Benign adipocytic neoplasm composed of mature adipocytes, bland spindle cells, +/- pleomorphic/floret giant cells, and ropey collagen bundles, often in a myxoid stroma. Considered a spectrum.

Clinical ─ Older adults (peak 45-60s), M >> F; subcutaneous tissue of posterior neck, upper back, shoulder ("buffalo hump")

Macro ─ Well-circumscribed, encapsulated nodule; yellow to gray-white depending on fat/stroma ratio

Micro ─ Mixture in variable proportions:

─ Mature adipocytes

─ Uniform, bland spindle cells with scant cytoplasm (Spindle Cell Lipoma component)

─ Pleomorphic multinucleated giant cells, wreath-like ("floret cells") (Pleomorphic Lipoma component)

─ Short bundles of "ropey" collagen

─ Myxoid stroma common

─ Mast cells numerous

─ No significant atypia (beyond floret cells) or mitoses

IHC ─ (+) CD34 (spindle cells); (+) S100 (adipocytes);(-) SMA, desmin, MDM2, CDK4

Molecular ─ Loss of RB1 gene / 13q deletion

Prognosis ─ Benign; recurrence rare

Media pathoutlines WSI WSI WSI WSI WSI WSI WSI WSI HE CD34

Pleomorphic WSI & video WSI & video WSI & video WSI & video

Chondroid Lipoma

Benign adipocytic neoplasm characterized by lipoblast-like cells in a myxochondroid matrix.

Clinical ─ Adults (20-40s), F > M; proximal extremities, trunk, head/neck; slow-growing, painless mass

Macro ─ Well-circumscribed, encapsulated; lobulated, yellow-tan cut surface; size< 5 cm

Micro

─ nests/cords/strands of cells in myxochondroid matrix; fibrous pseudocapsule

─ lipoblasts in myxochondroid matrix

─ lacks significant atypia, no mitosis, no necrosis

─ plexiform vessels absent (unlike myxoid LPS)

Molecular ─ C11orf95::MKL2 fusion characteristic

Prognosis ─ Benign; recurrence rare

Absolutely! Here are the notes on Synovial Lipomatosis/Lipoma Arborescens following the provided format:

Media ─ pathoutlines WSI

Synovial Lipomatosis / Lipoma Arborescens

Benign condition characterized by villous proliferation of synovium with replacement by mature adipose tissue. Also known as Villous lipomatous proliferation of synovial membrane.

Clinical ─ Older adults; knee joint most common site; associated with osteoarthritis, trauma, chronic irritation; joint swelling, pain, limited motion

Macro ─ Villous, frond-like synovial proliferation; yellow, fatty appearance ("lipoma arborescens" = tree-like lipoma)

Micro

- Villous synovial proliferation

- Villous cores replaced by mature adipose tissue

- Overlying synovium may be hyperplastic or attenuated

- +/- chronic inflammation, fibrin deposition

IHC ─ (+) S100 (adipocytes); Synovial lining cells (+) vimentin, CD68

Molecular ─ Not specified in provided references

Prognosis ─ Benign; symptoms relieved by synovectomy; recurrence possible if underlying cause persists

Media ─ pathoutlines WSI

Neural fibrolipoma

Benign hamartomatous lesion characterized by infiltration of peripheral nerves by fibroadipose tissue. Also known as Lipomatosis of nerve.

Clinical ─ Presents at birth or before age 30; upper extremities (Median nerve mc); slow-growing mass, often associated with macrodactyly and nerve compression symptoms

Macro ─ Fusiform nerve enlargement; yellow, fatty appearance on cross-section

Micro

─ Nerve fascicles separated and expanded by mature adipose tissue and fibrous tissue (fibroadipose tissue)

─ Fibrous tissue often arranged concentrically around nerve fibers ("perineurial fibrosis")

─ Nerve fibers themselves are normal, not neoplastic

IHC ─ (+) S100 (adipocytes, Schwann cells, perineurial cells - weak); (+) EMA (perineurial cells)

Molecular ─ Not specified in provided references

Prognosis ─ Benign; surgical excision difficult due to nerve involvement; recurrence common if incompletely excised

Media ─ pathoutlines WSI WSI

Massive Tumorous Lymphedema

Massive localized lymphedema, often seen in morbidly obese individuals, mimicking a soft tissue neoplasm.

Clinical ─ Morbidly obese adults; lower extremities (esp. thigh), abdominal wall, scrotum; large, elephantiasis-like swelling; may be associated with sleep apnea or venous stasis

Macro ─ Large, poorly defined mass; edematous subcutaneous tissue with thickened fibrous septa; serous fluid leakage; skin may show acanthosis, papillomatosis

Micro ─

─ Expansion of dermis/subcutis by edema and fibrosis

─ Thickened fibrous septa containing scattered bland spindle cells (fibroblasts/myofibroblasts) and chronic inflammation (lymphocytes, plasma cells)

─ Dilated lymphatic channels, often prominent

─ +/- fat necrosis, hemosiderin deposition

─ Dermal sclerosis, hyperkeratosis, acanthosis in overlying skin common

─ No significant atypia or increased mitoses in spindle cells

IHC ─ Non-specific; spindle cells may be (+) SMA; lymphatic channels (+) D2-40/podoplanin

Molecular ─ No specific recurrent genetic alteration known; importantly, lacks MDM2 amplification (unlike WDLS/ALT)

Prognosis ─ Benign, reactive process; can cause significant morbidity; rarely associated with secondary angiosarcoma (Stewart-Treves syndrome analog)

Atypical Spindle Cell Tumor / Pleomorphic Lipomatous Tumor

Low-grade adipocytic neoplasm with features intermediate between spindle cell/pleomorphic lipoma and WDLS/ALT, characterized by atypical spindle cells +/- pleomorphic cells and lipoblasts. Considered part of the WDLS/ALT spectrum by some.

Clinical ─ Adults (wide age range); limbs, trunk; subcutaneous > deep

Macro ─ well-circumscribed, lobulated, yellow-gray mass

Micro

─ Admixture of mature fat, bland spindle cells, and scattered atypical cells

─ Atypical spindle cells: Mildly enlarged, hyperchromatic nuclei

─ +/- Pleomorphic multinucleated cells (similar to pleomorphic lipoma)

─ +/- Lipoblasts (often small, univacuolated)

─ Myxoid or collagenous stroma

─ Low mitotic activity, lacks necrosis

IHC ─ (+) CD34 (spindle cells); (+) S100 (adipocytes, lipoblasts); (-) MDM2, CDK4 (unlike WDLS/ALT)

Molecular ─ Loss of RB1 gene / 13q deletion (like spindle cell/pleomorphic lipoma); lacks MDM2/CDK4 amplification

Prognosis ─ Low risk of local recurrence; potential for dedifferentiation considered very low/absent; essentially benign behavior

Media ─ pathoutlines

Well-Differentiated Liposarcoma/Atypical Lipomatous Tumor

Low-grade malignant adipocytic neoplasm, locally aggressive. ALT is the term used for lesions in sites amenable to complete excision (e.g., limbs), while WDLS is used for lesions in locations where complete excision is difficult or impossible (e.g., retroperitoneum). They represent the same entity.

Clinical ─ Adults (peak 50-70s); deep soft tissues; limbs (especially thigh) and retroperitoneum most common sites

Macro ─ Large, well-circumscribed, lobulated, yellow-tan mass; may have areas of sclerosis

Micro

─ Lipoma-like areas with mature adipocytes, but with variation in adipocyte size and shape

─ Scattered atypical stromal cells with hyperchromatic nuclei

─ Sclerosing areas with dense collagen and atypical cells ("sclerosing WDLS")

─ +/- Lipoblasts (often difficult to find)

─ No significant mitotic activity or necrosis (in classic WDLS/ALT)

IHC ─ (+) MDM2, CDK4 (nuclear staining, reflects gene amplification); (+) S100 (adipocytes)

Molecular ─ Amplification of 12q13-15 region containing MDM2 and CDK4 genes (key diagnostic feature)

Prognosis ─ Locally aggressive; high risk of local recurrence if incompletely excised (especially in retroperitoneum); low risk of distant metastasis (unless dedifferentiated)

Media ─ pathoutlines WSI case & WSI WSI & video WSI & video

WSI HE & p16 & video

Dedifferentiated Liposarcoma (DDLPS)

High-grade sarcoma arising in association with a well-differentiated liposarcoma (WDLS/ALT). The dedifferentiated component is a nonlipogenic sarcoma with variable morphology.

Clinical ─ Adults (peak 50-70s); retroperitoneum most common site; also limbs, paratesticular region; large, deep-seated masses

Macro ─ Large, complex masses; often with areas resembling WDLS/ALT (yellow, fatty) admixed with firm, gray-white areas of dedifferentiated sarcoma; may have hemorrhage and necrosis

Micro

─ Abrupt transition from WDLS/ALT to a high-grade sarcoma (dedifferentiated component)

─ Dedifferentiated component: Variable morphology (most common: undifferentiated pleomorphic sarcoma-like, also fibrosarcoma-like, myxofibrosarcoma-like)

─ May have heterologous elements (e.g., rhabdomyosarcoma, osteosarcoma, chondrosarcoma) in the dedifferentiated component

─ High mitotic activity, necrosis common in the dedifferentiated component

IHC ─ WDLS/ALT component: (+) MDM2, CDK4; Dedifferentiated component: May retain MDM2, CDK4 but often shows variable or loss of expression; other markers depend on the type of dedifferentiation

Molecular ─ MDM2 amplification (present in both WDLS/ALT and often retained in DDLPS); complex karyotype changes in dedifferentiated component

Prognosis ─ Aggressive tumor; high risk of local recurrence and distant metastasis; prognosis depends on the grade and extent of the dedifferentiated component

Media ─ pathoutlines WSI

Myxoid Liposarcoma (MLS)

Malignant adipocytic neoplasm characterized by uniform round/oval cells, univacuolated lipoblasts, and a prominent plexiform ("chicken-wire") capillary network in a myxoid matrix.

Clinical ─ Young to middle-aged adults (peak 30-50s); deep soft tissues of extremities (esp. thigh)

Macro ─ Well-circumscribed, lobulated, gelatinous mass; gray-white to yellow

Micro

─ Uniform, round to oval primitive non-lipogenic mesenchymal cells

─ Variable numbers of univacuolated lipoblasts (signet-ring like)

─ Abundant myxoid stroma (Alcian blue positive)

─ Characteristic branching, plexiform ("chicken-wire") capillary network

─ +/- "Round cell" component (hypercellular areas, indicates higher grade)

IHC ─ (+) S100 (lipoblasts); (+/-) CD34 (vasculature)

Molecular ─ FUS::DDIT3 fusion t(12;16) most common; EWSR1::DDIT3 fusion t(12;22) less common

Prognosis ─ Intermediate malignancy; prone to local recurrence; metastasizes (often to unusual soft tissue sites, bone) especially if round cell component present (>5% round cell = high grade)

Media ─ pathoutlines WSI WSI WSI WSI WSI WSI WSI

WSI & video WSI & video WSI & video WSI & video case & WSI case & WSI

Pleomorphic Liposarcoma (PLS)

High-grade malignant adipocytic neoplasm characterized by marked pleomorphism and the presence of pleomorphic lipoblasts.

Clinical ─ Older adults (peak 50-70s); deep soft tissues of extremities, trunk

Macro ─ Large, fleshy mass; often with hemorrhage and necrosis

Micro

─ High-grade pleomorphic sarcoma

─ Pleomorphic lipoblasts (large, bizarre, multivacuolated cells with scalloped nuclei)

─ Marked nuclear pleomorphism, high mitotic rate, necrosis common

IHC ─ (+) S100 (lipoblasts, variable); (-) MDM2, CDK4

Molecular ─ Complex karyotypes; no specific recurrent translocation; lacks MDM2 amplification and DDIT3 fusions

Prognosis ─ Aggressive sarcoma; high rates of local recurrence and distant metastasis (lung)

Media ─ pathoutlines WSI WSI WSI & video WSI & video WSI & video WSI & video

Myxoid Pleomorphic Liposarcoma (MPLS)

High-grade liposarcoma with features of myxoid liposarcoma and pleomorphic liposarcoma. Rare, possibly represents high-grade MLS or PLS with myxoid change.

Clinical ─ Adults; deep soft tissues

Macro ─ Often large; appearance variable, may resemble MLS or PLS

Micro ─ Areas resembling myxoid liposarcoma (myxoid stroma, plexiform vessels, +/- round cells) juxtaposed with areas resembling pleomorphic liposarcoma (marked pleomorphism, pleomorphic lipoblasts)

Molecular ─ Complex; lacks DDIT3 (unlike MLS) and MDM2 (unlike WDLS/DDLPS)

Prognosis ─ Aggressive; similar to high-grade MLS or PLS

Media ─ pathoutlines

Soft Tissue, Fibroblastic

Nodular Fasciitis

Benign, rapidly growing myofibroblastic proliferation, often following trauma.

Clinical ─ Young adults (peak 20-40s); upper extremities (esp. forearm), trunk; subcutaneous > intramuscular/fascial; rapidly growing (< 6 weeks), sometimes painful; history of trauma in subset

Macro ─ Poorly circumscribed, nodular, gray-white mass; gelatinous; < 3 cm

Micro

─ Unencapsulated with infiltrative borders, esp. fascial/intramuscular

─ More cellular peripherally

─ Plump spindle to stellate cells (myofibroblasts) in short, irregular fascicles

─ "Tissue culture" / "feathery" appearance characteristic

─ Loose, myxoid stroma with extravasated RBCs and chronic inflammation

─ Mitotic figures frequent and can be atypical

IHC ─ (+) SMA (patchy); (-) desmin, S100, keratins, CD34

Molecular ─ MYH9::USP6 fusion

Prognosis ─ Benign; self-limited, may regress spontaneously

Media ─ pathoutlines WSI

Proliferative Fasciitis & Myositis

Rapidly growing pseudosarcomatous proliferation similar to nodular fasciitis but with ganglion-like cells. Fasciitis involves fascia/subcutis, myositis involves skeletal muscle.

Clinical ─ Adults (peak 40-60s, older than nodular fasciitis); extremities (esp. forearm, thigh); rapid growth, often painful

Macro ─ Poorly defined, firm, gray-white mass; infiltrative; usually 1-5 cm

Micro

─ Background similar to nodular fasciitis

─ Characteristic large, polygonal "ganglion-like" cells

─ Mitotic activity can be brisk

IHC ─ Spindle cells (+) SMA; (-) SMA, desmin, S100, keratins

Molecular ─ FOS or FOSB rearrangements in subset

Prognosis ─ Benign; may be self-limited; recurrence rare

Media ─Proliferative fasciitis pathoutlines WSI WSI WSI WSI with video

Proliferative myositis pathoutlines

Myositis Ossificans & Fibro-Osseous Pseudotumor of Digits

Benign, self-limited reactive process characterized by zonal fibroblastic/myofibroblastic proliferation and heterotopic ossification, often following trauma.

Clinical ─ Adolescents and young adults (peak teens-30s); M > F; often history of trauma (~50-60%); extremities (esp. thigh, arm, buttocks) mc site for MO; digits (hands/feet) for FOPD

Macro ─ Well-circumscribed, firm to hard mass; gritty cut surface; may be attached to underlying bone periosteum but distinct

Micro

─ Center: Highly cellular, immature spindle/stellate cells (~nodular fasciitis), myxoid stroma

─ Intermediate zone: Lace-like osteoid production rimmed by plump osteoblasts

─ Periphery: Mature lamellar bone trabeculae, may resemble cortex

─ +/- cartilage formation (esp. near joints)

─ FOPD: Similar but often more cellular, less distinct zonation, may lack mature bone

IHC ─ Spindle cells (+) SMA; osteoblasts (+) SATB2

Molecular ─ USP6 rearrangements in subset

Prognosis ─ Benign; self-limited, matures over time ("burns out"); recurrence uncommon after excision, may resolve spontaneously

Media ─ pathoutlines WSI with video WSI with video video

Keloid

Exuberant scar formation extending beyond the boundaries of the original wound, characterized by thick, hyalinized collagen bundles.

Clinical ─ Any age, more common in darker skin types; sites of prior trauma/surgery/inflammation (earlobes, chest, shoulders, upper back); raised, firm, often pruritic nodule/plaque; may continue to grow over time

Macro ─ Irregular shape extending beyond original injury site

Micro

─ Proliferation of thick, glassy, brightly eosinophilic collagen bundles ("keloidal collagen")

─ Collagen bundles arranged haphazardly

─ Relatively hypocellular with scattered bland fibroblasts

─ Overlying epidermis atrophic with loss of rete ridges

─ Extends beyond the boundaries of the original wound/scar

─ Early lesions may be more cellular and vascular

IHC ─ Not required for diagnosis

Molecular ─ Not applicable

Prognosis ─ Benign; primarily a cosmetic concern

Media WSI WSI WSI WSI

Hypertrophic Scar

Raised scar resulting from excessive collagen deposition during wound healing, but confined to the boundaries of the original wound.

Clinical ─ Develops after skin injury (surgery, trauma, burns, inflammation); raised, often erythematous scar; may be pruritic or tender; tends to regress over time

Macro ─ Raised scar confined to the area of original injury

Micro

─ Increased cellularity (fibroblasts/myofibroblasts) compared to mature scar

─ Collagen bundles finer and more wavy than keloid collagen

─ Collagen bundles arranged parallel to epidermis

─ Increased number of small blood vessels, oriented vertically

─ Lacks brightly eosinophilic collagen bundles characteristic of keloid

IHC ─ Not required

Molecular ─ Not applicable

Prognosis ─ Benign; may regress over time

Media ─ WSI

Elastofibroma

Benign fibroelastic proliferation, typically in subscapular region.

Clinical ─ Elderly (60-70s), F > M; subscapular area (between scapula and chest wall, deep to muscle) mc site; often bilateral

Macro ─ Poorly circumscribed, rubbery; gray-white fibrous tissue with entrapped mature adipose tissue; size ~5-10 cm

Micro

─ Mixture of dense collagenous tissue and mature adipose

─ Abundant, enlarged, fragmented elastic fibers

─ Elastic fibers appear as coarse, brightly eosinophilic, serrated or beaded structures

─ Bland spindle/stellate fibroblasts scattered throughout

IHC ─ Elastic stain (e.g., VVG) highlights abnormal elastic fibers (black)

Molecular ─ No specific recurrent genetic alteration known

Prognosis ─ Benign; recurrence rare

Media ─ pathoutlines WSI WSI

Ischemic Fasciitis

Reactive pseudosarcomatous proliferation associated with chronic pressure/ischemia, typically over bony prominences. Also known as atypical decubital fibroplasia.

Clinical ─ Elderly, debilitated, or immobilized patients; occurs over bony prominences (sacrum, greater trochanter, ischial tuberosity, heel, elbow); often presents as ulcerated nodule or mass

Macro ─ Poorly defined, firm mass associated with ulceration; gray-white to yellow cut surface, may show cystic change

Micro

─ Zonal architecture present

─ Central: Fibrinoid necrosis/degeneration, often with cystic change (pseudocyst)

─ Peripheral: Plump, reactive fibroblasts/myofibroblasts, enlarged/atypical nuclei (degenerative atypia, "ganglion-like cells")

─ Prominent vascular proliferation, with fibrin thrombi, vessels may be perpendicular to surface

─ Chronic inflammation, hemosiderin deposition common

IHC ─ Non-specific

Molecular ─ Not relevant

Prognosis ─ Benign, reactive process

Media ─ pathoutlines WSI WSI WSI H&E CD68 S100 SMA

Fibrous hamartoma of infancy

Benign triphasic proliferation of fibrous tissue, primitive mesenchyme, and mature adipose tissue, occurring in infants and young children.

Clinical ─ Infants & young children (< 2 years); M > F; axilla, upper arm, shoulder, inguinal mc; rapidly growing, painless subcutaneous mass

Macro ─ Poorly circumscribed, firm, gray-white mass with fatty areas

Micro ─ Triphasic pattern with variable proportions:

─ Fascicles of bland spindle cells (fibroblasts/myofibroblasts) resembling fibromatosis

─ Nests/nodules of immature-appearing mesenchymal cells in myxoid stroma

─ Mature adipose tissue interspersed

─ Organoid appearance

─ No significant atypia or mitotic activity

IHC ─ Spindle cells (+) SMA; mesenchymal cells (+) CD34; Adipose (+) S100; (-) Desmin, nuclear β-catenin

Molecular ─ EGFR rearrangements in some

Prognosis ─ Benign; recurrence uncommon

Media ─ pathoutlines WSI WSI WSI WSI WSI WSI & video

Fibromatosis colli

Benign fibroblastic proliferation within the sternocleidomastoid muscle of infants, associated with birth trauma.

Clinical ─ Infants; M > F; firm, painless mass in lower sternocleidomastoid muscle; may cause torticollis (head tilt)

Macro ─ Poorly defined, firm, white-tan fibrous thickening within muscle

Micro

─ Bland spindle cells replacing and entrapping skeletal muscle

─ Entrapped muscle fibers atrophic and degenerated

─ Collagenous stroma

─ No significant atypia or mitotic activity

IHC ─ (+) SMA (spindle cells); (+) Desmin (entrapped muscle)

Molecular ─ Not relevant

Prognosis ─ Benign; resolves spontaneously or with physical therapy; surgery rare

Media ─ pathoutlines

Juvenile hyaline fibromatosis

AR disorder characterized by deposits of hyaline in skin, gingiva, and other tissues.

Clinical ─ Infants and young children; papules/nodules on skin (esp. head/neck, hands, back), gingival hypertrophy, joint contractures

Macro ─ Skin nodules firm, pearly white; gingiva enlarged

Micro

─ Dermal nodules composed of abundant, dense, eosinophilic hyaline material (amorphous glycoprotein)

─ Sparsely cellular with bland spindle to stellate fibroblasts embedded within hyaline material, often arranged in cords

─ Overlying epidermis may be atrophic

IHC ─ Spindle cells (+) Vimentin; Hyaline material (+) PAS

Molecular ─ Germline mutations in ANTXR2 (also called CMG2) gene

Prognosis ─ Benign proliferation but can cause significant morbidity due to joint contractures and organ involvement; skin lesions may recur

Media ─ pathoutlines WSI WSI

Inclusion body fibromatosis

Benign myofibroblastic proliferation on the digits of infants and young children, characterized by intracytoplasmic inclusions. AKA infantile digital fibromatosis.

Clinical ─ Infants and young children (usually < 1 year); digits, typically dorsal/lateral aspects, spares thumb/great toe; firm, painless nodule; often recurs after excision

Macro ─ Poorly defined, firm, gray-white nodule

Micro

─ Dermal proliferation of bland spindle cells (myofibroblasts) in intersecting fascicles

─ Intracytoplasmic, round, eosinophilic inclusions within spindle cells, indenting nucleus

─ Low mitotic activity, no significant atypia

IHC ─ (+) SMA (spindle cells and inclusions); (-) S100, keratins

Molecular ─ None

Prognosis ─ Benign; high rate of recurrence

Media ─ pathoutlines WSI WSI WSI WSI WSI of HE & trichrome

Fibroma of tendon sheath

Benign fibrous nodule attached to tendon or tendon sheath.

Clinical ─ Adults (20-50s), M > F; fingers, hand, wrist; painless nodule attached to tendon

Macro ─ Well-circumscribed, lobulated, firm, gray-white nodule; < 3 cm

Micro

─ Lobulated proliferation of bland spindle cells in dense collagenous stroma

─ Slit-like vascular spaces, prominent at periphery

─ Cellularity varies between lobules (hypo- to moderately cellular)

─ No significant atypia; mitoses rare

─ Cellular variant: More cellular, less collagen, may resemble nodular fasciitis

IHC ─ (+) SMA (variable); (-) S100, desmin, keratins

Molecular ─ USP6 rearrangements in cellular variant

Prognosis ─ Benign; low recurrence rate (~10-25%) after excision

Media ─ pathoutlines WSI WSI & video

Desmoplastic fibroblastoma

Benign fibroblastic neoplasm characterized by paucicellularity and abundant collagenous stroma. AKA collagenous fibroma.

Clinical ─ Middle-aged adults (40-60s), M > F; subcutaneous or skeletal muscle of upper extremities, neck, back, lower extremities; slow-growing, painless mass

Macro ─ Well-circumscribed, firm, white-gray mass; 1-5 cm

Micro ─

─ Circumscribed but unencapsulated, often multinodular

─ Paucicellular proliferation of bland spindle to stellate fibroblasts

─ Abundant dense collagenous to edematous/myxoid stroma

─ Cells have scant cytoplasm, indistinct borders, bland nuclei

─ Minimal vascularity within the tumor nodules

─ Peripheral entrapment of fat or muscle common

─ No significant atypia or mitotic activity

IHC ─ (+) Vimentin; (+/-) SMA, MSA; (-) Desmin, S100, CD34, keratins

Molecular ─ FOSL1 rearrangements in some

Prognosis ─ Benign; recurrence very rare

Media ─ Pathoutlines WSI WSI

Myofibroblastoma

Benign mesenchymal neoplasm of myofibroblasts, often in the breast

Clinical ─ Adults (wide age range); breast, inguinal region, trunk, ext

Macro ─ Well-circumscribed, firm, gray-white nodule

Micro ─

─ Well-circumscribed proliferation of bland spindle cells (myofibroblasts)

─ Cells arranged in short fascicles, separated by thick hyalinized collagen bundles

─ Scant to moderate eosinophilic cytoplasm, oval nuclei, inconspicuous nucleoli

─ Variable cellularity and stromal collagen

─ Low mitotic activity, no necrosis

─ Variants: Cellular, epithelioid, collagenized/fibrous, lipomatous, myxoid

IHC ─ (+) CD34, desmin (diffuse), ER, PR, AR (variable); (+/-) SMA; (-) S100, keratins

Molecular ─ Loss of 13q14 (including RB1 and FOXO1)

Prognosis ─ Benign; recurrence rare

Media ─ WSI WSI

Calcifying aponeurotic fibroma

Distinctive fibroblastic proliferation of childhood and adolescence characterized by calcification and chondroid metaplasia, typically involving distal extremities. AKA juvenile aponeurotic fibroma.

Clinical ─ Children and adolescents (peak 5-15 years), M > F; hands (palms) and feet (soles) mc; slow-growing, firm nodule, may be fixed to deep structures

Macro ─ Poorly defined, firm, gray-white mass with gritty areas; infiltrative

Micro ─

─ Poorly circumscribed, infiltrative proliferation of bland spindle cells

─ Central calcification, surrounded by palisading epithelioid fibroblasts/chondrocyte-like cells

─ +/- islands of chondroid metaplasia

─ Background stroma fibrous

─ Low mitotic activity, minimal atypia

IHC ─ (+) SMA (variable in spindle cells); (+) S100 (chondroid); (-) CD34, desmin

Molecular ─ FN1::EGF fusion

Prognosis ─ Benign; high rate of recurrence due to infiltration; mets do not occur

Media ─ pathoutlines WSI WSI WSI WSI WSI WSI

EWSR1::SMAD3-positive fibroblastic tumor

Rare fibroblastic tumor characterized by specific fusion, presenting in acral sites.

Clinical ─ Young adults (~30s); distal extremity (hands/feet) mc; subcutaneous tissue

Macro ─ Small (< 3 cm), well-circumscribed nodule

Micro ─

─ Well-circumscribed nodule, multilobulated

─ Bland spindle cells in fascicles or sheets

─ Characteristic peripheral hypercellularity with central hypocellular hyalinized or myxoid area

─ Central areas may show calcification or ossification

─ Minimal atypia, low mitotic activity

IHC ─ (+) ERG (nuclear); (+/-) CD34, SMA, desmin; (-) S100, keratins, MUC4

Molecular ─ EWSR1::SMAD3 fusion

Prognosis ─ Low potential for recurrence

Media ─ pathoutlines

Angiomyofibroblastoma

Benign mesenchymal neoplasm of bland spindle/epithelioid cells and numerous small-to-medium sized blood vessels, occurring in vulvovaginal region.

Clinical ─ Adult women (reproductive age, 25-50s); vulva > vagina, perineum; rare in men (inguinoscrotal); well-circumscribed, painless subcutaneous mass

Macro ─ Well-circumscribed, soft to rubbery; often gelatinous; usually < 5 cm

Micro ─

─ Well-circumscribed, often pseudocapsule

─ Alternating hypercellular and hypocellular/edematous areas

─ Bland, plump spindle to epithelioid cells, cluster around small to medium-sized vessels

─ Vessels often hyalinized

─ Stroma edematous to myxoid

─ No significant atypia or mitotic activity

IHC ─ (+) Desmin, ER, PR; (+/-) SMA; (-) CD34, S100, keratins

Molecular ─ MTG1(ETV6)::CYP2E1 fusion in some

Prognosis ─ Benign; recurrence rare

Media ─ Pathoutlines WSI WSI & video WSI & video WSI video

Gardner fibroma

Benign fibroblastic proliferation associated with familial adenomatous polyposis (FAP) and Gardner syndrome.

Clinical ─ Infants and children (< 10 years); trunk (esp. paraspinal), head/neck; subcutaneous nodule

Macro ─ Poorly defined, firm, white fibrous mass

Micro ─

─ Poorly circumscribed, infiltrative proliferation

─ Hypocellular proliferation of bland spindle cells (fibroblasts)

─ Dense, haphazardly arranged collagen bundles ("cracked collagen" appearance)

─ Minimal vascularity

─ Entrapment of adipose tissue and adnexal structures common

─ No atypia or mitotic activity

IHC ─ (+) Nuclear β-catenin (variable); (-) SMA, desmin, S100

Molecular ─ Associated with germline APC mutations

Prognosis ─ Benign; may recur locally; potential association/progression to desmoid fibromatosis in FAP patients

Media ─ pathoutlines

Palmar fibromatosis and plantar fibromatosis

Benign fibroblastic/myofibroblastic proliferations involving the palmar or plantar aponeurosis. Palmar = Dupuytren contracture; Plantar = Ledderhose disease.

Clinical ─ Adults (palmar older > plantar); M > F; palmar fascia or plantar aponeurosis; presents as nodules/cords causing finger contractures (palmar) or foot pain (plantar)

Macro ─ Nodular or cord-like fibrous thickening of fascia

Micro ─

─ Nodular proliferation of bland spindle cells (fibroblasts/myofibroblasts)

─ Cells arranged in short fascicles or nodules

─ Dense collagenous stroma

─ Cellularity varies (early lesions more cellular, older lesions more collagenous)

─ Low mitotic activity, no significant atypia

─ Infiltrates surrounding structures (tendons, fat)

IHC ─ (+) SMA; (+/-) Nuclear β-catenin (less consistent than desmoid)

Molecular ─ Often trisomies 7 and/or 8; distinct from desmoid (CTNNB1/APC)

Prognosis ─ Benign; high rate of recurrence after excision, especially plantar

Media ─ pathoutlines video WSI (plantar) WSI (palmar)

Desmoid fibromatosis

Myofibroblastic neoplasm with infiltrative growth and tendency for local recurrence, but no metastatic potential. AKA deep fibromatosis, aggressive fibromatosis.

Clinical ─ Young to middle-aged adults (peak 30s); F > M; intra-abdominal, abdominal wall, extra-abdominal (limb girdles, head/neck); slow-growing, firm mass; associated with FAP/Gardner syndrome (APC mutation) or sporadic (CTNNB1 mutation)

Macro ─ Poorly circumscribed, firm, rubbery, gray-white mass; infiltrative

Micro ─

─ Infiltrative proliferation of bland, uniform spindle cells (myofibroblasts)

─ Cells arranged in long, sweeping fascicles

─ Pale eosinophilic cytoplasm, oval nuclei with fine chromatin, small nucleoli

─ Collagenous stroma, variable myxoid change

─ Characteristic thin-walled, elongated vessels

─ Infiltrates adjacent skeletal muscle (causing atrophy) and fat

─ Low mitotic activity (usually < 2/10 HPF), no atypia or necrosis

IHC ─ (+) Nuclear β-catenin; (+) SMA; (+/-) Desmin; (-) S100, CD34, keratins

Molecular ─ CTNNB1 (sporadic) or germline APC mutations (FAP-associated)

Prognosis ─ Locally aggressive; high recurrence; does not metastasize

Media ─ pathoutlines WSI WSI WSI WSI WSI

case & WSI WSI of HE β-catenin Desmin SMA CD34

Lipofibromatosis

Benign fibroblastic/adipocytic tumor of infancy and early childhood characterized by infiltration of adipose tissue by bland spindle cells.

Clinical ─ Infants and young children (usually < 2 years); M > F; hands and feet mc sites; painless, slow-growing mass

Macro ─ Poorly circumscribed, firm, yellow-gray mass

Micro ─

─ Poorly circumscribed, infiltrative proliferation

─ Bland spindle cells (fibroblasts) infiltrating and replacing mature adipose tissue

─ Adipocytes often appear entrapped

─ Spindle cells arranged in fascicles

─ Stroma variably collagenous or myxoid

─ No significant atypia or mitotic activity

IHC ─ (+) CD34; (-) S100 (except fat), keratins

Molecular ─ No specific recurrent genetic alteration known; distinct from infantile fibrosarcoma

Prognosis ─ Benign; prone to recurrence

Media ─ pathoutlines WSI WSI

Calcifying fibrous tumor

Rare benign mesenchymal neoplasm characterized by hyalinized collagenous stroma, bland spindle cells, psammomatous/dystrophic calcifications, and a lymphoplasmacytic infiltrate.

Clinical ─ Children and young adults (wide age range); deep soft tissues (extremities, trunk, neck, Mediastinum, pleura, peritoneum); slow-growing, painless mass

Macro ─ Well-circumscribed, unencapsulated, firm, white-gray nodule; may feel gritty

Micro ─

─ Well-circumscribed, often multinodular

─ Paucicellular proliferation of bland spindle cells (fibroblasts)

─ Dense, hyalinized collagenous stroma

─ Characteristic psammomatous and/or dystrophic calcifications

─ Prominent lymphoplasmacytic infiltrate, often forming lymphoid aggregates/follicles

─ No atypia or mitotic activity

IHC ─ (+) Factor XIIIa, CD34 (variable); (-) SMA, desmin, S100, keratins, ALK

Molecular ─ None

Prognosis ─ Benign; very low rate of local recurrence

Media ─ pathoutlines case & WSI

Giant cell fibroblastoma (GCFP)

Low-grade fibroblastic neoplasm characterized by spindle cells and multinucleated giant cells lining pseudovascular spaces.

Clinical ─ Children (mc < 10 years), M > F; trunk (esp. back), thigh, inguinal region; slow-growing subcutaneous nodule

Micro ─

─ Poorly circumscribed dermal/subcutaneous tumor

─ Hypocellular areas with myxoid stroma alternating with more cellular areas

─ Bland spindle cells, arranged loosely or around pseudovascular spaces

─ Irregular, branching, sinusoid-like pseudovascular spaces lined by bland spindle cells and multinucleated giant cells

─ Minimal atypia, low mitotic activity

IHC ─ (+) CD34 (diffuse); (-) S100, SMA, desmin, keratins

Molecular ─ COL1A1::PDGFB fusion (same as DFSP)

Prognosis ─ Low-grade malignancy; high rate of recurrence

Media ─ pathoutlines WSI & video

Dermatofibrosarcoma protuberans (DFSP)

Low-intermediate grade fibroblastic neoplasm characterized by storiform growth pattern and infiltration into subcutaneous fat.

Clinical ─ Young to middle-aged (peak 30-50s); trunk > proximal extremities, head/neck; slow-growing plaque or nodule(s)

Macro ─ Firm, plaque-like or multinodular mass; gray-white cut surface; infiltrative

Micro ─

─ Dermal-based, infiltrative proliferation of uniform, bland spindle cells

─ Characteristic storiform ("cartwheel") arrangement of cells

─ Infiltration into subcutaneous fat in a "honeycomb" pattern (entraps adipocytes)

─ Low mitotic activity, minimal pleomorphism, necrosis rare

─ Variants: Myxoid, pigmented (Bednar tumor), giant cell fibroblastoma (see above)

─ Fibrosarcomatous transformation (DFSP-FS): high-grade fascicular areas resembling fibrosarcoma, increased mitoses/necrosis

IHC ─ (+) CD34 (diffuse); (-) Factor XIIIa, S100, SMA, desmin, keratins

Molecular ─ COL1A1::PDGFB fusion t(17;22)

Prognosis ─ Low-grade malignancy; high rate of recurrence due to infiltrative growth

Media ─ pathoutlines case & WSI

Solitary fibrous tumor (SFT)

Ubiquitous mesenchymal neoplasm, characterized by spindle cells in "patternless" pattern with “staghorn”-like vessels.

Clinical ─ Adults (wide age); pleura, deep soft tissues, meninges; slow-growing

Macro ─ Well-circumscribed, lobulated; gray-white, fibrous cut surface; size varies

Micro ─

─ Variable cellularity, often alternating hypo- and hypercellular areas ("patternless pattern")

─ Bland spindle to ovoid cells with indistinct cytoplasm

─ Stroma variably collagenous (keloidal collagen common) or myxoid

─ Characteristic branching, thin-walled, "staghorn" or hemangiopericytoma-like vessels

─ Mitoses usually low (< 4/10 HPF in benign/intermediate)

─ Malignant SFT criteria: Increased cellularity, pleomorphism, high mitoses (≥ 4/10 HPF), necrosis

IHC ─ (+) STAT6 (nuclear, highly sensitive/specific); (+) CD34 (most cases); (+) CD99, BCL2 (variable); (-) S100, SMA, desmin, keratins

Molecular ─ NAB2::STAT6 fusion

Prognosis ─ Most benign/intermediate; risk based on age, size, mitoses, necrosis

Media ─ pathoutlines WSI WSI WSI WSI HE CD34 video

Inflammatory myofibroblastic tumor (IMT)

Neoplasm of myofibroblastic cells with prominent lymphoplasmacytic infiltrate.

Clinical ─ Children and young adults (Median ~10-30s); lung, mesentery, retroperitoneum common, can occur anywhere

Macro ─ Well-circumscribed or infiltrative; fleshy; +/- myxoid or hemorrhagic areas

Micro ─

─ Spindle cells (myofibroblasts) in fascicles or loosely arranged

─ Variable cellularity; often myxoid or edematous stroma

─ Prominent infiltrate: Plasma cells, lymphocytes, eosinophils, +/- neutrophils

─ +/- Large ganglion-like cells in spindle cell component

─ Mitotic activity variable, atypical mitoses rare

IHC ─ (+) SMA, ALK (cytoplasmic, ~50% cases); (+/-) desmin, CD68; (-) S100, keratins

Molecular ─ ALK >> ROS1, NTRK3, RET rearrangements

Prognosis ─ Intermediate (rarely metastasizing); recurrence common; rare cases metastasize (RANBP2::ALK fusion or epithelioid morphology)

Media ─ Pathoutlines WSI of HE actin CD10 desmin WSI

WSI & video WSI & video WSI & video video video

Myxoinflammatory fibroblastic sarcoma (MIFS)

Low-grade sarcoma characterized by a bizarre mix of cells including large ganglion-like cells and pseudolipoblasts, set in myxoid and inflammatory background.

Clinical ─ Adults (40-60s); distal extremities (hands/feet mc), subcutaneous tissue

Macro ─ Multinodular, poorly circumscribed; gelatinous

Micro ─

─ Multinodular growth, often infiltrative

─ Myxoid stroma with prominent infiltrate (lymphs, plasma cells, neutrophils, eosinophils)

─ Characteristic bizarre cell population:

─ Ganglion-like cells (Reed-Sternberg-like) with large nuclei, prominent nucleoli

─ Spindle cells with enlarged, hyperchromatic nuclei

─ Pseudolipoblasts (vacuolated cells resembling lipoblasts)

─ Low mitotic activity

IHC ─ Non-specific; tumor cells often (+) histiocytic markers

Molecular ─ TGFBR3 rearrangements

Prognosis ─ Low-grade; high rate of recurrence; metastasis rare

Media ─ pathoutlines WSI WSI WSI WSI WSI

WSI with video WSI with video

Infantile fibrosarcoma

Malignant spindle cell neoplasm occurring in infancy, characterized by ETV6::NTRK3 fusion.

Clinical ─ Infants; extremities > trunk, head/neck; rapidly growing, may be congenital

Macro ─ Poorly circumscribed, fleshy; hemorrhage and necrosis common

Micro ─

─ Densely cellular proliferation of relatively uniform spindle cells

─ Intersecting fascicles ("herringbone" pattern)

─ Primitive round cell component may be present

─ Mitotic activity brisk

─ Minimal pleomorphism

IHC ─ (+) Pan-TRK (surrogate for fusion); (-) S100, desmin, keratins

Molecular ─ ETV6::NTRK3 fusion

Prognosis ─ Intermediate; better than adult fibrosarcoma; chemoresponsive

Media ─ pathoutlines WSI WSI WSI

Adult fibrosarcoma

Malignant neoplasm composed of spindle cells in fascicles, showing variable collagen production; considered a diagnosis of exclusion.

Clinical ─ Adults (wide age); deep soft tissue of extremity (esp. thigh), trunk, head/neck

Macro ─ Unencapsulated, fleshy; appears circumscribed; +/- hemorrhage, necrosis

Micro ─

─ Monomorphic spindle cells in intersecting fascicles ("herringbone" pattern)

─ Variable collagen

─ High cellularity, high mitotic rate

─ Minimal pleomorphism (unlike UPS) or inflammation

─ Necrosis common

IHC ─ Non-specific

Molecular ─ None

Prognosis ─ Aggressive; high rate of recurrence and distant metastasis (lung)

Media ─ pathoutlines WSI WSI

Myxofibrosarcoma

Malignant fibroblastic neoplasm with variable myxoid stroma, cellularity, pleomorphism, and prominent curvilinear vessels.

Clinical ─ Older adults (60-80s); extremities (lower) > trunk; dermal/subq > deep

Macro ─ Multinodular, gelatinous cut surface; infiltrative; size variable

Micro ─

─ Infiltrative growth, often multinodular

─ Variable cellularity, often hypocellular myxoid areas peripherally, more cellular centrally

─ Spindle to stellate cells, variable pleomorphism (key feature for grading)

─ Abundant myxoid stroma (Alcian blue positive)

─ Prominent elongated, curvilinear, thin-walled vessels

─ Pseudolipoblasts (vacuolated cells) common

─ Grading (3-tiered): Based on cellularity, pleomorphism, necrosis, mitoses

IHC ─ Non-specific; (+) vimentin (often); (+/-) SMA, CD34; (-) S100, desmin, keratins

Molecular ─ Complex karyotypes with gains/losses; no specific recurrent genetic alteration

Prognosis ─ High rate of local recurrence (esp. low grade due to infiltrative margins); metastasis risk correlates with grade and depth (HG/deep tumors more likely to metastasize, mainly to lung)

Media ─ pathoutlines WSI WSI WSI WSI with video WSI with video

Low-Grade Fibromyxoid sarcoma (LGFMS)

Malignant fibroblastic neoplasm characterized by bland spindle cells alternating between fibrous and myxoid areas, often with curvilinear vessels.

Clinical ─ Young to middle-aged adults (peak 30-50s); deep soft tissues of trunk, proximal extremities (esp. thigh); slow-growing, often painless mass

Macro ─ Well-circumscribed, firm, lobulated; white-tan fibrous cut surface with glistening myxoid areas

Micro ─

─ Alternating fibrous and myxoid zones

─ Bland, uniform spindle cells with scant cytoplasm

─ Whorling or fascicular growth pattern in fibrous areas

─ Hypocellular myxoid areas with curvilinear capillaries

─ Low mitotic activity, minimal atypia, necrosis usually absent

─ +/- Giant collagen rosettes (Hyalinizing Spindle Cell Tumor with Giant Rosettes variant)

IHC ─ (+) MUC4 (highly sensitive/specific); (+/-) EMA, CD99, BCL2; (-) S100, SMA, desmin, CD34

Molecular ─ FUS::CREB3L2 >> FUS::CREB3L1 or EWSR1::CREB3L1

Prognosis ─ Indolent but persistent; high rate of recurrence; late metastasis (lung)

Media ─ pathoutlines WSI WSI

WSI Hyalinizing Spindle Cell Tumor with Giant Rosettes

WSI Sclerosing epithelioid fibrosarcoma

Infantile fibromatosis

Benign fibroblastic/myofibroblastic proliferation occurring in infancy and early childhood.

Clinical ─ Within first 2 years of life; M > F; extremities (esp. distal), head/neck, trunk; often rapid initial growth

Macro ─ Poorly circumscribed, firm, gray-white mass; infiltrative

Micro ─

─ Variably cellular proliferation of bland spindle cells (fibroblasts/myofibroblasts)

─ Fascicular or storiform growth pattern

─ Infiltrates skeletal muscle and adipose tissue

─ Myxoid or collagenous stroma

─ Mitotic activity can be brisk, but no atypical mitoses

─ No significant nuclear atypia or pleomorphism

IHC ─ (-) S100, keratins, β-catenin (nuclear)

Molecular ─ None

Prognosis ─ Benign; does not metastasize; may recur or spontaneously regress

Soft Tissue, Fibrohistiocytic

Tenosynovial giant cell tumor (TGCT)

Benign neoplasm arising from synovium; characterized by mononuclear cells, multinucleated giant cells, foam cells, and hemosiderin deposition. Includes localized (GCT of tendon sheath) and diffuse (PVNS) types.

Clinical ─ Young to middle-aged (30-50s)

─ Localized (Giant Cell Tumor of Tendon Sheath): hand (fingers); painless nodule

─ Diffuse (Pigmented Villonodular Synovitis - PVNS): large joints (knee > hip); pain, swelling

Macro ─

─ Localized: Well-circumscribed, lobulated, firm nodule; yellow-brown cut surface

─ Diffuse: Ill defined, villous or nodular synovial thickening; red-brown due to hemosiderin

Micro ─

─ Variable mixture of:

─ Mononuclear cells: Round to oval stromal/histiocytoid cells (likely neoplastic component)

─ Osteoclast-like multinucleated giant cells

─ Foam cells (lipid-laden macrophages)

─ Hemosiderin-laden macrophages

─ Background chronic inflammation (lymphocytes)

─ Fibrous stroma, variable collagen

─ Localized: Well-circumscribed nodules, fibrous pseudocapsule

─ Diffuse: Infiltrative growth into synovium/soft tissue; villous projections common

IHC ─ (+) CD68, CD163; (-) S100, keratins

Molecular ─ CSF1 rearrangement

Prognosis

─ Benign; does not metastasize

─ Localized: Low recurrence rate after complete excision

─ Diffuse: High rate of local recurrence due to infiltrative nature; can cause significant joint destruction

Media ─ pathoutlines WSI WSI WSI WSI WSI WSI desmin WSI HE trichrome iron

Fibrous histiocytoma

Common benign dermal neoplasm composed of fibroblasts, histiocytes, and myofibroblasts. Also known as Dermatofibroma or Benign fibrous histiocytoma.

Clinical ─ Adults (any age, peak 20-50s); lower > upper extremities, trunk; firm, pigmented papule or nodule

Macro ─ Small (< 1-2 cm), firm, dermal nodule; color varies

Micro ─

─ Dermal-based, poorly circumscribed proliferation (spares papillary dermis)

─ Admixture of bland spindle cells (fibroblasts/myofibroblasts) and histiocytoid cells

─ Arranged in short fascicles or storiform pattern

─ Trapping of collagen bundles at periphery ("collagen trapping") common

─ Overlying epidermal hyperplasia (acanthosis) frequent

─ +/- hemosiderin deposition, foam cells, multinucleated giant cells (Touton type rare)

─ Variants: Cellular, aneurysmal, epithelioid, atypical, deep

IHC ─ (+) Factor XIIIa (variable); (-) CD34 (DDx with DFSP), S100, keratins

Molecular ─ None

Prognosis ─ Benign; recurrence uncommon after simple excision

Media ─ pathoutlines WSI WSI WSI WSI WSI

Deep Fibrous Histiocytoma

Benign fibrous histiocytoma arising in deep soft tissue or subcutis rather than dermis.

Clinical ─ Adults (wide age); extremities, head/neck, trunk

Macro ─ Well-circumscribed;larger than dermal FH

Micro ─

─ Similar to dermal FH but located deeper

─ Storiform pattern often prominent

─ Admixture of spindle cells and histiocytoid cells

─ +/- foam cells, multinucleated giant cells, hemosiderin

─ Usually lacks epidermal changes (acanthosis) seen in dermal FH

─ Low mitotic activity, minimal atypia

IHC ─ (+) Factor XIIIa (variable); (+/-) SMA, CD68; (-) CD34, S100, keratins

Molecular ─ None

Prognosis ─ Benign; higher recurrence rate than dermal FH

Media ─ pathoutlines WSI WSI HE FXIIIa CD34

Epithelioid fibrous histiocytoma

Variant of fibrous histiocytoma characterized by a prominent epithelioid cells.

Clinical ─ Young adults; extremities mc; often presents as reddish papule or nodule

Macro ─ Small (< 1 cm), well-circumscribed dermal nodule; often reddish or brown

Micro ─

─ Dermal proliferation, often well-circumscribed, may have epidermal collarette

─ Plump epithelioid cells with round vesicular nuclei, small nucleoli, abundant cytoplasm

─ Cells arranged in sheets, nests, or singly

─ Variable admixture of conventional spindle cells, lymphocytes, eosinophils

─ +/- hemosiderin, foam cells, giant cells

─ Low mitotic activity

IHC ─ (+) ALK (nuclear and/or cytoplasmic, characteristic but not always present)

Molecular ─ ALK rearrangements

Prognosis ─ Benign; recurrence uncommon

Media ─ Pathoutlines WSI of EMA & HE WSI WSI video & WSI

Cellular Fibrous Histiocytoma

Variant of fibrous histiocytoma characterized by high cellularity and fascicular growth, potentially extending into subcutaneous fat.

Clinical ─ Adults; extremities, trunk; larger and deeper than conventional FH

Macro ─ Firm nodule, poorly circumscribed

Micro ─

─ Dermal-based, often extending into subcutis

─ Highly cellular proliferation of spindle cells

─ Often arranged in fascicles or storiform pattern

─ Higher mitotic activity than conventional FH, but usually lacks atypical mitoses

─ Minimal pleomorphism

─ +/- hemosiderin, foam cells, giant cells

IHC ─ (+) Factor XIIIa (variable); (+) SMA (more prominent than conventional FH)

Molecular ─ No specific recurrent genetic alteration known

Prognosis ─ Benign; may have slightly higher recurrence rate than conventional FH, especially if deep extension or incomplete excision

Media ─ atypical WSI WSI

Plexiform fibrohistiocytic tumor

Intermediate (rarely metastasizing) fibrohistiocytic neoplasm occurring in children and young adults, characterized by a plexiform arrangement of cellular nodules.

Clinical ─ Children & young adults (~15 years), F > M; upper extremities (hand/wrist) > lower extremities; painless subcutaneous or dermal nodule/plaque

Macro ─ Poorly circumscribed, firm nodule or plaque

Micro ─

─ Dermal and/or subcutaneous tumor with infiltrative growth

─ Characteristic plexiform pattern (at least focally)

─ Biphasic components:

─ Cellular nodules: Composed of mononuclear histiocytoid cells, osteoclast-like giant cells, +/- inflammatory cells

─ Spindle cell fascicles: Fibroblast/myofibroblast-like cells arranged between the nodules

─ Low to moderate mitotic activity, minimal pleomorphism

IHC ─ Mononuclear cells (+) CD68, CD163

Molecular ─ None

Prognosis ─ Intermediate; high rate of recurrence

Media ─ pathoutlines WSI WSI

Giant cell tumor of soft tissue

Rare mesenchymal neoplasm histologically similar to giant cell tumor of bone, but arising in soft tissue without bone involvement.

Clinical ─ Adults (wide age range, peak 40-50s); superficial soft tissues (dermis/subcutis) of extremities (esp. lower) > trunk; usually presents as painless nodule

Macro ─ Well-circumscribed, lobulated nodule; red-brown or tan cut surface; usually small (< 3 cm)

Micro ─

─ Well-circumscribed, often lobulated

─ Composed of two main cell types:

─ Mononuclear stromal cells: Round to oval cells with vesicular nuclei, indistinct cytoplasm (neoplastic component)

─ Osteoclast-like multinucleated giant cells: Evenly distributed

─ +/- hemosiderin deposition, secondary aneurysmal bone cyst-like changes, reactive bone formation at periphery

─ Mitotic activity present in mononuclear cells, but usually low and lacks atypical forms

IHC ─ Mononuclear cells (+/-) SMA, CD68; Giant cells (+) CD68; (-) S100, keratins, desmin; Importantly (-) H3.3 G34W/V/R/L (unlike GCT of bone)

Molecular ─ Lacks H3F3A mutations (unlike GCT of bone)

Prognosis ─ Mostly benign/intermediate; local recurrence possible (~15%); rare metastases reported (considered low malignant potential)

Media ─ pathoutlines

Soft Tissue, Vascular

Papillary endothelial hyperplasia

Reactive intravascular papillary proliferation of endothelial cells, associated with thrombus. Also known as Masson's tumor or intravascular papillary endothelial hyperplasia (IPEH).

Clinical ─ Any age, any site (skin/subcutis mc); often presents as small, sometimes tender, reddish-blue nodule; may occur within organizing hematomas or pre-existing vascular lesions (e.g., hemangioma, vascular malformation)

Macro ─ Small nodule within a vessel lumen or hematoma; reddish-blue

Micro ─

─ Intravascular location (within a dilated vessel or organizing thrombus) is key

─ Papillary structures with hyaline or fibrin cores

─ Papillae lined by a single layer of bland, plump endothelial cells

─ Associated organizing thrombus frequently present

─ No significant cytologic atypia, necrosis, or increased/atypical mitoses

IHC ─ (+) CD31, CD34, ERG, FLI1 (endothelial cells); (-) markers to exclude mimics (e.g., keratins)

Molecular ─ Not applicable (reactive process)

Prognosis ─ Benign reactive process; excision is curative if symptomatic

Media ─ pathoutlines WSI WSI

Cavernous Hemangioma

Benign vascular lesion composed of large, dilated vascular channels; often considered a type of venous malformation.

Clinical ─ Any age, often congenital or childhood; skin/subcutis, liver, spleen, deep soft tissues; soft, compressible mass, may be blue

Macro ─ Poorly circumscribed, spongy mass; red-blue; may contain phleboliths

Micro ─

─ Large, dilated, irregularly shaped vascular channels lined by flattened endothelial cells

─ Thin walls composed mainly of fibrous tissue, variable smooth muscle

─ Channels often closely packed with minimal intervening stroma

─ +/- organizing thrombi, phleboliths, hemosiderin deposition

─ No significant atypia or increased mitoses

IHC ─ Not specific; endothelial cells (+) CD31, CD34, ERG; smooth muscle (+/-) SMA

Molecular ─ None specific mentioned in references

DDx ─

─ Venous Malformation (Often considered synonymous or overlapping)

─ Lymphatic Malformation (Lacks RBCs, D2-40+)

─ Angiosarcoma (Atypia, mitoses, infiltrative growth, complex architecture)

Prognosis ─ Benign; may cause symptoms due to mass effect or thrombosis

Media ─ WSI

Synovial hemangioma

Benign vascular lesion involving synovium, representing a vascular malformation.

Clinical ─ Children and young adults; knee mc site; joint pain, swelling, hemarthrosis

Macro ─ Lobulated, spongy, red-brown mass involving synovium

Micro ─

─ Proliferation of variably sized vascular channels within synovial tissue

─ Vessels thin-walled, cavernous, or capillary-sized; may resemble venous or AV malformation

─ +/- organizing thrombi, hemosiderin deposition, papillary synovial hyperplasia

─ No significant atypia or mitoses

IHC ─ Not specific; endothelial cells (+) CD31, CD34, ERG

Molecular ─ none

DDx ─

─ Tenosynovial giant cell tumor, diffuse type (PVNS) (Lacks prominent vascular channels, characteristic mononuclear/giant cells)

─ Angiosarcoma (Rare in synovium; shows atypia, mitoses, infiltrative growth)

Prognosis ─ Benign; may recur if incompletely excised; can cause joint damage

Media ─ WSI

Intramuscular hemangioma

Benign vascular lesion within skeletal muscle, representing a vascular malformation.

Clinical ─ Children and young adults (mc < 30 years); extremities (esp. lower), trunk, head/neck

Macro ─ Poorly circumscribed, infiltrative mass within muscle; spongy, red-brown; +/- adipose tissue component

Micro ─

─ Infiltrative proliferation of vascular channels within skeletal muscle

─ Vessel type varies: capillary, cavernous (venous), thick-walled (arterial/venous) or mixed

─ Often admixed with mature adipose (confusingly called "infiltrating angiolipoma" - unrelated to true angiolipoma)

─ Entrapped, often atrophic skeletal muscle fibers

─ +/- organizing thrombi, phleboliths, hemosiderin

─ No significant atypia or mitoses

IHC ─ Not specific; endothelial cells (+) CD31, CD34, ERG; smooth muscle (+/-) SMA

Molecular ─ none

DDx ─

─ Angiosarcoma (Atypia, mitoses, necrosis, prominent endothelial tufting)

─ Kaposiform Hemangioendothelioma (More cellular, spindle cell component, in children)

─ Arteriovenous Malformation (More prominent thick-walled arteries)

Prognosis ─ Benign; high rate of recurrence

Media ─ WSI

Arteriovenous malformation (AVM) / Arteriovenous hemangioma

Developmental vascular anomaly characterized by abnormal direct connections between arteries and veins, bypassing the capillary bed.

Clinical ─ Present at birth or develops later; head/neck, brain, extremities common sites; may present as pulsatile mass

Macro ─ Tangled mass of abnormal vessels; may be poorly defined

Micro ─

─ Collection of abnormally formed arteries, veins, and intermediate vessels

─ Arteries often show irregular wall thickness, fragmented internal elastic lamina

─ Veins often dilated, may show "arterialization" (thickened walls)

─ Intervening stroma may show fibrosis, inflammation, hemosiderin

─ Capillary component may be present

─ No significant endothelial atypia or mitoses

IHC ─ Not specific; endothelial markers (+); elastic stain highlights arterial components

Molecular ─ Sporadic; some associated with syndromes

DDx ─

─ Other vascular malformations (Venous, Capillary, Lymphatic) (Lack direct AV shunting, different vessel morphology)

─ Angiosarcoma (Malignant features)

─ Intramuscular Hemangioma (May have AVM component but often mixed)

Prognosis ─ Benign, significant morbidity; recurrence/persistence common

Media ─ pathoutlines

Venous hemangioma / Venous malformation (VM)

Developmental anomaly composed of abnormally dilated vein-like channels.

Clinical ─ Present at birth, may become apparent later

Macro ─ Poorly circumscribed, spongy mass; blue/purple; may contain phleboliths

Micro ─

─ Irregularly shaped, dilated vascular channels resembling veins

─ Thin walls composed of fibrous tissue and variable amounts of smooth muscle

─ Lined by flattened endothelial cells

─ +/- organizing thrombi, phleboliths, dystrophic calcification

─ No significant atypia or mitoses

IHC ─ Not specific; endothelial markers (+); smooth muscle (+/-) SMA

Molecular ─ Sporadic; activating mutations in TEK (TIE2) common; PIK3CA mutations also occur

DDx ─

─ Cavernous Hemangioma (Often considered synonymous or overlapping)

─ Lymphatic Malformation (Lacks RBCs, D2-40+)

─ Other vascular malformations (Capillary, AVM)

─ Angiosarcoma (Malignant features)

Prognosis ─ Benign malformation; does not regress

Media ─ pathoutlines WSI

Anastomosing hemangioma

Benign vascular neoplasm characterized by anastomosing sinusoidal capillary-sized vessels.

Clinical ─ Adults (wide age range); kidney (esp. near hilum) mc site; also occurs in soft tissue (para-testicular, retroperitoneum, extremities); often incidental finding

Macro ─ Poorly defined, hemorrhagic, spongy mass; variable size

Micro ─

─ Lobular proliferation of anastomosing sinusoidal-like vessels

─ Mildly hobnailed endothelial cells, minimal atypia

─ Intraluminal fibrin, +/- organizing thrombi

─ Extramedullary hematopoiesis common (esp. in renal/retroperitoneal)

─ Hyaline globules (PAS+) within cytoplasm or stroma

─ No significant mitoses or necrosis

IHC ─ (+) CD31, CD34, ERG, FLI1 (endothelial cells); (-) GLUT1, D2-40, keratins

Molecular ─ Recurrent GNAQ, GNA11, or GNA14 mutations

DDx ─

─ Angiosarcoma (Marked atypia, mitoses, necrosis, infiltrative growth)

─ Kaposi Sarcoma (Spindle cells, slit-like spaces, HHV8+)

─ Papillary Endothelial Hyperplasia (Intravascular location, association with thrombus)

Prognosis ─ Benign; recurrence rare even with positive margins

Media ─ pathoutlines H&E video

Epithelioid hemangioma

Benign vascular neoplasm of epithelioid endothelial cells, associated with larger vessels and an inflammatory infiltrate rich in eosinophils. AKA angiolymphoid hyperplasia with eosinophilia (ALHE).

Clinical ─ Young to middle-aged; head/neck (esp. preauricular) > extremities, trunk; skin/subcutis; reddish papules/nodules, may be multiple

Macro ─ Small (< 2 cm) nodules

Micro ─

─ Well-circumscribed, often lobular proliferation of small vessels

─ Plump, epithelioid endothelial cells with abundant cytoplasm, vesicular nuclei, +/- vacuoles

─ Endothelial cells may protrude into lumen ("hobnailing", "tombstoning")

─ Often arises around a medium-sized artery or vein

─ Background inflammatory infiltrate rich in eosinophils and lymphocytes

─ Mitoses rare, no significant atypia or necrosis

IHC ─ (+) CD31, CD34, ERG, FLI1 (endothelial cells); (-) keratins

Molecular ─ FOS or FOSB rearrangements in bone/soft tissue lesions

DDx ─

─ Epithelioid Hemangioendothelioma (infiltrative, myxohyaline stroma, WWTR1-CAMTA1)

─ Epithelioid Angiosarcoma (Marked atypia, mitoses, necrosis, infiltrative)

─ Kimura Disease (Similar inflammation but lacks characteristic epithelioid vessels)

─ Insect Bite Reaction (Wedge-shaped inflammation, more superficial)

Prognosis ─ Benign; recur locally

Media ─ pathoutlines WSI WSI WSI WSI WSI WSI

WSI with video WSI with video

Lymphangioma and lymphangiomatosis

Malformations of lymphatics. Lymphangioma localized; lymphangiomatosis diffuse.

Clinical ─ Mostly children (< 2 years), often congenital; head/neck, axilla; skin/subcutis or deep tissues; soft, cystic mass

─ Macrocystic (Cystic Hygroma): Large cysts

─ Microcystic: Small, vesicle-like channels

Macro ─ Spongy, cystic mass; clear or chylous fluid; may be poorly defined

Micro ─

─ Network of dilated, irregular lymphatic channels lined by flattened endothelial cells

─ Thin walls, often contain focal smooth muscle aggregates

─ Lumen contains proteinaceous fluid, lymphocytes; lacks RBCs

─ Intervening stroma variable (fibrous, adipose, lymphoid aggregates)

─ No atypia or mitoses

IHC ─ (+) D2-40/podoplanin, PROX1 (lymphatic); (+) CD31, ERG; (-) GLUT1

Molecular ─ Sporadic; PIK3CA in some generalized anomalies

DDx ─

─ Venous Malformation / Cavernous Hemangioma (Contain RBCs, D2-40-)

─ Angiosarcoma (Malignant features)

Prognosis ─ Benign; recurrence common due to infiltrative nature, especially for lymphangiomatosis

Media ─ pathoutlines

Tufted angioma

Benign vascular neoplasm characterized by discrete lobules ("tufts") of capillaries scattered in the dermis and subcutis.

Clinical ─ Infants and young children (< 5 years); trunk, neck, proximal extremities

Micro ─

─ Discrete lobules ("tufts"/"cannonballs") of packed capillaries scattered in dermis/subcutis

─ Capillaries lined by plump endothelial cells, lumina often inconspicuous

─ +/- Crescent-shaped lymphatic-like vessels at periphery of tufts

─ Minimal atypia, rare mitoses

IHC ─ (+) CD31, CD34, ERG (capillaries); (-) GLUT1

Molecular ─ GNA14 mutations

DDx ─

─ Kaposiform Hemangioendothelioma ( infiltrative, confluent lobules, spindle cell component)

─ Infantile Hemangioma (GLUT1+, different morphology)

─ Kaposi Sarcoma (Spindle cells, slit-like spaces, HHV8+)

Prognosis ─ Benign; locally persistent; rarely associated with thrombocytopenia

Media ─ pathoutlines WSI gross

WSI HE CD31 D2-40 SMA video for WSI

Kaposiform Hemangioendothelioma (KHE)

Locally aggressive vascular neoplasm of intermediate malignancy, characterized by infiltrating nodules resembling Kaposi sarcoma and tufted angioma.

Clinical ─ Infants and young children (most < 2 years); retroperitoneum, deep soft tissues of trunk/extremities, head/neck; large, poorly defined mass; frequently associated with Kasabach-Merritt phenomenon (severe thrombocytopenia, consumptive coagulopathy)

Macro ─ Ill-defined, firm, violaceous mass; infiltrative

Micro ─

─ Infiltrating nodules and sheets of spindle cells mixed with poorly formed vascular channels

─ Lobules often confluent, lacking sharp circumscription of tufted angioma

─ Spindle cells resemble Kaposi sarcoma (fascicular growth, slit-like spaces)

─ Glomeruloid capillary clusters may be present

─ +/- Lymphatic-like channels, hemosiderin, entrapped fat/muscle

─ Minimal atypia, low mitotic activity

IHC ─ (+) CD31, CD34, ERG (spindle/endothelial cells); (+) D2-40 (lymphatic, variable in spindle cells); (-) GLUT1, HHV8

Molecular ─ GNA14 mutations

DDx ─

─ Tufted Angioma (Discrete lobules, less infiltrative, less spindle cell component)

─ Infantile Hemangioma (GLUT1+, different morphology)

─ Kaposi Sarcoma (HHV8+, distinct clinical setting)

─ Spindle Cell Hemangioma (Cavernous spaces, epithelioid cells)

Prognosis ─ Intermediate (locally aggressive, rarely metastasizing); high morbidity/mortality if associated with Kasabach-Merritt phenomenon

Media ─ pathoutlines WSI WSI WSI with video WSI with video

Retiform hemangioendothelioma

Low-grade angiosarcoma characterized by an arborizing network of vascular channels resembling rete testis.

Clinical ─ Young to middle-aged adults; lower extremities mc

Macro ─ Plaque or nodule, often violaceous

Micro ─

─ Elongated, arborizing vascular channels resembling rete testis

─ Lined by prominent endothelial cells with scant cytoplasm ("hobnail" or "matchstick")

─ Monotonous cytology, minimal atypia, rare mitoses

─ Prominent lymphocytic infiltrate common

─ +/- Papillary projections into vascular lumina

IHC ─ (+) CD31, CD34, ERG, FLI1, D2-40/podoplanin (lymphatic)

DDx ─

─ Dabska Tumor (Papillary Intralymphatic Angioendothelioma) (Prominent intraluminal papillae, younger age)

─ Angiosarcoma (Greater atypia, mitoses, necrosis, solid areas)

─ Hobnail Hemangioma (Targetoid Hemangioma) (More superficial, biphasic pattern)

Prognosis ─ Low-grade malignancy; high rate of local recurrence; metastasis very rare

Media ─ pathoutlines WSI video video & WSI

Papillary intralymphatic angioendothelioma

Rare, low-grade angiosarcoma occurring in children, characterized by intralymphatic papillary growth. Also known as Dabska tumor.

Clinical ─ Infants and children; skin/subcutis of extremities, trunk, head/neck

Macro ─ Ill-defined nodule or plaque, often violaceous

Micro ─

─ Dermal tumor involving dilated lymphatic-like spaces

─ Intraluminal papillary projections lined by hobnail endothelial cells

─ Papillary cores often hyalinized

─ Lymphocytic infiltrate common in surrounding stroma

─ Minimal atypia, rare mitoses

IHC ─ (+) CD31, ERG, FLI1; (+) D2-40 (lymphatic)

Molecular ─ Not specified in provided references

DDx ─

─ Retiform Hemangioendothelioma (Rete testis-like pattern, less prominent papillae)

─ Angiosarcoma (Greater atypia, mitoses, necrosis)

─ Lymphangioma (Lacks papillae and hobnail cells)

Prognosis ─ Low-grade malignancy; local recurrence common; metastasis rare

Media ─ pathoutlines WSI

Composite hemangioendothelioma

Low-grade malignant vascular neoplasm showing a mixture of different benign and low-grade vascular patterns (e.g., epithelioid hemangioma, retiform hemangioendothelioma, spindle cell hemangioma, lymphangioma).

Clinical ─ Wide age range, often young adults; distal extremities (hands/feet) mc site; slow-growing nodule or plaque

Macro ─ Ill-defined, firm nodule or plaque; color variable

Micro ─

─ Admixture of two or more distinct vascular patterns within the same lesion

─ Components may include patterns resembling retiform HE, spindle cell hemangioma, epithelioid HE, lymphangioma, etc.

─ Cytology generally bland within each component, low mitotic activity

IHC ─ Variable depending on components

Molecular ─ Heterogeneous; some show WWTR1::CAMTA1 or YAP1::TFE3 (like EHE)

Prognosis ─ Low-grade; local recurrence; metastasis rare

Media ─ pathoutlines WSI WSI & video

Kaposi sarcoma (KS)

Vascular neoplasm caused by HHV8, occurring in the setting of immunodeficiency.

Clinical ─ Associated with AIDS (epidemic KS), immunosuppression (iatrogenic KS), older men of Mediterranean/Eastern European descent (classic KS), or endemic in parts of Africa. Skin mc site (esp. lower extremities), can involve lymph nodes and viscera

Macro ─ Red-purple macules, papules, plaques, or nodules

Micro ─

─ Patch stage: Subtle proliferation of small, irregular vascular channels around pre-existing vessels/adnexa ("promontory sign"); sparse spindle cells, lymphoplasmacytic infiltrate

─ Plaque stage: More prominent vascular proliferation with increased spindle cells forming fascicles; extravasated RBCs, hemosiderin, plasma cells

─ Nodule stage: Densely cellular proliferation of spindle cells forming slit-like vascular spaces; extravasated RBCs, hemosiderin, eosinophilic hyaline globules (PAS+); mitoses variable

IHC ─ (+) HHV8; (+) CD34, ERG, FLI1 (spindle/endothelial); (+) D2-40 (lymphatic)

Molecular ─ HHV8 DNA detectable

DDx ─

─ Angiosarcoma (HHV8-, greater atypia, necrosis)

─ Spindle cell hemangioma (Cavernous spaces, lacks HHV8)

─ Fibrous histiocytoma (Factor XIIIa+, lacks vascular slits/HHV8)

─ Bacillary angiomatosis (Neutrophils, granular material = bacteria, Bartonella+)

Prognosis ─ Indolent in classic KS, more aggressive in AIDS-associated/iatrogenic KS

Media ─ pathoutlines WSI video for WSI WSI WSI WSI

Pseudomyogenic hemangioendothelioma

Vascular neoplasm of intermediate malignancy, characterized by plump spindle and epithelioid cells resembling muscle cells, involving multiple tissue planes.

Clinical ─ Young adults (20-30s), M > F; lower > upper extremities, trunk; often multifocal within one limb (skin, subcutis, muscle, bone); presents as painful nodules

Macro ─ Ill-defined nodules or plaques

Micro ─

─ Infiltrative proliferation of plump spindle and epithelioid cells

─ Cells in loose fascicles or sheets

─ Abundant eosinophilic cytoplasm, resembling rhabdomyoblasts

─ Nuclei round to oval, vesicular chromatin, +/- small nucleoli

─ Background shows loose edematous or fibrous stroma with neutrophils

─ Low mitotic activity

IHC ─ (+) ERG, FLI1 (endothelial); (+) AE1/AE3 keratin (characteristic)

Molecular ─ SERPINE1::FOSB fusion characteristic; rarely ACTB::FOSB

DDx ─

─ Epithelioid Sarcoma (Keratin+, INI1 loss, lacks vascular markers)

─ Rhabdomyosarcoma (Myogenin+, MyoD1+, lacks vascular markers)

─ Epithelioid Hemangioma (Lacks spindle cells, FOS/FOSB rearranged, keratin-)

─ Epithelioid Angiosarcoma (Greater atypia, mitoses, necrosis)

Prognosis ─ Intermediate; frequent recurrence, occasional nodal metastasis

Media ─ pathoutlines WSI WSI WSI video for WSI

Epithelioid hemangioendothelioma (EHE)

Vascular neoplasm of intermediate malignancy composed of epithelioid endothelial cells in a characteristic myxohyaline stroma.

Clinical ─ Adults (wide age range); soft tissue, liver, lung, bone common sites; presentation variable depending on site

Macro ─ Firm, gray-white nodule(s); may appear infiltrative

Micro ─

─ Cords, nests, or strands of epithelioid endothelial cells

─ Embedded in abundant myxohyaline or chondroid-like stroma

─ Cells often contain intracytoplasmic vacuoles/lumina, sometimes with RBCs ("blister cells")

─ Minimal to moderate atypia, low mitotic activity usually

─ +/- Solid areas, spindle cell component

─ YAP1::TFE3 variant: More solid, less stroma, vasoformative

IHC ─ (+) CD31, ERG, FLI1 (endothelial); (-) SMA, desmin, S100, HHV8

Molecular ─ WWTR1::CAMTA1 >> YAP1::TFE3

DDx ─

─ Metastatic Carcinoma (esp. mucinous/signet ring) (Keratin+, vascular markers-)

─ Epithelioid Hemangioma (Lacks significant stroma, FOS/FOSB rearranged)

─ Epithelioid Angiosarcoma (Greater atypia, mitoses, necrosis)

─ Myoepithelial Tumors (S100+, SMA+, p63+, vascular markers-)

Prognosis ─ Intermediate; variable behavior

Media ─ pathoutlines WSI WSI WSI video for WSI WSI WSI WSI WSI

Angiosarcoma

Malignant neoplasm of endothelial cells.

Clinical ─ Older adults mc; skin (esp. scalp/face of elderly), deep soft tissue, breast, liver, spleen, bone; presentation variable (bruise-like lesion, nodule, mass)

Macro ─ Ill-defined, hemorrhagic mass or lesion; infiltrative

Micro ─

─ Ranges from well-differentiated (resembling benign vascular lesions) to poorly differentiated (epithelioid or spindle cell sarcoma)

─ Characteristic feature: Anastomosing vascular channels lined by atypical endothelial cells

─ Endothelial cells show hyperchromasia, pleomorphism, increased mitoses, +/- prominent nucleoli

─ Endothelial tufting, multilayering common

─ Solid epithelioid or spindle cell areas in high-grade tumors

─ Infiltration/dissection of surrounding tissues (e.g., collagen bundles in dermis)

─ Necrosis, hemorrhage common

IHC ─ (+) CD31, ERG, FLI1 (endothelial markers); (-) SMA, desmin, S100, HHV8

Molecular ─ Complex karyotypes; MYC amplification in radiation/lymphedema-associated cases; KDR, PLCG1 mutations in some sporadic cases

DDx ─

─ Hemangioma/Vascular Malformation (Lack atypia, mitoses, infiltrative growth)

─ Epithelioid Hemangioendothelioma (Myxohyaline stroma, specific fusions)

─ Kaposi Sarcoma (HHV8+)

─ Spindle cell/pleomorphic sarcomas (UPS, melanoma, carcinoma) (Lack vascular markers)

Prognosis ─ Aggressive; high rate of recurrence and distant metastasis (lung)

Media ─ pathoutlines video for WSI WSI WSI WSI WSI

Epithelioid Angiosarcoma

Variant of angiosarcoma composed predominantly (>50%) of epithelioid endothelial cells.

Clinical ─ Adults; deep soft tissues mc site > skin, bone, viscera

Macro ─ Fleshy, gray-white mass; often hemorrhagic/necrotic

Micro ─

─ Sheets, nests, or cords of large polygonal cells with abundant eosinophilic cytoplasm (epithelioid)

─ Vesicular nuclei, prominent nucleoli, marked atypia

─ +/- Intracytoplasmic vacuoles/lumina (may contain RBCs)

─ Focal vasoformation (anastomosing channels) usually present

─ High mitotic rate, necrosis common

IHC ─ (+) CD31, ERG, FLI1 (endothelial); (+) Keratins (AE1/AE3, CAM5.2)

Molecular ─ Complex karyotype; MYC amplification absent (unless post-radiation)

DDx ─

─ Metastatic Carcinoma (esp. poorly differentiated) (Vascular markers-)

─ Melanoma (S100+, SOX10+, HMB45+, vascular markers-)

─ Epithelioid Hemangioendothelioma (Less atypia/mitoses, myxohyaline stroma, fusions)

─ Epithelioid Sarcoma (INI1 loss, CD34+, vascular markers-)

Prognosis ─ Aggressive; similar to conventional angiosarcoma

Media ─ WSI + WSI & their video

Post-radiation & Lymphedema-associated angiosarcoma

Angiosarcoma arising in the setting of prior radiation therapy or chronic lymphedema (e.g., Stewart-Treves syndrome post-mastectomy).

Clinical ─ Occurs years after radiation (latency usually >5 years) or in areas of chronic lymphedema; skin mc site (breast, chest wall, extremities)

Macro ─ Bruise-like patches, papules, nodules; often multifocal

Micro ─

─ Often starts as subtle proliferation of anastomosing vascular channels in dermis

─ May resemble benign vascular lesion initially

─ Progresses to more obvious angiosarcoma with atypia, mitoses, infiltration

─ Lymphatic differentiation common (D2-40+)

IHC ─ (+) CD31, ERG, FLI1; (+) MYC (characteristic)

Molecular ─ MYC amplification

DDx ─

─ Atypical Vascular Lesion (AVL) (Post-radiation benign/low-grade lesion, MYC-)

─ Other angiosarcomas (MYC- unless radiation hx)

─ Kaposi Sarcoma (HHV8+)

Prognosis ─ Aggressive; presents at advanced stage

Media ─ pathoutlines WSI & video

Perivascular Epithelioid Cell Tumor (PEComa)

Mesenchymal neoplasm composed of histologically and immunohistochemically distinctive perivascular epithelioid cells, co-express melanocytic and smooth muscle markers.

Clinical ─ Wide age range, F > M; uterus, retroperitoneum, kidney common sites; can occur anywhere; often associated with Tuberous Sclerosis Complex (TSC)

Macro ─ Variable; often well-circumscribed, fleshy or firm mass

Micro ─

─ Sheets or nests of epithelioid cells arranged around blood vessels

─ Cells typically polygonal with clear to granular eosinophilic cytoplasm

─ Nuclei round, often vesicular with small nucleoli; atypia variable

─ +/- Spindle cell component, adipose tissue (AML), cystic change (LAM)

─ +/- Intracytoplasmic glycogen (CCST)

IHC ─ (+) HMB45, MelanA (melanocytic); (+) SMA, calponin, desmin (smooth muscle)

Molecular ─ TSC1 or TSC2; TFE3 rearrangements in subset

DDx ─

─ Melanoma (Lacks smooth muscle markers, different clinical context)

─ Clear Cell Sarcoma (Lacks smooth muscle markers, EWSR1::ATF1/CREB1 fusion)

─ Epithelioid Smooth Muscle Tumors (Lack melanocytic markers)

─ Epithelioid GIST (CD117+, DOG1+, lacks melanocytic markers)

─ Clear Cell RCC (PAX8+, lacks melanocytic/smooth muscle markers)

Prognosis ─ Spectrum from benign to malignant

Media ─ pathoutlines WSI WSI

Skin video WSI HEHMB45MelanA video video

Glomus tumor

Benign neoplasm composed of modified smooth muscle cells resembling those of the normal glomus body.

Clinical ─ Adults (wide age range); distal extremities (esp. subungual region of fingers) mc site; often presents as small, painful (esp. with cold/pressure), blue-red nodule

Macro ─ Small (< 1 cm), well-circumscribed, reddish-blue nodule

Micro ─

─ Solid sheets or nests of uniform, round cells with scant eosinophilic cytoplasm and sharply defined borders

─ Cells arranged around capillary-sized vessels

─ Nuclei round, centrally located, punched-out appearance, no atypia/mitoses

─ Variants: Glomangioma (more prominent vascular component), Glomangiomyoma (prominent smooth muscle component)

IHC ─ (+) SMA; (+) Type IV collagen (highlights cell nests); (-) Desmin, S100, keratins

Molecular ─ NOTCH rearrangements

DDx ─

─ Myopericytoma (More concentric perivascular growth, less uniform cells)

─ Eccrine Spiradenoma/Poroma (Keratin+, EMA+)

─ Epithelioid Vascular Tumors (CD31+, ERG+)

Prognosis ─ Benign; malignant transformation rare

Media ─ pathoutlines

Glomangioma WSI WSI WSI WSI

Solid glomus tumor WSI WSI WSI

Myopericytoma

Benign perivascular neoplasm composed of oval to spindle cells with concentric growth around blood vessels.

Clinical ─ Adults; skin/subcutis of extremities mc site; slow-growing, usually painless nodule

Macro ─ Well-circumscribed nodule, gray-white

Micro ─

─ Concentric, proliferation of bland myoid-appearing spindle/oval cells around blood vessels

─ Cells have indistinct eosinophilic cytoplasm

─ Vessels often hyalinized

─ Low mitotic activity, no significant atypia or necrosis

IHC ─ (+) SMA; (-) Desmin, S100, CD34, keratins

Molecular ─ PDGFRB

DDx ─

─ Glomus Tumor (More uniform round cells, less concentric growth, lacks PDGFRB alterations)

─ Angioleiomyoma (More prominent thick-walled vessels, interlocking smooth muscle fascicles, desmin+)

─ Solitary Fibrous Tumor (STAT6+, CD34+, different morphology)

Prognosis ─ Benign; recurrence rare

Media ─ pathoutlines WSI WSI WSI WSI

Myofibroma / Myofibromatosis

Benign neoplasm(s) composed of myofibroblasts, often showing a biphasic pattern with primitive round cells and more differentiated spindle cells, typically with a hemangiopericytoma-like vascular pattern. Myofibroma is solitary; myofibromatosis is multiple/systemic.

Clinical ─ Infants and young children mc (infantile myofibromatosis); also occurs in adults; skin/subcutis, deep soft tissue, bone, viscera; solitary nodule or multiple lesions

Macro ─ Well-circumscribed, firm nodule(s); gray-white

Micro ─

─ Often biphasic:

─ Nodules/fascicles of bland spindle cells (myofibroblasts) with eosinophilic cytoplasm

─ Less differentiated areas with small primitive round/oval cells

─ Characteristic hemangiopericytoma-like (staghorn) vessels

─ +/- Central necrosis or hyalinization

─ Low mitotic activity, minimal atypia

IHC ─ (+) SMA; (-) S100, keratins

Molecular ─ PDGFRB

DDx ─

─ Infantile Fibromatosis (Lacks biphasic pattern and HP-like vessels)

─ Leiomyoma (More distinctly smooth muscle, desmin+)

─ Myopericytoma (More concentric perivascular growth)

─ Solitary Fibrous Tumor (STAT6+, CD34+)

Prognosis ─ Benign; cured by excision; myofibromatosis may regress spontaneously

Media ─ pathoutlines WSI WSI & video WSI & video

Angioleiomyoma

Benign smooth muscle tumor arising from the tunica Media of small veins or arteries, characterized by admixed vascular channels.

Clinical ─ Adults (peak 40-60s); F > M; subcutaneous tissue of lower extremities mc site; often presents as small, sometimes painful nodule

Macro ─ Well-circumscribed, encapsulated, firm nodule; gray-white to tan

Micro ─

─ Well-circumscribed proliferation of mature smooth muscle cells

─ Intermixed with numerous small to medium-sized, thick-walled blood vessels

─ Smooth muscle cells arranged in intersecting fascicles, often whorling around vessels

─ +/- Adipose tissue, myxoid change, calcification

─ No atypia or significant mitoses

IHC ─ (+) SMA, MSA, desmin, h-caldesmon (smooth muscle); (+) CD31, ERG (vessels)

Molecular ─ None

DDx ─

─ Leiomyoma (Less prominent vascular component)

─ Myopericytoma (Concentric perivascular growth, desmin-)

─ Glomus Tumor (Different cell morphology, desmin-)

Prognosis ─ Benign; excision curative

Media ─ pathoutlines video WSI WSI WSI WSI HE caldesmon

Soft Tissue, Muscular

Leiomyoma

Benign neoplasm composed of mature smooth muscle cells.

Clinical ─ Adults; common in uterus, but can occur in soft tissue (skin - pilar leiomyoma, deep soft tissue, retroperitoneum), GI tract; often presents as firm nodule, may be painful (esp. pilar leiomyoma)

Macro ─ Well-circumscribed, firm, gray-white, whorled cut surface

Micro ─

─ Intersecting fascicles of bland spindle cells with eosinophilic fibrillar cytoplasm

─ Elongated, blunt-ended ("cigar-shaped") nuclei

─ Minimal atypia, rare/absent mitoses, no necrosis

─ Variants: Cellular, epithelioid, myxoid, hydropic, symplastic (bizarre nuclei)

IHC ─ (+) SMA, MSA, desmin, h-caldesmon; (+/-) ER, PR (esp. genital tract)

Molecular ─ MED12 in uterine leiomyomas; soft tissue lacks specific alterations

DDx ─

─ Leiomyosarcoma (Significant atypia, necrosis, and/or increased mitoses)

─ Myofibroma/Myofibromatosis (Biphasic pattern, HP-like vessels, desmin often negative)

─ Schwannoma (Wavy nuclei, Verocay bodies, S100+)

─ Solitary Fibrous Tumor (Staghorn vessels, STAT6+, CD34+)

Prognosis ─ Benign; recurrence rare unless incompletely excised

Media ─ pathoutlines

Leiomyosarcoma

Malignant neoplasm showing smooth muscle differentiation.

Clinical ─ Adults (peak 50-70s); deep soft tissues of extremities (esp. thigh), retroperitoneum, uterus, large vessels (IVC); often large, deep-seated mass

Macro ─ Fleshy, gray-white mass; often appears circumscribed but infiltrative; hemorrhage and necrosis common

Micro ─

─ Intersecting fascicles of atypical spindle cells with eosinophilic cytoplasm

─ Blunt-ended ("cigar-shaped") nuclei, but with hyperchromasia, pleomorphism

─ Diagnosis requires significant atypia + necrosis OR significant atypia + high mitoses (site-dependent criteria, e.g. >10/10 HPF in retroperitoneum)

─ Variants: Epithelioid, myxoid

IHC ─ (+) SMA, MSA, desmin, h-caldesmon (may be focal in high-grade tumors)

Molecular ─ Complex karyotypes; TP53 and RB1 alterations common; no specific recurrent translocation

DDx ─

─ Leiomyoma (Lacks significant atypia, necrosis, high mitoses)

─ Spindle cell sarcomas (UPS, fibrosarcoma, MPNST, synovial sarcoma - use IHC panel)

─ GIST (CD117+, DOG1+, occurs in GI tract)

Prognosis ─ Aggressive sarcoma; high rate of local recurrence and distant metastasis (lung); prognosis depends on grade, size, depth, site (retroperitoneal worse)

Media ─ pathoutlines WSI WSI WSI WSI WSI

EBV-associated smooth muscle tumor

Smooth muscle neoplasm occurring in the setting of immunodeficiency (congenital, acquired e.g., HIV, or iatrogenic e.g., post-transplant), associated with Epstein-Barr virus (EBV).

Clinical ─ Immunocompromised patients (any age); CNS, viscera, soft tissues; often multifocal

Macro ─ Variable; often well-circumscribed nodule(s)

Micro ─

─ Spindle cells resembling smooth muscle, often arranged in fascicles

─ Variable cytologic atypia (can range from bland to pleomorphic)

─ Prominent intratumoral lymphocytic infiltrate common

─ +/- Primitive round cell component

─ Necrosis may be present

IHC ─ (+) SMA, MSA, desmin; (+) EBER (in situ hybridization for EBV - diagnostic); (+/-) CD21 (highlights FDCs in lymphoid infiltrate)

Molecular ─ EBV infection of tumor cells

DDx ─

─ Conventional Leiomyoma/Leiomyosarcoma (EBER-, occurs in immunocompetent)

─ Inflammatory Myofibroblastic Tumor (ALK+, different morphology)

─ Kaposi Sarcoma (HHV8+, CD31+, CD34+)

Prognosis ─ Variable; depends on underlying immune status and extent of disease; may regress with restoration of immunity

Media ─ pathoutlines

Inflammatory leiomyosarcoma

Rare variant of leiomyosarcoma characterized by a prominent inflammatory infiltrate. (Note: Not a formally recognized WHO entity, may represent leiomyosarcoma with inflammation or potentially overlap with IMT).

Clinical ─ Adults; site variable (retroperitoneum, uterus mentioned)

Macro ─ Fleshy mass, may have inflammatory appearance

Micro ─

─ Features of leiomyosarcoma (atypical spindle cells, mitoses, +/- necrosis)

─ Prominent inflammatory infiltrate, often lymphoplasmacytic, may include eosinophils, neutrophils, histiocytes

─ Inflammation may obscure underlying tumor cells

IHC ─ (+) Smooth muscle markers (SMA, desmin, etc.); inflammatory cells show expected markers

Molecular ─ Complex karyotypes expected (as in conventional LMS)

DDx ─

─ Inflammatory Myofibroblastic Tumor (IMT) (Usually less atypia, ALK+ in subset)

─ Xanthogranulomatous inflammation (Prominent foamy histiocytes, lacks malignant spindle cells)

─ Leiomyosarcoma with reactive inflammation (Distinction may be difficult)

Prognosis ─ Likely similar to conventional leiomyosarcoma of similar grade/stage, but data limited

Media ─ pathoutlines

Adult Rhabdomyoma

Benign skeletal muscle tumor composed of large polygonal cells with abundant eosinophilic cytoplasm.

Clinical ─ Adults (Median 60s), M > F; head/neck region (esp. larynx, pharynx); slow-growing mass, may cause obstructive symptoms

Macro ─ Well-circumscribed, lobulated, tan-pink to red-brown mass

Micro ─

─ Large polygonal cells with abundant granular eosinophilic cytoplasm (packed mitochondria)

─ Cytoplasmic vacuoles (glycogen) common, may create "spider cell" appearance

─ Nuclei round, often central, may have prominent nucleoli

─ Intracytoplasmic crystalline inclusions (jackstraw-like) may be seen

─ Minimal atypia, rare mitoses

IHC ─ (+) Desmin, MSA, Myoglobin, MyoD1 (patchy), Myogenin (patchy); (-) S100, keratins

Molecular ─ PTCH1 mutations reported in some

DDx ─

─ Granular Cell Tumor (S100+, SOX10+, lacks cross-striations)

─ Hibernoma (Brown fat, lacks cross-striations, UCP1+)

─ Oncocytoma (Occurs in glands, lacks cross-striations)

─ Rhabdomyosarcoma (Malignant features, atypia, high mitoses)

Prognosis ─ Benign; local recurrence possible if incompletely excised

Media ─ pathoutlines WSI & video WSI WSI WSI

Fetal Rhabdomyoma, Classic -Type

Benign skeletal muscle tumor composed of immature skeletal muscle cells resembling fetal muscle development.

Clinical ─ Infants and young children (mc < 3 years), M > F; head/neck (esp. preauricular) mc site

Macro ─ Poorly defined subcutaneous mass

Micro ─

─ Immature spindle cells mixed with differentiating rhabdomyoblasts in various stages

─ Cells resemble developing fetal muscle (around 7-10 weeks gestation)

─ Background often myxoid

─ Minimal atypia, mitoses may be present but not atypical

IHC ─ (+) Desmin, MSA; (+) Myogenin, MyoD1 (more diffuse than adult type)

Molecular ─ Not specified in provided references

DDx ─

─ Embryonal Rhabdomyosarcoma (More cellular, greater atypia, cambium layer if botryoid)

─ Infantile Fibromatosis/Fibrosarcoma (Lack myogenic markers)

Prognosis ─ Benign; recurrence rare

Media ─ pathoutlines WSI

Fetal Rhabdomyoma, Intermediate-Type

Variant of fetal rhabdomyoma showing features intermediate between classic fetal and adult types. Also known as juvenile rhabdomyoma.

Clinical ─ Older children and adults; head/neck

Macro ─ Similar to classic fetal or adult types

Micro ─

─ Features overlap between classic fetal (immature spindle cells, myxoid stroma) and adult rhabdomyoma (larger polygonal cells, less myxoid stroma)

─ More cellular than classic fetal type

─ Less prominent cytoplasmic granularity/vacuolization than adult type

IHC ─ (+) Desmin, MSA, Myogenin, MyoD1

Molecular ─ Not specified in provided references

DDx ─

─ Classic Fetal Rhabdomyoma

─ Adult Rhabdomyoma

─ Embryonal Rhabdomyosarcoma

Prognosis ─ Benign

Media ─ pathoutlines

Rhabdomyoma, Genital-Type

Benign skeletal muscle tumor occurring primarily in the vulvovaginal region of reproductive-age women.

Clinical ─ Reproductive-age women (peak 30-40s); vulva, vagina; presents as polypoid mass

Macro ─ Polypoid, fleshy mass

Micro ─

─ Hypocellular proliferation of bland spindle and stellate cells in a loose, edematous or myxoid stroma

─ Cells have scant eosinophilic cytoplasm, elongated nuclei

─ Scattered larger cells with more abundant cytoplasm and cross-striations may be seen

─ Low mitotic activity, no atypia

IHC ─ (+) Desmin, MSA; (+/-) Myogenin, MyoD1 (often focal)

Molecular ─ None

DDx ─

─ Aggressive Angiomyxoma (Prominent vessels, infiltrative, lacks cross-striations, HMGA2 rearranged)

─ Embryonal Rhabdomyosarcoma (Botryoid variant) (Cambium layer, hypercellular, atypia)

─ Fibroepithelial Stromal Polyp (Lacks myogenic differentiation)

Prognosis ─ Benign; local excision is curative

Media ─ pathoutlines

Embryonal Rhabdomyosarcoma (ERMS)

Malignant neoplasm composed of cells resembling embryonic skeletal muscle at various stages of differentiation. Most common type of RMS overall.

Clinical ─ Primarily infants and young children (< 10 years); head/neck (orbit common), genitourinary tract (vagina, bladder, paratestis) mc sites

Macro ─ Variable; often gray-white, fleshy mass; botryoid variant is polypoid, grape-like (occurs in mucosa-lined hollow organs like vagina/bladder)

Micro ─

─ Primitive round to spindle cells with hyperchromatic nuclei and scant cytoplasm

─ Variable cellularity, often alternating hypocellular myxoid areas and hypercellular areas ("marbled" appearance)

─ Rhabdomyoblasts (strap cells, tadpole cells, racquet cells with eosinophilic cytoplasm, +/- cross-striations) are characteristic but may be sparse or absent

─ Cambium layer (subepithelial condensation of tumor cells) seen in botryoid variant

─ Mitotic activity variable

IHC ─ (+) Desmin, Myogenin (nuclear, often patchy), MyoD1 (nuclear, often patchy); (+/-) SMA, myoglobin

Molecular ─ Lacks ARMS translocations; RAS (HRAS, KRAS, NRAS), TP53, FGFR4

DDx ─

─ Other small round blue cell tumors

─ Spindle cell RMS (Distinct morphology, different molecular in infants)

─ Alveolar RMS (Alveolar pattern, PAX-FOXO1 fusion, diffuse Myogenin/MyoD1)

Prognosis ─ Intermediate; better than ARMS; botryoid better

Media ─ pathoutlines WSI WSI WSI WSI case & WSI myogenin HE (botyroid)

Alveolar Rhabdomyosarcoma (ARMS)

Malignant neoplasm composed of primitive round cells often arranged in nests resembling pulmonary alveoli, typically defined by PAX3/7-FOXO1 fusions.

Clinical ─ Adolescents and young adults; deep soft tissues of extremities mc site > trunk, head/neck

Macro ─ Fleshy, gray-tan mass; often large and deeply situated

Micro ─

─ Characteristic alveolar pattern: Nests/aggregates of primitive round cells separated by fibrous septa; cells often discohesive centrally, clinging to septa peripherally

─ Solid variant: Lacks distinct alveolar spaces but has similar cytology (sheets of primitive round cells)

─ Tumor cells: Uniform, round nuclei, scant cytoplasm, inconspicuous nucleoli

─ Multinucleated tumor giant cells (wreath-like) may be present

─ Mitotic activity usually high, necrosis common

IHC ─ (+) Desmin, Myogenin (strong/diffuse nuclear), MyoD1 (strong/diffuse nuclear)

Molecular ─ PAX3::FOXO1 or PAX7::FOXO1

DDx ─

─ Embryonal RMS (Lacks alveolar pattern, Myogenin/MyoD1 often patchy, lacks fusion)

─ Other small round blue cell tumors (Ewing, neuroblastoma, lymphoma - distinct IHC)

─ Poorly differentiated synovial sarcoma (Biphasic pattern sometimes, TLE1+, SS18::SSX)

Prognosis ─ Aggressive; worse prognosis than ERMS; fusion status may impact prognosis (PAX7 better than PAX3)

Media ─ pathoutlines WSI WSI WSI WSI HE reticulin myogenin

Pleomorphic Rhabdomyosarcoma

High-grade sarcoma composed of pleomorphic cells with definitive evidence of skeletal muscle differentiation, occurring almost exclusively in adults. Diagnosis of exclusion among RMS subtypes.

Clinical ─ Adults (usually > 40 years); deep soft tissues of extremities (esp. thigh), trunk

Macro ─ Large, fleshy mass; often with hemorrhage and necrosis

Micro ─

─ High-grade pleomorphic sarcoma resembling UPS

─ Diagnostic feature: Presence of large, bizarre, pleomorphic rhabdomyoblasts (strap cells, tadpole cells, racquet cells) with abundant eosinophilic cytoplasm, +/- cross-striations; must be unequivocal

─ Marked nuclear pleomorphism throughout, high mitotic rate (incl. atypical), necrosis common

─ Lacks features of ERMS or ARMS (no primitive round cells, no alveolar pattern)

IHC ─ (+) Desmin, Myogenin (nuclear), MyoD1 (nuclear) - may be focal, confirms diagnosis; (+) SMA, MSA (variable)

Molecular ─ Complex karyotypes; lacks RMS-specific translocations (PAX-FOXO1)

DDx ─

─ Dedifferentiated Liposarcoma with rhabdomyoblastic differentiation (WDLS present)

─ Malignant Peripheral Nerve Sheath Tumor (MPNST) with rhabdomyoblastic differentiation (Triton Tumor) (S100+, SOX10+, loss of H3K27me3)

Prognosis ─ Aggressive; high rate of recurrence and metastasis

Media ─ pathoutlines

Spindle cell / Sclerosing Rhabdomyosarcoma

Subtype of RMS characterized by fascicular growth of spindle cells +/- prominent sclerosis. Includes distinct molecular/clinical subgroups.

Clinical ─ Bimodal age distribution: Infants/children (often paratesticular - spindle cell) and adults (head/neck, extremities - often sclerosing)

Macro ─ Firm, gray-white mass; may appear circumscribed

Micro ─

─ Predominantly spindle cells arranged in fascicles ("herringbone") or storiform pattern

─ Cells range from bland (low-grade infantile) to moderately atypical (adult)

─ Rhabdomyoblasts may be sparse or absent

─ Sclerosing variant: Prominent hyalinized/sclerotic stroma separating tumor cells/fascicles; may form pseudovascular spaces or resemble osteosarcoma matrix

─ Low-grade (infantile) vs High-grade (adult) based on atypia/mitoses

IHC ─ (+) Desmin, Myogenin (nuclear), MyoD1 (nuclear) - often diffuse in spindle cells

Molecular ─ Distinct molecular subgroups:

─ Congenital/Infantile: VGLL2, NCOA2, or CITED2 fusions (e.g., NCOA2::ETV4); good prognosis

─ Adolescent/Adult (MYOD1-mutant): MYOD1 mutations (esp. L122R); poor prognosis

─ Other adult cases: May lack specific mutations or have TFCP2 or MEIS1 fusions

DDx ─

─ Leiomyosarcoma (More distinct fascicles, blunt-ended nuclei, lacks Myogenin/MyoD1)

─ Infantile Fibrosarcoma (ETV6::NTRK3 fusion, lacks Myogenin/MyoD1)

─ MPNST (Wavier nuclei, S100/SOX10+, lacks Myogenin/MyoD1)

─ Low-grade fibromyxoid sarcoma (MUC4+, lacks Myogenin/MyoD1)

─ Fibromatosis (β-catenin+, lacks Myogenin/MyoD1)

Prognosis ─ Variable; congenital/infantile type has excellent prognosis; MYOD1-mutant type is aggressive

Media ─ pathoutlines WSI

Ectomesenchymoma

Rare malignant neoplasm showing features of rhabdomyosarcoma (usually embryonal) and neuroectoderm elements (ganglion cells, Schwann cells, neuroblasts).

Clinical ─ Primarily infants and young children; head/neck, GU tract, trunk, extremities

Macro ─ Variable; often fleshy, gray-white mass

Micro ─

─ Biphasic tumor with two distinct components:

─ Skeletal muscle component: Typically resembles embryonal rhabdomyosarcoma (primitive round/spindle cells, rhabdomyoblasts)

─ Neuroectodermal component: Ganglion cells (mature or immature), Schwannian stroma (spindle cells resembling neurofibroma/schwannoma), +/- neuroblasts or neuropil

IHC ─

─ Skeletal muscle component: (+) Desmin, Myogenin, MyoD1

─ Neuroectodermal component: (+) S100, SOX10, GFAP (Schwannian/glial elements); (+) Synaptophysin, Chromogranin, Neurofilament (ganglion cells/neuroblasts)

Molecular ─ Complex karyotypes; lacks specific fusions associated with RMS

DDx ─

─ Embryonal Rhabdomyosarcoma (Lacks neuroectodermal component)

─ MPNST with rhabdomyoblastic differentiation (Triton Tumor) (Neuroectodermal component malignant, often S100+/SOX10+, lacks ganglion cells)

─ Ganglioneuroblastoma (Neuroblastic component predominates, lacks RMS component)

─ Teratoma with RMS differentiation (Contains elements from all three germ layers)

Prognosis ─ Generally considered aggressive, similar to intermediate/high-risk RMS; prognosis depends on age, stage, location, and extent of components

Media ─ pathoutlines

Soft Tissue, Nerve Sheath

Schwannoma

Benign peripheral nerve sheath tumor composed of differentiated Schwann cells.

Clinical ─ Adults (peak 20-50s); common sites include head/neck, flexor surfaces of extremities (esp. near joints), posterior Mediastinum, retroperitoneum; associated with Neurofibromatosis type 2 (NF2) if multiple/bilateral vestibular

Macro ─ Encapsulated, fusiform or eccentric mass attached to a nerve; cut surface often yellow-tan, +/- cystic change, hemorrhage

Micro ─

─ Encapsulated tumor, nerve fibers typically splayed over the capsule, not within tumor

─ Biphasic pattern:

─ Antoni A: Cellular areas with spindle cells arranged in fascicles, whorls, or showing nuclear palisading around fibrillary processes (Verocay bodies)

─ Antoni B: Hypocellular areas with loosely arranged spindle/oval cells in a myxoid or edematous stroma; microcystic change common

─ Blood vessels often prominent, thick-walled, and hyalinized

─ Degenerative changes common ("ancient schwannoma"): Nuclear atypia (large hyperchromatic nuclei), hemorrhage, hemosiderin, cystic change; mitoses remain rare

IHC ─ (+) S100, SOX10; (-) Neurofilament (axons), EMA (except capsule), keratins

Molecular ─ NF2 gene inactivation (loss of merlin protein) in most sporadic and NF2-associated cases

DDx ─

─ Neurofibroma (Not encapsulated [except plexiform], mixed cell types, axons within tumor, S100 patchy)

─ Malignant Peripheral Nerve Sheath Tumor (MPNST) (Infiltrative, mitotic activity, necrosis, cellular atypia, S100 often weak/patchy or negative, H3K27me3 loss common)

─ Perineurioma (EMA+, S100-)

─ Cellular Schwannoma (Hypercellular Antoni A, lacks Antoni B, may have mitoses but lacks significant atypia/necrosis; retains S100)

Prognosis ─ Benign; malignant transformation exceedingly rare

Media ─ pathoutlines WSI WSI WSI WSI WSI HE S100 WSI HE S100 EMA

ancient WSI cellular WSI

Neurofibroma

Benign peripheral nerve sheath tumor composed of a mixture of Schwann cells, perineurial-like cells, fibroblasts, mast cells, and embedded axons.

Clinical ─ Any age; associated with Neurofibromatosis type 1 (NF1), especially plexiform and diffuse types; can be sporadic (localized cutaneous type mc)

─ Localized cutaneous: Common, skin, small papule/nodule

─ Diffuse cutaneous: Plaque-like infiltration of dermis/subcutis, often head/neck

─ Plexiform: Pathognomonic for NF1; fascicles of large nerve ("bag of worms")

Macro ─

─ Localized/Diffuse: Soft, fleshy, poorly defined

─ Plexiform: Diffuse enlargement of nerve trunk(s)

Micro ─

─ Not encapsulated (except plexiform type may retain epineurium)

─ Hypocellular proliferation of mixed cell types in loose collagenous or myxoid stroma:

─ Schwann cells: Wavy nuclei, indistinct cytoplasm

─ Fibroblasts: Spindle cells

─ Perineurial-like cells: Epithelioid/spindle cells

─ Mast cells numerous

─ Axons: Present within the tumor (key feature)

─ Collagen often fine, "shredded carrot" appearance

─ Diffuse type infiltrates dermis/subcutis, often surrounds adnexa; may contain Meissner-like bodies

─ Plexiform type shows expansion of multiple nerve fascicles by tumor

IHC ─ (+) S100, SOX10 (highlights Schwann cells, patchy); (+) CD34 (highlights fibroblasts); (+/-) EMA (perineurial-like cells, focal); (+) Neurofilament (highlights embedded axons)

Molecular ─ NF1 gene inactivation in NF1-associated and some sporadic cases

DDx ─

─ Schwannoma (Encapsulated, Antoni A/B, diffuse S100+, lacks axons within tumor)

─ MPNST (Atypia, mitoses, necrosis, often arises from plexiform NF in NF1)

─ Perineurioma (EMA+, S100-, lacks axons)

─ Desmoid Fibromatosis (β-catenin+, lacks S100+)

Prognosis ─ Benign; localized/diffuse types rarely recur; plexiform neurofibromas have a significant risk (~5-10%) of malignant transformation to MPNST in NF1 patients

Media ─ pathoutlines localized WSI WSI WSI diffuse WSI WSI

Malignant Peripheral Nerve Sheath Tumor (MPNST)

Malignant sarcoma arising from peripheral nerves or showing nerve sheath differentiation; often associated with Neurofibromatosis type 1 (NF1).

Clinical ─ Adults (peak 20-50s); ~50% arise in NF1 patients (at younger age); major nerve trunks (sciatic, brachial plexus, sacral plexus) mc sites; often large, deep-seated mass, may cause pain/neurologic deficit

Macro ─ Fusiform or eccentric nerve expansion; fleshy, gray-white cut surface; often with hemorrhage and necrosis; infiltrative margins

Micro ─

─ Cellular spindle cell sarcoma, often with fascicular or herringbone pattern

─ Cells typically wavy, tapered nuclei, hyperchromatic, variable pleomorphism

─ High mitotic rate (often >10/10 HPF), including atypical forms

─ Geographic necrosis common

─ Characteristic features (variable): Perivascular hypercellularity, alternating cellularity ("marbling")

─ +/- Heterologous elements (rhabdomyosarcoma - Triton tumor, cartilage, bone, angiosarcoma)

─ Epithelioid variant: Sheets/nests of epithelioid cells, often lacks obvious nerve sheath morphology

IHC ─ Diagnosis often relies on morphology and exclusion

─ (+) S100 (patchy/weak in ~50-70%), SOX10 (patchy/weak in ~50%)

─ Loss of H3K27me3 (common, esp. in NF1-associated/high-grade)

─ Loss of NF1 protein expression (in NF1-associated)

─ Epithelioid variant: (+) S100 often diffuse, (-) INI1/SMARCB1 in ~50%

─ (-) Desmin, SMA, keratins, CD34 (to exclude mimics)

Molecular ─ Complex karyotypes; inactivation of NF1, CDKN2A/B, TP53 common; SUZ12 or EED inactivation (PRC2 complex) associated with H3K27me3 loss

DDx ─

─ Schwannoma (Cellular) (Diffuse S100+, lacks significant atypia/necrosis, NF2 loss)

─ Neurofibroma (Atypical) (Usually in NF1, lower grade atypia, lacks high mitoses/necrosis)

─ Synovial Sarcoma (Keratin+, TLE1+, SS18 fusion)

─ Fibrosarcoma/UPS (S100-, SOX10-, H3K27me3 retained)

─ Melanoma (Spindle Cell) (More diffuse S100/SOX10+, other melanocytic markers+)

Prognosis ─ Aggressive sarcoma; high rate of local recurrence and distant metastasis (lung); prognosis worse for large size, high grade, NF1 association, truncal location, positive margins

Media ─ pathoutlines WSI WSI WSI WSI WSI WSI WSI & WSI WSI WSI video

Granular cell tumor

Benign neoplasm showing Schwann cell differentiation, characterized by cells with abundant granular eosinophilic cytoplasm.

Clinical ─ Adults (peak 30-60s), F > M, more common in Black individuals; tongue mc site > skin/subcutis, breast, respiratory tract, GI tract; usually solitary, painless nodule

Macro ─ Small (< 3 cm), poorly circumscribed, firm, yellow-gray nodule

Micro ─

─ Infiltrative nests, cords, or sheets of large polygonal cells

─ Abundant granular eosinophilic cytoplasm (due to lysosomes)

─ Nuclei small, round/oval, often eccentric, bland

─ Overlying pseudoepitheliomatous hyperplasia common in skin/mucosa

─ No significant atypia or mitoses (malignant variant is rare)

IHC ─ (+) S100 (strong, diffuse), SOX10, CD68 (lysosomal marker), Inhibin-alpha, Calretinin, PGP9.5; (-) GFAP, SMA, desmin, keratins

Molecular ─ ATP6AP1 or ATP6AP2 gene mutations reported

DDx ─

─ Rhabdomyoma (Desmin+, lacks S100)

─ Leiomyoma (Epithelioid) (Desmin+, SMA+, lacks S100/granules)

─ Xanthoma/Xanthogranuloma (Foamy cells, Touton giant cells, lacks S100)

─ Alveolar Soft Part Sarcoma (Nests, crystals, TFE3+)

─ Melanoma (Balloon cell) (Other melanocytic markers+, lacks granules)

Prognosis ─ Benign; recurrence rare; malignant variant exceedingly rare (defined by necrosis, spindling, atypia, high mitoses)

Media ─ pathoutlines WSI WSI WSI WSI

Dermal nerve sheath myxoma

Benign cutaneous nerve sheath tumor with prominent myxoid stroma, showing Schwann cell differentiation. Also known as Myxoid Neurothekeoma (Note: Cellular neurothekeoma is now considered distinct and likely fibrohistiocytic).

Clinical ─ Young adults (peak 20-40s); extremities (esp. hands/fingers), head/neck; slow-growing dermal/subcutaneous nodule

Macro ─ Small (< 3 cm), well-circumscribed, gelatinous nodule

Micro ─

─ Multinodular growth pattern in dermis/subcutis

─ Lobules composed of bland spindle and epithelioid cells

─ Set in abundant myxoid stroma (Alcian blue positive)

─ Cells may form cords or small nests

─ Minimal atypia, low mitotic activity

IHC ─ (+) S100 (variable, often patchy), SOX10, GFAP, PG9.5; (-) EMA, SMA, keratins

Molecular ─ None

DDx ─

─ Cellular Neurothekeoma (More cellular, nested growth, lacks S100, often NKI/C3+)

─ Superficial Angiomyxoma (More vascular, epithelial mucin, lacks S100)

─ Myxoid Neurofibroma (Contains axons, less lobulated)

─ Low-grade Myxofibrosarcoma (Curvilinear vessels, more atypia, S100-)

Prognosis ─ Benign; local recurrence common (~30-50%)

Media ─ pathoutlines WSI WSI video

Solitary Circumscribed Neuroma

Benign cutaneous neural tumor composed of Schwann cells and embedded axons. Also known as Palisaded Encapsulated Neuroma (PEN).

Clinical ─ Adults (peak 40-60s); face (esp. perioral, nasal) mc site; solitary, skin-colored papule or nodule

Macro ─ Small (< 1 cm), well-circumscribed dermal nodule

Micro ─

─ Well-circumscribed, encapsulated (EMA+) dermal nodule

─ Composed of interlacing fascicles of bland spindle cells (Schwann cells)

─ Nuclei wavy or oval, minimal atypia

─ Clefts often present between fascicles

─ Embedded small axons present within fascicles (key feature)

─ No Antoni A/B pattern or Verocay bodies

IHC ─ (+) S100, SOX10 (Schwann cells); (+) Neurofilament (axons); (+) EMA (capsule)

Molecular ─ None specific reported

DDx ─

─ Schwannoma (Lacks axons within tumor, Verocay bodies, Antoni A/B)

─ Neurofibroma (Mixed cell types, less circumscribed, S100 patchy)

─ Traumatic Neuroma (Haphazard nerve bundles in scar tissue)

Prognosis ─ Benign; recurrence rare

Media ─ pathoutlines WSI WSI

Ectopic meningioma and meningothelial hamartoma

Meningothelial proliferations outside the CNS, often in the head/neck region or skin.

Clinical ─ Adults; head/neck (scalp, orbit, ear, sinonasal), skin; slow-growing nodule

Macro ─ Well-circumscribed, firm nodule

Micro ─

─ Resembles intracranial meningioma

─ Lobules or whorls of meningothelial cells with syncytial appearance

─ Oval nuclei, fine chromatin, inconspicuous nucleoli, +/- intranuclear pseudoinclusions

─ +/- Psammoma bodies

─ Hamartoma may show entrapment of adnexal structures

IHC ─ (+) EMA, vimentin; (+/-) S100, PR; (-) keratins, CD34

Molecular ─ May show NF2 alterations, similar to intracranial meningioma

DDx ─

─ Glomus Tumor (SMA+, EMA-)

─ Epithelioid Schwannoma (S100+, EMA-)

─ Metastatic Carcinoma (Keratin+, EMA+)

Prognosis ─ Benign

Media ─pathoutlines WSI

Benign triton tumor / Neuromuscular choristoma

Rare hamartomatous lesion composed of mature nerve elements intimately admixed with mature skeletal muscle.

Clinical ─ Infants and children (most < 10 years); large peripheral nerves (sciatic, brachial plexus) mc sites; presents as fusiform nerve enlargement, may cause mass effect or neurologic symptoms

Macro ─ Diffuse enlargement of involved nerve

Micro ─

─ Intimate admixture of mature peripheral nerve elements (Schwann cells, axons) and mature skeletal muscle fibers (rhabdomyocytes)

─ Haphazard arrangement within nerve fascicles

─ No cytologic atypia or increased mitoses

IHC ─ (+) S100, SOX10 (Schwann cells); (+) Neurofilament (axons); (+) Desmin, Myogenin, MyoD1 (skeletal muscle)

Molecular ─ CTNNB1 mutations reported

DDx ─

─ Malignant Triton Tumor (MPNST with rhabdomyosarcomatous differentiation) (Malignant features, atypia, mitoses)

─ Embryonal Rhabdomyosarcoma (Primitive cells, lacks mature nerve elements)

─ Desmoid Fibromatosis (Can arise after biopsy; lacks skeletal muscle, β-catenin+)

Prognosis ─ Benign hamartoma; potential association with subsequent desmoid fibromatosis development, especially post-biopsy

Media ─ pathoutlines WSI

Malignant melanotic nerve sheath tumor

Rare malignant neoplasm with features of both Schwann cell and melanocytic differentiation. Also known as Malignant Melanotic Schwannoma.

Clinical ─ Wide age range; associated with Carney complex (multiple myxomas, endocrine tumors, pigmented lesions) in ~50% cases; spinal nerve roots, paraspinal ganglia mc sites; can occur in soft tissue

Macro ─ Circumscribed or infiltrative mass; often pigmented (brown/black)

Micro ─

─ Fascicles or sheets of plump spindle and epithelioid cells

─ Variable amounts of melanin pigment within tumor cells and melanophages

─ Nuclei often vesicular with prominent nucleoli

─ +/- Psammoma bodies (esp. Carney complex-associated)

─ Mitotic activity variable, necrosis may be present

IHC ─ (+) S100, SOX10 (diffuse); (+) Melanocytic markers (HMB45, Melan-A, MITF); (-) EMA, keratins

Molecular ─ Loss of PRKAR1A in Carney complex-associated cases; sporadic cases lack specific recurrent alterations

DDx ─

─ Malignant Melanoma (Lacks psammoma bodies, usually lacks diffuse S100/SOX10, may have BRAF mutation)

─ Pigmented Neurofibroma (Melanin confined to benign melanocytes, lacks atypia/mitoses)

─ Clear Cell Sarcoma (Melanocytic markers+, S100 variable, EWSR1::ATF1/CREB1 fusion)

Prognosis ─ Malignant; prone to local recurrence and metastasis

Media ─ pathoutlines

Chondro-osseous tumors

Soft tissue chondroma

Benign cartilaginous neoplasm arising in soft tissue, unconnected to bone or joint.

Clinical ─ Adults (peak 30-60s); hands and feet mc sites; slow-growing, firm nodule, may cause pain

Macro ─ Well-circumscribed, lobulated, firm, gray-blue translucent mass; often < 3 cm

Micro ─

─ Lobules of mature hyaline cartilage

─ Chondrocytes situated within lacunae, typically bland with small nuclei

─ +/- Myxoid change, calcification, ossification

─ Minimal atypia, rare binucleation, mitoses absent

IHC ─ (+) S100 (chondrocytes)

Molecular ─ FN1 gene rearrangements reported in some

DDx ─

─ Extraskeletal Myxoid Chondrosarcoma (Myxoid matrix, cords/clusters of cells, NR4A3 fusion)

─ Extraskeletal Osteosarcoma (Malignant osteoid production)

─ Synovial Chondromatosis (Intra-articular or juxta-articular location, multiple nodules)

─ Calcifying Aponeurotic Fibroma (Different morphology, occurs in children/adolescents)

Prognosis ─ Benign; low recurrence rate after excision

Media ─ pathoutlines

Extraskeletal osteosarcoma

Malignant bone-forming neoplasm arising in soft tissue without connection to the skeleton.

Clinical ─ Older adults (peak 50-70s); deep soft tissues of extremities (esp. thigh), retroperitoneum; often large, painful mass

Macro ─ Poorly circumscribed, firm to hard mass; gritty cut surface; hemorrhage and necrosis common

Micro ─

─ Malignant spindle or pleomorphic cells producing osteoid matrix (lace-like or trabecular)

─ Osteoid must be produced directly by tumor cells

─ High-grade atypia, high mitotic rate, necrosis common

─ +/- Cartilaginous or fibrous components

IHC ─ (+) SATB2 (often), Osterix, Alkaline Phosphatase; (+/-) SMA, S100 (chondroid areas); (-) keratins

Molecular ─ Complex karyotypes; lacks specific recurrent alterations

DDx ─

─ Myositis Ossificans (Zonal pattern, lacks atypia)

─ Osteosarcoma arising from bone with soft tissue extension (Connection to bone)

─ Malignant Mesenchymal Tumors with osseous metaplasia (Osteoid not produced directly by tumor cells)

─ Calcifying pseudoneoplasms (e.g., tumoral calcinosis) (Acellular calcified deposits)

Prognosis ─ Aggressive sarcoma; high rate of metastasis (lung); poor prognosis similar to high-grade conventional osteosarcoma

Media ─ pathoutlines

Soft Tissue, Uncertain Differentiation

Intramuscular Myxoma

Benign mesenchymal neoplasm of uncertain origin, composed of bland spindle cells in abundant myxoid matrix, arising within skeletal muscle.

Clinical ─ Middle-aged adults (peak 50-60s), F > M; large muscles (thigh, buttock, shoulder); slow-growing, painless mass; may be associated with fibrous dysplasia (Mazabraud syndrome)

Macro ─ Well-circumscribed, often appears encapsulated; gelatinous cut surface; often large (>5 cm)

Micro ─

─ Hypocellular proliferation of bland spindle and stellate cells

─ Abundant myxoid stroma (Alcian blue positive)

─ Delicate, inconspicuous capillary network

─ Infiltrates adjacent skeletal muscle at periphery

─ +/- cystic degeneration, hemorrhage

─ Cellular variant: Increased cellularity, more collagen, more prominent vessels, but still lacks atypia/mitoses

IHC ─ (+) Vimentin; (+/-) CD34, SMA (focal); (-) S100, desmin, keratins

Molecular ─ Activating mutations in GNAS (codon 201) common

DDx ─

─ Myxoid Liposarcoma (Lipoblasts, plexiform capillaries, DDIT3 fusion)

─ Low-grade Myxofibrosarcoma (Curvilinear vessels, more cellular/atypical areas)

─ Myxoid Neurofibroma (S100+, wavy nuclei)

─ Aggressive Angiomyxoma (Deep pelvic/perineal location, prominent vessels, HMGA2 rearranged)

Prognosis ─ Benign; recurrence rare even if incompletely excised

Media ─ pathoutlines WSI WSI

Juxta Articular Myxoma

Benign myxoid soft tissue lesion occurring near large joints, similar histologically to intramuscular myxoma but often with cystic changes and more prominent vascularity.

Clinical ─ Adults (wide age range); vicinity of large joints (esp. knee); may be associated with osteoarthritis or trauma

Macro ─ Lobulated, gelatinous mass; often contains cystic spaces

Micro ─

─ Similar to intramuscular myxoma (hypocellular, bland spindle/stellate cells, myxoid stroma)

─ Often shows prominent cystic degeneration

─ Vasculature may be more prominent than typical intramuscular myxoma

─ +/- Inflammation, hemorrhage, fibrin deposition

IHC ─ Similar to intramuscular myxoma: (+/-) CD34, SMA; (-) S100, desmin

Molecular ─ Generally lacks GNAS mutations (unlike intramuscular myxoma)

DDx ─

─ Intramuscular Myxoma (GNAS mutated, less cystic typically)

─ Ganglion Cyst (Lacks true cellular lining, different location)

─ Myxoid Liposarcoma (Lipoblasts, plexiform capillaries, DDIT3 fusion)

─ Low-grade Myxofibrosarcoma (Curvilinear vessels, atypia)

Prognosis ─ Benign; may recur locally if incompletely excised

Media ─ pathoutlines WSI & video

Deep (aggressive) angiomyxoma

Locally aggressive myxoid mesenchymal neoplasm occurring primarily in the pelvic/perineal region of adults.

Clinical ─ Adults (peak 30-50s), F >> M; deep soft tissues of pelvis, perineum, vulva, scrotum, inguinal region; slow-growing, often large, painless mass

Macro ─ Large, bulky, poorly circumscribed, gelatinous mass; infiltrative

Micro ─

─ Hypocellular proliferation of bland spindle and stellate cells

─ Abundant loose, myxoid stroma, often edematous

─ Characteristic feature: Numerous small to medium-sized blood vessels, often with hyalinized walls

─ Tumor cells often cluster around vessels

─ Extravasated RBCs common

─ Infiltrative growth pattern

─ Minimal atypia, low mitotic activity

IHC ─ (+) Desmin, SMA (variable); (+) CD34 (variable); (+) ER, PR (common in females); (-) S100

Molecular ─ HMGA2 gene rearrangements (chromosome 12q14-15) characteristic

DDx ─

─ Angiomyofibroblastoma (Vulvovaginal, more cellular, circumscribed, desmin+)

─ Cellular Angiofibroma (Vulvovaginal/scrotal, more cellular, less myxoid, RB1 loss)

─ Myxoid Liposarcoma (Lipoblasts, plexiform capillaries, DDIT3 fusion, different location)

─ Intramuscular/Juxta-articular Myxoma (Different location, less vascular, GNAS altered or wt)

Prognosis ─ Intermediate (locally aggressive, non-metastasizing); high rate of local recurrence due to infiltrative nature; does not metastasize

Media ─ Pathoutlines WSI WSI WSI with video WSI with video case & WSI

Atypical fibroxanthoma (AFX)

Superficial pleomorphic dermal sarcoma occurring in sun-damaged skin of the elderly, considered a superficial variant of undifferentiated pleomorphic sarcoma (UPS).

Clinical ─ Elderly (usually > 70 years); sun-exposed skin of head/neck (scalp, face, ear); rapidly growing, often ulcerated nodule

Macro ─ Small (< 2 cm), reddish, often ulcerated nodule

Micro ─

─ Dermal-based (usually confined to dermis, may involve superficial subcutis), often ulcerated

─ Highly pleomorphic spindle and epithelioid cells with bizarre nuclei

─ Abundant mitotic activity, including atypical forms

─ No involvement of deep subcutis, fascia, or muscle (distinction from UPS)

─ +/- Osteoclast-like giant cells, foam cells, inflammation

─ Grenz zone often present beneath epidermis

IHC ─ Diagnosis of exclusion

─ (+) Vimentin, CD10, CD68 (variable); (+/-) SMA

─ (-) Pan-keratin, S100, SOX10, desmin, ERG (to exclude SCC, melanoma, LMS, angiosarcoma)

Molecular ─ Complex karyotypes, UV-signature mutations (TP53 common); lacks specific alterations of mimics

DDx ─

─ Spindle Cell Squamous Cell Carcinoma (Keratin+, p40/p63+)

─ Spindle Cell/Desmoplastic Melanoma (S100+, SOX10+)

─ Leiomyosarcoma (Desmin+, SMA+)

─ Undifferentiated Pleomorphic Sarcoma (UPS) (Deep extension, identical cytology)

Prognosis ─ Favorable compared to UPS; low risk of recurrence or metastasis if confined to dermis and completely excised

Media ─ pathoutlines WSI WSI with video WSI with video

Angiomatoid fibrous histiocytoma (AFH)

Mesenchymal neoplasm of uncertain differentiation, typically occurring in children and young adults, characterized by nodules of histiocytoid/spindle cells, pseudoangiomatoid spaces, and a prominent lymphoid cuff.

Clinical ─ Children and young adults (peak 10-25 years); extremities (esp. near joints) mc site; subcutaneous or deep soft tissue; slow-growing, painless mass

Macro ─ Well-circumscribed, pseudoencapsulated nodule; tan-white with cystic/hemorrhagic areas

Micro ─

─ Multinodular growth pattern

─ Thick fibrous pseudocapsule

─ Sheets/nodules of bland ovoid to spindle cells with eosinophilic cytoplasm (histiocytoid/myoid appearance)

─ Characteristic feature: Blood-filled cystic spaces resembling aneurysmal bone cyst or dilated vessels ("pseudoangiomatoid spaces")

─ Prominent peripheral cuff of lymphocytes and plasma cells, often with germinal centers

─ Hemosiderin deposition common

─ Low mitotic activity, minimal atypia

IHC ─ (+) Desmin (variable, often dot-like), CD68, EMA (variable); (+/-) CD99; (-) S100, keratins, vascular markers (CD31, ERG), ALK1

Molecular ─ Recurrent translocations involving EWSR1 gene (mc EWSR1::CREB1, also EWSR1::ATF1, FUS::ATF1)

DDx ─

─ Hematoma (Lacks cellular nodules and lymphoid cuff)

─ Follicular Dendritic Cell Sarcoma (CD21+, CD35+)

─ Lymphoma (Hodgkin or NHL) (Specific lymphoma markers+)

─ Aneurysmal Bone Cyst (if bone involved) (USP6 rearranged)

Prognosis ─ Intermediate (rarely metastasizing); local recurrence common (~15%); metastasis rare (<1%), usually to lymph nodes

Media ─ pathoutlines WSI WSI WSI

Ossifying fibromyxoid tumor (OFMT)

Mesenchymal neoplasm of uncertain differentiation characterized by cords and nests of small round/oval cells in a fibromyxoid stroma, often with a peripheral shell of metaplastic bone.

Clinical ─ Adults (peak 40-60s); subcutaneous tissue of extremities mc site; slow-growing, usually painless nodule

Macro ─ Well-circumscribed, firm nodule; gray-white; often gritty due to calcification/ossification

Micro ─

─ Lobulated growth pattern

─ Uniform small round to oval cells arranged in cords, nests, or trabeculae

─ Set in a variably fibrous and myxoid stroma

─ Characteristic feature: Incomplete peripheral shell of lamellar bone (present in most cases)

─ +/- Calcification, cartilage, increased cellularity, atypia (atypical/malignant variants)

IHC ─ (+) S100 (variable, ~75% cases); (+/-) Desmin, SMA, EMA, GFAP; (-) Keratins, SOX10

Molecular ─ PHF1 gene rearrangements (chromosome 6p21) common; other fusions (EPC1, MEAF6) also occur

DDx ─

─ Schwannoma (Diffuse S100+, Antoni A/B)

─ Myoepithelioma/Myoepithelial Carcinoma (Keratin+, EMA+, S100+, other myoepithelial markers)

─ Extraskeletal Myxoid Chondrosarcoma (Myxoid matrix, NR4A3 fusion)

─ Low-grade Fibromyxoid Sarcoma (MUC4+, different morphology)

Prognosis ─ Mostly benign/intermediate; recurrence ~20%; rare metastasis, usually associated with atypical/malignant features (high cellularity, atypia, >2 mitoses/50 HPF)

Media ─ pathoutlines WSI WSI

Myoepithelioma / Myoepithelial carcinoma of soft tissue

Neoplasms composed purely of myoepithelial cells, occurring primarily in soft tissue (distinct from salivary gland counterparts). Myoepithelioma is benign; myoepithelial carcinoma is malignant.

Clinical ─ Adults (wide age range); extremities (esp. deep soft tissue) mc site; slow-growing mass

Macro ─ Well-circumscribed nodule (myoepithelioma) or infiltrative mass (carcinoma); gray-white, often gelatinous/myxoid

Micro ─

─ Architecture variable: Reticular, nested, solid

─ Cells variable: Epithelioid, spindle, plasmacytoid, clear cells

─ Stroma often myxoid or hyalinized

─ Myoepithelioma: Bland cytology, low mitotic activity

─ Myoepithelial Carcinoma: Defined by moderate to marked cytologic atypia; may have increased mitoses, necrosis, infiltrative growth

IHC ─ Variable expression defines myoepithelial lineage:

─ (+) S100 (most cases); (+) Keratins (AE1/AE3, CAM5.2, CK14); (+) EMA (variable); (+) GFAP (variable); (+) SMA, Calponin, p63/p40 (variable, esp. spindle cells)

─ INI1/SMARCB1 loss in a subset of malignant cases (esp. pediatric)

Molecular ─ EWSR1 rearrangements common (various fusion partners, e.g., PBX1, POU5F1, ZNF444); FUS rearrangements less common; PLAG1 fusions also reported

DDx ─

─ Extraskeletal Myxoid Chondrosarcoma (Lacks epithelial markers, NR4A3 fusion)

─ Chordoma (Brachyury+, different morphology)

─ Ossifying Fibromyxoid Tumor (Lacks epithelial markers, PHF1 fusion)

─ Parachordoma (Similar IHC but different morphology/location)

─ Metastatic Carcinoma (Different morphology/IHC profile)

Prognosis ─ Myoepithelioma: Benign, low recurrence rate; Myoepithelial Carcinoma: Malignant, risk of recurrence and metastasis (~30-40%)

Media ─ pathoutlines

Pleomorphic hyalinizing angiectatic tumor (PHAT)

Rare mesenchymal neoplasm of uncertain differentiation, characterized by clusters of hyalinized, ectatic blood vessels and surrounding pleomorphic stromal cells with hemosiderin. Considered related to HFLT and MIFS.

Clinical ─ Adults (peak 40-70s); subcutaneous tissue of lower extremities (esp. ankle/foot) mc site; slow-growing, often painful mass

Macro ─ Poorly circumscribed, brownish mass; may have hemorrhagic or gelatinous areas

Micro ─

─ Poorly circumscribed, infiltrative growth

─ Characteristic clusters of thin-walled, ectatic blood vessels with thick perivascular hyalinization/fibrinoid material

─ Surrounding stroma is variably cellular, often edematous or myxoid

─ Stromal cells show marked pleomorphism, bizarre hyperchromatic nuclei, intranuclear pseudoinclusions

─ Abundant hemosiderin deposition (within stromal cells and macrophages)

─ Mitotic activity is typically very low, necrosis absent

IHC ─ Non-specific; tumor cells (+) vimentin, CD34 (variable); (+/-) CD68; (-) S100, keratins, SMA, desmin

Molecular ─ Recurrent t(1;10)(p22;q24) resulting in TGFBR3::MGEA5 fusion (shared with HFLT and MIFS)

DDx ─

─ Hemosiderotic Fibrolipomatous Tumor (HFLT) (Overlapping features, prominent adipose tissue, less prominent vascular changes/pleomorphism)

─ Myxoinflammatory Fibroblastic Sarcoma (MIFS) (More prominent inflammation, ganglion-like/virocyte cells, may lack prominent ectatic vessels)

─ Ancient Schwannoma (Diffuse S100+, Verocay bodies, lacks ectatic vessels)

─ Malignant Peripheral Nerve Sheath Tumor (MPNST) (More overt malignancy, higher mitoses, S100 often patchy/neg)

─ Myxofibrosarcoma (Curvilinear vessels, lacks prominent hyalinization/hemosiderin)

Prognosis ─ Intermediate (locally aggressive, rarely metastasizing); high rate of local recurrence; metastasis very rare

Media ─ pathoutlines WSI with video WSI with video WSI WSI WSI HE

Hemosiderotic fibrolipomatous tumor (HFLT)

Rare mesenchymal neoplasm characterized by an admixture of adipose tissue, fibrous tissue with hemosiderin deposition, and bland spindle cells. Considered related to PHAT and MIFS.

Clinical ─ Adults (peak 40-60s), F > M; ankle/foot mc site; slow-growing, often painful or tender mass/plaque

Macro ─ Poorly circumscribed, firm or infiltrative plaque/mass; yellowish-brown cut surface

Micro ─

─ Poorly circumscribed, infiltrative growth in subcutaneous tissue

─ Admixture of mature adipose tissue and fibrous tissue

─ Fibrous component contains bland spindle cells (fibroblasts)

─ Prominent hemosiderin deposition within spindle cells and macrophages

─ Chronic inflammatory infiltrate (lymphocytes) common

─ +/- Scattered pleomorphic cells or pseudolipoblasts

─ +/- Areas resembling PHAT (ectatic hyalinized vessels)

─ Low mitotic activity

IHC ─ (+) CD34 (spindle cells); (+) CD68 (macrophages); (-) S100 (except fat), keratins, SMA, desmin

Molecular ─ Recurrent t(1;10)(p22;q24) resulting in TGFBR3::MGEA5 fusion (shared with PHAT and MIFS)

DDx ─

─ Pleomorphic Hyalinizing Angiectatic Tumor (PHAT) (More prominent vascular changes and pleomorphism, less prominent fat)

─ Myxoinflammatory Fibroblastic Sarcoma (MIFS) (More myxoid, prominent inflammation, ganglion-like cells)

─ Dermatofibroma (Hemosiderotic variant) (More superficial, Factor XIIIa+)

─ Tenosynovial Giant Cell Tumor (Localized) (More defined nodules, osteoclast giant cells)

Prognosis ─ Intermediate (locally aggressive, rarely metastasizing); high rate of local recurrence; metastasis very rare

Media ─ WSI & video

Phosphaturic mesenchymal tumor (PMT)

Rare mesenchymal neoplasm characterized by bland spindle cells, distinctive "grungy" calcified matrix, and association with tumor-induced osteomalacia (TIO) due to FGF23 production.

Clinical ─ Adults (wide age range); soft tissue (esp. extremities) or bone; often presents with symptoms of osteomalacia (bone pain, fractures, weakness) due to hypophosphatemia caused by tumor-produced FGF23

Macro ─ Variable size, often circumscribed; gritty or firm; yellowish-tan

Micro ─

─ Bland spindle to stellate cells with indistinct cytoplasm

─ Set in a variable stroma (myxoid, fibrous, adipose)

─ Characteristic feature: Distinctive flocculent, "grungy" basophilic calcified matrix (smudgy calcification)

─ Prominent vascularity, often hemangiopericytoma-like vessels

─ +/- Osteoclast-like giant cells, hemosiderin, metaplastic bone/cartilage

─ Minimal atypia, low mitotic activity

IHC ─ (+) FGF23 (variable); (+) CD56, ERG, SATB2 (variable); (+/-) SMA; (-) S100, keratins, desmin

Molecular ─ Recurrent FN1::FGFR1 or FN1::FGF1 fusions common

DDx ─

─ Chondroblastoma (Epiphyseal bone location, "chicken-wire" calcification, H3.3 K36M+)

─ Giant Cell Tumor of Soft Tissue/Bone (Lacks grungy matrix, H3F3A mutation in bone GCT)

─ Calcifying fibrous tumor (Different type of calcification, lacks grungy matrix)

─ Mesenchymal Chondrosarcoma (Biphasic, SRBC component, HEY1::NCOA2 fusion)

Prognosis ─ Mostly benign; complete excision usually cures osteomalacia; rare malignant variants with atypia/mitoses/necrosis can metastasize

Media ─ pathoutlines WSI WSI

Synovial Sarcoma

Malignant mesenchymal neoplasm of uncertain differentiation, defined by SS18 gene rearrangement, showing variable epithelial differentiation. Despite its name, it does not arise from synovium.

Clinical ─ Adolescents and young adults (peak 15-40s); deep soft tissues of extremities (esp. near large joints, knee mc) > trunk, head/neck; often slow-growing, painful mass

Macro ─ Appears circumscribed but infiltrative; gray-white to tan; +/- cystic change, calcification, hemorrhage

Micro ─

─ Monophasic type: Composed exclusively of spindle cells

─ Biphasic type: Shows both spindle cell and epithelial components (glands, nests, or cords)

─ Poorly differentiated type: High-grade round cell or epithelioid areas, may obscure typical features

─ Spindle cells: Uniform, scant cytoplasm, dark oval nuclei, arranged in dense fascicles ("herringbone" pattern)

─ Epithelial cells: Cuboidal to columnar, form glands or nests, eosinophilic cytoplasm

─ Characteristic features: Staghorn/hemangiopericytoma-like vessels, stromal hyalinization, mast cells common, +/- calcification

IHC ─ (+) Keratins (AE1/AE3, CAM5.2), EMA (epithelial markers, often positive even in monophasic type, esp. focally); (+) TLE1 (nuclear, sensitive but not specific); (+) BCL2, CD99 (variable); (-) CD34, S100, SOX10, desmin

Molecular ─ Characteristic translocation t(X;18)(p11;q11) resulting in SS18::SSX1, SS18::SSX2, or rarely SS18::SSX4 fusion

DDx ─

─ Malignant Peripheral Nerve Sheath Tumor (MPNST) (S100/SOX10+, H3K27me3 loss common, lacks epithelial markers/fusion)

─ Fibrosarcoma/Spindle Cell Sarcoma NOS (Diagnosis of exclusion, lacks specific IHC/fusion)

─ Solitary Fibrous Tumor (STAT6+, CD34+, lacks epithelial markers/fusion)

─ Ewing Sarcoma (Poorly diff variant) (CD99+, NKX2.2+, EWSR1 fusion)

Prognosis ─ Aggressive sarcoma; high risk of local recurrence and distant metastasis (lung, bone); prognosis depends on size, grade (poorly diff worse), stage, necrosis

Media ─ pathoutlines Monophasic WSI WSI WSI WSI & video Biphasic WSI

Epithelioid Sarcoma

Malignant neoplasm of uncertain differentiation characterized by epithelioid and spindle cells, often showing central necrosis resembling a granuloma or carcinoma.

Clinical ─ Adolescents and young adults (peak 10-35s), M > F; distal extremities (hand, wrist, forearm, foot/ankle) mc site (classic type); proximal type (pelvis, perineum, trunk) occurs in older adults

─ Classic type: Slow-growing, firm nodules/ulcers in dermis/subcutis/fascia

─ Proximal type: Deep-seated, larger, more aggressive mass

Macro ─ Ill-defined, firm, gray-white nodule(s) or mass; often ulcerated (classic); may show central necrosis

Micro ─

─ Nodular growth pattern

─ Central geographic necrosis often present ("pseudogranuloma")

─ Tumor cells: Plump epithelioid cells with abundant eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli; often admixed with spindle cells

─ Cells arranged in nests or sheets

─ Infiltrative growth common

IHC ─ (+) Keratins (AE1/AE3, CAM5.2), EMA (epithelial markers); (+) CD34 (variable, ~50%); (+) Vimentin; (-) INI1/SMARCB1 (loss of nuclear expression is characteristic, ~90% cases); (-) S100, SOX10, Desmin, FLI1

Molecular ─ Inactivation of SMARCB1 (INI1) gene (chromosome 22q11.2) via deletion or mutation

DDx ─

─ Granulomatous inflammation (Necrotizing granuloma) (Lacks atypia, INI1 retained)

─ Squamous Cell Carcinoma (More cohesive, p40/p63+, INI1 retained)

─ Melanoma (S100+, SOX10+, HMB45+, INI1 retained)

─ Synovial Sarcoma (Biphasic pattern sometimes, TLE1+, SS18 fusion, INI1 retained)

─ Rhabdoid Tumor (Often younger age, different morphology, INI1 loss)

Prognosis ─ Aggressive sarcoma; high rate of local recurrence, lymph node metastasis (~30-40%), and distant metastasis (lung); proximal type generally has worse prognosis

Media ─ pathoutlines WSI WSI video

Alveolar soft part sarcoma (ASPS)

Malignant neoplasm of uncertain differentiation characterized by nests of large polygonal cells with granular eosinophilic cytoplasm and characteristic intracytoplasmic crystals.

Clinical ─ Adolescents and young adults (peak 15-35s), F > M; deep soft tissues of lower extremities (esp. thigh), head/neck (esp. orbit/tongue in children)

Macro ─ Appears circumscribed but unencapsulated; soft, tan-pink mass; often highly vascular

Micro ─

─ Organoid/nested ("alveolar") pattern: Nests of tumor cells separated by delicate fibrovascular septa

─ Central discohesion within nests common

─ Cells: Large, polygonal, abundant granular eosinophilic cytoplasm, round vesicular nuclei, prominent nucleoli

─ Characteristic feature: Intracytoplasmic rhomboid or rod-shaped crystals (PAS+, diastase-resistant) - may not be present in all cells/cases

─ Low mitotic activity usually, despite malignant behavior

IHC ─ (+) TFE3 (nuclear, reflects fusion); (+/-) Desmin, MyoD1 (aberrant); (-) Keratins, EMA, S100, SOX10, HMB45, Melan-A, SMA, CD34, Synaptophysin, Chromogranin

Molecular ─ Characteristic unbalanced translocation der(17)t(X;17)(p11;q25) resulting in ASPSCR1::TFE3 fusion

DDx ─

─ Paraganglioma/Pheochromocytoma (S100+ sustentacular cells, Synapto/Chromo+, lacks crystals/fusion)

─ Granular Cell Tumor (S100+, SOX10+, lacks crystals/fusion)

─ Rhabdomyoma/Rhabdomyosarcoma (Desmin+, Myogenin+, lacks crystals/fusion)

─ Melanoma (S100+, SOX10+, Melanocytic markers+, lacks crystals/fusion)

─ Renal Cell Carcinoma (Metastatic) (PAX8+, CD10+, CAIX+, lacks crystals/fusion)

Prognosis ─ Indolent but highly metastatic; high rate of metastasis (lung, brain, bone), often late; relatively resistant to conventional chemotherapy

Media ─ pathoutlines WSI HE TFE3 WSI

Clear cell sarcoma of soft tissue

Malignant neoplasm showing melanocytic differentiation, characterized by nests/fascicles of cells with clear/pale cytoplasm. Also known as Malignant Melanoma of Soft Parts.

Clinical ─ Young adults (peak 20-40s); deep soft tissues of distal extremities (esp. foot/ankle), often associated with tendons/aponeuroses

Macro ─ Circumscribed, firm, gray-white mass

Micro ─

─ Nests and short fascicles of relatively uniform polygonal or spindle cells

─ Separated by delicate fibrous septa

─ Cells have clear to pale eosinophilic cytoplasm, round vesicular nuclei, prominent nucleoli

─ Wreath-like multinucleated giant cells may be present

─ Mitotic activity variable

IHC ─ (+) S100 (strong, diffuse), SOX10, Melan-A, HMB45, MITF (melanocytic markers); (-) Keratins, Desmin, SMA

Molecular ─ Characteristic translocation t(12;22)(q13;q12) resulting in EWSR1::ATF1 fusion; less commonly EWSR1::CREB1

DDx ─

─ Malignant Melanoma (Metastatic or primary desmoplastic/spindle) (Lacks EWSR1 fusion, may have BRAF mutation)

─ Malignant Peripheral Nerve Sheath Tumor (MPNST) (S100 often patchy/neg, lacks melanocytic markers/fusion)

─ Synovial Sarcoma (Monophasic) (TLE1+, Keratin/EMA+, lacks melanocytic markers, SS18 fusion)

─ PEComa (Smooth muscle markers+, lacks S100/SOX10)

Prognosis ─ Aggressive sarcoma; high rate of lymph node and distant metastasis (lung); poor prognosis

Media ─ pathoutlines in skin WSI WSI WSI

Extraskeletal Myxoid Chondrosarcoma (EMC)

Malignant neoplasm of uncertain differentiation characterized by cords and clusters of cells in an abundant myxoid matrix, typically harboring NR4A3 rearrangements. Despite its name, it usually lacks true cartilage.

Clinical ─ Adults (peak 40-60s); deep soft tissues of proximal extremities (esp. thigh) and limb girdles

Macro ─ Well-circumscribed, multinodular, gelatinous mass

Micro ─

─ Multinodular architecture with fibrous septa

─ Cords, strands, clusters, or lace-like arrangements of relatively uniform round, oval, or spindle cells

─ Abundant myxoid stroma (Alcian blue positive)

─ Cells often have eosinophilic cytoplasm, may show rhabdoid features

─ Mitotic activity usually low

─ +/- Hemorrhage, cystic change; true hyaline cartilage rare

IHC ─ (+) Vimentin; (+/-) S100 (variable, often weak/patchy), EMA (variable), NSE, Synaptophysin (subset); (-) Keratins, SMA, Desmin, SOX10, Brachyury

Molecular ─ NR4A3 gene rearrangements (chromosome 9q22) characteristic (mc EWSR1::NR4A3, also TAF15::NR4A3, TCF12::NR4A3, etc.)

DDx ─

─ Myxoid Liposarcoma (Lipoblasts, plexiform capillaries, DDIT3 fusion)

─ Myxofibrosarcoma (Curvilinear vessels, more pleomorphism, lacks fusion)

─ Chordoma (Physaliphorous cells, Brachyury+, S100+, lacks fusion)

─ Myoepithelial Tumors (Keratin+, EMA+, S100+, EWSR1 fusion possible but different partners)

─ Ossifying Fibromyxoid Tumor (Peripheral bone shell, S100+, PHF1 fusion)

Prognosis ─ Relatively indolent course initially, but high rate of late local recurrence and metastasis (lung); overall long-term survival is poor

Media ─ pathoutlines WSI WSI WSI WSI WSI WSI

Desmoplastic small round cell tumor (DSRCT)

Aggressive malignant neoplasm composed of nests of small round blue cells within a prominent desmoplastic stroma, characterized by EWSR1::WT1 fusion.

Clinical ─ Adolescents and young adults (peak 15-30s), M >> F; typically arises from abdominal/pelvic serosa (peritoneum); presents with abdominal mass, pain, ascites

Macro ─ Multiple firm nodules studding peritoneal surfaces; gray-white

Micro ─

─ Sharply demarcated nests and islands of small, primitive round cells

─ Cells have scant cytoplasm, hyperchromatic nuclei, inconspicuous nucleoli

─ Embedded in abundant desmoplastic (fibrous) stroma

─ Mitotic activity and apoptosis common

─ +/- Rosette formation, central necrosis within nests

IHC ─ Characteristic polyphenotypic expression:

─ (+) Keratins (AE1/AE3, CAM5.2 - often dot-like), EMA

─ (+) Desmin (often dot-like)

─ (+) WT1 (nuclear, C-terminus antibody)

─ (+) NSE, CD99 (variable); (-) Myogenin, MyoD1, Chromogranin, Synaptophysin, LCA, S100

Molecular ─ Characteristic translocation t(11;22)(p13;q12) resulting in EWSR1::WT1 fusion

DDx ─

─ Ewing Sarcoma (CD99+, NKX2.2+, FLI1+, lacks keratin/desmin, different fusion)

─ Rhabdomyosarcoma (Alveolar/Embryonal) (Myogenin+, MyoD1+, Desmin+, lacks keratin/WT1)

─ Lymphoma (LCA+, specific lymphoma markers+)

─ Wilms Tumor (If renal) (Triphasic pattern, WT1 N-terminus+)

─ Mesothelioma (Calretinin+, WT1 N-terminus+)

Prognosis ─ Very aggressive; poor prognosis despite multimodality therapy; widespread metastasis common

Media ─ pathoutlines WSI WSI WSI WSI WSI WSI & WSI case & WSI video

Extrarenal rhabdoid tumor

Highly aggressive malignant neoplasm composed of "rhabdoid" cells (large cells with eccentric nuclei, prominent nucleoli, eosinophilic cytoplasm +/- inclusions), characterized by loss of INI1/SMARCB1 expression. Occurs outside the kidney/CNS.

Clinical ─ Primarily infants and young children (< 3 years); can occur in older children/adults; deep soft tissues (neck, paraspinal, limbs, retroperitoneum), viscera; presents as rapidly growing mass

Macro ─ Fleshy, gray-white mass; often large with hemorrhage and necrosis

Micro ─

─ Diffuse sheets of poorly cohesive cells

─ Characteristic "rhabdoid" cells: Large polygonal cells, abundant eosinophilic cytoplasm, eccentric vesicular nucleus, prominent central nucleolus

─ +/- Intracytoplasmic eosinophilic hyaline inclusions (aggregated intermediate filaments)

─ High mitotic rate, extensive necrosis common

─ Minimal stroma

IHC ─ Loss of nuclear INI1/SMARCB1 (or rarely BRG1/SMARCA4) is diagnostic

─ (+) Vimentin, EMA, Keratins (AE1/AE3, CAM5.2 - often dot-like); (+/-) SMA, Synaptophysin, CD99; (-) Desmin, Myogenin, S100, HMB45

Molecular ─ Biallelic inactivation of SMARCB1 (INI1) gene (chromosome 22q11.2) via deletion or mutation; rarely SMARCA4 (BRG1) inactivation

DDx ─

─ Epithelioid Sarcoma (Also INI1 loss, but different morphology/clinical setting, often CD34+)

─ Rhabdomyosarcoma (Pleomorphic) (Retained INI1, Myogenin/MyoD1+)

─ Melanoma (S100+, SOX10+, Melanocytic markers+, retained INI1)

─ Poorly Differentiated Carcinoma (Retained INI1, different IHC profile)

Prognosis ─ Highly aggressive; very poor prognosis, often fatal despite intensive therapy

Media ─ pathoutlines WSI

Intimal sarcoma

Rare malignant mesenchymal neoplasm arising from the intima of large blood vessels, typically the pulmonary artery or aorta.

Clinical ─ Adults (wide age range); pulmonary artery > aorta > large veins; presents with symptoms mimicking pulmonary embolism, heart failure, or aortic dissection

Macro ─ Polypoid, gelatinous mass filling and expanding the vessel lumen; often extends along vessel branches

Micro ─

─ Poorly differentiated spindle and/or pleomorphic cells

─ Often arranged loosely in myxoid stroma, may have fascicular areas

─ High mitotic rate, necrosis common

─ +/- Heterologous differentiation (osteosarcoma, chondrosarcoma, rhabdomyosarcoma)

IHC ─ Non-specific; tumor cells often (+) vimentin; (+/-) SMA, MDM2 (reflects amplification); (-) Desmin, S100, keratins, endothelial markers (CD31, ERG)

Molecular ─ MDM2 gene amplification common, often with CDK4 co-amplification; complex karyotypes

DDx ─

─ Thrombus (Organized) (Lacks atypical cells, inflammatory cells present)

─ Myxoma (Cardiac) (Different morphology, lacks atypia/mitoses)

─ Leiomyosarcoma (Arising from vessel wall) (Desmin+, SMA+, lacks MDM2 amp)

─ Angiosarcoma (Endothelial markers+, lacks MDM2 amp)

Prognosis ─ Very aggressive; poor prognosis due to location and frequent metastasis

Media ─ pathoutlines WSI WSI WSI WSI WSI WSI WSI

Thoracic aorta WSI & bone mets WSIWSI

Bone, Chondrogenic

Subungual exostosis

Benign osteocartilaginous proliferation arising from the distal phalanx beneath the nail bed. Also known as Dupuytren exostosis.

Clinical ─ Adolescents and young adults; slight F > M predilection; great toe mc site > other toes/fingers; presents as painful nodule elevating the nail plate; often history of trauma or infection

Radiology ─ Well-defined bony outgrowth from the dorsal aspect of the distal phalanx; trabeculated bone continuous with underlying phalanx cortex but not medulla; cartilaginous cap may or may not be visible/calcified

Macro ─ Small (< 2 cm), sessile or pedunculated bony nodule covered by a cartilaginous or fibrous cap; often ulcerates overlying skin/nail bed

Micro ─

─ Base of mature trabecular bone continuous with underlying phalanx

─ Overlying cap composed initially of proliferating spindle cells (fibroblasts), progressing through enchondral ossification:

─ Hyaline cartilage cap (often hypercellular, may show mild atypia)

─ Fibrocartilaginous cap (mixture of fibrous tissue and cartilage)

─ Fibrous cap (later stage, less common)

─ Surface may show ulceration, inflammation

IHC ─ Not required; S100 highlights chondrocytes

Molecular ─ IRS4 rearrangements reported; distinct from EXT1/EXT2

DDx ─

─ Osteochondroma (Arises from metaphysis of long bones, medullary continuity, EXT1/EXT2 mutated)

─ Bizarre Parosteal Osteochondromatous Proliferation (BPOP) (Hands/feet, "blue bone," lacks continuity, different genetics)

─ Glomus Tumor (Subungual location, painful, different histology/IHC)

─ Squamous Cell Carcinoma (Subungual) (Malignant cytology, keratin+)

Prognosis ─ Benign; recurrence possible (~10%) if incompletely excised

Media ─ Pathoutlines

Bizarre parosteal osteochondromatous proliferation (BPOP)

Reactive, benign osteocartilaginous proliferation arising from the surface of bone, typically in the hands and feet. Also known as Nora Lesion.

Clinical ─ Young adults (peak 20-30s); hands and feet (phalanges, metacarpals, metatarsals) mc sites; often presents as painless swelling, may follow trauma

Radiology ─ Well-demarcated, calcified/ossified mass arising directly from the cortical surface without underlying bone involvement or medullary continuity; periosteal reaction usually absent

Macro ─ Sessile or pedunculated nodular mass attached to bone surface; firm to hard; blue-gray cartilaginous areas mixed with bony tissue

Micro ─

─ Irregular mixture of hypercellular cartilage, bone, and spindle cells

─ Cartilage often markedly hypercellular, chondrocytes enlarged and atypical (bizarre, binucleated), arranged irregularly, not in columns

─ Bone trabeculae are irregular, often immature woven bone, may have blue tinge ("blue bone")

─ Spindle cell stroma is often cellular and interspersed between cartilage and bone

─ No medullary continuity with underlying bone

IHC ─ Not specific; S100 highlights chondrocytes

Molecular ─ Recurrent t(1;17)(q32;q21) reported; distinct from osteochondroma and subungual exostosis

DDx ─

─ Osteochondroma (Metaphyseal long bones, medullary continuity, organized cap, EXT1/EXT2 mutated)

─ Subungual Exostosis (Distal phalanx, fibrocartilaginous cap, different genetics)

─ Periosteal Chondroma/Chondrosarcoma (Distinct cartilage lobules, +/- atypia, different location/genetics)

─ Parosteal Osteosarcoma (Malignant spindle cells producing osteoid, MDM2 amplified)

─ Myositis Ossificans (Soft tissue location, zonal pattern)

Prognosis ─ Benign; high rate of local recurrence (~50%) after simple excision, but does not metastasize

Media ─ Pathoutlines WSI WSI

Periosteal chondroma

Benign cartilaginous neoplasm arising from the surface of bone, beneath the periosteum. Also known as juxtacortical chondroma.

Clinical ─ Children and young adults (peak 10-30s), M > F; proximal humerus, distal femur, hands/feet common sites; presents as slow-growing, often painless mass

Radiology ─ Well-defined, lobulated mass on bone surface causing saucerization/erosion of underlying cortex; often sclerotic rim at base; +/- matrix calcification (rings/arcs); no medullary involvement

Macro ─ Lobulated, firm, gray-blue translucent cartilaginous mass beneath periosteum; usually < 3 cm

Micro ─

─ Lobules of mature hyaline cartilage, often more cellular and slightly more atypical than enchondroma

─ Surrounded by fibrous periosteum

─ Underlying cortex may be eroded but not permeated

─ +/- Myxoid change, calcification, ossification at periphery

─ Low mitotic activity

IHC ─ (+) S100 (chondrocytes)

Molecular ─ IDH1 or IDH2 mutations common

DDx ─

─ Periosteal Osteosarcoma (Malignant spindle cells producing osteoid)

─ Periosteal Chondrosarcoma (Larger size, greater atypia, cortical destruction/soft tissue extension)

─ BPOP (Different location - hands/feet, "blue bone", different genetics)

─ Enchondroma (Intramedullary location)

Prognosis ─ Benign; low recurrence rate after complete excision

Media ─ Pathoutlines WSI WSI video HE

Enchondroma

Benign intramedullary cartilaginous neoplasm composed of mature hyaline cartilage.

Clinical ─ Wide age range (peak 10-40s); solitary or multiple (enchondromatosis - Ollier disease, Maffucci syndrome); small tubular bones of hands/feet mc site > long bones (femur, humerus); often incidental finding or presents with pathologic fracture

Radiology ─ Well-defined, geographic lytic lesion in medullary cavity; +/- matrix calcification (rings/arcs, stippled, flocculent); +/- endosteal scalloping (mild); no cortical destruction or soft tissue mass

Macro ─ Lobulated, gray-blue translucent cartilage within medullary cavity

Micro ─

─ Lobules of mature hyaline cartilage embedded in marrow space

─ Hypocellular, chondrocytes in lacunae, small bland nuclei

─ Minimal atypia, rare binucleation

─ Matrix often shows myxoid change

─ +/- Peripheral enchondral ossification

─ Entrapment of pre-existing lamellar bone is not seen (key feature vs LG chondrosarcoma)

IHC ─ (+) S100 (chondrocytes)

Molecular ─ IDH1 or IDH2 mutations common

DDx ─

─ Low-grade Chondrosarcoma (Permeative growth, entrapment of lamellar bone, greater cellularity/atypia, clinical/radiologic correlation crucial)

─ Chondroblastoma (Epiphyseal location, different morphology, H3-3B K36M mutated)

─ Bone Infarct (Serpiginous calcification, necrotic marrow)

Prognosis ─ Benign; malignant transformation to chondrosarcoma rare in solitary lesions, more common in enchondromatosis (~25-30%)

Media ─ Pathoutlines WSI WSI WSI WSI x-ray video HE HE

Osteochondroma

Benign cartilage-capped bony projection arising from the external surface of a bone, showing continuity of cortex and medulla with the underlying bone. Most common benign bone tumor.

Clinical ─ Children and adolescents (growth ceases with skeletal maturity); solitary or multiple (Multiple Hereditary Exostoses - MHE); metaphysis of long bones (esp. distal femur, proximal tibia/humerus) mc sites; presents as painless mass, may cause mechanical symptoms or nerve compression

Radiology ─ Pedunculated or sessile bony outgrowth from bone surface; cortex and medulla are continuous with underlying native bone (pathognomonic); cartilage cap visible (variable calcification), thickness decreases with age

Macro ─ Mushroom-shaped bony mass covered by smooth, gray-blue cartilage cap

Micro ─

─ Cartilage cap resembles epiphyseal growth plate with chondrocytes arranged in columns undergoing enchondral ossification

─ Thickness of cap varies (<1 cm in adults, thicker in children)

─ Underlying bone trabeculae continuous with host bone medulla

─ +/- Bursa formation over cap

IHC ─ Not typically required; S100 highlights chondrocytes

Molecular ─ Inactivation of EXT1 or EXT2 genes (involved in heparan sulfate synthesis) in sporadic and MHE cases

DDx ─

─ Chondrosarcoma (Secondary) (Thickened cartilage cap >2cm in adult, increased cellularity/atypia in cap)

─ Subungual Exostosis (Distal phalanx, lacks medullary continuity, different genetics)

─ BPOP (Hands/feet, lacks medullary continuity, different genetics)

─ Periosteal Chondroma (Lacks medullary continuity, cortical saucerization)

Prognosis ─ Benign; malignant transformation to secondary chondrosarcoma rare (<1% solitary, ~5% MHE), suspected with pain or growth after skeletal maturity/cap thickening

Media ─ Pathoutlines WSI WSI WSI WSI WSI WSI WSI video video HE

Chondroblastoma

Benign cartilaginous neoplasm typically arising in the epiphyses of long bones in adolescents, composed of chondroblasts.

Clinical ─ Adolescents and young adults (peak 10-20s, usually before physeal closure), M > F; epiphysis or apophysis of long bones (proximal humerus, distal femur, proximal tibia mc sites); presents with joint pain

Radiology ─ Well-defined, geographic lytic lesion in epiphysis; thin sclerotic rim common; matrix calcification frequent; may extend into metaphysis after physeal closure

Macro ─ Grayish-pink, granular or gritty tissue; +/- cystic change, hemorrhage

Micro ─

─ Sheets of relatively uniform, mononuclear round/polygonal cells (chondroblasts)

─ Cells have distinct cytoplasmic borders, eosinophilic cytoplasm, round/oval nuclei often with longitudinal grooves

─ Characteristic feature: Pericellular "chicken-wire" calcification (calcification outlining individual cells)

─ Admixed osteoclast-like giant cells common

─ Mitotic activity usually low

─ +/- Secondary aneurysmal bone cyst changes

IHC ─ (+) S100, SOX9 (chondroblasts); (+) DOG1 (membranous); (+/-) Keratins (focal); (-) CD68 (vs GCT)

Molecular ─ H3-3B (H3F3B) K36M mutation highly specific

DDx ─

─ Giant Cell Tumor of Bone (Epiphyseal, but lacks chicken-wire calcification/chondroid matrix, H3F3A mutated, DOG1-)

─ Clear Cell Chondrosarcoma (Older age, more atypia, clear cells, S100+, lacks K36M mutation)

─ Langerhans Cell Histiocytosis (Eosinophils prominent, CD1a+, Langerin+)

─ Enchondroma (Different location/morphology, IDH mutated)

Prognosis ─ Benign; local recurrence possible (~10-20%); rare "metastases" (typically benign implants to lung/soft tissue) reported

Media ─ Pathoutlines WSI WSI WSI & WSI video video

Chondromyxoid fibroma (CMF)

Benign cartilaginous neoplasm characterized by lobules of spindle and stellate cells in a myxoid or chondroid matrix, separated by cellular fibrous septa.

Clinical ─ Adolescents and young adults (peak 10-30s); metaphysis of long bones (esp. proximal tibia) mc site; also flat bones, small bones; presents with pain or swelling

Radiology ─ Eccentric, geographic lytic lesion in metaphysis; well-defined sclerotic rim; lobulated ("soap bubble") appearance; cortical expansion common; matrix calcification rare

Macro ─ Lobulated, firm, gray-white or yellowish tissue; glistening myxoid appearance

Micro ─

─ Lobulated architecture

─ Hypocellular lobule centers: Spindle or stellate cells in abundant myxoid or chondromyxoid matrix; +/- large cells with bizarre nuclei (degenerative atypia)

─ Hypercellular lobule peripheries: More cellular zones with round or spindle cells, admixed osteoclast-like giant cells, chronic inflammation

─ Mitotic activity low

IHC ─ (+) S100 (variable, often patchy in myxoid areas); (+) SMA (variable in peripheral spindle cells); (-) keratins

Molecular ─ Recurrent rearrangements involving 6q13-21, often resulting in GRM1 gene fusions

DDx ─

─ Chondrosarcoma (More uniform atypia, lacks lobular architecture with peripheral hypercellularity, IDH mutated)

─ Chondroblastoma (Epiphyseal, chicken-wire calcification, DOG1+, H3-3B K36M mutated)

─ Fibrous Dysplasia (Intramedullary, woven bone without osteoblastic rimming, GNAS mutated)

─ Aneurysmal Bone Cyst (Secondary ABC changes can occur, but primary CMF has solid areas)

Prognosis ─ Benign; local recurrence possible (~10-25%), especially after curettage

Media ─ Pathoutlines WSI WSI WSI WSI WSI video & WSI HE HE video

Osteochondromyxoma

Extremely rare benign tumor showing mixed osteochondromatous and myxoid features. (Note: Limited information available in standard texts, may represent variant of other entities).

Clinical ─ Primarily reported in children/young adults

Radiology ─ Not well established; likely complex bony/cartilaginous mass with myxoid areas

Macro ─ Likely mixed solid, cartilaginous, and myxoid/gelatinous appearance

Micro ─

─ Admixture of bony, cartilaginous (often hyaline), and myxoid components

─ Cellularity and atypia generally low

IHC ─ S100 likely positive in cartilaginous areas

Molecular ─ Not well characterized

DDx ─

─ Chondromyxoid Fibroma (Lacks significant bone/mature cartilage)

─ Mesenchymal Chondrosarcoma (Malignant SRBC component)

─ Osteosarcoma (Chondroblastic) (Malignant osteoid production)

Prognosis ─ Presumed benign based on limited reports

Media ─ Pathoutlines

Synovial chondromatosis

Benign condition characterized by cartilaginous metaplasia within the synovial membrane of joints, bursae, or tendon sheaths, resulting in multiple cartilaginous nodules.

Clinical ─ Adults (peak 30-50s), M > F; large joints (knee mc > hip, elbow, shoulder); pain, swelling, limited motion, locking; primary (idiopathic) or secondary (due to underlying joint disease like osteoarthritis)

Radiology ─ Multiple round, calcified loose bodies within the joint space or bursa; +/- extrinsic erosion of adjacent bone; calcification may be variable (rings/arcs)

Macro ─ Synovium thickened, nodular; numerous cartilaginous nodules (loose bodies) within joint space, variable size, white/gray-blue, glistening

Micro ─

─ Nodules of hyaline cartilage within synovial lining or loose within joint space

─ Cartilage nodules often show hypercellularity, chondrocyte clustering, mild atypia (binucleation), especially in early/active phase

─ +/- Myxoid change, calcification, enchondral ossification within nodules

─ Synovial lining may show hyperplasia, inflammation

IHC ─ (+) S100 (chondrocytes)

Molecular ─ FN1::ACVR2A fusion reported in primary synovial chondromatosis

DDx ─

─ Degenerative Joint Disease (Osteophytes, detached cartilage fragments lack clustering/atypia)

─ Chondrosarcoma (Secondary) (Rare complication; marked atypia, invasion into adjacent bone/soft tissue)

─ Pigmented Villonodular Synovitis (PVNS) (Hemosiderin, mononuclear/giant cells, lacks cartilage nodules)

─ Soft Tissue Chondroma (Extra-articular location)

Prognosis ─ Benign; symptoms often require synovectomy and removal of loose bodies; recurrence common, especially if primary; rare malignant transformation to chondrosarcoma

Media ─ Pathoutlines WSI WSI WSI video

Chondrosarcoma (Conventional Intramedullary)

Malignant cartilaginous neoplasm arising within the medullary cavity of bone.

Clinical ─ Adults (peak 40-60s); pelvis, proximal femur, ribs, proximal humerus mc sites; pain, swelling, pathologic fracture; primary or secondary (from enchondroma/osteochondroma)

Radiology ─ Permeative or geographic lytic lesion with cortical destruction/thickening; endosteal scalloping (>2/3 cortical thickness); soft tissue mass; matrix calcification common (rings/arcs, flocculent)

Macro ─ Lobulated, gray-blue translucent cartilaginous tumor filling medullary cavity; +/- myxoid change, necrosis, cystic change

Micro ─

─ Lobules of hyaline and/or myxoid cartilage infiltrating bone marrow spaces

─ Key feature: Permeation of marrow spaces and entrapment of pre-existing lamellar bone trabeculae

─ Increased cellularity, cytologic atypia (enlarged/hyperchromatic nuclei, binucleation) compared to enchondroma

─ Grading (Grade 1, 2, 3 based on increasing cellularity, atypia, mitoses):

─ Grade 1 (Low): Mild hypercellularity/atypia, rare mitoses, +/- myxoid change

─ Grade 2 (Intermediate): Moderate cellularity/atypia, myxoid change common, mitoses present but low

─ Grade 3 (High): Marked cellularity/atypia, pleomorphism, high mitoses, necrosis

IHC ─ (+) S100 (chondrocytes); (-) Keratins (vs metastatic carcinoma)

Molecular ─ IDH1 or IDH2 mutations common (esp. Grade 1/2); alterations in COL2A1, CDKN2A, TP53 associated with higher grade/dedifferentiation

DDx ─

─ Enchondroma (Lacks permeation/entrapment, less cellularity/atypia, location often different - hands/feet)

─ Chondroblastoma (Epiphyseal, chicken-wire calcification, H3-3B K36M+)

─ Chordoma (Axial skeleton, physaliphorous cells, Brachyury+)

─ Metastatic Carcinoma (Keratin+, S100-)

Prognosis ─ Correlates strongly with grade; Grade 1 has low metastatic potential but recurs locally; Grade 2/3 have significant metastatic potential (lung)

Media ─ Pathoutlines WSI + video WSI WSI WSI WSI video

Periosteal chondrosarcoma

Malignant cartilaginous neoplasm arising on the surface of bone, beneath the periosteum.

Clinical ─ Adults (peak 20-40s); metaphysis or diaphysis of long bones (femur, humerus, tibia); presents as slow-growing mass, may be painful

Radiology ─ Lobulated mass on bone surface with cortical erosion/saucerization; periosteal reaction common; matrix calcification; no medullary involvement

Macro ─ Lobulated cartilaginous mass on bone surface, beneath thickened periosteum

Micro ─

─ Lobules of hyaline cartilage showing features of chondrosarcoma (increased cellularity, atypia compared to periosteal chondroma)

─ Typically low to intermediate grade (Grade 1 or 2)

─ Invasion into underlying cortex or adjacent soft tissue may be present

─ Medullary cavity is spared

IHC ─ (+) S100

Molecular ─ IDH1/IDH2 mutations less common than in conventional chondrosarcoma

DDx ─

─ Periosteal Chondroma (Smaller size <3-5cm, less cellularity/atypia, no cortical/soft tissue invasion)

─ Periosteal Osteosarcoma (Malignant osteoid production)

─ BPOP (Hands/feet, "blue bone", different genetics)

Prognosis ─ Better prognosis than conventional intramedullary chondrosarcoma of similar grade; metastasis rare if low grade

Media ─ WSI video

Clear cell chondrosarcoma

Low-grade malignant cartilaginous neoplasm characterized by cells with clear cytoplasm, typically arising in the epiphyses of long bones.

Clinical ─ Young adults (peak 20-40s), M > F; epiphysis of long bones (proximal femur, proximal humerus mc sites); presents with joint pain

Radiology ─ Geographic lytic lesion in epiphysis; well-defined sclerotic margin; +/- matrix calcification; may resemble chondroblastoma

Macro ─ Firm, gray-white tissue; may have gritty calcified areas or cystic change

Micro ─

─ Lobules separated by fibrous septa

─ Tumor cells large, polygonal with abundant clear cytoplasm (glycogen)

─ Nuclei centrally located, moderate atypia, +/- prominent nucleoli

─ Admixed osteoclast-like giant cells common

─ +/- Reactive woven bone production, conventional low-grade chondrosarcoma component

─ Low mitotic activity

IHC ─ (+) S100 (strong); (+) Type II Collagen; (-) Keratins, EMA, CD68

Molecular ─ Lacks IDH, H3-3B, or H3F3A mutations

DDx ─

─ Chondroblastoma (Younger age, chicken-wire calcification, grooved nuclei, DOG1+, H3-3B K36M+)

─ Giant Cell Tumor of Bone (Lacks clear cells/cartilage matrix, H3F3A mutated)

─ Metastatic Clear Cell Carcinoma (esp. Renal Cell) (Keratin+, PAX8+, CAIX+)

─ Osteosarcoma (Clear cell variant) (Malignant osteoid production, SATB2+)

Prognosis ─ Low-grade malignancy; prone to local recurrence; late metastasis possible (~15%)

Media ─ Pathoutlines WSI video HE S100

Mesenchymal chondrosarcoma

High-grade malignant neoplasm composed of a bimorphic pattern of primitive small round blue cells and islands of well-differentiated hyaline cartilage.

Clinical ─ Adolescents and young adults (peak 10-30s); bone (jaw, ribs, vertebrae mc) > extraskeletal soft tissue; presents with pain, swelling

Radiology ─ Destructive lesion, often large; irregular margins; prominent matrix calcification common; may have soft tissue mass

Macro ─ Gray-white, firm tumor; +/- gritty calcified areas, hemorrhage, necrosis

Micro ─

─ Bimorphic pattern:

─ Undifferentiated small round blue cells: Sheets or lobules, scant cytoplasm, hyperchromatic nuclei, high mitotic rate

─ Islands/nodules of well-differentiated hyaline cartilage: Abrupt transition from small cell component

─ Hemangiopericytoma-like vascular pattern often prominent within small cell areas

IHC ─ Small cells (+) CD99 (variable), NKX2.2, SOX9; Cartilage (+) S100, SOX9; (-) Myogenin, FLI1, keratins

Molecular ─ Characteristic HEY1::NCOA2 fusion; less commonly IRF2BP2::CDX1

DDx ─

─ Ewing Sarcoma (Lacks cartilage, CD99+, FLI1+, NKX2.2+, EWSR1-ETS fusion)

─ Small Cell Osteosarcoma (Osteoid production, SATB2+)

─ Synovial Sarcoma (Poorly differentiated) (TLE1+, Keratin/EMA+, SS18 fusion)

─ Embryonal Rhabdomyosarcoma (Myogenin/MyoD1+)

Prognosis ─ Aggressive sarcoma; high rate of metastasis (lung, bone); poor long-term survival

Media ─ Pathoutlines WSI WSI WSI WSI WSI HE CD99 SOX9 WSI

Dedifferentiated chondrosarcoma

High-grade non-cartilaginous sarcoma arising abruptly from a low-grade conventional chondrosarcoma.

Clinical ─ Older adults (peak 50-70s); pelvis, proximal femur mc sites; often presents with pain, rapid enlargement of a known cartilaginous tumor, or pathologic fracture

Radiology ─ Features of low-grade chondrosarcoma juxtaposed with an aggressive, non-calcified lytic component with cortical destruction and large soft tissue mass

Macro ─ Biphasic tumor: Areas of gray-blue cartilage adjacent to fleshy, gray-white sarcomatous areas; necrosis common

Micro ─

─ Abrupt interface between a well-differentiated (usually Grade 1) conventional chondrosarcoma and a high-grade, non-cartilaginous sarcoma

─ Dedifferentiated component most commonly resembles UPS, fibrosarcoma, or osteosarcoma

─ High mitotic rate, necrosis in dedifferentiated component

IHC ─ Chondrosarcoma component (+) S100; Dedifferentiated component usually (-) S100, expresses markers depending on lineage (e.g., none specific for UPS/fibrosarcoma, SATB2 for osteosarcoma)

Molecular ─ IDH1/IDH2 mutations in chondrosarcoma component; complex alterations (TP53, CDKN2A) in dedifferentiated component

DDx ─

─ Conventional High-Grade Chondrosarcoma (Grade 3) (Gradual transition, retains cartilaginous nature)

─ Mesenchymal Chondrosarcoma (Different small cell morphology, specific fusion)

─ Osteosarcoma (Primary) (Malignant osteoid throughout)

Prognosis ─ Very aggressive; poor prognosis similar to other high-grade sarcomas; metastasis common and early

Media ─ Pathoutlines video

Bone, Osteogenic

Osteoma

Benign neoplasm composed exclusively of mature lamellar bone, typically arising on the surface of craniofacial bones.

Clinical ─ Adults (wide age range); M=F; craniofacial bones (esp. skull, paranasal sinuses) mc sites; often incidental finding, may cause cosmetic deformity or sinus obstruction; multiple osteomas associated with Gardner syndrome (FAP)

Radiology ─ Sessile or pedunculated, densely sclerotic, well-demarcated bony mass projecting from bone surface ("stuck-on" appearance); no cortical destruction or periosteal reaction

Macro ─ Round to oval, very hard, bony mass attached to bone surface

Micro ─

─ Dense, mature lamellar bone

─ May resemble normal cortical bone

─ +/- Haversian systems, minimal fibrovascular stroma, scant osteoblasts/osteoclasts

─ No atypia, no cartilage, no immature woven bone (unless healing fracture)

IHC ─ Not required

Molecular ─ Not typically characterized; APC mutations in Gardner syndrome-associated cases

DDx ─

─ Exostosis/Torus (Developmental bony outgrowth, site specific e.g., torus palatinus)

─ Osteochondroma (Cartilage cap present, different location/genetics)

─ Surface Osteosarcoma (Parosteal/Periosteal) (Malignant features, atypia, different location)

─ Reactive bone formation/Callus (History of trauma/inflammation, more cellular stroma, woven bone)

Prognosis ─ Benign; does not recur or transform

Media ─ Pathoutlines WSI WSI HE CT video

Osteoid Osteoma & Osteoblastoma

Benign bone-forming neoplasms composed of immature woven bone trabeculae rimmed by prominent osteoblasts, set in a vascular fibrous stroma. Distinguished primarily by size and location.

Clinical ─ Children and young adults (peak 10-25s), M > F

─ Osteoid Osteoma (< 1.5-2 cm): Long bones (femur, tibia) mc site, often cortical; nocturnal pain relieved by NSAIDs

─ Osteoblastoma (≥ 1.5-2 cm): Spine (posterior elements) mc site;less responsive to NSAIDs

Radiology ─

─ Osteoid Osteoma: Small, round radiolucent nidus (<1.5-2 cm) with surrounding dense reactive sclerosis (esp. cortical lesions); central calcification may be present

─ Osteoblastoma: Larger (>1.5-2 cm), expansile lytic lesion, often with thin sclerotic rim; less surrounding sclerosis than osteoid osteoma

Macro ─

─ Osteoid Osteoma: Small (<1.5-2 cm), reddish, granular nidus surrounded by sclerotic bone

─ Osteoblastoma: Larger, hemorrhagic, granular mass

Micro ─ (Nidus of OO / Main lesion of OB)

─ Interconnecting trabeculae of immature woven bone

─ Prominent osteoblastic rimming of trabeculae

─ Intervening highly vascular, loose fibrovascular stroma

─ Minimal atypia, mitoses rare

─ Osteoblastoma may show larger epithelioid osteoblasts ("aggressive osteoblastoma" - higher recurrence risk, but still benign)

─ No permeation of host bone, no cartilage formation (except fracture callus)

IHC ─ Not required; osteoblasts (+) SATB2, alkaline phosphatase

Molecular ─ FOS or FOSB rearrangements in subset

DDx ─

─ Osteosarcoma Infiltrative growth, cytologic atypia, malignant osteoid)

─ Osteoma (Mature lamellar bone only)

─ Fibrous Dysplasia (Curvilinear woven bone without osteoblastic rimming, GNAS mutated)

─ Chronic Osteomyelitis/Brodie Abscess (Inflammation, necrosis, lack osteoblastic rimming)

Prognosis ─ Benign; Osteoid osteoma often treated with radiofrequency ablation or excision; Osteoblastoma treated with curettage or excision

Media ─ Pathoutlines WSI WSI WSI X-ray CT HE HE video video

Osteoblastoma Pathoutlines WSI WSI WSI

Osteosarcoma (Conventional)

High-grade malignant mesenchymal neoplasm in which the tumor cells produce osteoid (immature bone). Most common primary malignant bone tumor (excluding hematopoietic).

Clinical ─ Bimodal age distribution: Adolescents/young adults (peak 10-25s) and elderly (>60s, often secondary); metaphysis of long bones (esp. distal femur, proximal tibia, proximal humerus - "around the knee") mc site; presents with pain, swelling, pathologic fracture; elevated serum alkaline phosphatase common

Radiology ─ Destructive intramedullary lesion (permeative or moth-eaten); cortical destruction; aggressive periosteal reaction (Codman triangle, sunburst); soft tissue mass; variable tumor matrix mineralization (cloud-like, dense ivory)

Macro ─ Large, fleshy, gray-white tumor filling medullary cavity; often extends through cortex into soft tissue; +/- gritty calcified areas, hemorrhage, necrosis, cystic change

Micro ─

─ Malignant spindle or pleomorphic cells directly producing osteoid matrix (lace-like, trabecular, or sheet-like immature bone) - REQUIRED for diagnosis

─ High-grade cytologic atypia (hyperchromasia, pleomorphism, irregular nuclei)

─ High mitotic rate, including atypical forms

─ Infiltrative growth pattern permeating host bone

─ Necrosis common

─ Subtypes based on predominant matrix/cell type: Osteoblastic (mc), Chondroblastic, Fibroblastic, Telangiectatic (blood-filled spaces), Small cell, Giant cell-rich

IHC ─ (+) SATB2 (nuclear, relatively specific for osteoblastic differentiation); (+/-) Alkaline Phosphatase, Osteocalcin, SMA, S100 (chondroblastic areas), Keratins (rare)

Molecular ─ Complex karyotypes with numerous gains/losses; TP53 and RB1 pathway alterations common (esp. in hereditary syndromes like Li-Fraumeni, Retinoblastoma)

DDx ─

─ Other high-grade sarcomas (UPS, fibrosarcoma, leiomyosarcoma, chondrosarcoma) (Lack tumor osteoid production; use IHC)

─ Ewing Sarcoma (Small round blue cells, CD99+, NKX2.2+, EWSR1 fusion)

─ Osteoblastoma (Lacks high-grade atypia, infiltrative growth, necrosis)

─ Fibrous Dysplasia (Lacks atypia, lacks osteoblastic rimming, GNAS mutated)

─ Fracture Callus/Myositis Ossificans (Zonal pattern, lacks atypia)

Prognosis ─ Aggressive; high risk of metastasis (lung); requires neoadjuvant chemotherapy followed by surgery; prognosis depends on stage, location, histologic response to chemotherapy (% necrosis)

Media ─ Pathoutlines WSI WSI WSI WSI WSI WSI & video X-ray video video

Low-grade central Pathoutlines video

Parosteal Pathoutlines HE MDM2 video

Periosteal Pathoutlines

High-grade surface Pathoutlines WSI video

Secondary osteosarcoma WSI

Bone, Osteoclast-Rich

Aneurysmal bone cyst (ABC)

Benign cystic bone lesion characterized by blood-filled spaces separated by fibrous septa containing bland spindle cells, osteoclast-like giant cells, and reactive bone.

Clinical ─ Children and young adults (peak 10-20s); metaphysis of long bones (femur, tibia, humerus), posterior elements of spine mc sites; pain, swelling, pathologic fracture; primary (de novo) or secondary (arising in association with another bone lesion)

Radiology ─ Eccentric, expansile, lytic lesion; often well-defined margin +/- thin sclerotic rim; characteristic fluid-fluid levels on MRI/CT; may show cortical thinning or "blown-out" appearance; periosteal reaction possible

Macro ─ Blood-filled cystic spaces; fibrous septa; thin bony shell

Micro ─

─ Multiloculated cystic spaces filled with blood, lacking endothelial lining

─ Separated by fibrous septa containing:

─ Bland spindle cells (fibroblasts/myofibroblasts)

─ Numerous osteoclast-like multinucleated giant cells (often near hemorrhage)

─ Reactive woven bone formation within septa (often linear, "streamers")

─ +/- Hemosiderin, chronic inflammation, mitotic figures (in spindle cells, no atypia)

─ Solid variant: Less prominent cystic spaces, solid cellular areas resembling GCT or NOF

IHC ─ Not specific; spindle cells (+/-) SMA; giant cells (+) CD68

Molecular ─ Primary ABC characterized by USP6 gene rearrangements (chromosome 17p13), often fused with CDH11 or TRAP150; secondary ABC lacks USP6 rearrangement

DDx ─

─ Giant Cell Tumor of Bone (Epiphyseal, lacks blood-filled cysts/fibrous septa, H3F3A)

─ Telangiectatic Osteosarcoma (Malignant spindle cells making osteoid, atypia, infiltrative)

─ Simple (Unicameral) Bone Cyst (Usually central, lacks cellular septa/giant cells)

─ Brown Tumor (History of hyperparathyroidism, more prominent hemosiderin/fibrosis)

Prognosis ─ Benign; high recurrence rate (~20-30%) after curettage, lower with more aggressive treatment (e.g., sclerotherapy, en bloc resection)

Media ─ Pathoutlines WSI WSI WSI WSI WSI WSI WSI video

Giant cell tumor of bone (GCTB)

Locally aggressive neoplasm composed of mononuclear stromal cells (neoplastic component) and numerous osteoclast-like giant cells.

Clinical ─ Young adults (peak 20-40s, after physeal closure); F > M slightly; epiphysis of long bones (esp. distal femur, proximal tibia, distal radius) mc sites; presents with pain, swelling near a joint, pathologic fracture

Radiology ─ Eccentric, geographic lytic lesion in epiphysis extending to articular surface; usually well-defined non-sclerotic margin; cortical expansion/thinning common; lacks significant matrix mineralization

Macro ─ Soft, friable, red-brown tissue; often with cystic/hemorrhagic areas

Micro ─

─ Sheets of mononuclear stromal cells: Round to oval/spindle shape, indistinct cytoplasm, vesicular nuclei resembling osteoclast nuclei

─ Numerous, evenly distributed osteoclast-like multinucleated giant cells

─ Mitotic figures present in mononuclear cells, but typically lack atypia

─ +/- Hemorrhage, hemosiderin, foam cells, reactive bone formation (at periphery), secondary ABC changes

─ Malignant GCTB (rare, primary or secondary): Sarcomatous stroma (resembling UPS/fibrosarcoma/osteosarcoma) alongside conventional GCT areas

IHC ─ Mononuclear cells (+) RANKL; Giant cells (+) RANK, CD68; (+) H3.3 G34W/V/R/L (specific antibody for mutated protein); (-) S100, keratins

Molecular ─ Driver mutations in H3F3A (encoding histone H3.3, G34W mc) >90%

DDx ─

─ Chondroblastoma (Chicken-wire calcification, chondroid matrix, S100, DOG1, H3F3B K36M)

─ Brown Tumor (Hyperparathyroidism, more fibrosis/hemosiderin, lacks H3F3A mutation)

─ Non-ossifying Fibroma (Metaphyseal, storiform pattern, foam cells, lacks H3F3A mutation)

─ Aneurysmal Bone Cyst (Primary) (Blood-filled cysts, fibrous septa, USP6 rearranged)

─ Giant Cell-Rich Osteosarcoma (Malignant osteoid production, atypia)

Prognosis ─ Locally aggressive; high recurrence rate (~25-50%) after curettage; metastasis (typically lung) occurs in ~2% ("benign metastasizing GCT"), usually histologically bland; primary/secondary malignant GCT is rare but highly aggressive

Media ─ Pathoutlines WSI WSI WSI WSI WSI WSI video H&E

Non-ossifying fibroma (NOF)

Benign, self-limiting fibrohistiocytic lesion occurring in the metaphysis of long bones in children and adolescents. Also known as fibrous cortical defect (if small, <2-3 cm, and confined to cortex) or metaphyseal fibrous defect.

Clinical ─ Children and adolescents (peak 5-15s); very common incidental finding (~30-40% of children); metaphysis of long bones (esp. distal femur, proximal/distal tibia) mc sites; usually asymptomatic, may present with pathologic fracture if large

Radiology ─ Eccentric, geographic lytic lesion in metaphysis; well-defined sclerotic rim; often lobulated or "bubbly" appearance; thins overlying cortex; usually regresses and ossifies with skeletal maturity

Macro ─ Yellow-brown or reddish, firm tissue within medullary cavity

Micro ─

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

─ Admixed osteoclast-like multinucleated giant cells (variable number)

─ Clusters of foam cells (lipid-laden macrophages) common

─ Hemosiderin deposition frequent

─ Minimal atypia, low mitotic activity

─ +/- Reactive bone at periphery

IHC ─ Not specific; spindle cells (+/-) SMA; giant cells/foam cells (+) CD68

Molecular ─ Mutations in KRAS, FGFR1, or other RAS/MAPK pathway genes reported

DDx ─

─ Giant Cell Tumor of Bone (Epiphyseal location, more uniform giant cell distribution, H3F3A mutated)

─ Fibrous Dysplasia (Woven bone without osteoblastic rimming, GNAS mutated)

─ Chondromyxoid Fibroma (Lobulated, myxochondroid matrix, S100+)

─ Benign Fibrous Histiocytoma of Bone (Rare, older adults, less common foam cells/giant cells)

Prognosis ─ Benign; typically involutes spontaneously with skeletal maturity; pathologic fractures heal normally; excision usually only needed if symptomatic or very large

Media ─ Pathoutlines WSI WSI WSI & video

Brown tumor

Non-neoplastic bone lesion resulting from excessive osteoclast activity due to hyperparathyroidism (primary, secondary, or tertiary).

Clinical ─ Associated with hyperparathyroidism (check serum calcium, phosphate, PTH); any age/site, often multiple; presents with bone pain, swelling, or pathologic fracture

Radiology ─ Well-defined lytic lesion(s); may be expansile; cortical thinning common; lacks sclerotic rim or matrix mineralization; underlying features of hyperparathyroidism in skeleton may be present (subperiosteal resorption, osteopenia)

Macro ─ Soft, friable, red-brown tissue (due to hemorrhage/hemosiderin)

Micro ─

─ Highly vascular fibrous stroma

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

─ Abundant hemosiderin deposition within macrophages and stroma

─ Reactive woven bone formation may be present

─ Background bone may show changes of hyperparathyroidism (osteoclastic resorption, marrow fibrosis - osteitis fibrosa cystica)

─ Minimal atypia, mitoses rare in stromal cells

IHC ─ Not specific; giant cells (+) CD68

Molecular ─ Not applicable (reactive lesion)

DDx ─

─ Giant Cell Tumor of Bone (Lacks prominent hemosiderin/fibrosis, uniform giant cell distribution, H3F3A mutated, normal PTH)

─ Aneurysmal Bone Cyst (Blood-filled cystic spaces, USP6 rearranged in primary ABC, normal PTH)

─ Non-ossifying Fibroma (Storiform pattern, foam cells, normal PTH)

─ Giant Cell Reparative Granuloma (Jaw location, less prominent hemosiderin)

Prognosis ─ Benign reactive lesion; resolves with treatment of underlying hyperparathyroidism

Media ─ pathoutlines WSI CT X-ray

Bone, Other

Osteoarthritis (OA)

Degenerative joint disease characterized by loss of articular cartilage and changes in underlying bone.

Clinical ─ Most common joint disease; prevalence increases with age; affects weight-bearing joints (knee, hip) and hands; pain, stiffness, decreased range of motion

Radiology ─ Joint space narrowing (asymmetric), subchondral sclerosis, osteophyte formation (marginal lipping), subchondral cysts

Macro ─ Articular cartilage shows fibrillation, erosion, eburnation (polished bone); osteophytes at joint margins; thickened synovium; loose bodies (cartilage/bone fragments)

Micro ─

─ Articular cartilage: Fibrillation (vertical clefts), erosion/loss of cartilage matrix, chondrocyte cloning (clusters), chondrocyte necrosis

─ Subchondral bone: Sclerosis (thickened trabeculae), subchondral cysts (fibromyxoid degeneration), microfractures

─ Synovium: Mild hyperplasia, chronic inflammation (variable)

─ Osteophytes: Cartilage-capped bony outgrowths at joint margins

IHC ─ Not applicable

Molecular ─ Not applicable (degenerative process)

DDx ─

─ Inflammatory Arthritis (e.g., Rheumatoid Arthritis) (Symmetric joint space narrowing, erosions without sclerosis, pannus formation, specific serology)

─ Crystal Arthropathy (e.g., Gout, CPPD) (Crystal deposition, specific inflammatory patterns)

─ Septic Arthritis (Acute inflammation, purulence, positive cultures)

Prognosis ─ Chronic, progressive degenerative condition; management focused on symptom control; may require joint replacement

Media ─ Pathoutlines

Benign notochordal cell tumor (BNCT)

Benign lesion composed of physaliphorous-like cells resembling notochordal remnants, typically found incidentally within vertebral bodies or clivus.

Clinical ─ Usually incidental finding on imaging or autopsy; any age, more common in older adults; axial skeleton (clivus, vertebrae - esp. sacrococcygeal)

Radiology ─ Well-defined, often sclerotic intraosseous lesion; may have bubbly or trabeculated appearance; no cortical destruction or soft tissue mass

Macro ─ Gelatinous or mucoid tissue within bone

Micro ─

─ Intraosseous lesion replacing marrow

─ Sheets or cords of large cells with abundant vacuolated/bubbly cytoplasm (physaliphorous-like)

─ Bland nuclei, minimal atypia, no mitoses

─ Embedded within sclerotic bone trabeculae

─ Lacks lobular architecture, myxoid stroma, and destructive growth of chordoma

IHC ─ (+) Brachyury (nuclear), S100, Pan-Keratin (AE1/AE3, CAM5.2), EMA

Molecular ─ No specific recurrent genetic alteration known; lacks chordoma-associated changes

DDx ─

─ Chordoma (Lobulated architecture, myxoid stroma, destructive growth, cytologic atypia possible)

─ Ecchordosis Physaliphora (Extraosseous location, often attached to clivus by stalk, less cellular)

─ Metastatic Carcinoma (esp. Clear Cell/Mucinous) (Different IHC profile, lacks Brachyury)

Prognosis ─ Benign; considered non-neoplastic or benign neoplasm; no malignant potential reported

Media ─ Pathoutlines WSI

Chordoma

Low-to-intermediate grade malignant neoplasm from notochordal remnants along axial skeleton.

Clinical ─ Adults (peak 50-70s), M > F; axial skeleton: sacrococcygeal region (~50%) > spheno-occipital/clivus (~35%) > mobile spine (~15%); slow-growing, locally destructive mass, presents with pain or neurologic symptoms

Radiology ─ Destructive midline bone lesion (lytic); often large soft tissue mass; +/- calcification; T2 hyperintensity on MRI common due to myxoid matrix

Macro ─ Lobulated, gelatinous; destroys bone, extends into soft tissue

Micro ─

─ Lobulated architecture separated by fibrous septa

─ Tumor cells arranged in cords, nests, or sheets within abundant myxoid/chondromyxoid stroma

─ Characteristic physaliphorous cells (large cells with abundant bubbly/vacuolated cytoplasm)

─ +/- Spindle cell component, mild to moderate atypia, mitoses usually low

─ Variants: Conventional, Chondroid (contains hyaline cartilage - better prognosis?), Dedifferentiated (abrupt transition to high-grade sarcoma - poor prognosis), Poorly differentiated (pediatric, INI1 loss)

IHC ─ (+) Brachyury (nuclear, specific and sensitive), Pan-Keratin (AE1/AE3, CAM5.2), EMA, S100; (-) INI1/SMARCB1 in poorly differentiated variant

Molecular ─ Complex karyotype; gains/losses common; TBXT (Brachyury) gene duplication/amplification in subset; SMARCB1 inactivation in poorly differentiated variant

DDx ─

─ Chondrosarcoma (esp. myxoid) (Lacks physaliphorous cells, Brachyury-, IDH mutated)

─ Benign Notochordal Cell Tumor (Intraosseous only, lacks lobules/myxoid stroma/destruction)

─ Metastatic Carcinoma (Mucinous/Clear Cell) (Lacks physaliphorous cells, Brachyury-, different IHC)

─ Myoepithelial Tumors (Different morphology, other myoepithelial markers+)

Prognosis ─ Locally aggressive with high recurrence rate; metastasizes late (~20-40%, lung, bone, nodes); dedifferentiated variant highly aggressive

Media ─ Pathoutlines WSI WSI WSI WSI video

Desmoplastic fibroma of bone

Benign but locally aggressive intraosseous fibrous neoplasm, the bony counterpart of desmoid fibromatosis.

Clinical ─ Children and young adults (peak 10-30s); mandible mc site > long bones (femur, tibia), pelvis; presents as painless swelling or incidental finding

Radiology ─ Well-defined, expansile lytic lesion ("soap bubble" appearance); often multiloculated; +/- cortical thinning/breach; no matrix mineralization or periosteal reaction

Macro ─ Firm, rubbery, gray-white fibrous tissue; resembles scar tissue

Micro ─

─ Hypo- to moderately cellular proliferation of bland spindle cells (fibroblasts)

─ Arranged in sweeping fascicles or storiform pattern

─ Abundant collagenous stroma

─ Minimal atypia, very low mitotic activity, no necrosis

─ Infiltrative growth into surrounding bone trabeculae

IHC ─ (+) Vimentin; (+/-) SMA, MSA; (-) S100, Keratins, Desmin, CD34; (-) β-catenin (nuclear staining usually absent, unlike soft tissue desmoid)

Molecular ─ Lacks CTNNB1/APC mutations typical of soft tissue desmoid fibromatosis; some show chromosomal abnormalities

DDx ─

─ Low-grade Central Osteosarcoma (Malignant osteoid production, atypia, MDM2 amplified)

─ Fibrous Dysplasia (Woven bone without osteoblastic rimming, GNAS mutated)

─ Non-ossifying Fibroma (Storiform pattern, giant cells, foam cells, different location)

─ Fibrosarcoma of Bone (Higher cellularity, atypia, mitoses)

Prognosis ─ Benign (does not metastasize) but locally aggressive; high recurrence rate after curettage; requires wide excision if possible

Media ─ Pathoutlines WSI WSI WSI WSI WSI

Fibrosarcoma of bone

Malignant neoplasm composed of spindle cells producing collagen, arising primarily within bone; considered a diagnosis of exclusion.

Clinical ─ Adults (wide age range, peak 30-60s); metaphysis of long bones (femur, tibia) mc site; presents with pain, swelling, pathologic fracture; primary or secondary (arising in Paget disease, irradiated bone, bone infarct)

Radiology ─ Permeative or moth-eaten lytic lesion; cortical destruction; soft tissue mass; lacks tumor matrix mineralization

Macro ─ Fleshy, gray-white mass replacing marrow; often hemorrhagic/necrotic

Micro ─

─ Cellular proliferation of spindle cells arranged in intersecting fascicles ("herringbone" pattern)

─ Variable collagen production

─ Cytologic atypia (hyperchromasia, pleomorphism)

─ High mitotic rate, necrosis common

─ Grading (Low vs High) based on cellularity, atypia, mitoses, necrosis

─ Must exclude other spindle cell sarcomas

IHC ─ Non-specific; (+) Vimentin; (-) Keratins, S100, SOX10, Desmin, SMA, CD34, SATB2 (to exclude mimics like metastatic carcinoma, melanoma, MPNST, LMS, SFT, osteosarcoma)

Molecular ─ No specific recurrent genetic alteration; complex karyotypes

DDx ─

─ Undifferentiated Pleomorphic Sarcoma (UPS) of Bone (More pleomorphism)

─ Fibroblastic Osteosarcoma (Requires identification of tumor osteoid)

─ Malignant Peripheral Nerve Sheath Tumor (MPNST) (S100/SOX10+ often patchy, H3K27me3 loss)

─ Leiomyosarcoma of Bone (Desmin+, SMA+)

─ Desmoplastic Fibroma (Lacks atypia, low mitoses)

Prognosis ─ Aggressive sarcoma; prognosis depends on grade, stage; high rate of metastasis (lung)

Media ─ Pathoutlines

Chondromesenchymal hamartoma of chest wall

Rare benign lesion of infants, composed of mixed mesenchymal and cartilaginous elements, occurring in the ribs/chest wall.

Clinical ─ Infants (usually < 1 year); chest wall (ribs); presents as painless, firm mass, may cause respiratory distress

Radiology ─ Expansile mass arising from rib(s) with variable calcification/ossification; may show cystic changes or cortical disruption

Macro ─ Firm, lobulated mass involving ribs; gray-white, tan, +/- cystic areas

Micro ─

─ Poorly circumscribed, lobulated proliferation replacing normal bone/marrow

─ Admixture of:

─ Spindle cell mesenchyme (bland fibroblasts/myofibroblasts)

─ Islands of hyaline cartilage (often cellular, may show atypia)

─ Woven bone trabeculae (reactive)

─ +/- Cystic spaces (may resemble aneurysmal bone cyst)

─ +/- Extramedullary hematopoiesis

IHC ─ Not specific; Cartilage (+) S100; Spindle cells (+/-) SMA

Molecular ─ No specific recurrent genetic alteration known

DDx ─

─ Mesenchymal Chondrosarcoma (Malignant small round cell component, HEY1::NCOA2 fusion)

─ Aneurysmal Bone Cyst (Lacks prominent cartilage/spindle mesenchyme, USP6 rearranged)

─ Fibrous Dysplasia (Lacks cartilage, "Chinese character" bone, GNAS mutated)

Prognosis ─ Benign; local recurrence possible if incompletely excised

Osteofibrous dysplasia (OFD)

Benign fibro-osseous lesion almost exclusively occurring in the cortex of the tibia and fibula of children. Also known as ossifying fibroma of long bones.

Clinical ─ Children and adolescents (mc < 10 years); anterior cortex of tibia mc site, often also involves ipsilateral fibula; presents as painless swelling or bowing deformity ("anterior tibial bowing"), may have pathologic fracture

Radiology ─ Eccentric, intracortical, multi-loculated lytic lesion in tibial diaphysis; sclerotic rim; cortical expansion and bowing common

Macro ─ Firm, gray-white fibrous tissue replacing cortex

Micro ─

─ Fibrous stroma containing bland spindle cells (fibroblasts)

─ Irregular trabeculae of immature woven bone

─ Characteristic feature: Prominent osteoblastic rimming of bone trabeculae (distinguishes from fibrous dysplasia)

─ Zonal pattern often seen: More fibrous centrally, more mature lamellar bone peripherally

─ +/- Foam cells, giant cells, secondary ABC changes

IHC ─ Not specific; osteoblasts (+) SATB2; (+/-) Keratin (scattered epithelial cells, esp. near adamantinoma-like areas)

Molecular ─ No specific recurrent genetic alteration known

DDx ─

─ Adamantinoma (Contains overt epithelial nests, Keratin+, older age group usually)

─ Fibrous Dysplasia (Lacks prominent osteoblastic rimming, often intramedullary, GNAS mutated)

─ Non-ossifying Fibroma (Storiform pattern, more foam cells/giant cells, lacks osteoblastic rimming)

Prognosis ─ Benign; may recur locally after curettage; some cases may progress to or represent low-grade adamantinoma (relationship debated); often managed conservatively until skeletal maturity

Media ─ Pathoutlines WSI video video HE HE CK MRI CT

Adamantinoma of long bones

Low-grade malignant epithelial neoplasm primarily occurring in the tibia.

Clinical ─ Adolescents and young adults (peak 20-30s); tibia (diaphysis) mc site >> fibula, other long bones; presents with pain, swelling, may mimic benign lesion

Radiology ─ Eccentric or central, multi-loculated ("soap bubble") lytic lesion in tibial diaphysis; often sclerotic margin; cortical expansion/destruction

Macro ─ Firm, gray-white to yellowish tumor; may have cystic areas

Micro ─

─ Biphasic tumor:

─ Epithelial component: Nests, strands, or tubules of basaloid or squamous-like epithelial cells, often with peripheral palisading; may show glandular or spindle cell features

─ Stromal component: Fibrous stroma, often bland but can be cellular or desmoplastic

─ Osteofibrous dysplasia-like areas common at periphery

IHC ─ Epithelial cells (+) Keratins (AE1/AE3, CK19, CK14), p63, EMA; (-) S100, CD34

Molecular ─ Complex karyotypes, gains of chromosomes 7, 8, 12, 19, 21 reported

DDx ─

─ Osteofibrous Dysplasia (Lacks overt epithelial nests, prominent osteoblastic rimming, Keratin usually negative/sparse)

─ Metastatic Carcinoma (esp. Squamous) (Older age, history of primary, different morphology/IHC profile)

─ Synovial Sarcoma (Biphasic) (TLE1+, SS18 fusion)

─ Fibrous Dysplasia (Lacks epithelial component)

Prognosis ─ Low-grade malignancy; indolent course but prone to local recurrence; late metastasis (lung, lymph nodes) occurs in ~15-30%

Media ─ Pathoutlines WSI WSI WSI

Simple bone cyst

Benign, fluid-filled, non-neoplastic cavity within bone. Also known as unicameral bone cyst (UBC) or solitary bone cyst.

Clinical ─ Children and adolescents (peak 5-15s), M > F; metaphysis of long bones (proximal humerus mc > proximal femur); usually asymptomatic until pathologic fracture; "falling fragment" sign (fragment falls to dependent portion of cyst) may be seen on radiographs after fracture

Radiology ─ Central, geographic lytic lesion in metaphysis abutting physis; well-defined thin sclerotic rim; usually unilocular; expansile, may thin cortex

Macro ─ Cyst cavity filled with clear serous or serosanguinous fluid; thin fibrous lining

Micro ─

─ Cyst wall composed of thin fibrous membrane

─ +/- Fibrin deposition, hemosiderin, reactive woven bone, scattered inflammatory cells

─ Lacks true epithelial or endothelial lining

─ No solid cellular component (unlike ABC)

IHC ─ Not applicable

Molecular ─ Not applicable

DDx ─

─ Aneurysmal Bone Cyst (ABC) (Blood-filled spaces, cellular septa with giant cells, USP6 rearranged)

─ Giant Cell Tumor of Bone (Epiphyseal location, solid cellular tumor)

─ Fibrous Dysplasia (Solid fibro-osseous lesion)

─ Intraosseous Ganglion Cyst (Juxta-articular location, myxoid degeneration)

Prognosis ─ Benign; high recurrence rate after curettage, especially in younger active patients; often treated with aspiration/injection or curettage/grafting

Media ─ Pathoutlines WSI video x-ray

Fibrocartilaginous mesenchymoma

Rare benign bone tumor composed of bland spindle cells, nodules of hyaline cartilage, and woven bone trabeculae.

Clinical ─ Children and adolescents (most < 20 years); long bones (esp. femur, tibia, fibula), ribs, hands/feet; presents as painless mass or incidental finding

Radiology ─ Expansile, lytic lesion, often with sclerotic rim; variable matrix mineralization (cartilaginous/osseous)

Macro ─ Firm, gray-white tissue with cartilaginous and bony areas

Micro ─

─ Admixture of three components:

─ Bland spindle cell mesenchyme (fibroblast-like)

─ Nodules of hyaline cartilage (often resembling growth plate cartilage, may show atypia)

─ Trabeculae of woven or lamellar bone (often with osteoblastic rimming)

─ Low mitotic activity

IHC ─ Cartilage (+) S100; Spindle cells (+/-) SMA

Molecular ─ Not well characterized

DDx ─

─ Chondromesenchymal Hamartoma of Chest Wall (Rib location, lacks prominent bone usually)

─ Fibrous Dysplasia (Lacks cartilage component, lacks osteoblastic rimming)

─ Mesenchymal Chondrosarcoma (Malignant small round cell component)

─ Osteosarcoma (Chondroblastic) (Malignant osteoid production, high-grade atypia)

Prognosis ─ Benign; local recurrence possible

Fibrous dysplasia (FD)

Benign developmental fibro-osseous lesion characterized by replacement of normal bone with fibrous tissue and immature woven bone.

Clinical ─ Children and young adults (usually presents < 30 years); monostotic (one bone) or polyostotic (multiple bones); ribs, femur, tibia, craniofacial bones mc sites; presents with pain, swelling, deformity, pathologic fracture; associated with McCune-Albright syndrome (polyostotic FD, café-au-lait spots, endocrine abnormalities) or Mazabraud syndrome (FD + intramuscular myxomas)

Radiology ─ Variable appearance; often expansile lesion with "ground glass" opacity; well-defined sclerotic rim common; +/- cystic change, bowing deformity

Macro ─ Firm, gritty, gray-white fibrous tissue replacing marrow and cortex

Micro ─

─ Moderately cellular fibrous stroma composed of bland spindle cells (fibroblasts)

─ Irregular, curvilinear trabeculae of immature woven bone ("Chinese characters", "alphabet soup")

─ Characteristic feature: Woven bone trabeculae lack prominent osteoblastic rimming

─ Bone trabeculae arise directly from fibrous stroma

─ +/- Cystic degeneration, foam cells, giant cells, myxoid change, cartilaginous nodules (fibrocartilaginous dysplasia)

IHC ─ Not specific; spindle cells (+) vimentin

Molecular ─ Activating mutations in GNAS gene (encoding Gs-alpha protein)

DDx ─

─ Osteofibrous Dysplasia (Tibial location, prominent osteoblastic rimming, lacks GNAS mutation)

─ Low-grade Central Osteosarcoma (Infiltrative growth, cytologic atypia, malignant osteoid, MDM2 amplified)

─ Ossifying Fibroma (Jaw location, more cellular, lamellar bone with osteoblastic rimming)

─ Simple Bone Cyst / ABC (Cystic lesions, lack fibro-osseous proliferation)

Prognosis ─ Benign developmental anomaly; lesions stabilize after skeletal maturity; malignant transformation (usually osteosarcoma) very rare (<1%), more common in polyostotic/syndromic cases or after radiation

Media ─ Pathoutlines WSI WSI WSI video video gross HE HE X-ray

Undifferentiated Small Round Cells

Ewing sarcoma

Malignant small round blue cell tumor, most commonly arising in bone, characterized by EWSR1 or FUS gene rearrangements with ETS family transcription factors.

Clinical ─ Children and young adults (peak 10-20s), M > F slightly; diaphysis of long bones (femur mc) > flat bones (pelvis); presents with pain, swelling, systemic symptoms (fever, weight loss); can occur primarily in soft tissue

Radiology ─ Permeative or moth-eaten lytic lesion in diaphysis/metadiaphysis; large soft tissue mass common; characteristic "onion skin" (lamellated) or "hair-on-end" (sunburst) periosteal reaction

Macro ─ Soft, gray-white tumor; often hemorrhagic and necrotic; infiltrates marrow and soft tissue

Micro ─

─ Diffuse sheets of uniform small round blue cells

─ Scant clear or eosinophilic cytoplasm (may be glycogen-rich, PAS+)

─ Round nuclei, fine "powdery" chromatin, inconspicuous nucleoli

─ Minimal intervening stroma, delicate vasculature

─ +/- Homer-Wright rosettes (neuroectodermal differentiation)

─ Mitotic activity variable, necrosis common

─ Atypical variant: Larger cells, more irregular nuclei, prominent nucleoli

IHC ─ (+) CD99 (membranous, strong/diffuse); (+) NKX2.2 (nuclear, highly specific); (+) FLI1 (nuclear, reflects common fusion partner); (+/-) Keratins (AE1/AE3, CAM5.2 - often dot-like), Synaptophysin; (-) Desmin, Myogenin, LCA (CD45), S100, WT1 (C-term)

Molecular ─ Characteristic EWSR1::FLI1 fusion t(11;22) (~85%); EWSR1::ERG t(21;22) (~10%); other EWSR1/FUS fusions with ETS family members (ETV1, ETV4, FEV) less common

DDx ─

─ Other small round blue cell tumors (Lymphoma (LCA+), Rhabdomyosarcoma (Desmin+, Myogenin+), Neuroblastoma (Synaptophysin+, PHOX2B+), DSRCT (Keratin+, Desmin+, WT1+))

─ Mesenchymal Chondrosarcoma (Cartilage component, S100+, lacks EWSR1-ETS fusion)

─ CIC-rearranged Sarcoma (Different morphology, WT1+, ETV4+, lacks EWSR1-ETS fusion)

─ BCOR-rearranged Sarcoma (Different morphology, BCOR+, SATB2+, lacks EWSR1-ETS fusion)

Prognosis ─ Aggressive; requires multi-agent chemotherapy and local control (surgery/radiation); prognosis depends on stage (metastases bad), location, size, age, response to therapy

Media ─ Pathoutlines WSI WSI Video

CIC-rearranged sarcoma

Aggressive sarcoma characterized by round to epithelioid cells and specific CIC gene fusions, often negative for Ewing markers.

Clinical ─ Adolescents and young adults (peak 15-30s); deep soft tissue mc site > bone, viscera; presents as rapidly growing mass

Radiology ─ Soft tissue mass or destructive bone lesion

Macro ─ Lobulated, gray-white mass; often necrotic/hemorrhagic

Micro ─

─ Lobular or nested pattern common

─ Round, oval, or epithelioid cells with vesicular nuclei, prominent nucleoli

─ Cytoplasm often scant, may be clear or eosinophilic

─ Myxoid stromal change common ("bubbly" appearance)

─ Brisk mitotic activity, necrosis common

─ +/- Spindle cell component

IHC ─ (+) WT1 (nuclear, C-terminus), ETV4 (nuclear); (+/-) CD99 (often patchy/weak or negative), Calretinin; (-) NKX2.2, FLI1, ERG, Keratins, Desmin, Myogenin, S100

Molecular ─ Defined by CIC gene rearrangements (chromosome 19q13), mc CIC::DUX4; less commonly CIC::FOXO4, CIC::NUTM1

DDx ─

─ Ewing Sarcoma (CD99+, NKX2.2+, FLI1+, lacks WT1/ETV4, EWSR1-ETS fusion)

─ Poorly Differentiated Synovial Sarcoma (TLE1+, Keratin/EMA+, SS18 fusion)

─ Other round cell sarcomas (BCOR, EWSR1-non-ETS)

Prognosis ─ Highly aggressive; high rate of metastasis; poor prognosis

Media ─ Pathoutlines video

Sarcoma with BCOR genetic alterations

Group of sarcomas characterized by alterations in the BCOR gene, including internal tandem duplications (ITD) or fusions (e.g., BCOR::CCNB3).

Clinical ─ Variable depending on specific alteration; BCOR::CCNB3 typically bone tumors in male children/adolescents; BCOR-ITD often soft tissue/viscera in young children

Radiology ─ Destructive bone lesion or soft tissue mass

Macro ─ Gray-white, fleshy tumor

Micro ─

─ Variable morphology, often includes primitive round cells and spindle cells

─ Myxoid stroma common

─ Delicate branching ("chicken-wire") or arcuate vascular pattern often prominent

─ Mitotic activity variable

IHC ─ (+) BCOR (nuclear, strong/diffuse); (+) SATB2, TLE1, Cyclin D1; (+/-) CD99 (often patchy); (-) NKX2.2, FLI1, ERG, WT1, ETV4, Myogenin, Desmin, S100, Keratins

Molecular ─ Defined by BCOR alteration (BCOR::CCNB3 fusion, BCOR-ITD, other BCOR fusions)

DDx ─

─ Ewing Sarcoma (CD99+, NKX2.2+, FLI1+, BCOR-)

─ CIC-rearranged Sarcoma (WT1+, ETV4+, BCOR-)

─ Other round cell sarcomas

Prognosis ─ Generally aggressive sarcomas, but prognosis may vary with specific alteration/clinical setting

Media ─ Pathoutlines video

Round cell sarcoma with EWSR1-non-ETS fusions

Group of sarcomas resembling Ewing sarcoma morphologically but lacking the canonical EWSR1/FUS-ETS fusions. Includes tumors with EWSR1::NFATC2, EWSR1::PATZ1, EWSR1::SMAD3, etc.

Clinical ─ Variable, often affects young adults/children; bone or soft tissue

Radiology ─ Often destructive bone lesions or soft tissue masses, similar to Ewing

Macro ─ Similar to Ewing sarcoma

Micro ─

─ Often sheets of small round blue cells similar to Ewing sarcoma

─ Morphology can be variable depending on fusion partner (e.g., EWSR1::PATZ1 may show spindle cells/myxoid stroma)

IHC ─ Variable; often (+) CD99 (membranous); NKX2.2 usually negative (unlike Ewing); may show divergent differentiation markers (e.g., S100, SMA, Desmin in EWSR1::PATZ1)

Molecular ─ Defined by EWSR1 fusion with a non-ETS partner gene (e.g., NFATC2, PATZ1, SMAD3, VEZT, etc.)

DDx ─

─ Ewing Sarcoma (NKX2.2+, EWSR1-ETS fusion)

─ Other specific round cell sarcomas (CIC, BCOR - specific IHC/fusions)

─ Other small round blue cell tumors

Prognosis ─ Variable, often aggressive; depends on specific fusion and clinical factors

Media ─ Pathoutlines WSI video