembolic disease
Clinical ─ Typically affects adults (wide age range, median ~50-60s); slight male predominance for aortic, female for pulmonary artery; pulmonary artery intimal sarcoma presents with symptoms mimicking pulmonary embolism (dyspnea, chest pain, cough, hemoptysis, pulmonary hypertension); aortic intimal sarcoma presents with symptoms of arterial occlusion, dissection, or systemic embolization; prognosis is generally very poor due to late diagnosis and aggressive behavior
Macro ─ Polypoid, gelatinous, or fleshy mass filling and expanding the lumen of the affected large vessel; often extends along vessel branches, following the direction of blood flow; may appear attached to the intima and can invade the vessel wall; color is typically gray-white, tan, or hemorrhagic
Micro

─ Composed of poorly differentiated spindle, pleomorphic, or epithelioid malignant cells, often arranged loosely in a myxoid or collagenous stroma, or forming more solid, cellular fascicles or sheets
─ Tumor cells typically show moderate to marked cytologic atypia, hyperchromasia, irregular nuclear contours, and prominent nucleoli
─ High mitotic activity and necrosis are common
─ Heterologous differentiation (eg, osteosarcoma, chondrosarcoma, rhabdomyosarcoma, angiosarcoma) can occur in a subset of cases and may dominate the histology
─ The tumor grows along the intimal surface, often forming polypoid projections into the lumen, and may invade the Media ─ placeholderand adventitia of the vessel wall
─ Vasoformative areas may be present, but typically lack the well-formed anastomosing channels of conventional angiosarcoma unless angiosarcomatous differentiation is present
Ancillary studies ─
─ IHC: Tumor cells are positive for vimentin; MDM2 and CDK4 co-expression (by IHC, reflecting gene amplification) is seen in a significant proportion of cases (especially those resembling UPS or fibrosarcoma), suggesting a link to DDLPS for some; SMA, desmin, S100 protein may be positive if corresponding heterologous differentiation is present; Endothelial markers (CD31, ERG, FLI1) are typically negative in the main tumor cells (unless angiosarcomatous differentiation), helping to distinguish from angiosarcoma arising in large vessels; Cytokeratins are negative (rules out carcinosarcoma)
─ Molecular: MDM2 gene amplification (often with CDK4 co-amplification) is common, especially in tumors with UPS-like or fibrosarcoma-like morphology; complex karyotypes with numerous gains and losses are typical
DDx

─ Organizing thrombus / Pulmonary embolism (lacks atypical cells, composed of fibrin, blood cells, inflammatory cells, and organizing granulation tissue)
─ Myxoma (cardiac, if involving great vessels near heart) (bland stellate cells in myxoid stroma, lacks atypia/mitoses, specific IHC for myxoma cells usually negative for sarcoma markers)
─ Angiosarcoma arising in large vessels (diffusely positive for endothelial markers CD31/ERG, typically lacks MDM2 amplification unless post-radiation)
─ Leiomyosarcoma arising from vessel wall (smooth muscle markers desmin/h-caldesmon positive, typically lacks MDM2 amplification)
─ Dedifferentiated liposarcoma (if retroperitoneal involving aorta; MDM2 amplified but usually arises adjacent to WDLPS)
─ Sarcomatoid carcinoma invading vessels (keratin positive)
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─ pathoutlines WSI WSI WSI WSI WSI WSI WSI

Thoracic aorta [WSI](https://dpa-dapa.com/public/display?token=4f54d511) & bone mets [WSIWSI](https://dpa-dapa.com/public/display?token=612c74f0)

Undifferentiated Pleomorphic Sarcoma

A high-grade malignant mesenchymal neoplasm composed of pleomorphic spindle, epithelioid, and giant cells that lacks any identifiable line of specific differentiation by morphology, immunohistochemistry, or molecular genetics; it is a diagnosis of exclusion, formerly known as Malignant Fibrous Histiocytoma (MFH), storiform-pleomorphic type
Clinical ─ Most common sarcoma in adults, typically affecting older individuals (peak age 60-70s), M>F slightly; common in deep soft tissues of the extremities (especially thigh), trunk, and retroperitoneum; less commonly in skin (pleomorphic dermal sarcoma) or bone; presents as a rapidly enlarging, often large (>5 cm), deep-seated, painless or painful mass
Macro ─ Large, fleshy, often poorly circumscribed or pseudoencapsulated mass; cut surface is typically variegated, with gray-white to tan sarcomatous tissue, extensive hemorrhage, necrosis, and sometimes cystic change; infiltrative margins are common
Micro

─ Highly cellular proliferation of malignant cells showing marked cytologic pleomorphism and atypia:
─ Spindle cells: Atypical fusiform cells arranged in fascicles, a storiform pattern, or haphazardly
─ Epithelioid cells: Large polygonal cells with abundant eosinophilic cytoplasm and vesicular nuclei
─ Bizarre multinucleated giant cells (tumor giant cells): Often numerous and highly pleomorphic
─ Nuclei are hyperchromatic, irregular, with coarse chromatin and prominent, often bizarre nucleoli
─ High mitotic activity, including numerous atypical mitoses, is characteristic (often >10-20/10 HPF)
─ Extensive geographic necrosis and hemorrhage are very common features
─ Prominent inflammatory infiltrate (lymphocytes, neutrophils, eosinophils, foamy histiocytes) may be present in some areas ("inflammatory UPS/MFH" - though specific DDLPS variant should be excluded)
─ By definition, no specific line of differentiation (eg, lipoblastic, rhabdomyoblastic, chondroblastic, osteoblastic, neural, vascular, epithelial) is identifiable despite thorough sampling and ancillary studies
Ancillary studies ─
─ IHC: Diagnosis of exclusion; Tumor cells are positive for vimentin; May show focal, non-specific staining for SMA, CD68, or other markers, but lack diffuse, convincing expression of lineage-specific markers (eg, keratins, S100, SOX10, desmin, myogenin, CD31, ERG, STAT6, MDM2 - unless DDLPS, etc)
─ Molecular: Characterized by complex, highly aneuploid karyotypes with numerous chromosomal gains and losses; no specific recurrent translocations or gene fusions define UPS (their presence would classify the tumor as a specific sarcoma type)
DDx

─ Dedifferentiated liposarcoma (must exclude by identifying WDLPS component and/or MDM2/CDK4 amplification, especially in retroperitoneum/deep limb)
─ Pleomorphic variants of specific sarcomas (eg, pleomorphic leiomyosarcoma, pleomorphic rhabdomyosarcoma, pleomorphic liposarcoma - show specific differentiation by IHC or morphology)
─ Sarcomatoid carcinoma (keratin positive)
─ Melanoma (S100/SOX10/melanocytic markers positive)
─ Anaplastic large cell lymphoma (CD30/ALK positive, lymphoid markers)
─ Atypical fibroxanthoma / Pleomorphic dermal sarcoma (superficial/dermal location, better prognosis if truly confined)
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Malignant Mesenchymoma

A historically used and controversial term for a rare, aggressive sarcoma showing two or more distinct lines of heterologous mesenchymal differentiation (eg, rhabdomyosarcoma + chondrosarcoma, or osteosarcoma + liposarcoma), in addition to a fibroblastic or undifferentiated spindle cell component; its existence as a distinct entity is debated, as many cases can be reclassified as specific sarcomas with heterologous differentiation (eg, DDLPS with heterologous elements, MPNST with heterologous elements)
Clinical ─ Rare, affects children and adults; deep soft tissues of extremities, trunk, retroperitoneum; aggressive clinical course with high rates of recurrence and metastasis
Macro ─ Large, fleshy, infiltrative mass, often with variegated appearance reflecting different components (eg, firm/gritty for bone/cartilage, yellowish for fat, fleshy for rhabdomyoblastic)
Micro

─ Requires the presence of two or more distinct lines of malignant mesenchymal differentiation, excluding the background fibroblastic or undifferentiated sarcoma component
─ Each differentiated component must be unequivocally malignant and constitute a significant portion of the tumor (not just focal metaplasia)
─ Examples of components: Rhabdomyosarcoma, osteosarcoma, chondrosarcoma, liposarcoma, angiosarcoma, leiomyosarcoma
─ The undifferentiated background component is typically a high-grade spindle cell or pleomorphic sarcoma
─ Precise definition and criteria have varied historically, leading to diagnostic ambiguity
Ancillary studies ─
─ IHC: Essential to confirm the different lines of differentiation present:
─ Rhabdomyosarcoma: Desmin, MyoD1, myogenin positive
─ Osteosarcoma: SATB2 positive (tumor osteoid)
─ Chondrosarcoma: S100 positive (malignant cartilage)
─ Liposarcoma: S100 positive (lipoblasts), MDM2/CDK4 positive if WDLPS/DDLPS-related component
─ Angiosarcoma: CD31/ERG positive
─ Leiomyosarcoma: Desmin/SMA/h-caldesmon positive
─ Molecular: Genetic findings would reflect the specific components present; eg, MDM2 amplification if a DDLPS-related component with heterologous differentiation, or complex karyotypes
DDx

─ Dedifferentiated liposarcoma (DDLPS) with heterologous differentiation (arises from WDLPS/ALT, MDM2 amplified; most common scenario for lesions previously called malignant mesenchymoma in adults)
─ Malignant peripheral nerve sheath tumor (MPNST) with heterologous differentiation (Triton tumor if rhabdo, etc; arises from nerve/NF1, S100/SOX10 variable, H3K27me3 loss common)
─ Teratoma with malignant transformation (germ cell tumor context, elements from all three germ layers)
─ Specific sarcomas with extensive divergent differentiation (eg, osteosarcoma with prominent chondroblastic areas)
─ Collision tumor (extremely rare, two separate synchronous sarcomas)
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Unclassified Spindle Cell Sarcomas

A heterogeneous category of malignant mesenchymal neoplasms composed predominantly of spindle cells that lack specific morphologic, immunophenotypic, or molecular features allowing for classification into a more defined sarcoma type; it is a diagnosis of exclusion after an extensive workup
Clinical ─ Can occur at any age, but more common in adults; arises in deep soft tissues, viscera, or bone; presentation is usually a growing mass, may be painful; behavior is generally aggressive, similar to other high-grade sarcomas
Macro ─ Often large, fleshy, infiltrative mass; gray-white to tan; hemorrhage and necrosis are common
Micro

─ Predominantly composed of atypical spindle cells arranged in fascicles, herringbone pattern, storiform pattern, or sheets
─ Cytologic atypia (hyperchromasia, pleomorphism, irregular nuclei) is usually evident and can range from moderate to marked
─ Mitotic activity is typically brisk, often with atypical forms
─ Necrosis is common
─ By definition, lacks definitive features of specific sarcoma types (eg, no unequivocal lipoblasts, rhabdomyoblasts, osteoid/chondroid production by tumor cells, specific vascular patterns, or pathognomonic immunophenotypes/molecular alterations)
Ancillary studies ─
─ IHC: Tumor cells are positive for vimentin; May show focal or weak positivity for non-specific markers like SMA, CD68, or rarely S100/keratins, but lack diffuse, convincing expression of lineage-specific markers that would define a specific sarcoma type (eg, strong/diffuse desmin, MyoD1, S100/SOX10, keratins, CD31/ERG, STAT6, MDM2, MUC4, ALK, etc)
─ Molecular: Generally characterized by complex, aneuploid karyotypes with numerous gains and losses; lacks specific recurrent translocations or gene fusions that define other sarcoma entities (eg, SS18::SSX, EWSR1 fusions, DDIT3 fusions, MDM2 amplification)
DDx

─ Specific types of spindle cell sarcomas that may have subtle or unusual features (eg, fibrosarcoma - a diagnosis also largely of exclusion, monophasic synovial sarcoma, MPNST, leiomyosarcoma, DDLPS, UPS - if pleomorphism is also prominent) - requires extensive IHC and possibly molecular studies to exclude these
─ Spindle cell melanoma (S100/SOX10/melanocytic markers positive)
─ Sarcomatoid carcinoma (keratin positive)
─ Reactive spindle cell proliferations (eg, nodular fasciitis, postoperative spindle cell nodule - less atypia, specific clinical/histologic context, USP6 rearranged in some)
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Undifferentiated Sarcoma in Childhood

A category for malignant mesenchymal neoplasms occurring in children that cannot be classified into any specific sarcoma type based on current morphologic, immunophenotypic, and molecular criteria; it is a diagnosis of exclusion, often representing biologically diverse and aggressive tumors
Clinical ─ Affects infants, children, and adolescents; can arise in various locations (soft tissue, viscera, bone); clinical presentation and behavior are variable but often aggressive
Macro ─ Typically large, fleshy, infiltrative masses with hemorrhage and necrosis
Micro

─ Can show a variety of patterns: spindle cell, round cell, epithelioid, or pleomorphic, but lacks definitive features of any well-defined pediatric sarcoma type
─ High-grade cytologic atypia, high mitotic activity, and necrosis are common
─ Extensive immunophenotyping and molecular testing are crucial to exclude known entities
Ancillary studies ─
─ IHC: Usually positive for vimentin; may show aberrant or focal expression of various markers, but lacks a consistent profile for a specific sarcoma type; critical to exclude rhabdomyosarcoma (MyoD1/myogenin), Ewing sarcoma (CD99/NKX2.2/FLI1, EWSR1 fusion), synovial sarcoma (TLE1/keratin/EMA, SS18 fusion), neuroblastoma (synaptophysin/PHOX2B), lymphoma (LCA/lymphoid markers), infantile fibrosarcoma (Pan-TRK, ETV6::NTRK3), and other specific pediatric sarcomas
─ Molecular: A key role is to exclude specific fusion-driven sarcomas common in childhood; some undifferentiated sarcomas in childhood may harbor novel or rare genetic alterations (eg, CIC fusions, BCOR alterations, NTRK fusions not typical for infantile fibrosarcoma, DICER1 mutations) that might reclassify them as emerging entities or provide therapeutic targets
DDx

─ All specific types of pediatric sarcomas (rhabdomyosarcoma, Ewing sarcoma, synovial sarcoma, infantile fibrosarcoma, PMMTI, etc - distinction based on specific IHC/molecular)
─ Poorly differentiated carcinoma or melanoma (rare in this age group, specific markers)
─ High-grade lymphoma (lymphoid markers)
─ Wilms tumor or other embryonal tumors (if organ-based; specific histology and markers)
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Ependymoma of Soft Tissue

A rare malignant neoplasm occurring in soft tissues, histologically and immunophenotypically resembling its central nervous system (CNS) counterpart, but arising extraneurally, often in deep soft tissues or subcutis, particularly in children and young adults; also known as extraspinal or extraskeletal ependymoma
Clinical ─ Rare, affects a wide age range, but more common in children and young adults; common sites include deep soft tissues of the extremities (especially lower limb), trunk (paraspinal, sacrococcygeal region), pelvis, and rarely other locations; presents as a slow-growing, often well-circumscribed mass, may be painful; behavior is variable, can recur locally, and a subset can metastasize (lungs, lymph nodes)
Macro ─ Well-circumscribed or infiltrative, firm, gray-white to tan mass; cut surface may be fleshy, lobulated, or show cystic change or hemorrhage; size is variable
Micro

─ Histologic features recapitulate those of CNS ependymomas, with various subtypes recognized:
─ Classic (Cellular) Ependymoma: Moderately cellular proliferation of cells with uniform, round to oval nuclei, finely granular ("salt-and-pepper") chromatin, and indistinct eosinophilic cytoplasm, often forming characteristic perivascular pseudorosettes (tumor cells radially arranged around blood vessels, separated by an anuclear fibrillary zone) and less commonly true ependymal rosettes (tumor cells forming a central lumen)
─ Myxopapillary Ependymoma: Papillary structures with central hyalinized or myxoid fibrovascular cores, lined by cuboidal to columnar epithelioid cells, often with abundant extracellular mucin; typically occurs in sacrococcygeal region in soft tissue
─ Other variants (eg, tanycytic, clear cell) are rare in soft tissue
─ Mitotic activity is variable, generally low in well-differentiated forms; atypia is usually mild to moderate
─ Necrosis may be present, especially in higher-grade lesions (anaplastic ependymoma of soft tissue)
Ancillary studies ─
─ IHC: Tumor cells are characteristically positive for GFAP (glial fibrillary acidic protein - often strong and diffuse), S100 protein (variable), and vimentin; EMA (epithelial membrane antigen) may be positive (often dot-like or outlining rosettes); Cytokeratins are typically negative (or only very focally positive); Negative for desmin, SMA, MyoD1/myogenin, CD34, STAT6, neuroendocrine markers (usually)
─ Molecular: Spinal ependymomas often have NF2 mutations or chromosome 22q loss; supratentorial CNS ependymomas in children frequently have C11orf95::RELA (RELA) fusions or YAP1 fusions; molecular data for soft tissue ependymomas is limited, but some RELA fusions have been reported, particularly in pediatric cases, linking them to supratentorial CNS ependymoma Group A
DDx

─ Metastatic carcinoma (especially adenocarcinoma or neuroendocrine carcinoma) (keratin positive, specific carcinoma/neuroendocrine markers, lacks GFAP usually)
─ Myoepithelioma / Myoepithelial carcinoma (S100/GFAP/keratin/SMA variably positive, EWSR1 fusions common)
─ Synovial sarcoma (TLE1 positive, keratin/EMA often positive, SS18 fusion, GFAP negative)
─ Ossifying fibromyxoid tumor (S100 often positive, PHF1 fusion, lacks GFAP, different morphology)
─ Chordoma (brachyury positive, S100/keratin positive, axial location, lacks GFAP consistently)
─ Other glial tumors in soft tissue (eg, nasal glioma - congenital, different location/context)
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SMARCA4-Deficient Thoracic Sarcoma

An aggressive, undifferentiated malignant neoplasm primarily arising in the thoracic cavity (pleura, mediastinum, lung), characterized by loss of SMARCA4 (BRG1) protein expression, often with rhabdoid or epithelioid cytology, and a strong association with smoking
Clinical ─ Predominantly affects adult males (median age ~50-60s) with a significant smoking history; arises in thoracic locations (pleura, mediastinum, lung parenchyma); highly aggressive with rapid progression, early metastasis, and poor prognosis; presents with symptoms like chest pain, dyspnea, cough, weight loss, or incidental finding on imaging
Macro ─ Large, infiltrative, fleshy, gray-white to tan mass, often with extensive necrosis and hemorrhage; may encase lung or invade chest wall
Micro

─ Sheets, nests, or diffuse infiltrates of poorly differentiated, medium to large polygonal cells with epithelioid, rhabdoid, or plasmacytoid features
─ Cells have vesicular nuclei, prominent nucleoli, and variably abundant eosinophilic or clear cytoplasm; rhabdoid cells show eccentric nuclei and paranuclear eosinophilic inclusions
─ Cytologic atypia is usually marked, pleomorphism can be significant
─ High mitotic activity, including atypical mitoses, and extensive geographic necrosis are characteristic
─ Stroma is often scant or desmoplastic; inflammatory infiltrate may be present
─ Vasoformative areas are absent
Ancillary studies ─
─ IHC: Definitive feature is complete loss of nuclear SMARCA4 (BRG1) protein expression in tumor cells (internal control in benign stromal/inflammatory cells should be positive); SMARCA2 (BRM) expression is usually retained (but can be lost in a small subset); Tumor cells are often positive for vimentin; Cytokeratins (AE1/AE3, CAM5.2) are positive in a subset (~30-50%, often focal or weak); S100 protein, SOX2, and CD34 are frequently positive (each in ~50-70% of cases); Claudin-4 is typically negative (helps distinguish from adenocarcinoma); Negative for TTF1, napsin A, calretinin, WT1, desmin, MyoD1/myogenin, melanocytic markers
─ Molecular: Characterized by biallelic inactivation (mutations, deletions) of the SMARCA4 gene (encoding BRG1, a core subunit of the SWI/SNF chromatin remodeling complex)
DDx

─ Malignant mesothelioma (epithelioid or sarcomatoid) (calretinin/WT1/CK5/6/D2-40 positive, SMARCA4 retained, BAP1 loss common)
─ Poorly differentiated lung carcinoma (especially non-small cell or sarcomatoid) (TTF1/napsin A/p40 may be positive, more diffuse/strong keratins, SMARCA4 retained)
─ Other undifferentiated sarcomas (eg, UPS, synovial sarcoma - specific IHC/molecular profiles, SMARCA4 retained)
─ Extrarenal rhabdoid tumor (SMARCB1/INI1 loss, younger age group usually, different typical locations)
─ Melanoma (S100/SOX10/melanocytic markers positive, SMARCA4 retained)
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Biphenotypic Sinonasal Sarcoma

A rare, low-grade spindle cell sarcoma arising in the sinonasal tract, characterized by dual neural (S100 protein) and myogenic (smooth muscle actin) differentiation, and recurrent PAX3 gene fusions (typically with MAML3)
Clinical ─ Affects a wide age range, including children and adults (median age ~40-50s), slight female predominance; exclusively arises in the sinonasal tract (nasal cavity, paranasal sinuses, nasopharynx); presents with symptoms of nasal obstruction, epistaxis, pain, or swelling; generally indolent behavior with a high rate of local recurrence but low metastatic potential
Macro ─ Polypoid, fleshy, or firm, unencapsulated mass filling sinonasal cavities; cut surface is gray-white to tan
Micro

─ Cellular proliferation of relatively uniform, bland spindle cells arranged in long, intersecting fascicles, often with a herringbone or storiform pattern
─ Cells have elongated, tapering nuclei with fine chromatin and inconspicuous nucleoli, and scant eosinophilic cytoplasm
─ Stroma is variably collagenous, sometimes with myxoid areas
─ Mitotic activity is typically low (usually <5/10 HPF), cytologic atypia is minimal
─ Necrosis is usually absent
─ Infiltrative growth into adjacent tissues is common
─ Hemangiopericytoma-like (staghorn) vascular pattern may be prominent
Ancillary studies ─
─ IHC: Tumor cells characteristically show co-expression of:
─ Neural markers: S100 protein (diffuse, strong nuclear and cytoplasmic) and SOX10 (nuclear)
─ Myogenic markers: SMA (smooth muscle actin - diffuse, strong cytoplasmic) and often MSA (muscle-specific actin)
─ Desmin and calponin are typically negative or only focally positive (distinguishes from leiomyosarcoma)
─ Negative for keratins, EMA, CD34 (except vessels), STAT6, TLE1, MyoD1/myogenin, HMB45
─ Molecular: Defined by recurrent gene fusions involving PAX3 (paired box 3 gene), most commonly with MAML3 (mastermind like transcriptional coactivator 3), resulting in PAX3::MAML3 fusion; other PAX3 partners (eg, NCOA1, FOXO1) are rare
DDx

─ Monophasic synovial sarcoma (TLE1 positive, keratin/EMA often focally positive, SS18 fusion, S100/SMA usually negative or very focal)
─ Malignant peripheral nerve sheath tumor (MPNST) (S100/SOX10 often patchy/lost, lacks diffuse SMA, H3K27me3 loss common, lacks PAX3 fusion)
─ Leiomyosarcoma (diffusely desmin/h-caldesmon positive, S100/SOX10 negative, lacks PAX3 fusion)
─ Solitary fibrous tumor (STAT6 positive, CD34 positive, lacks S100/SMA, lacks PAX3 fusion)
─ Fibrosarcoma (diagnosis of exclusion, lacks S100/SMA and PAX3 fusion)
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Melanotic Neuroectodermal Tumor of Infancy

A rare, typically benign but locally aggressive pigmented neoplasm of neural crest origin, occurring almost exclusively in infants (usually <1 year), characterized by a biphasic population of small neuroblast-like cells and larger melanin-producing epithelioid cells
Clinical ─ Primarily affects infants (most cases <6 months, often congenital); M=F; most common site is the maxilla (anterior portion), followed by skull, mandible, brain, epididymis, and rarely other soft tissue sites; presents as a rapidly enlarging, firm, non-tender mass, often bluish-black or pigmented; may cause displacement of teeth or facial asymmetry; serum and urine levels of vanillylmandelic acid (VMA) and homovanillic acid (HVA) are usually normal (unlike neuroblastoma)
Macro ─ Well-circumscribed or infiltrative, firm mass; cut surface is often variegated, with gray-white to tan areas and prominent black or dark brown pigmentation (melanin)
Micro

─ Biphasic tumor composed of two distinct cell types arranged in nests, tubules, or alveolar structures, embedded in a dense fibrous stroma:
─ Small neuroblast-like cells: Primitive, small round blue cells with scant cytoplasm, hyperchromatic nuclei, and inconspicuous nucleoli; these cells are typically S100/SOX10 negative but may express neuroendocrine markers like synaptophysin
─ Large epithelioid cells: Polygonal cells with abundant eosinophilic or clear cytoplasm containing coarse brown melanin pigment (Fontana-Masson positive); nuclei are vesicular with prominent nucleoli; these cells line alevolar spaces or are admixed with small cells, and are positive for HMB45, Melan-A, and often keratins and S100 protein
─ Stroma is densely collagenous and may contain inflammatory cells
─ Mitotic activity can be variable, but is generally not very high in most cases; necrosis is rare
─ Infiltrative growth into surrounding bone and soft tissue is common
Ancillary studies ─
─ IHC: Small neuroblast-like cells: Positive for synaptophysin, NSE, CD56 (NCAM); Variable PGP9.5; Negative for S100, melanocytic markers, keratins
─ IHC: Large melanin-producing epithelioid cells: Positive for HMB45, Melan-A/MART-1, MITF (melanocytic markers); Often positive for keratins (AE1/AE3, CAM5.2), EMA, and S100 protein; Vimentin positive
─ Molecular: Some cases show chromosomal gains (eg, chromosome 7, 8); specific recurrent translocations are not well established, though BRAF V600E mutations have been reported in a subset, and rare CRTC1::TRIM11 or EWSR1 fusions have been described
DDx

─ Neuroblastoma (lacks melanin-producing epithelioid cells, Homer-Wright rosettes common, MYCN amplification in aggressive cases, different IHC profile for large cells)
─ Rhabdomyosarcoma (embryonal) (myogenic markers MyoD1/myogenin positive, lacks biphasic pattern with melanin)
─ Ewing sarcoma (CD99/NKX2.2 positive, EWSR1-ETS fusion, lacks biphasic pattern with melanin)
─ Melanoma (malignant) (extremely rare in infants, lacks biphasic pattern, typically diffuse S100/SOX10 in all tumor cells)
─ Pigmented odontogenic tumors (if maxillary/mandibular; specific odontogenic features and IHC)
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Gastrointestinal Stromal Tumor (GIST)

A mesenchymal neoplasm arising from or differentiating towards interstitial cells of Cajal (ICCs) or their precursors, most commonly occurring in the gastrointestinal tract, characterized by activating mutations in KIT or PDGFRA receptor tyrosine kinase genes; extragastrointestinal stromal tumors (EGISTs) are histologically and molecularly identical tumors arising outside the GI tract (eg, omentum, mesentery, retroperitoneum, rarely other soft tissues)
Clinical ─ Typically affects adults (peak age 50-70s), rare in children (pediatric GISTs often KIT/PDGFRA wild-type and associated with syndromes like Carney triad or Carney-Stratakis syndrome, or SDH deficiency); most common in stomach (~60%) and small intestine (~30%), less often colorectum, esophagus; EGISTs account for <5-10% of all GISTs; presentation varies by site and size, from incidental finding to abdominal pain, mass, bleeding, or obstruction; risk of aggressive behavior (metastasis, primarily to liver and peritoneum) is stratified based on tumor size, mitotic rate, site (gastric better, small bowel worse), and presence of rupture
Macro ─ Well-circumscribed or infiltrative mass, often arising from muscularis propria of GI wall or as a serosal/mesenteric mass for EGISTs; cut surface is typically fleshy, tan-white to pink, may show hemorrhage, necrosis, or cystic change, especially in larger/higher-risk tumors; size is highly variable
Micro

─ Highly variable histology, main patterns:
─ Spindle cell type (most common, ~70%): Relatively uniform spindle cells with pale eosinophilic or fibrillar cytoplasm and ovoid to elongated nuclei, arranged in fascicles, whorls, or a storiform pattern; perinuclear vacuoles may be present; stroma can be collagenous or myxoid
─ Epithelioid type (~20%): Sheets, nests, or cords of polygonal epithelioid cells with abundant eosinophilic or clear cytoplasm and round, centrally or eccentrically placed nuclei; may show plasmacytoid or rhabdoid features
─ Mixed spindle and epithelioid type (~10%)
─ Cytologic atypia is variable, from bland to moderately pleomorphic
─ Mitotic activity is a key prognostic factor (counted per 5 mm² or 50 HPF, depending on criteria)
─ Other features: Skeinoid fibers (eosinophilic, collagenous aggregates), paranuclear vacuoles, stromal hyalinization, hemorrhage, necrosis (especially in higher-risk tumors)
Ancillary studies ─
─ IHC: Tumor cells are characteristically positive for KIT (CD117) (membranous, cytoplasmic, or Golgi-like staining, ~95% of cases) and DOG1 (Discovered on GIST 1, anoctamin 1 - membranous/cytoplasmic, also ~95%, can be positive in some KIT-negative GISTs); CD34 is positive in ~60-70% (more common in gastric GISTs); SMA is positive in ~30-40%; S100 protein is positive in ~5%; Desmin and keratins are typically negative
─ IHC (for specific subtypes): SDHB loss by IHC indicates SDH-deficient GIST (often KIT/PDGFRA wild-type, pediatric/young adult, gastric, indolent or metastatic)
─ Molecular: Activating mutations in KIT gene (most common, esp exon 11, also exon 9, 13, 17) or PDGFRA gene (platelet-derived growth factor receptor alpha - esp exon 18 D842V, also exon 12, 14) are found in ~85-90% of GISTs and are targets for tyrosine kinase inhibitor (TKI) therapy (eg, imatinib, sunitinib); KIT/PDGFRA wild-type GISTs (~10-15%) may have other alterations (eg, SDH complex mutations, BRAF V600E mutation, NF1 inactivation, NTRK fusions)
DDx (for EGIST in soft tissue) ─

─ Leiomyoma / Leiomyosarcoma (desmin/h-caldesmon positive, KIT/DOG1 negative)
─ Solitary fibrous tumor (STAT6 positive, CD34 positive, KIT/DOG1 negative)
─ Schwannoma / MPNST (S100/SOX10 positive, KIT/DOG1 negative)
─ Fibromatosis (desmoid-type) (nuclear beta-catenin positive, KIT/DOG1 negative)
─ Undifferentiated sarcoma (diagnosis of exclusion, lacks specific markers)
─ Melanoma (S100/SOX10/melanocytic markers positive, can be KIT positive but different mutations)
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Epithelioid Gastrointestinal Stromal Tumor

A subtype of Gastrointestinal Stromal Tumor (GIST) characterized by a predominant proliferation of epithelioid cells, often with clear or eosinophilic cytoplasm, round nuclei, and prominent nucleoli; accounts for ~20-30% of GISTs
Clinical ─ Similar to spindle cell GIST, typically adults (peak 50-70s); most common in stomach, but can occur throughout GI tract and as extragastrointestinal stromal tumors (EGISTs); presentation and risk stratification (size, mitotic rate, site) are similar to GISTs overall
Macro ─ Well-circumscribed or infiltrative mass; cut surface is typically fleshy, tan-white to pink, may show hemorrhage, necrosis, or cystic change
Micro

─ Predominantly composed of sheets, nests, cords, or diffuse infiltrates of polygonal epithelioid cells
─ Cells have abundant eosinophilic, amphophilic, or clear cytoplasm and distinct cell borders
─ Nuclei are typically round to oval, centrally or eccentrically located, with vesicular chromatin and often prominent, centrally located nucleoli
─ Plasmacytoid, rhabdoid, or signet ring-like features may be present
─ A minor spindle cell component may be admixed
─ Cytologic atypia is variable; mitotic activity is a key prognostic factor
─ Stroma can be scant, hyalinized, or myxoid
Ancillary studies ─
─ IHC: Positive for KIT (CD117) (~95%) and DOG1 (~95%); CD34 is positive in a lower percentage of epithelioid GISTs compared to spindle cell GISTs (especially in small bowel); SMA may be focally positive; S100 protein is positive in ~5%; Desmin and keratins are typically negative
─ IHC (for specific subtypes): SDHB loss in SDH-deficient GISTs (often epithelioid, gastric, pediatric/young adult)
─ Molecular: Activating mutations in KIT or PDGFRA are common; PDGFRA mutations (especially D842V in exon 18) are more frequent in epithelioid GISTs (particularly gastric) than in spindle cell GISTs; SDH complex mutations in SDH-deficient GISTs; NTRK fusions rare
DDx

─ Carcinoma (especially poorly differentiated or signet ring cell) (keratin positive, specific carcinoma markers, KIT/DOG1 negative)
─ Melanoma (S100/SOX10/melanocytic markers positive, can be KIT positive but different mutations/context)
─ PEComa (co-expresses melanocytic and smooth muscle markers, often HMB45/Melan-A positive)
─ Leiomyosarcoma (epithelioid variant) (desmin/h-caldesmon positive, KIT/DOG1 negative)
─ Clear cell sarcoma of soft tissue (if EGIST; EWSR1::ATF1/CREB1 fusion, S100/SOX10/melanocytic markers positive)
─ Alveolar soft part sarcoma (ASPSCR1::TFE3 fusion, TFE3 IHC positive, characteristic crystals)
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Gastrointestinal Stromal Tumor, Mixed Type

A subtype of Gastrointestinal Stromal Tumor (GIST) that displays a significant admixture of both spindle cell and epithelioid cell components within the same tumor
Clinical ─ Similar to GISTs overall, typically adults; can occur throughout GI tract and as EGISTs; presentation and risk stratification follow general GIST principles (size, mitotic rate, site)
Macro ─ Similar to other GISTs: well-circumscribed or infiltrative mass, fleshy, tan-white, may have hemorrhage/necrosis/cystic change
Micro

─ Characterized by the presence of distinct areas of both spindle cell GIST morphology and epithelioid cell GIST morphology, or an intimate intermingling of the two cell types
─ Spindle cell component: Fascicles of cells with elongated nuclei and fibrillar cytoplasm
─ Epithelioid component: Sheets or nests of polygonal cells with eosinophilic or clear cytoplasm and round nuclei
─ The proportion of each component can vary widely
─ Cytologic atypia and mitotic activity are assessed overall and are key for risk stratification
Ancillary studies ─
─ IHC: Both components are typically positive for KIT (CD117) and DOG1; CD34 expression may be variable, often more prominent in spindle cell areas; Other markers (SMA, S100) similar to their pure counterparts
─ Molecular: Activating mutations in KIT or PDGFRA are present, similar to other GISTs; the specific mutation may influence the predominant morphology or arise from a common precursor
DDx

─ Carcinosarcoma / Sarcomatoid carcinoma (if arising in GI tract; malignant epithelial component keratin positive, distinct from GIST immunoprofile)
─ Other biphasic tumors (eg, synovial sarcoma if EGIST - SS18 fusion, TLE1/keratin positive)
─ GIST with degenerative atypia or reactive changes (may mimic a mixed pattern if cellularity varies)
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Gastrointestinal Clear Cell Sarcoma-like Tumor (GNET)

A rare malignant mesenchymal neoplasm primarily arising in the wall of the small intestine or stomach, characterized by nests of epithelioid to oval cells with clear or pale eosinophilic cytoplasm, S100 protein positivity, and a lack of KIT/PDGFRA mutations; also known as clear cell sarcoma-like tumor of the GI tract (CCSLGT)
Clinical ─ Affects adults (wide age range, median ~40-50s), slight female predominance; most common in small intestine (jejunum, ileum), also stomach, rarely colon; presents with abdominal pain, mass, bleeding, or obstruction; aggressive behavior with frequent local recurrence and metastasis (liver, peritoneum, lymph nodes)
Macro ─ Typically a well-circumscribed or infiltrative mural mass, often ulcerated; cut surface is firm, gray-white to tan
Micro

─ Nests, sheets, or fascicles of relatively uniform, medium to large polygonal, epithelioid, or oval cells with distinct cell borders
─ Cytoplasm is characteristically clear, pale eosinophilic, or finely granular
─ Nuclei are round to oval, vesicular, with prominent, centrally located, eosinophilic or amphophilic nucleoli (similar to clear cell sarcoma of soft tissue)
─ Stroma is typically scant and fibrous, may contain a sparse lymphocytic infiltrate
─ Osteoclast-like multinucleated giant cells may be present
─ Mitotic activity is variable but often low; necrosis can occur
─ Lymphovascular invasion is common
Ancillary studies ─
─ IHC: Tumor cells are characteristically positive for S100 protein (strong, diffuse) and SOX10 (nuclear); Vimentin positive; Negative for KIT (CD117), DOG1, CD34, SMA, desmin, HMB45, Melan-A, keratins
─ Molecular: Defined by EWSR1 gene rearrangements, most commonly EWSR1::CREB1 fusion (t(2;22)(q33;q12)); less frequently EWSR1::ATF1 fusion (t(12;22)(q13;q12)) - these are the same fusions seen in clear cell sarcoma of soft tissue
DDx

─ Clear cell sarcoma of soft tissue (metastatic to GI tract or arising primarily as EGIST - histologically and molecularly identical, distinction is clinical/site-based)
─ Gastrointestinal stromal tumor (GIST) (KIT/DOG1 positive, S100 usually negative or focal, different molecular - KIT/PDGFRA mutations)
─ Melanoma (metastatic or primary GI) (HMB45/Melan-A positive, S100/SOX10 positive, may have BRAF/NRAS mutations, lacks EWSR1 fusion)
─ PEComa (co-expresses melanocytic and smooth muscle markers, HMB45/Melan-A positive, lacks EWSR1 fusion)
─ Schwannoma (if epithelioid/GI; S100/SOX10 positive but different morphology, lacks EWSR1 fusion, benign)
─ Poorly differentiated carcinoma with clear cells (keratin positive)
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Inflammatory Fibroid Polyp

A benign, localized, reactive mesenchymal proliferation of the gastrointestinal tract, characterized by bland spindle to stellate cells, a prominent inflammatory infiltrate (especially eosinophils), and a distinctive perivascular onion-skin or "targetoid" arrangement of stromal cells around small blood vessels; also known as Vanek's tumor
Clinical ─ Typically affects adults (peak age 50-70s), but can occur at any age; most common in the stomach (antrum) and small intestine (ileum), less frequently colorectum or esophagus; presents as a solitary, sessile or pedunculated polyp, usually <3-4 cm; often an incidental finding during endoscopy, or may cause symptoms like abdominal pain, bleeding, obstruction (if large, acting as lead point for intussusception)
Macro ─ Well-demarcated, firm, polypoid lesion projecting into the lumen; cut surface is gray-white to tan, may appear edematous or hemorrhagic; overlying mucosa may be ulcerated
Micro

─ Submucosal (sometimes extending into mucosa or muscularis propria) proliferation of relatively bland, plump spindle-shaped to stellate mesenchymal cells with pale eosinophilic cytoplasm and ovoid to fusiform vesicular nuclei
─ Cells are arranged loosely or in short fascicles within an edematous, myxoid, or collagenous stroma
─ Characteristic feature: Prominent inflammatory infiltrate, typically rich in eosinophils, but also including lymphocytes, plasma cells, and mast cells
─ Another hallmark: Concentric, "onion-skin," or "targetoid" perivascular cuffing of stromal cells and collagen around small to medium-sized blood vessels
─ Blood vessels are often numerous and may be thick-walled or hyalinized
─ Overlying mucosa is usually intact but may show ulceration or reactive changes
─ No significant cytologic atypia, mitotic activity is very low or absent, necrosis is not a feature
Ancillary studies ─
─ IHC: Spindle cells are positive for vimentin; CD34 is characteristically positive (often strong and diffuse); Cyclin D1 may be positive; Negative for KIT (CD117), DOG1, S100 protein, SMA (except vessels), desmin, keratins, ALK1
─ Molecular: Activating mutations in PDGFRA gene (platelet-derived growth factor receptor alpha - various exons, but distinct from the D842V mutation common in GISTs) are found in the majority of cases and are considered a defining feature
DDx

─ Gastrointestinal stromal tumor (GIST) (KIT/DOG1 positive, lacks prominent eosinophilic infiltrate and characteristic perivascular cuffing, different PDGFRA mutations if present)
─ Inflammatory myofibroblastic tumor (IMT) (ALK positive in a subset, SMA/desmin often positive, lacks consistent CD34 positivity in tumor cells and PDGFRA mutations)
─ Eosinophilic gastroenteritis (diffuse eosinophilic infiltration of bowel wall, lacks distinct polypoid mesenchymal proliferation)
─ Schwannoma (S100 positive, lacks eosinophils and perivascular cuffing)
─ Leiomyoma (smooth muscle markers desmin/h-caldesmon positive, lacks eosinophils)
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Plexiform Fibromyxoma

A rare, benign mesenchymal neoplasm of the stomach, characterized by a distinctive plexiform or multinodular growth pattern of bland spindle cells within a fibromyxoid stroma; also known as plexiform angiomyxoid myofibroblastic tumor (a term reflecting its variable features, though pure myogenic differentiation is often limited)
Clinical ─ Typically affects adults (wide age range, median ~50s); almost exclusively occurs in the stomach (antrum is the most common site); presents with symptoms like abdominal pain, nausea, vomiting, bleeding, or found incidentally during endoscopy or imaging; generally benign behavior, though local recurrence after incomplete excision has been reported
Macro ─ Well-demarcated but unencapsulated, intramural or submucosal mass in the stomach wall; cut surface is typically firm, gray-white, and may show gelatinous or myxoid areas; size varies, often 2-5 cm
Micro

─ Characteristic plexiform, multinodular, or lobulated growth pattern, often with infiltrative finger-like projections into the surrounding muscularis propria or submucosa
─ Composed of relatively uniform, bland spindle cells with scant, pale eosinophilic cytoplasm and ovoid to fusiform nuclei
─ Cells are arranged in short fascicles, whorls, or a vaguely storiform pattern within a variably fibrous and myxoid stroma
─ Myxoid areas can be prominent and hypocellular
─ Blood vessels are often numerous and can be small capillaries or larger, sometimes thick-walled or hyalinized vessels; a hemangiopericytoma-like vascular pattern may be seen focally
─ Minimal to no cytologic atypia, mitotic activity is very low or absent (usually <1/50 HPF)
─ Overlying gastric mucosa is usually intact but may be ulcerated
Ancillary studies ─
─ IHC: Spindle cells are positive for vimentin; SMA (smooth muscle actin) is often positive (variable extent, from focal to diffuse); CD34 may be positive in some cells or highlight vasculature; Desmin is typically negative or only very focally positive; S100 protein is negative; KIT (CD117) and DOG1 are negative (crucial for distinguishing from GIST); Keratins are negative
─ Molecular: Some cases show loss of SDHB expression by IHC, suggesting a link to SDH-deficient GISTs or other SDH-deficient tumors, but this is not a consistent finding and specific mutations are not well-defined for this entity as a whole; distinct from GISTs (no KIT/PDGFRA mutations)
DDx

─ Gastrointestinal stromal tumor (GIST) (KIT/DOG1 positive, different morphology usually, KIT/PDGFRA mutated)
─ Leiomyoma (more distinctly smooth muscle, desmin/h-caldesmon positive)
─ Schwannoma (S100 positive, Antoni A/B areas)
─ Inflammatory fibroid polyp (prominent eosinophilic infiltrate, characteristic perivascular cuffing, CD34 positive, PDGFRA mutated)
─ Fibromatosis (desmoid-type) (more infiltrative, nuclear beta-catenin positive)
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Follicular Dendritic Cell Sarcoma

A rare neoplastic proliferation of spindle to ovoid cells showing differentiation towards follicular dendritic cells, typically arising in lymph nodes but also occurring in extranodal sites including soft tissue, often associated with hyaline-vascular Castleman disease
Clinical ─ Affects adults (wide age range, median ~40-50s); M=F; most common in cervical, axillary, or mediastinal lymph nodes; extranodal sites include tonsil, spleen, liver, GI tract, soft tissue (head/neck, trunk, extremities); presents as a painless, slowly enlarging mass or lymphadenopathy; may be associated with Epstein-Barr virus (EBV) in a subset, particularly inflammatory pseudotumor-like variant
Macro ─ Well-circumscribed or infiltrative, firm, lobulated mass; cut surface is typically gray-white, tan, or yellowish, may show whorled appearance or areas of hemorrhage/necrosis
Micro

─ Variable architectural patterns: storiform, fascicular, whorled, sheet-like, or pseudoangiomatoid (hemangiopericytoma-like)
─ Composed of spindle, ovoid, or epithelioid cells with indistinct cell borders, pale eosinophilic or clear cytoplasm, and oval to irregular nuclei with vesicular chromatin and small to prominent nucleoli
─ Tumor cells often have long, delicate cytoplasmic processes that intermingle
─ Characteristic feature: Sprinkling of small, mature lymphocytes (T and B cells) throughout the tumor, often intimately admixed with tumor cells
─ Multinucleated giant cells may be present
─ Cytologic atypia can range from bland to markedly pleomorphic; mitotic activity is variable (low to high)
─ Hyaline stroma or myxoid change can be seen
─ Inflammatory pseudotumor-like variant: More prominent inflammatory infiltrate (plasma cells, eosinophils), often EBV-positive
Ancillary studies ─
─ IHC: Tumor cells are characteristically positive for follicular dendritic cell markers: CD21, CD23, CD35, and often CNA.42, D2-40 (podoplanin), clusterin; EMA may be positive in some cases; Vimentin positive; Negative for S100 protein (usually), keratins (usually), CD1a, Langerin, lysozyme, CD30, CD45 (except admixed lymphocytes), HMB45, desmin, SMA
─ EBV (EBER in situ hybridization) is positive in a subset, especially the inflammatory pseudotumor-like variant
─ Molecular: No specific recurrent genetic alterations define all FDC sarcomas; some show BRAF V600E mutations or complex karyotypes; NFkB pathway activation is common
DDx

─ Interdigitating dendritic cell sarcoma (S100 positive, CD1a positive, lacks CD21/CD23/CD35)
─ Langerhans cell histiocytosis / sarcoma (CD1a/Langerin positive, S100 positive, characteristic grooved nuclei)
─ Fibroblastic reticular cell sarcoma (cytokeratin positive usually, specific FRC markers if available, lacks FDC markers)
─ Inflammatory myofibroblastic tumor (ALK positive in subset, SMA/desmin often positive, lacks FDC markers)
─ Undifferentiated pleomorphic sarcoma / Spindle cell sarcoma NOS (lacks FDC markers)
─ Thymoma (if mediastinal; keratin positive, CD1a positive thymocytes, lacks FDC markers)
─ Lymphoma (especially diffuse large B-cell or anaplastic large cell) (specific lymphoid markers positive)
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Fibroblastic Reticular Cell Sarcoma

An extremely rare malignant neoplasm derived from fibroblastic reticular cells of lymphoid tissue, typically arising in lymph nodes but can occur in extranodal sites like spleen or soft tissue
Clinical ─ Affects adults (wide age range); presents as lymphadenopathy or a mass in extranodal sites; aggressive clinical course with potential for recurrence and metastasis
Macro ─ Enlarged lymph node or fleshy mass; gray-white, firm cut surface
Micro

─ Diffuse or vaguely nodular proliferation of plump spindle to epithelioid cells with abundant eosinophilic cytoplasm and vesicular nuclei, often with prominent nucleoli
─ Cells may be arranged in sheets, fascicles, or a storiform pattern
─ Stroma is often delicate, with a rich network of reticulin fibers encasing individual cells or small groups (highlighted by reticulin stain)
─ Admixed small lymphocytes and plasma cells are typically present
─ Cytologic atypia can be significant, mitotic activity is often brisk, necrosis may be present
Ancillary studies ─
─ IHC: Tumor cells are positive for vimentin; Cytokeratins (AE1/AE3, CAM5.2) are often positive (a key feature, can be focal or diffuse); Smooth muscle actin (SMA) may be positive; Desmin is typically negative; Negative for follicular dendritic cell markers (CD21, CD23, CD35), Langerhans cell markers (CD1a, Langerin), S100 protein (usually), HMB45, CD30, CD45 (except admixed lymphocytes); Specific fibroblastic reticular cell markers (eg, CXCL12, CXCL13, CCL19, CCL21) may be expressed but are not widely available or standardized for diagnostic use
─ Molecular: No specific recurrent genetic alterations are well established
DDx

─ Follicular dendritic cell sarcoma (CD21/CD23/CD35 positive, keratins usually negative)
─ Interdigitating dendritic cell sarcoma (S100/CD1a positive, keratins usually negative)
─ Sarcomatoid carcinoma (metastatic or primary) (more overt epithelial morphology, other carcinoma markers, clinical history)
─ Undifferentiated pleomorphic sarcoma / Spindle cell sarcoma NOS (keratins negative usually)
─ Inflammatory myofibroblastic tumor (ALK positive in subset, often SMA positive but lacks consistent keratin expression)
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Interdigitating Dendritic Cell Sarcoma

A rare malignant neoplasm derived from interdigitating dendritic cells, which are antigen-presenting cells normally found in T-cell zones of lymphoid tissue; typically arises in lymph nodes, but extranodal involvement (skin, soft tissue, spleen, lung) can occur
Clinical ─ Primarily affects adults (median age ~50s), slight male predominance; presents as lymphadenopathy (often cervical, axillary, or inguinal) or an extranodal mass; systemic symptoms like fever and weight loss may occur; aggressive clinical course with frequent recurrences and metastases (lymph nodes, lung, liver, bone)
Macro ─ Enlarged lymph node(s) or fleshy, gray-white to tan extranodal mass; may show hemorrhage or necrosis
Micro

─ Diffuse or sheet-like proliferation of large, atypical spindle to ovoid or epithelioid cells with abundant, pale eosinophilic or clear cytoplasm and indistinct cell borders
─ Nuclei are often large, irregular, vesicular, with prominent nucleoli; nuclear grooves or folds may be present
─ Tumor cells are typically admixed with a significant number of small, mature lymphocytes (especially T-cells) and sometimes eosinophils or plasma cells
─ Cytologic atypia is usually moderate to marked; mitotic activity is variable but often easily found, atypical mitoses can be seen
─ Necrosis may be present
─ A vague storiform or fascicular pattern may be seen focally
Ancillary studies ─
─ IHC: Tumor cells are characteristically positive for S100 protein (often strong and diffuse) and vimentin; CD1a is variably positive (often weaker or patchier than in Langerhans cell histiocytosis); Langerin (CD207) is typically negative (distinguishes from Langerhans cell histiocytosis); CD68 and lysozyme may be positive; Fascin may be positive; Negative for follicular dendritic cell markers (CD21, CD23, CD35), keratins, HMB45, Melan-A, CD30, CD45 (except admixed lymphocytes), desmin, SMA
─ Molecular: No specific recurrent genetic alterations are consistently identified; BRAF V600E mutations have been reported in a subset of cases
DDx

─ Langerhans cell histiocytosis / sarcoma (Langerin positive, characteristic grooved "coffee-bean" nuclei, Birbeck granules on EM)
─ Follicular dendritic cell sarcoma (CD21/CD23/CD35 positive, S100 usually negative)
─ Melanoma (HMB45/Melan-A positive, SOX10 positive)
─ Histiocytic sarcoma (CD163 positive, often lysozyme/CD68 positive, S100 negative, CD1a negative)
─ Anaplastic large cell lymphoma (CD30 positive, ALK positive in subset, lymphoid markers positive)
─ Undifferentiated pleomorphic sarcoma / Spindle cell sarcoma NOS (S100 negative, CD1a negative)
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Langerhans Cell Histiocytosis and Langerhans Cell Sarcoma

Langerhans Cell Histiocytosis (LCH) is a clonal neoplastic proliferation of Langerhans cells, which are specialized dendritic cells; it encompasses a spectrum of disorders from solitary or limited lesions (eg, eosinophilic granuloma of bone, cutaneous LCH) to multisystem disease (eg, Letterer-Siwe disease, Hand-Schüller-Christian disease); Langerhans Cell Sarcoma (LCS) is the rare, overtly malignant counterpart of LCH, showing frank cytologic atypia and aggressive behavior
Clinical (LCH) ─ Can occur at any age, but most common in children (peak 1-4 years); M>F slightly; sites of involvement include bone (most common, especially skull, femur, ribs - lytic lesions), skin (seborrheic dermatitis-like rash, papules, nodules, ulcers), lymph nodes, lung, liver, spleen, pituitary (diabetes insipidus); presentation varies by extent and site (eg, bone pain, rash, organ dysfunction, systemic symptoms)
Clinical (LCS) ─ Extremely rare, affects adults primarily; arises de novo or from pre-existing LCH; involves lymph nodes, skin, bone, lung, liver, spleen; highly aggressive with poor prognosis
Macro ─ LCH: Lesions vary from small papules to larger masses; bone lesions are lytic; cut surface often yellowish-tan or hemorrhagic; LCS: Fleshy, infiltrative masses, often with necrosis
Micro (LCH) ─

─ Proliferation of Langerhans cells, which are relatively large, ovoid to irregular cells with abundant eosinophilic or pale cytoplasm, indistinct cell borders, and characteristic longitudinally grooved or indented ("coffee-bean" or convoluted) nuclei with fine chromatin and small nucleoli
─ Langerhans cells are admixed with a variable number of eosinophils (often numerous), lymphocytes, plasma cells, neutrophils, and foamy histiocytes; multinucleated giant cells may be present
─ Architectural patterns vary (diffuse sheets, loose aggregates, granuloma-like clusters)
─ Mitotic activity is usually low, cytologic atypia is minimal in typical LCH
Micro (LCS) ─

─ Sheets of overtly malignant Langerhans cells showing significant cytologic atypia (pleomorphism, hyperchromasia, irregular nuclei, prominent nucleoli), often with high mitotic activity (including atypical forms) and necrosis
─ Eosinophilic infiltrate may be less prominent or absent compared to LCH
─ Infiltrative growth is characteristic
Ancillary studies (LCH & LCS) ─
─ IHC: Langerhans cells are characteristically positive for CD1a (strong membranous), Langerin (CD207 - cytoplasmic/Golgi), and S100 protein (nuclear and cytoplasmic); Vimentin positive; CD68 may be positive; Negative for CD21/CD23/CD35, lysozyme (usually), keratins, melanocytic markers
─ Ultrastructure (EM): Birbeck granules (tennis racket-shaped intracytoplasmic organelles) are pathognomonic for Langerhans cells but EM is rarely needed for diagnosis
─ Molecular: Activating mutations in BRAF (most commonly V600E) or other MAPK pathway genes (eg, MAP2K1) are found in a majority of LCH cases and also in LCS
DDx (LCH) ─

─ Non-Langerhans cell histiocytoses (eg, Juvenile xanthogranuloma, Rosai-Dorfman disease - different morphology and IHC: CD1a/Langerin negative)
─ Inflammatory conditions with eosinophils (eg, eosinophilic granuloma of skin/GI tract - lacks neoplastic Langerhans cells)
─ Hodgkin lymphoma (Reed-Sternberg cells CD30/CD15 positive, CD1a/Langerin negative)
DDx (LCS) ─

─ Interdigitating dendritic cell sarcoma (S100/CD1a positive but Langerin negative)
─ Melanoma (S100/SOX10/melanocytic markers positive, CD1a/Langerin negative)
─ Anaplastic large cell lymphoma (CD30/ALK positive, lymphoid markers, CD1a/Langerin negative)
─ Poorly differentiated carcinoma (keratin positive)
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Indeterminate Cell Histiocytosis

A rare dendritic cell proliferation composed of cells that share some immunophenotypic features with Langerhans cells (S100 protein, CD1a positive) but lack Birbeck granules by electron microscopy and are negative for Langerin (CD207) by immunohistochemistry; considered a distinct entity from Langerhans cell histiocytosis
Clinical ─ Affects adults primarily, but can occur in children; typically presents as solitary or multiple, yellowish-brown, reddish-brown, or skin-colored papules, plaques, or nodules on the skin; common sites include trunk, extremities, head/neck; generally follows a benign, indolent clinical course, may regress spontaneously or persist; systemic involvement is rare
Macro ─ Small (usually <1-2 cm), firm papules, nodules, or plaques on the skin
Micro

─ Dermal infiltrate of relatively uniform, medium to large histiocytoid cells with abundant eosinophilic or pale cytoplasm and oval to indented or slightly irregular nuclei, similar to Langerhans cells but often lacking prominent nuclear grooves
─ Cells are arranged in sheets, nests, or a diffuse interstitial pattern within the dermis, sometimes extending into superficial subcutis
─ Admixed inflammatory cells (lymphocytes, eosinophils, plasma cells) are usually present but typically less prominent than in Langerhans cell histiocytosis
─ Epidermotropism may be seen but is not a constant feature
─ Cytologic atypia is minimal, mitotic activity is low
─ Birbeck granules are absent by electron microscopy (historically a defining feature, now Langerin IHC is used)
Ancillary studies ─
─ IHC: Tumor cells (indeterminate cells) are characteristically positive for S100 protein and CD1a; Crucially, they are negative for Langerin (CD207); CD68 may be positive; Negative for CD21/CD23/CD35, lysozyme, keratins, melanocytic markers
─ Molecular: Pathogenesis is unclear; some cases have shown BRAF V600E mutations or other MAPK pathway alterations, similar to LCH, suggesting a possible relationship despite immunophenotypic differences
DDx

─ Langerhans cell histiocytosis (LCH) (Langerin positive, often more prominent eosinophils and characteristic grooved nuclei)
─ Non-Langerhans cell histiocytoses (eg, Juvenile xanthogranuloma, Rosai-Dorfman disease - CD1a negative, S100 often negative or different pattern)
─ Interdigitating dendritic cell sarcoma (S100/CD1a positive but Langerin negative, typically nodal/more aggressive, more atypia)
─ Spitz nevus / Melanoma (melanocytic markers positive, S100/SOX10 positive but CD1a usually negative)
─ Cutaneous lymphoma (lymphoid markers positive)
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Extranodal Rosai-Dorfman Disease

A rare, benign histiocytic proliferative disorder characterized by an accumulation of distinctive histiocytes exhibiting emperipolesis, occurring outside of lymph nodes; also known as Sinus Histiocytosis with Massive Lymphadenopathy (SHML) when nodal, but extranodal RDD is the focus here for soft tissue context
Clinical ─ Can affect a wide age range, including children and adults; M=F; common extranodal sites include skin and soft tissue (most frequent), bone, central nervous system, orbit, upper respiratory tract, genitourinary tract, and rarely other organs; presents as solitary or multiple painless masses, plaques, or nodules; systemic symptoms (fever, weight loss) are less common than in nodal RDD; may be associated with autoimmune or immunodeficiency disorders in some cases
Macro ─ Firm, well-demarcated or infiltrative nodules or masses; cut surface is typically yellowish-white, tan, or gray, may be fibrous
Micro

─ Diffuse or nodular infiltrate composed of characteristic large histiocytes (Rosai-Dorfman cells or R-D cells) within a fibrous or inflamed stroma
─ R-D cells: Large polygonal cells with abundant, pale eosinophilic or foamy cytoplasm, round to oval vesicular nuclei, and small, distinct nucleoli
─ Pathognomonic feature: Emperipolesis - presence of intact, viable inflammatory cells (lymphocytes, plasma cells, neutrophils, red blood cells) within the cytoplasm of R-D cells, residing in membrane-bound vacuoles
─ Background inflammatory infiltrate is common, consisting of lymphocytes, plasma cells (often polyclonal), neutrophils, and eosinophils
─ Stroma is variably fibrotic, may show areas of sclerosis or myxoid change
─ Vascular proliferation can be prominent
─ No significant cytologic atypia in R-D cells, mitotic activity is generally low
Ancillary studies ─
─ IHC: R-D cells are characteristically positive for S100 protein (strong nuclear and cytoplasmic) and CD68 (cytoplasmic); CD163 is also usually positive; Fascin may be positive; Negative for CD1a and Langerin (distinguishes from Langerhans cell histiocytosis); Negative for CD21/CD23/CD35 (FDC markers), lysozyme (usually), keratins, melanocytic markers
─ Molecular: Activating mutations in MAPK pathway genes (eg, KRAS, NRAS, MAP2K1, ARAF) have been identified in a significant proportion of both nodal and extranodal RDD cases, suggesting a neoplastic basis for many
DDx

─ Langerhans cell histiocytosis (CD1a/Langerin positive, characteristic grooved nuclei, lacks emperipolesis of intact cells by R-D cells)
─ Histiocytic sarcoma (overtly malignant cytologic features, more aggressive, S100 usually negative)
─ Interdigitating dendritic cell sarcoma (S100/CD1a positive, Langerin negative, more atypia, lacks emperipolesis by R-D cells)
─ Melanoma (S100/SOX10/melanocytic markers positive, lacks emperipolesis)
─ Xanthogranuloma / Other non-Langerhans cell histiocytoses (different morphology and IHC, eg, Factor XIIIa positive in some, S100 negative usually)
─ Lymphoma (especially Hodgkin or diffuse large B-cell) (specific lymphoid markers positive, Reed-Sternberg cells different)
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Histiocytic Sarcoma

A rare, aggressive malignant neoplasm showing morphologic and immunophenotypic evidence of histiocytic differentiation (macrophage/dendritic cell lineage), excluding tumors of Langerhans cells, follicular dendritic cells, or interdigitating dendritic cells
Clinical ─ Affects adults primarily (median age ~50s), rare in children; M>F slightly; can arise in lymph nodes (nodal) or extranodal sites, including skin, soft tissue (extremities, trunk, head/neck), GI tract, spleen, bone marrow; presents as a rapidly enlarging mass, often with systemic symptoms (fever, weight loss, cytopenias); aggressive clinical course with frequent recurrences and metastases (lymph nodes, lung, liver, bone, skin)
Macro ─ Fleshy, infiltrative mass, often large; cut surface is typically gray-white, tan, or hemorrhagic, with common necrosis
Micro

─ Diffuse or sheet-like proliferation of large, pleomorphic, atypical histiocytoid cells with abundant eosinophilic or clear cytoplasm and indistinct cell borders
─ Nuclei are large, irregular, vesicular or hyperchromatic, often with prominent, sometimes bizarre nucleoli; multinucleated tumor giant cells are common
─ Cytologic atypia is marked; mitotic activity is usually brisk, including atypical mitoses
─ Necrosis is frequently extensive
─ Phagocytosis of other cells (erythrocytes, inflammatory cells, tumor cells) by neoplastic histiocytes may be seen but is not specific
─ Background inflammatory infiltrate (lymphocytes, plasma cells, neutrophils, eosinophils) can be variable
─ Must exclude other poorly differentiated neoplasms with histiocyte-like features
Ancillary studies ─
─ IHC: Tumor cells are positive for histiocytic markers: CD68 (PGM1, KP1 - cytoplasmic), CD163 (more specific for macrophage lineage), and lysozyme; CD45 (LCA) may be positive (often weak or variable); CD4 may be expressed; Vimentin positive; Negative for Langerhans cell markers (CD1a, Langerin), follicular dendritic cell markers (CD21, CD23, CD35), myeloid markers (MPO, CD33 - unless arising from monocytic leukemia), keratins, S100 protein (usually, though focal S100 can occur and cause confusion), melanocytic markers, desmin, SMA
─ Molecular: Complex karyotypes are common; BRAF V600E mutations or other MAPK pathway alterations (eg, ALK fusions, ROS1 fusions, NTRK fusions) have been identified in a subset of cases, particularly those arising in association with or from pre-existing LCH, ECD, or other histiocytoses, or de novo; these may have therapeutic implications
DDx

─ Langerhans cell sarcoma / Interdigitating dendritic cell sarcoma / Follicular dendritic cell sarcoma (specific IHC markers for these dendritic cell lineages)
─ Anaplastic large cell lymphoma (CD30 positive, ALK positive in subset, lymphoid markers)
─ Melanoma (S100/SOX10/melanocytic markers positive)
─ Poorly differentiated carcinoma (keratin positive)
─ Undifferentiated pleomorphic sarcoma (lacks convincing histiocytic marker expression)
─ Hemophagocytic lymphohistiocytosis (HLH) (reactive proliferation of benign histiocytes with hemophagocytosis, different clinical context)
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Mass-Forming Idiopathic Fibroinflammatory Disorders (Conceptual Category)

A heterogeneous group of chronic inflammatory and fibrosing conditions of unknown etiology that can form tumor-like masses in various anatomic locations, potentially mimicking neoplasms; these are generally considered reactive or immune-mediated processes rather than true neoplasms, although some may have clonal elements or an association with IgG4-related disease
Clinical ─ Affects adults primarily; sites are diverse, including retroperitoneum (idiopathic retroperitoneal fibrosis), mesentery (sclerosing mesenteritis), orbit (orbital inflammatory pseudotumor/idiopathic orbital inflammation), thyroid (Riedel thyroiditis), mediastinum, lung, salivary glands, pancreas, biliary tract, and other soft tissues; presentation depends on site and extent, often insidious onset with pain, mass effect, organ dysfunction, or systemic symptoms (fever, weight loss)
Macro ─ Ill-defined, indurated, fibrotic masses or plaque-like thickenings; typically gray-white and firm, may encase or infiltrate adjacent structures (vessels, nerves, ureters)
Micro

─ Common features include:
─ Dense fibroblastic or myofibroblastic proliferation with abundant collagen deposition (sclerosis)
─ Mixed chronic inflammatory infiltrate, often prominent, composed of lymphocytes, plasma cells (may be polyclonal or show light chain restriction in some IgG4-RD contexts), eosinophils, histiocytes, and sometimes neutrophils or lymphoid follicles
─ Vascular changes, such as obliterative phlebitis (inflammation and fibrosis of vein walls leading to luminal narrowing/occlusion), may be present, especially in IgG4-related disease
─ Specific histologic patterns vary by entity (eg, storiform fibrosis and prominent eosinophils in some IgG4-RD, fat necrosis and lipogranulomas in sclerosing mesenteritis)
─ Cytologic atypia in fibroblastic/myofibroblastic cells is typically minimal or absent; mitotic activity is low
─ Important to exclude specific infectious, autoimmune, or neoplastic conditions that can mimic these fibroinflammatory processes
Ancillary studies ─
─ IHC: Spindle cells are vimentin positive, may show SMA; Inflammatory cells show expected markers; IgG4 immunostaining is crucial if IgG4-related disease is suspected (increased IgG4+ plasma cells and IgG4/IgG ratio >40%)
─ Molecular: Generally non-neoplastic, but some entities within this spectrum (eg, some cases of sclerosing mesenteritis) have shown clonal alterations or mutations (eg, CTNNB1, BRAF) suggesting a possible link to low-grade fibromatosis-like neoplasia in a subset
DDx

─ Desmoid-type fibromatosis (more uniform spindle cells, nuclear beta-catenin positive, less inflammation usually)
─ Inflammatory myofibroblastic tumor (IMT) (ALK positive in a subset, more organized spindle cells, often distinct inflammatory pattern)
─ Low-grade sarcomas (eg, fibrosarcoma, myofibroblastic sarcoma - more atypia, infiltrative sarcomatous growth)
─ Lymphoma (especially Hodgkin or some NHLs with sclerosis - specific lymphoid markers)
─ Metastatic carcinoma with desmoplasia (keratin positive)
─ Specific infectious processes (eg, tuberculosis, fungal infections - special stains/cultures positive)
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Sclerosing Mesenteritis

A rare, idiopathic fibroinflammatory disorder affecting the mesentery of the small or large intestine, characterized by chronic inflammation, fat necrosis, and fibrosis, leading to a mesenteric mass or diffuse thickening; also known as mesenteric panniculitis or retractile mesenteritis, representing a spectrum of the same process
Clinical ─ Typically affects middle-aged to older adults (peak 50-70s), slight male predominance; presents with chronic abdominal pain (most common), palpable abdominal mass, altered bowel habits (diarrhea, constipation), weight loss, nausea, vomiting, or fever; may be associated with other autoimmune conditions, prior surgery, trauma, or malignancy in some cases
Macro ─ Ill-defined, firm, rubbery, or woody mass or diffuse thickening involving the mesentery, often at the root; cut surface is typically gray-white, tan, or yellowish, with thickened fibrous tissue and entrapped mesenteric fat; may encase mesenteric vessels or bowel loops, causing tethering or retraction
Micro

─ Variable admixture of three main components, with one often predominating:
─ Chronic inflammation: Infiltrate of lymphocytes, plasma cells (can be dense), histiocytes (often foamy - lipophages), and eosinophils; lymphoid aggregates or follicles may be present
─ Fat necrosis: Degenerating adipocytes, foamy macrophages (lipophages), lipid-filled cystic spaces (lipogranulomas), and cholesterol clefts
─ Fibrosis/Sclerosis: Proliferation of bland spindle cells (fibroblasts and myofibroblasts) with deposition of dense collagen, leading to stromal hyalinization and sclerosis; can be paucicellular or more cellular
─ Vascular changes, including obliterative phlebitis, may be seen, especially if related to IgG4-related disease
─ No significant cytologic atypia in spindle cells, mitotic activity is low
─ Entrapment of normal mesenteric structures (vessels, nerves, lymphatics) within the fibroinflammatory process
Ancillary studies ─
─ IHC: Spindle cells positive for vimentin, may show SMA; Histiocytes CD68 positive; IgG4 immunostaining may show increased IgG4+ plasma cells and IgG4/IgG ratio >40% in a subset of cases, indicating possible IgG4-related sclerosing mesenteritis
─ Molecular: Some cases have shown CTNNB1 (beta-catenin) or BRAF V600E mutations, suggesting a link to fibromatosis-like neoplasia in a subset, but most are considered reactive/inflammatory; no consistent diagnostic molecular marker
DDx

─ Desmoid-type fibromatosis (intra-abdominal) (more uniform spindle cells, nuclear beta-catenin positive, usually lacks prominent fat necrosis and mixed inflammation)
─ Gastrointestinal stromal tumor (GIST) (KIT/DOG1 positive, different morphology)
─ Inflammatory myofibroblastic tumor (IMT) (ALK positive in subset, more organized spindle cells)
─ Lymphoma (mesenteric) (specific lymphoid markers positive)
─ Carcinoid tumor with desmoplasia (neuroendocrine markers positive, keratin positive)
─ Metastatic carcinoma with desmoplastic response (keratin positive, specific carcinoma markers)
─ Peritoneal mesothelioma (keratin/calretinin/WT1 positive)
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Idiopathic Retroperitoneal Fibrosis

A rare disorder characterized by the development of dense, fibrous tissue in the retroperitoneum, typically encasing the aorta, inferior vena cava, and ureters, leading to potential obstruction; also known as Ormond's disease; a significant proportion of cases are now recognized as a manifestation of IgG4-related disease
Clinical ─ Typically affects middle-aged to older adults (peak 40-60s), with a male predominance; presents insidiously with dull, non-colicky pain (back, flank, abdomen), weight loss, fatigue, fever, or symptoms related to ureteral obstruction (hydronephrosis, renal insufficiency) or vascular compression; may be associated with other autoimmune conditions or exposure to certain drugs (eg, methysergide - historical)
Macro ─ Ill-defined, plaque-like or sheath-like, firm to woody, gray-white fibrous mass centered in the retroperitoneum, typically anterior to the lumbar spine, encasing the aorta, IVC, and ureters; does not typically invade these structures but constricts them externally
Micro

─ Dense, paucicellular to moderately cellular fibroinflammatory tissue
─ Composed of bland spindle cells (fibroblasts and myofibroblasts) set in abundant, dense, hyalinized collagenous stroma
─ Prominent chronic inflammatory infiltrate, often forming lymphoid aggregates or follicles, composed of lymphocytes, plasma cells (key for IgG4 assessment), eosinophils, and histiocytes
─ Characteristic vascular changes, especially in IgG4-related cases: obliterative phlebitis (inflammation and fibrosis of small to medium-sized vein walls with luminal narrowing/occlusion) and/or aortitis
─ Storiform fibrosis (fibroblasts arranged in a swirling, storiform pattern) may be present, particularly in IgG4-related cases
─ No significant cytologic atypia in spindle cells, mitotic activity is low
─ Entrapment of nerves, vessels, and adipose tissue is common
Ancillary studies ─
─ IHC: Spindle cells positive for vimentin, may show SMA; IgG4 immunostaining is crucial: increased numbers of IgG4-positive plasma cells (eg, >10-50/HPF depending on criteria) and an elevated IgG4/IgG plasma cell ratio (often >40%) support a diagnosis of IgG4-related retroperitoneal fibrosis
─ Molecular: Generally considered non-neoplastic, though some rare cases associated with underlying malignancy (eg, lymphoma, carcinoma causing desmoplastic reaction) need exclusion
DDx

─ Retroperitoneal sarcoma (eg, WDLPS/DDLPS, leiomyosarcoma, SFT - show specific morphology, IHC, and molecular features of sarcoma, usually lack prominent mixed inflammation and obliterative phlebitis)
─ Lymphoma (especially sclerosing variants like Hodgkin or some NHLs - specific lymphoid markers positive)
─ Metastatic carcinoma with desmoplastic response (keratin positive, evidence of primary)
─ Inflammatory myofibroblastic tumor (IMT) (ALK positive in subset, more organized spindle cells, different inflammatory pattern)
─ Sclerosing mesenteritis (similar process but centered in mesentery, may overlap if extensive)
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Immunoglobulin G4–Related Disease

A systemic fibroinflammatory condition characterized by tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and often obliterative phlebitis, capable of affecting virtually any organ or soft tissue site; also known as IgG4-related sclerosing disease
Clinical ─ Typically affects middle-aged to older adults, with a male predominance; can involve single or multiple organs/sites, either synchronously or metachronously; common sites include pancreas (autoimmune pancreatitis type 1), biliary tract (sclerosing cholangitis), salivary glands (Mikulicz disease/Küttner tumor), lacrimal glands, retroperitoneum (idiopathic retroperitoneal fibrosis), aorta (aortitis), lymph nodes, thyroid (Riedel thyroiditis), lung, kidney, orbit, and soft tissues; presentation varies by site, often with mass effect, organ dysfunction, or systemic symptoms; frequently associated with elevated serum IgG4 levels (though not required for diagnosis) and peripheral eosinophilia
Macro ─ Affected tissues are often enlarged, indurated, and fibrotic, forming ill-defined masses or plaque-like thickenings; cut surface is typically gray-white and firm
Micro

─ Key histologic features include:
─ Dense lymphoplasmacytic infiltrate: Composed of lymphocytes (often forming lymphoid follicles) and numerous plasma cells
─ Storiform fibrosis: Spindle cells (fibroblasts/myofibroblasts) arranged in a characteristic swirling, "cartwheel," or storiform pattern within a collagenous stroma
─ Obliterative phlebitis: Inflammation and fibrosis of small to medium-sized vein walls, leading to luminal narrowing or occlusion; arteries may also be involved (obliterative arteritis)
─ Increased numbers of IgG4-positive plasma cells: Diagnostically important, quantified by IHC (eg, >10-50 IgG4+ plasma cells/HPF depending on site/criteria, and IgG4/IgG plasma cell ratio often >40%)
─ Eosinophilic infiltrate may be present but is variable
─ Cytologic atypia in fibroblastic/myofibroblastic cells is minimal or absent; mitotic activity is low
─ The specific combination and prominence of these features can vary by site and stage of disease
Ancillary studies ─
─ IHC: IgG4 immunostain is essential to demonstrate increased IgG4+ plasma cells and an elevated IgG4/IgG ratio; IgG immunostain for total plasma cells; CD138 highlights plasma cells; CD20/CD3 for lymphocytes; SMA may highlight myofibroblasts
─ Serum IgG4 levels: Elevated in many but not all patients
─ Molecular: Generally considered an immune-mediated inflammatory condition, not a true neoplasm, although some fibroinflammatory lesions in this spectrum may show clonality or rare mutations (eg, CTNNB1 in some sclerosing mesenteritis cases that can overlap)
DDx

─ Specific organ-based inflammatory conditions (eg, pancreatitis, cholangitis not IgG4-related - requires IgG4 staining)
─ Mass-forming idiopathic fibroinflammatory disorders not meeting full IgG4-RD criteria (eg, some sclerosing mesenteritis, retroperitoneal fibrosis)
─ Lymphoma (especially plasma cell neoplasms, MALT lymphoma, Hodgkin lymphoma - specific lymphoid markers, light chain restriction in plasma cell myeloma)
─ Castleman disease (hyaline vascular or plasma cell types - different nodal architecture, often HHV8 associated in plasma cell type, lacks diffuse IgG4+ plasma cell infiltrate and storiform fibrosis typically)
─ Inflammatory myofibroblastic tumor (IMT) (ALK positive in a subset, different inflammatory pattern usually, IgG4 infiltrate less prominent/specific)
─ Rosai-Dorfman disease (S100 positive histiocytes with emperipolesis, IgG4 infiltrate can be seen but different primary cells)
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Fibroepithelial Stromal Polyp

A benign mesenchymal polypoid lesion composed of bland spindle and stellate stromal cells within an edematous or collagenous stroma, covered by squamous or transitional epithelium, typically occurring on mucosal surfaces of the lower female genital tract, urinary tract, or anal canal
Clinical ─ Most common in adult women of reproductive age, but can occur at any age and in males (urethra, bladder, anal canal); common sites include vagina, vulva, cervix, less often bladder, urethra, ureter, or anal canal; often presents as a solitary, painless, polypoid or pedunculated mass; may be an incidental finding or cause symptoms like bleeding, discharge, or urinary obstruction depending on size and location; can enlarge during pregnancy (hormonal influence)
Macro ─ Soft, fleshy, polypoid or pedunculated mass, often with a smooth or slightly bosselated surface; color is typically pink, tan, or reddish; size varies from small (<1 cm) to large (several cm)
Micro

─ Polypoid structure with a fibrovascular core and overlying intact surface epithelium (squamous, transitional, or glandular depending on site)
─ Stroma is typically loose, edematous, or myxoid, but can be more collagenous or fibrous, especially in older lesions
─ Cellular component consists of bland, slender spindle-shaped to stellate mesenchymal cells (fibroblasts/myofibroblasts) with pale eosinophilic cytoplasm and ovoid to fusiform nuclei
─ Atypical stromal cells (pseudosarcomatous atypia): Scattered large, pleomorphic, multinucleated stromal cells with hyperchromatic, smudged, or bizarre nuclei may be present, especially in hormonally active settings (eg, pregnancy) or irritated lesions; these cells lack mitotic activity and do not indicate malignancy
─ Blood vessels are often prominent within the stroma, sometimes with thickened or hyalinized walls
─ Chronic inflammatory infiltrate (lymphocytes, plasma cells) is common in the stroma
─ Mitotic activity is generally low (usually <1-2/10 HPF) outside of areas with atypical stromal cells where it remains low; atypical mitoses are absent
Ancillary studies ─
─ IHC: Stromal cells are positive for vimentin; Desmin is often positive (variable extent); SMA may be focally positive; Estrogen receptor (ER) and progesterone receptor (PR) are frequently positive in stromal cells (especially in female genital tract lesions); CD34 may be positive in some stromal cells or vessels; Negative for S100 protein, keratins (except overlying epithelium), HMB45
─ Molecular: No specific recurrent genetic alterations are consistently identified
DDx

─ Sarcoma botryoides (embryonal rhabdomyosarcoma of vagina/cervix) (children, cambium layer, malignant rhabdomyoblasts, MyoD1/myogenin positive)
─ Angiomyofibroblastoma (vulvovaginal, more cellular, prominent epithelioid cells around vessels, lacks pseudosarcomatous atypia)
─ Aggressive angiomyxoma (deep pelvic/perineal, infiltrative, HMGA2 rearranged, lacks pseudosarcomatous atypia)
─ Leiomyoma (more distinct smooth muscle fascicles, h-caldesmon positive, lacks pseudosarcomatous atypia)
─ Squamous cell carcinoma or other epithelial malignancies (if surface epithelium is atypical or ulcerated; keratin positive malignant cells)
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Cellular Angiofibroma

A benign mesenchymal neoplasm composed of bland spindle cells and numerous small to medium-sized, often thick-walled or hyalinized blood vessels, characteristically occurring in the vulvovaginal region of women and inguinoscrotal region of men
Clinical ─ Primarily affects adults (peak age 40-60s), with a slight female predominance; most common in the vulva, vagina, perineum in females, and scrotum, inguinal canal, or paratesticular soft tissues in males; presents as a solitary, slow-growing, painless, well-circumscribed subcutaneous or submucosal nodule, usually <3-5 cm
Macro ─ Well-circumscribed, often pseudoencapsulated, firm, rubbery nodule; cut surface is typically gray-white to tan, sometimes with a vaguely lobulated or whorled appearance; may appear vascular
Micro

─ Well-demarcated, often lobulated proliferation with a fibrous pseudocapsule
─ Composed of two main components:
─ Cellular spindle cell component: Relatively uniform, bland spindle cells with scant, pale eosinophilic cytoplasm and ovoid to fusiform nuclei, arranged in short fascicles, storiform pattern, or haphazardly
─ Vascular component: Numerous small to medium-sized blood vessels, which are characteristically thick-walled due to mural hyalinization or smooth muscle cuffing; vessels are evenly distributed throughout the tumor
─ Stroma is variably edematous, collagenous, or myxoid; wispy collagen bundles are common
─ Mature adipose tissue may be entrapped at the periphery or focally within the tumor
─ Minimal to no cytologic atypia, pleomorphism is absent, mitotic activity is very low (usually <1/10 HPF)
─ Necrosis is absent
Ancillary studies ─
─ IHC: Spindle cells are positive for vimentin; Estrogen receptor (ER) and progesterone receptor (PR) are often positive; CD34 is typically negative or only positive in endothelial cells (unlike angiofibroma of soft tissue which can have CD34+ spindle cells); Desmin and SMA are variably positive in spindle cells (often patchy or focal, SMA highlights perivascular smooth muscle); S100 protein is negative (except entrapped fat/nerves); Keratins are negative
─ Molecular: Characterized by deletions of chromosome 13q14, leading to loss of RB1 (retinoblastoma) gene expression in many cases; distinct from aggressive angiomyxoma (HMGA2 rearranged) and angiomyofibroblastoma (which can also have 13q14 loss but is morphologically different)
DDx

─ Angiomyofibroblastoma (more epithelioid cells clustered around vessels, more edematous/myxoid stroma usually, often stronger/diffuse desmin, can also have RB1 loss but morphology differs)
─ Aggressive angiomyxoma (more infiltrative, larger, less cellular, more prominent large vessels, HMGA2 rearranged)
─ Solitary fibrous tumor (STAT6 positive, CD34 diffusely positive in spindle cells, characteristic staghorn vessels)
─ Myofibroblastoma (CD34 positive spindle cells, desmin positive, prominent collagen bundles, RB1 loss - can overlap if vascularity is low in CA)
─ Angioleiomyoma (more prominent smooth muscle fascicles, desmin/h-caldesmon strongly positive, less stromal component)
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Prepubertal Vulval Fibroma

A rare, benign fibroblastic mesenchymal proliferation occurring exclusively in the vulva of prepubertal girls, characterized by bland spindle cells in a variably collagenous or myxoid stroma; may represent a specific clinicopathologic entity or a variant of other benign fibrous tumors in this age group and location
Clinical ─ Exclusively affects prepubertal girls (typically <10 years old, often much younger); presents as a solitary, slow-growing, painless, firm, subcutaneous or submucosal nodule or polypoid mass in the vulva (labia majora most common)
Macro ─ Well-circumscribed, firm, rubbery, gray-white to tan nodule or polypoid mass; size usually <3 cm
Micro

─ Well-demarcated but unencapsulated proliferation of bland, uniform spindle cells (fibroblasts/myofibroblasts) with scant pale eosinophilic cytoplasm and ovoid to fusiform nuclei
─ Cells are arranged in short, intersecting fascicles, a storiform pattern, or haphazardly
─ Stroma is variably collagenous, sometimes with myxoid or edematous areas; "patterned" or "shredded" collagen may be seen
─ Vascularity is generally not prominent, composed of small, thin-walled vessels
─ Minimal to no cytologic atypia, mitotic activity is very low or absent
─ Overlying squamous epithelium is usually intact
Ancillary studies ─
─ IHC: Spindle cells are positive for vimentin; CD34 is often positive (variable extent); Estrogen receptor (ER) and progesterone receptor (PR) are typically negative or only weakly/focally positive (unlike many adult vulvovaginal mesenchymal tumors); SMA may be focally positive; Desmin is usually negative; S100 protein and keratins are negative
─ Molecular: Not well characterized due to rarity; no specific recurrent genetic alterations are consistently identified; some studies suggest a possible link to superficial acral fibromyxoma or related entities based on some shared IHC (CD34)
DDx

─ Fibroepithelial stromal polyp (can occur in children but often ER/PR positive, may have atypical stromal cells, more edematous/myxoid stroma usually)
─ Aggressive angiomyxoma (extremely rare in prepubertal girls, more infiltrative, prominent vessels, HMGA2 rearranged)
─ Embryonal rhabdomyosarcoma (sarcoma botryoides) (malignant, cambium layer, rhabdomyoblasts, MyoD1/myogenin positive)
─ Infantile fibromatosis/myofibromatosis (may involve vulva, often biphasic pattern or HP-like vessels)
─ Cellular angiofibroma / Angiomyofibroblastoma (extremely rare in prepubertal girls, specific IHC/morphology)
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Spindle Cell Epithelioma

A rare, benign biphasic adnexal neoplasm of the skin, typically occurring in the head/neck region or perineum of adults, characterized by an admixture of epithelial nests/cords and a prominent spindle cell stromal component; also known as Spindle Cell Hidradenoma or Mixed Tumor of skin, myoepithelial type (if myoepithelial cells prominent)
Clinical ─ Typically affects adults (wide age range); common on the head/neck, extremities, and perineal/anogenital region; presents as a solitary, slow-growing, firm, dome-shaped or nodular dermal or subcutaneous lesion, usually <2 cm; may be painful or tender
Macro ─ Well-circumscribed, firm, gray-white to tan nodule; cut surface may be solid or show small cystic spaces
Micro

─ Well-demarcated, often lobulated or multinodular dermal or subcutaneous tumor
─ Biphasic pattern with two intimately admixed components:
─ Epithelial component: Nests, cords, tubules, or duct-like structures lined by one or more layers of bland cuboidal, columnar, or squamoid epithelial cells; lumens may contain eosinophilic secretions; apocrine or eccrine differentiation may be evident
─ Spindle cell stromal component: Predominant component, composed of bland spindle cells with ovoid to fusiform nuclei and scant cytoplasm, arranged in fascicles, sheets, or a storiform pattern around the epithelial elements; stroma is often hyalinized, collagenous, or chondromyxoid
─ Myoepithelial cells (spindle, epithelioid, or clear cells) are often prominent, particularly at the periphery of epithelial structures or within the stroma (leading to overlap with myoepithelioma/mixed tumor of skin)
─ Cytologic atypia is minimal, mitotic activity is low
Ancillary studies ─
─ IHC: Epithelial component: Positive for keratins (AE1/AE3, CAM5.2, CK7, CK5/6), EMA, CEA
─ IHC: Spindle cell/Myoepithelial component: Positive for S100 protein (often strong), GFAP (variable), SMA (variable), calponin, p63; Vimentin positive
─ Molecular: Some cases, particularly those with prominent myoepithelial differentiation and chondromyxoid stroma (mixed tumor type), may show PLAG1 gene fusions or EWSR1 rearrangements (similar to soft tissue/salivary myoepithelial tumors)
DDx

─ Cutaneous myoepithelioma / Mixed tumor (predominantly myoepithelial cells, less prominent ductal differentiation, may have EWSR1/PLAG1 fusions)
─ Other benign adnexal tumors (eg, spiradenoma, cylindroma, hidradenoma - specific features of sweat gland differentiation, different stromal components)
─ Dermatofibroma (Factor XIIIa positive, lacks epithelial component and S100 positive spindle cells)
─ Schwannoma (S100 positive but lacks epithelial component, different morphology)
─ Basal cell carcinoma with stromal induction (malignant epithelial cells, different stromal reaction)
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Pleomorphic Fibroma

A benign, uncommon cutaneous mesenchymal neoplasm characterized by a paucicellular proliferation of bland spindle cells and scattered large, pleomorphic, multinucleated giant cells within a well-vascularized, collagenous, or myxoid stroma; also known as pleomorphic fibroma of skin
Clinical ─ Typically affects adults (wide age range, often middle-aged to older); common on the extremities, trunk, head/neck; presents as a solitary, slow-growing, painless, firm, skin-colored or brownish papule or nodule, usually small (<2 cm)
Macro ─ Small, well-demarcated, firm, whitish or tan dermal nodule
Micro

─ Well-circumscribed, unencapsulated, dermal proliferation, sometimes extending into superficial subcutis
─ Paucicellular to moderately cellular, composed of:
─ Bland, slender spindle cells (fibroblasts) with scant cytoplasm and ovoid to fusiform nuclei, arranged in loose fascicles or haphazardly
─ Characteristic feature: Scattered, large, pleomorphic, multinucleated giant cells with hyperchromatic, smudged, or bizarre nuclei, often forming floret-like or wreath-like arrangements; these cells are degenerative and lack mitotic activity
─ Stroma is variably collagenous, sometimes myxoid or edematous, often with prominent small blood vessels
─ Minimal to no cytologic atypia in the spindle cell component; mitotic activity is very low or absent in both spindle and giant cells
─ No necrosis or infiltrative growth into deep structures
Ancillary studies ─
─ IHC: Both spindle cells and pleomorphic giant cells are positive for vimentin; CD34 may be positive in a subset of spindle cells; Factor XIIIa can be positive; Negative for S100 protein, keratins, desmin, SMA (except vessels), HMB45, CD68 (usually negative in giant cells, distinguishing from histiocytic proliferations)
─ Molecular: No specific recurrent genetic alterations are consistently identified; considered a benign entity despite the pleomorphic giant cells
DDx

─ Atypical fibrous histiocytoma / Dermatofibroma with monster cells (more cellular, storiform pattern, Factor XIIIa often stronger, CD34 usually negative in tumor cells)
─ Atypical fibroxanthoma (AFX) (sun-damaged skin of elderly, more diffuse extreme pleomorphism, high mitotic rate, diagnosis of exclusion after ruling out SCC/melanoma)
─ Pleomorphic lipoma (contains mature fat, CD34 positive spindle cells, S100 positive adipocytes/floret cells, RB1 loss)
─ Neurofibroma with atypia (S100/SOX10 positive Schwann cells, embedded axons)
─ Sarcomas with pleomorphism (eg, UPS, pleomorphic liposarcoma - show overt malignant features, infiltrative growth, necrosis, higher mitoses)
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Cellular Neurothekeoma

A benign dermal mesenchymal neoplasm of uncertain histogenesis (possibly fibrohistiocytic or myofibroblastic, but not clearly neural despite the name), characterized by nests and fascicles of epithelioid to spindled cells with prominent nucleoli, often in a myxoid or sclerotic stroma; formerly grouped with myxoid neurothekeoma (dermal nerve sheath myxoma) but now considered distinct due to different immunophenotype (S100 negative)
Clinical ─ Typically affects children and young adults (peak age 10-30s), with a female predominance; common on the head/neck (especially face - nose, cheeks, ears) and upper trunk/shoulders; presents as a solitary, slow-growing, firm, skin-colored or reddish papule or nodule, usually <2 cm
Macro ─ Small, well-circumscribed, firm, whitish or tan dermal nodule
Micro

─ Well-demarcated, unencapsulated, dermal proliferation, sometimes extending into superficial subcutis
─ Composed of nests, lobules, or short fascicles of relatively uniform epithelioid, ovoid, or spindle cells
─ Cells have moderate amounts of eosinophilic or amphophilic cytoplasm, indistinct cell borders, and round to oval vesicular nuclei with prominent, often centrally located, eosinophilic or amphophilic nucleoli (a key feature)
─ Stroma is variably myxoid (common) or collagenous/sclerotic; myxoid areas may show stromal mucin clefting
─ Cytologic atypia is generally mild, but nuclear prominence can be striking; mitotic activity is usually low (0-3/10 HPF), atypical mitoses are rare
─ Multinucleated giant cells may be present focally
Ancillary studies ─
─ IHC: Tumor cells are characteristically negative or only very rarely and focally positive for S100 protein and SOX10 (distinguishes from dermal nerve sheath myxoma/myxoid neurothekeoma and other neural tumors); Positive for NKI-C3 (CD63 related, melanocytic lineage but also in other cells) in many cases; SMA (smooth muscle actin) is often positive (variable extent); PGP9.5 may be positive; Factor XIIIa may be positive in entrapped dermal dendrocytes but not tumor cells usually; Negative for keratins, EMA, desmin, HMB45, Melan-A, CD34 (usually)
─ Molecular: Activating mutations in HRAS, KRAS, or BRAF (especially BRAF V600E) have been identified in a significant subset of cases, particularly those with epithelioid morphology or ALK gene fusions in a small subset of epithelioid/atypical cases.
DDx

─ Dermal nerve sheath myxoma (myxoid neurothekeoma) (S100/SOX10 positive, lacks NKI-C3/SMA typically, different cell morphology)
─ Spitz nevus / Epithelioid melanocytic nevus (S100/SOX10/melanocytic markers positive, may have BRAF mutation but different morphology)
─ Epithelioid fibrous histiocytoma (ALK positive in subset, different morphology, often eosinophils)
─ Pilar leiomyoma (desmin/h-caldesmon positive, different morphology)
─ Plexiform fibrohistiocytic tumor (biphasic, osteoclast-like giant cells, different IHC)
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Distinctive Dermal Clear Cell Mesenchymal Neoplasm

A rare, low-grade mesenchymal neoplasm of the dermis, characterized by a proliferation of bland epithelioid cells with clear cytoplasm, often arranged in nests or cords, and typically showing EWSR1 gene rearrangements with CREB family transcription factors (ATF1 or CREB1)
Clinical ─ Affects adults (wide age range); common on the lower extremities (especially foot/ankle), also trunk and upper extremities; presents as a slow-growing, solitary, firm, skin-colored or yellowish papule or nodule, usually small (<2 cm)
Macro ─ Small, well-circumscribed, firm, whitish-yellow dermal nodule
Micro

─ Well-demarcated, unencapsulated, dermal proliferation, sometimes extending into superficial subcutis
─ Composed of nests, cords, or diffuse sheets of relatively uniform, medium-sized epithelioid cells with abundant clear or pale eosinophilic cytoplasm and distinct cell borders
─ Nuclei are round to oval, often vesicular, with inconspicuous or small nucleoli; cytologic atypia is minimal
─ Stroma is typically scant and fibrous, may be hyalinized focally
─ Mitotic activity is very low or absent
─ No necrosis, vascular invasion, or significant pleomorphism
Ancillary studies ─
─ IHC: Tumor cells are positive for vimentin; CD68 may be positive; Cyclin D1 is often positive (nuclear); Negative for S100 protein, SOX10, melanocytic markers (HMB45, Melan-A), keratins, EMA, desmin, SMA, CD34, DOG1, KIT
─ Molecular: Characterized by EWSR1 gene rearrangements, most commonly with ATF1 (EWSR1::ATF1 fusion, similar to clear cell sarcoma of soft tissue and angiomatoid fibrous histiocytoma) or CREB1 (EWSR1::CREB1 fusion, also seen in AFH and some clear cell sarcomas); despite the shared fusions, its behavior is generally indolent
DDx

─ Clear cell sarcoma of soft tissue (more aggressive, often larger/deeper, S100/SOX10/melanocytic markers positive, shares EWSR1-ATF1/CREB1 fusions but clinically distinct)
─ Metastatic clear cell renal cell carcinoma (PAX8/CAIX/keratin positive)
─ Cutaneous myoepithelioma (clear cell variant) (S100/keratin/EMA/GFAP/SMA variably positive, may have EWSR1 fusion but different partners usually)
─ Balloon cell nevus / melanoma (S100/SOX10/melanocytic markers positive)
─ Xanthoma / Xanthogranuloma (foamy histiocytes, Touton giant cells, CD68 positive but lacks EWSR1 fusion)
─ Clear cell hidradenoma / other adnexal tumors with clear cells (keratin positive, specific adnexal features)
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Juvenile Xanthogranuloma and Related Disorders

Juvenile Xanthogranuloma (JXG) is a common benign, self-limiting histiocytic proliferation of infancy and childhood, characterized by lipidized histiocytes and Touton giant cells; related disorders share overlapping features and may include benign cephalic histiocytosis, generalized eruptive histiocytoma, and others within the spectrum of non-Langerhans cell histiocytoses
Clinical (JXG) ─ Typically presents in infancy or early childhood (most <2 years, many congenital or in first 6 months); M>F slightly; most common on head/neck, trunk, and upper extremities, but can occur anywhere, including extracutaneous sites (eye - iris/ciliary body, lung, liver, spleen, testis, CNS - rare but important); skin lesions are usually solitary (can be multiple), asymptomatic, firm, dome-shaped papules or nodules, initially reddish-brown, later yellowish-tan ("xanthomatous")
Clinical (Related Disorders) ─ Benign cephalic histiocytosis: self-limiting, macules/papules on face/neck of infants; Generalized eruptive histiocytoma: successive crops of widespread papules in children/adults
Macro (JXG) ─ Small (usually 0.5-2 cm), firm, yellowish-tan or reddish-brown, dome-shaped papule or nodule
Micro (JXG) ─

─ Well-demarcated but unencapsulated, dense dermal infiltrate, sometimes extending into superficial subcutis
─ Composed of sheets of histiocytes (macrophages) with abundant eosinophilic or pale foamy (lipidized) cytoplasm and round to oval vesicular nuclei
─ Characteristic Touton giant cells are often present (multinucleated giant cells with a peripheral wreath of nuclei and central eosinophilic cytoplasm, surrounded by foamy cytoplasm)
─ Admixed inflammatory cells (lymphocytes, eosinophils, plasma cells) are common
─ Spindle cell areas, fibrosis, and hemosiderin deposition may be seen, especially in older lesions
─ Mitotic activity can be present but is not atypical; necrosis is rare
─ Epidermis may be flattened or slightly acanthotic; Grenz zone may be present
Ancillary studies (JXG) ─
─ IHC: Histiocytes are positive for CD68 (PGM1, KP1), CD163, Factor XIIIa, and vimentin; Fascin may be positive; Negative for S100 protein (usually, though scattered S100+ cells can be present), CD1a, and Langerin (CD207) - distinguishes from Langerhans cell histiocytosis
─ Molecular: Activating mutations in MAPK pathway genes (eg, BRAF, KRAS, NRAS, MAP2K1, ALK fusions) have been identified in a significant proportion of JXG and related non-LCH histiocytoses, suggesting a clonal neoplastic basis for many
DDx (JXG) ─

─ Langerhans cell histiocytosis (LCH) (CD1a/Langerin positive, characteristic grooved nuclei, Birbeck granules on EM)
─ Reticulohistiocytoma (larger cells with glassy cytoplasm, S100 often positive, different morphology)
─ Dermatofibroma (storiform pattern, collagen trapping, Factor XIIIa positive but different cell types usually)
─ Xanthoma (associated with hyperlipidemia, sheets of foamy histiocytes, lacks Touton giant cells typically)
─ Spitz nevus / Melanoma (melanocytic markers positive)
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Reticulohistiocytoma

A rare benign histiocytic proliferation characterized by large, distinctive histiocytes with abundant, finely granular, "ground-glass" eosinophilic cytoplasm, typically presenting as solitary or multiple cutaneous nodules, or as part of multicentric reticulohistiocytosis (a systemic syndrome)
Clinical ─ Solitary reticulohistiocytoma: Adults, wide age range; presents as a firm, skin-colored, reddish-brown, or yellowish papule or nodule, often on head/neck or extremities; usually <1 cm
Clinical ─ Multicentric reticulohistiocytosis (MRH): Rare systemic disorder, primarily affects adults (peak 40-50s), F>M; characterized by multiple cutaneous reticulohistiocytomas, destructive polyarthritis (arthritis mutilans), and potential internal organ involvement (lung, heart, muscle); associated with autoimmune diseases or malignancy in a subset
Macro ─ Small, firm, well-demarcated papule or nodule in the skin
Micro

─ Well-circumscribed dermal infiltrate (can extend to subcutis) composed of sheets or clusters of characteristic large histiocytes (reticulohistiocytes)
─ Reticulohistiocytes: Large, polygonal to round cells with abundant, finely granular, deeply eosinophilic or amphophilic "ground-glass" cytoplasm (PAS-positive, diastase-resistant)
─ Nuclei are large, round to oval, often vesicular, and may be single or multiple (multinucleated giant cells are common, sometimes with >20 nuclei, often arranged peripherally or haphazardly)
─ Cytologic atypia can be present (nuclear enlargement, pleomorphism) but overt malignant features are absent in benign reticulohistiocytoma
─ Admixed inflammatory cells (lymphocytes, plasma cells, neutrophils, eosinophils) are variable
─ Stroma is often fibrous; vascularity can be prominent
─ No necrosis in benign lesions
Ancillary studies ─
─ IHC: Reticulohistiocytes are positive for CD68 (PGM1, KP1) and CD163; Vimentin positive; S100 protein is variably positive (often in a subset of cells, can be strong); Factor XIIIa may be positive; Negative for CD1a and Langerin (distinguishes from LCH), HMB45, Melan-A, keratins, desmin, SMA
─ Molecular: MAPK pathway mutations (eg, BRAF, KRAS, NRAS, MAP2K1) have been reported in some cases, similar to JXG and LCH, suggesting a clonal basis

DDx

─ Juvenile xanthogranuloma (JXG) (foamy histiocytes, Touton giant cells, S100 usually negative, different granularity)
─ Langerhans cell histiocytosis (LCH) (CD1a/Langerin positive, grooved nuclei)
─ Granular cell tumor (S100 positive but different granular quality - lysosomal, ATP6AP1/2 mutations)
─ Spitz nevus / Melanoma (epithelioid variants) (melanocytic markers positive)
─ Rhabdomyoma (myogenic markers positive, may have granular cytoplasm but different type)
─ Xanthoma (sheets of foamy cells, associated with hyperlipidemia)
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Multicentric Reticulohistiocytosis

A rare systemic histiocytic proliferative disorder of unknown etiology, characterized by multiple cutaneous reticulohistiocytomas (papules and nodules) and a distinctive, often severe and deforming, erosive polyarthritis (arthritis mutilans); considered a systemic form of reticulohistiocytoma
Clinical ─ Primarily affects adults (peak age 40-50s), with a strong female predominance (F:M ~3:1); characterized by a triad of:
─ Multiple cutaneous papulonodules (reticulohistiocytomas): Firm, skin-colored, reddish-brown, or yellowish, often on face, ears, hands (especially periungual - "coral beads"), and extensor surfaces
─ Severe, symmetric, erosive polyarthritis: Affects small joints of hands and feet, wrists, knees, shoulders, hips; can lead to joint destruction and arthritis mutilans
─ Systemic manifestations: Fever, weight loss, fatigue, myalgia; involvement of mucous membranes, eyes, salivary glands, thyroid, bone, muscle, heart, or lungs can occur
Clinical ─ Approximately 25-30% of cases are associated with an underlying malignancy (various carcinomas, lymphoma, myeloma); another subset associated with autoimmune diseases
Macro ─ Skin lesions: Multiple, firm, discrete papules or nodules; Arthritic joints: Swelling, deformity, synovial thickening
Micro (cutaneous and synovial lesions) ─

─ Infiltrate of characteristic large histiocytes (reticulohistiocytes) and multinucleated giant cells, similar to solitary reticulohistiocytoma
─ Reticulohistiocytes: Large polygonal cells with abundant, finely granular, "ground-glass" eosinophilic or amphophilic cytoplasm (PAS-positive, diastase-resistant)
─ Nuclei are large, round to oval, vesicular, often with prominent nucleoli; multinucleated forms are common, sometimes with >20 nuclei, often arranged haphazardly or peripherally
─ Cytologic atypia can be present but frank malignant features are usually absent unless transforming to histiocytic sarcoma (rare)
─ Admixed inflammatory cells (lymphocytes, plasma cells, neutrophils, eosinophils) are variable
─ Fibrosis may be present in older lesions
─ Synovial involvement shows similar histiocytic infiltrate with synovial hyperplasia and destruction of cartilage/bone
Ancillary studies ─
─ IHC: Reticulohistiocytes are positive for CD68 (PGM1, KP1) and CD163; S100 protein is variably positive (often in a subset of cells); Factor XIIIa may be positive; Negative for CD1a and Langerin
─ Lab tests: Elevated ESR, CRP; rheumatoid factor usually negative; autoantibodies may be present if associated autoimmune disease
─ Molecular: MAPK pathway mutations (eg, BRAF, KRAS, NRAS, MAP2K1) have been reported in some cases, suggesting a clonal basis for this disorder similar to JXG and LCH spectrum
DDx ─

─ Rheumatoid arthritis / Other inflammatory arthropathies (different synovial pathology, specific serologies, lacks characteristic reticulohistiocytes)
─ Langerhans cell histiocytosis (CD1a/Langerin positive, grooved nuclei, Birbeck granules)
─ Juvenile xanthogranuloma (foamy histiocytes, Touton giant cells, S100 usually negative)
─ Gout / Pseudogout (crystal deposition)
─ Sarcoidosis (non-caseating granulomas, different giant cells)
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Subungual exostosis

A benign osteocartilaginous proliferation (exostosis) arising from the dorsal or dorsolateral aspect of the distal phalanx of a finger or toe, beneath or adjacent to the nail plate; also known as Dupuytren exostosis
Clinical ─ Typically affects adolescents and young adults (peak age 10-30s), slight female predominance; most common on the great toe, but can occur on other toes or fingers; presents as a painful, firm, slow-growing nodule under or next to the nail, often elevating or deforming the nail plate; frequently associated with a history of trauma or chronic irritation/infection
Macro ─ Small (usually <1-2 cm), sessile or pedunculated, hard, bony nodule covered by a cartilaginous or fibrous cap; often causes ulceration or inflammation of the overlying skin or nail bed
Radiology ─ Well-defined, mineralized bony outgrowth projecting from the dorsal or dorsolateral surface of the distal phalanx; trabeculated bone is often continuous with the underlying cortex of the phalanx but typically not the medullary cavity; the cap may be variably calcified
Micro ─

─ Composed of a base of mature trabecular bone that is continuous with the underlying distal phalanx
─ Overlying cap shows a progression of differentiation, typically from a proliferating fibroblastic/mesenchymal zone at the surface, through a zone of hyaline cartilage (chondroid cap), to a zone of endochondral ossification where the cartilage is replaced by woven and then lamellar bone merging with the bony stalk
─ The cartilaginous cap is often hypercellular, with chondrocytes sometimes showing mild atypia (enlarged nuclei, binucleation), which is acceptable in this reactive lesion
─ The surface is often covered by skin or nail bed epithelium, which may show reactive changes, ulceration, or inflammation
Ancillary studies ─
─ IHC: Not typically required for diagnosis; S100 protein highlights chondrocytes in the cartilaginous cap
─ Molecular: Some studies have reported IRS4 gene rearrangements or BRAF V600E mutations in a subset, distinguishing them genetically from osteochondromas (EXT1/EXT2 mutated)
DDx ─

─ Osteochondroma (true) (arises from metaphysis of long bones, shows medullary continuity, has EXT1/EXT2 mutations, different location)
─ Bizarre parosteal osteochondromatous proliferation (BPOP) / Nora lesion (hands/feet, arises from cortical surface without medullary continuity, characteristic "blue bone" and atypical cartilage, distinct genetics)
─ Glomus tumor (subungual location, painful, vascular tumor composed of glomus cells, S100 negative)
─ Squamous cell carcinoma (subungual) (malignant epithelial proliferation, keratin positive)
─ Pyogenic granuloma (lobular capillary proliferation, no bone/cartilage)
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Enchondroma

A benign intramedullary cartilaginous neoplasm composed of mature hyaline cartilage, typically arising within the medullary cavity of bones
Clinical ─ Affects a wide age range (peak 10-40s); common bone tumor; can be solitary or multiple (enchondromatosis); most common in the small tubular bones of the hands (phalanges, metacarpals) and feet (metatarsals), also occurs in long bones (femur, humerus, tibia) and flat bones; often an incidental finding on imaging, or may present with pain, swelling, or pathologic fracture
Clinical ─ Enchondromatosis syndromes:
─ Ollier disease: Multiple enchondromas, typically asymmetric distribution, increased risk of chondrosarcoma
─ Maffucci syndrome: Multiple enchondromas associated with multiple soft tissue spindle cell hemangiomas (vascular malformations); higher risk of chondrosarcoma and other malignancies
Macro ─ Well-demarcated, lobulated, gray-blue, translucent cartilaginous tumor replacing medullary bone; may have gritty calcifications; typically <3-5 cm in small bones, can be larger in long bones
Radiology ─ Well-defined, geographic lytic lesion in the medullary cavity, often with a thin sclerotic rim; characteristic matrix calcification (rings and arcs, stippled, flocculent) is common but not always present; endosteal scalloping may occur but is usually mild (<2/3 cortical thickness); no cortical destruction or soft tissue mass in uncomplicated enchondroma
Micro ─

─ Lobules of mature hyaline cartilage embedded within the marrow space, often surrounded by lamellar bone (especially in small bones where it may fill the medullary cavity)
─ Hypocellular to moderately cellular, composed of chondrocytes situated within lacunae
─ Chondrocytes are typically bland, with small, round, dark nuclei; binucleation may be present but is usually infrequent (<5-10% of cells)
─ Cytologic atypia is minimal or absent; mitotic activity is absent
─ Matrix is predominantly hyaline cartilage, may show focal myxoid change or calcification (punctate or enchondral ossification at periphery)
─ Crucially, lacks permeation of marrow spaces between pre-existing lamellar bone trabeculae (a key feature distinguishing from low-grade chondrosarcoma in long/flat bones)
Ancillary studies ─
─ IHC: Chondrocytes are positive for S100 protein
─ Molecular: Activating mutations in IDH1 (isocitrate dehydrogenase 1) or IDH2 genes are common in both solitary enchondromas and enchondromatosis syndromes
DDx ─

─ Low-grade conventional chondrosarcoma (especially in long/flat bones; distinguished by permeative growth, entrapment of lamellar bone, higher cellularity, more atypia, clinical/radiologic correlation is crucial; also IDH mutated)
─ Chondroblastoma (epiphyseal location, different cell morphology - "chondroblasts", chicken-wire calcification, H3-3B K36M mutated)
─ Bone infarct (serpiginous calcification, necrotic marrow and bone, lacks viable chondrocytes)
─ Clear cell chondrosarcoma (epiphyseal, clear cell morphology, S100 positive, lacks IDH mutations typically)
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Osteochondroma

A benign cartilage-capped bony projection (exostosis) arising from the external surface of a bone, characterized by continuity of the cortex and medullary cavity of the lesion with those of the underlying parent bone; it is the most common benign bone tumor
Clinical ─ Typically presents in children and adolescents (growth usually ceases with skeletal maturity); M>F slightly; can be solitary (most common) or multiple (Hereditary Multiple Exostoses - HME, an autosomal dominant disorder, now called Hereditary Multiple Osteochondromas - HMO); most common at the metaphysis of long bones, particularly around the knee (distal femur, proximal tibia) and proximal humerus, but can occur in any bone preformed in cartilage (flat bones, vertebrae, small bones); often asymptomatic, may present as a painless, hard, fixed mass, or cause symptoms due to mechanical irritation (bursitis, tendinitis, nerve/vessel compression, fracture of stalk, cosmetic deformity)
Macro ─ Pedunculated (stalked) or sessile (broad-based) bony outgrowth from the bone surface, covered by a smooth, glistening, gray-blue cartilage cap (thickness varies with age, <1-2 cm in adults, thicker in growing children)
Radiology ─ Pathognomonic appearance: bony exostosis showing direct continuity of its cortex and medullary cavity with the underlying native bone; cartilage cap may be visible and can show punctate or ring-and-arc calcifications
Micro ─

─ Composed of a bony stalk (continuous with parent bone cortex and medulla, containing fatty or hematopoietic marrow) and an overlying hyaline cartilage cap
─ Cartilage cap resembles an epiphyseal growth plate, with chondrocytes arranged in clusters or columns, undergoing enchondral ossification at the bone-cartilage interface
─ Thickness of the cartilage cap is important: in adults, a cap >2 cm (some use >1.5 cm or >3 cm) raises concern for malignant transformation to secondary chondrosarcoma
─ Chondrocytes are generally bland, but mild atypia and binucleation can be seen, especially in actively growing lesions in children
─ Mitotic activity is very low or absent in mature lesions
─ A thin fibrous perichondrium covers the cartilage cap
─ A reactive bursa may form over the lesion and can show synovial metaplasia
Ancillary studies ─
─ IHC: Not typically required for diagnosis; S100 protein highlights chondrocytes in the cartilage cap
─ Molecular: Caused by inactivating mutations in the EXT1 or EXT2 genes (tumor suppressors involved in heparan sulfate biosynthesis) in both solitary and HMO-associated osteochondromas
DDx ─

─ Secondary Chondrosarcoma arising in osteochondroma (thickened cartilage cap >2cm in adult, increased cellularity/atypia in cap, destructive growth)
─ Subungual exostosis (distal phalanx, lacks medullary continuity, different cap histology, different genetics - IRS4/BRAF)
─ Bizarre parosteal osteochondromatous proliferation (BPOP) / Nora lesion (hands/feet, lacks medullary continuity, characteristic "blue bone" and atypical cartilage, distinct genetics)
─ Periosteal chondroma (surface lesion, saucerization of cortex, lacks medullary continuity)
─ Juxtacortical (Parosteal/Periosteal) Osteosarcoma (malignant osteoid production, atypia)
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Chondroblastoma

A benign cartilaginous neoplasm, typically arising in the epiphyses or apophyses of long bones in adolescents and young adults, composed of characteristic mononuclear chondroblasts, osteoclast-like giant cells, and often "chicken-wire" calcification
Clinical ─ Primarily affects adolescents and young adults (peak age 10-25s, usually before physeal closure), with a male predominance; most common in the epiphysis or apophysis of long bones, particularly proximal humerus, distal femur, and proximal tibia; less commonly in flat bones or small bones of hands/feet; presents with joint pain, swelling, tenderness, limited range of motion, or pathologic fracture
Macro ─ Well-demarcated, often lobulated, hemorrhagic, friable, grayish-pink, granular, or gritty tissue; may show cystic change or areas of bluish cartilage; usually <5 cm
Radiology ─ Well-defined, geographic lytic lesion eccentric or central within the epiphysis (or apophysis); thin sclerotic rim is common; matrix calcification (punctate, "chicken-wire") is present in ~50% of cases; may extend into the metaphysis after physeal closure; periosteal reaction can occur
Micro

─ Cellular proliferation composed predominantly of sheets of relatively uniform, mononuclear round to polygonal cells (chondroblasts)
─ Chondroblasts have distinct cytoplasmic borders, moderate amounts of eosinophilic or clear cytoplasm, and round to oval nuclei, often with characteristic longitudinal nuclear grooves ("coffee-bean" appearance)
─ Characteristic feature: Pericellular "chicken-wire" calcification (calcification outlining individual or small groups of chondroblasts) is common and highly suggestive when present
─ Numerous osteoclast-like multinucleated giant cells are typically scattered throughout the tumor
─ Islands of hyaline cartilage or chondroid matrix may be present focally
─ Mitotic activity is usually low, but can be focally brisk; atypical mitoses are rare
─ Secondary aneurysmal bone cyst (ABC)-like changes (blood-filled cystic spaces) are common (in up to 25% of cases)
Ancillary studies ─
─ IHC: Chondroblasts are positive for S100 protein (often strong and diffuse) and SOX9; DOG1 (Discovered on GIST 1) shows characteristic membranous positivity in chondroblasts (useful marker); Vimentin positive; Osteoclast-like giant cells are CD68 positive; Negative for keratins, EMA, Factor XIIIa
─ Molecular: Defined by recurrent heterozygous mutations in the H3F3B gene (encoding histone H3.3, most commonly K36M substitution) or less commonly H3F3A; these mutations are highly specific for chondroblastoma
DDx

─ Giant cell tumor of bone (GCTB) (epiphyseal, but lacks chicken-wire calcification and chondroid matrix, composed of different mononuclear cells, H3F3A mutated, DOG1 negative)
─ Clear cell chondrosarcoma (older age group, more significant atypia, prominent clear cells, S100 positive but lacks H3F3B K36M mutation and DOG1)
─ Enchondroma (different location - metaphysis/diaphysis, different morphology, IDH mutated)
─ Low-grade conventional chondrosarcoma (older age, different location/morphology, IDH mutated)
─ Langerhans cell histiocytosis (eosinophils prominent, Langerhans cells CD1a/Langerin positive, grooved nuclei, lacks chicken-wire calcification)
─ Aneurysmal bone cyst (primary) (lacks solid chondroblastic component, USP6 rearranged; secondary ABC changes can occur in chondroblastoma)
Media ─ placeholder─
─ Pathoutlines WSI WSI WSI & WSI video video

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