Soft Tissue Tumors Part 3 - Muscle, Vascular, Nerve, Other
Update in Progress
Last revised 27 June 2009
Copyright (c) 2002-2009, PathologyOutlines.com, Inc.
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References in green are journals with free full text
Characteristic “string of pearls” appearance of adipose tissue in DFSP
Table of Contents for Soft Tissue Tumors Part 2 - Muscle, Vascular, Nerve, Other
Skeletal Muscle: normal, neuromuscular hamartoma, myxoma, rhabdomyoma, rhabdomyosarcoma: general, alveolar, anaplastic, embryonal, pleomorphic, sclerosing
Smooth Muscle: general, angioleiomyoma, leiomyoma, leiomyoma deep soft tissue, leiomyosarcoma
Vascular: normal
benign - hemangioma, intravascular papillary endothelial hyperplasia, lymphangioma, lymphangioendothelioma, lymphangiomyoma, lymphangiosarcoma, glomus tumor, vascular ectasias, bacillary angiomatosis, myopericytoma
low/intermediate grade - giant cell angioblastoma, hemangioendothelioma, Kaposi
high grade - angiosarcoma, hemangiopericytoma
Peripheral Nerve: normal, MPNST, myxopapillary ependymoma, nerve sheath myxoma, neurofibroma, neurofibromatosis type 1, type 2, neuroma, perineurioma, pigmented neuroectodermal tumor of infancy, schwannoma
Uncertain histogenesis: alveolar soft parts sarcoma, clear cell sarcoma, epithelioid sarcoma, fibrous hamartoma of infancy, granular cell tumor, malignant giant cell tumor of soft parts, myxoma, ossifying fibromyxoid tumor, rhabdoid tumor, synovial sarcoma
Perivascular epithelioid cell: PEComa-general, abdominopelvic sarcoma, falciform ligament / ligamentum teres
Mesenchymal: mesenchymoma, phosphaturic mesenchymal tumor
Extraskeletal “bone” tumors: aneurysmal bone cyst, chondroma, chondrosarcoma, Ewing/PNET, osteosarcoma
Miscellaneous tumors and staging: desmoplastic small round cell tumor, metastases, sinus histiocytosis with massive lymphadenopathy, teratoma, staging
Go to Soft Tissue Tumors Part 1 - Introduction, Fibrous, Fibrohistiocytic and Adipose tumors
Primary references - Soft Tissue Tumors Part 2
American Journal of Clinical Pathology (AJCP) [free full text and no registration after 1 year], January 2000 to April 2008
American Journal of Surgical Pathology (AJSP), January 2000 to April 2008
Archives of Pathology and Laboratory Medicine (Archives) [always free full text and no registration]; January 1999 to April 2008
Biomed Central [always free full text and no registration]; 24 July 2001 to 13 March 2008
Human Pathology (Hum Path), January 2000 to April 2008
Modern Pathology (Mod Path) [free full text and no registration after 1 year]; Jan 2000 to April 2008
Fletcher: Pathology and Genetics of Tumours of Soft Tissue and Bone (AFIP 3rd Series, Vol 30), 2004, not 64-8, 245-52
Fletcher:
Pathology and Genetics of Tumours of Soft Tissue and Bone (WHO, Vol 5), Chapter 4, Chapter 6
Rosai,
J: Ackerman’s Surgical Pathology (9th Ed, 2004)
Sternberg, S: Diagnostic Surgical Pathology (4th Ed, 2004)
Websites with images: PathoPic, PEIR digital library (not yet updated)
Journal search terms: each disease entity listed (not yet updated)
Tumors of Skeletal Muscle - soft tissue chapter
Normal skeletal muscle arises from mesectoderm in head and neck and from myotomes elsewhere via formation of myoblasts and myotubes (muscle fibers)
Contains myofibrils composed of thin (actin) and thick (myosin) filaments
Electron microscopy reveals structural components:
I (isotropic) band: thin filaments only
A (anisotropic) band: overlapping thin and thick filaments
H band: thick filaments only
Z line: divides center of I band; serves as attachment site for the sarcomere, the repeating individual unit of the muscle fiber
Micro images: normal striated muscle #1; #2
Neuromuscular hamartoma of soft tissue
Definition: rare developmental lesion of mature skeletal muscle and nerve
Not a WHO diagnosis
Also called benign Triton tumor (malignant Triton tumor refers to rhabdomyosarcoma plus MPNST), neuromuscular choristoma
Usually < 2 years old, affects brachial plexus or sciatic nerve
Treatment: biopsy for diagnosis plus observation, may develop fibromatosis after biopsy or complete excision
Gross: circumscribed, firm, gray-brown-white, multinodular, attached to nerve
Micro: multiple nodules, each 3-5 mm, separated by narrow bands of connective tissue; nodules are composed of fascicles of striated muscle of varying size with nerve fibers (myelinated or not) within same perimysial fibrous sheath; stroma may be more cellular with bland spindle cells and resemble fibromatosis
Micro images: nodules of skeletal muscle and neural elements that subdivide into smaller nodules by narrow bands of connective tissue; nodules contain fascicles of striated muscle fibers of variable size and nerve fibers (with or without myelination) in same perimysial fibrous sheath; rare case with haphazardly distributed skeletal muscle and nerve fibers, cellular stroma and bland spindle cells with scant cytoplasm and oval nuclei #1; #2; nerve fibers are S100+ (image #1); #2
Positive stains: striated muscle - desmin and muscle specific actin, nerve - S100
DD: fetal rhabdomyoma (S100-), embryonal rhabdomyosarcoma
Myxoma of soft tissue
Definition: gelatinous lesion often deep within muscle of extremity, avascular with occasional stellate cells in slightly basophilic matrix
Not a WHO diagnosis
Cardiac myxoma contains endothelial cells in fibromyxoid matrix, is associated with Carney syndrome
Treatment: excision, rarely recurs
Gross: extremely gelatinous, often circumscribed, deep within muscle, may be up to 13 cm
Gross images: intramuscular myxoma #1; #2
Micro: slightly basophilic matrix with a few spindle cells at high power with oval nuclei; slightly more cellular with collagenized capsule at periphery; may have central mucinous cyst; no significant vascularity
DD: nerve sheath myxoma (periphery has parallel rows of spindle cells with wavy nuclei representing the nerve)
Definition: benign tumor of skeletal muscle differentiation, either cardiac (probably a hamartoma), genital or extracardiac
Noncardiac, nongenital tumors are classified as adult or fetal based on differentiation
Rare, associated with tuberous sclerosis
Treatment: excision
Positive stains: myoglobin
Adult type rhabdomyoma of soft tissue
Definition: benign tumor of mature skeletal muscle, usually adults in head and neck (90%), particularly oral cavity
May be multifocal (25%)
Median age 60 years, 75% male
Case reports: 13 cm tumor (Hum Path 2000;31:1074)
Treatment: excision is curative, but may recur if incompletely excised
Gross: median 3 cm, circumscribed, soft, tan-red-brown, nodular or lobulated
Micro: well circumscribed, not encapsulated, sheets of large well differentiated cells, round or polygonal with abundant eosinophilic fibrillar or granular cytoplasm with frequent cross striations and intracytoplasmic rod-like inclusions, nuclei are small, round and vesicular, may have prominent nucleoli; may have spider cells with vacuolated cytoplasm (cells resemble spider webs); variable glycogen and lipid; no mitotic activity, no atypia
Micro images: distinct well demarcated lobules of polygonal cells; large closely packed polygonal cells up to 150 microns #1; #2; cells have abundant eosinophilic and granular cytoplasm, often with peripheral vacuoles, giving a spiderweb appearance to some cells, nuclei are round with vesicular chromatin and prominent nucleoli #1; #2; cells usually have haphazardly arranged crystalline material resembling sarcomeric bands; crystalline material resembles rods; actin+; desmin+
Positive stains: PAS+ diastase sensitive (glycogen), PTAH and Masson trichrome highlight cross striations and rod-like inclusions; also muscle specific actin, desmin and myoglobin (100%)
Negative stains: keratin, EMA, CD68, S100 (or weak)
EM: myofilaments, Z bands, glycogen granules
DD: granular cell tumor (no skeletal muscle differentiation, no glycogen, smaller cells have poorly defined cell borders, often overlying pseudoepitheliomatous hyperplasia, S100+), hibernoma (no skeletal muscle differentiation, no glycogen), well differentiated rhabdomyosarcoma, crystal storing histiocytosis, alveolar soft part sarcoma
Fetal type rhabdomyoma of soft tissue
Definition: rare benign tumor of immature skeletal muscle differentiation, usually head and neck; retroauricular in ages 0-3 years
Median age 4 years, 70% male
Treatment: complete excision, only rare recurrences, no metastases
Gross: median 3-5 cm, solitary, well circumscribed mass of soft tissue or mucosa, gray-white-tan-pink, soft with glistening cut surface
Micro: circumscribed but not encapsulated; myxoid or cellular
myxoid - bundles or fascicles of immature slender skeletal muscle with delicate cytoplasmic cross striations and thin tapering eosinophilic processes, resembling myotubules at week 7-12 of gestation; also undifferentiated round/oval or spindled mesenchymal cells; stroma is myxoid or fibromyxoid; skeletal muscle cells mature towards periphery, may have “pseudocambium” layer of plasma cells and lymphocytes under mucosal epithelium
cellular - bundles or fascicles of cells in parallel or plexiform patterns, sparse collagenous or myxoid stroma, cells have variable skeletal muscle differentiation ranging from immature cells of myxoid pattern (but in larger numbers) to ganglion cell-like rhabdomyoblasts with prominent nucleoli, or strap cells with abundant basophilic or eosinophilic cytoplasm and prominent cross-striations; infiltration of skeletal muscle may make margins difficult to determine; variable glycogen containing vacuoles, no/rare mitotic figures
Micro images: undifferentiated round mesenchymal cells and immature skeletal muscle cells within myxoid or edematous stroma #1; #2; the bipolar, immature skeletal muscle cells have tapered eosinophilic cytoplasmic processes and closely resemble the myotubular stage of striated muscle development, and the undifferentiated cells have minimal cytoplasm and round or oval nuclei; immature muscle cells and mesenchymal cells are often in central portion of tumor, with better differentiated skeletal muscle cells and mesenchymal cells at periphery #1; #2; #3; mucosal tumors have a pseudocambium layer of plasma cells and lymphocytes resembling embryonal rhabdomyosarcoma, but there is no atypia and no mitotic figures
cellular fetal type rhabdomyoma - tumor cells are arranged in fascicles with less stroma; ganglion cell like rhabdomyoblasts or strap cells are arranged in patternless pattern with undifferentiated mesenchymal cells #1; #2; immature skeletal muscle cells; ganglion cell-like rhabdomyoblasts; strap cells with abundant eosinophilic cytoplasm and cross striations
Fetal type rhabdomyoma of soft tissue (continued)
Positive stains: muscle specific actin, desmin and myoglobin (100%), GFAP (40%)
Negative stains: keratin, EMA, CD68
EM: hypertrophied Z band material, thick and thin filaments, numerous mitochondria, some with inclusions
DD: botyroid variant of embryonal rhabdomyosarcoma (resembles myxoid variant of fetal rhabdomyoma but has deep location, true cambium layer, atypia, numerous mitotic figures, tumor cell necrosis, infiltrative margins, no maturation of cells at periphery), spindle cell variant of embryonal rhabdomyosarcoma (resembles cellular variant of fetal rhabdomyoma but has cellular pleomorphism and tumor cell necrosis), infantile fibromatosis (deep location, fascicles of spindle cells, no cross striations, no undifferentiated cells), neuromuscular hamartoma (S100+ nerve fibers and skeletal muscle in same perimysial sheath)
Genital type rhabdomyoma - soft tissue chapter
Definition: rare benign tumor of vagina, vulva or cervix, usually in middle aged women, with skeletal muscle differentiation
Rarely occurs in males in paratesticular region or epididymis
Mean age 42 years
Treatment: local excision is curative
Gross: well circumscribed, solitary, up to 3 cm, resembles polyp, covered by smooth mucosa
Micro: submucosal, polypoid, well circumscribed, no capsule; haphazard strap-like or round striated muscle fibers in fibrous stroma with dilated vessels; cells have abundant eosinophilic cytoplasm with glycogen, cross striations, longitudinal myofibrils; nucleus is round, vesicular, central and uniform; may have bi- or multinucleated cells; no spider cells, no myxoid stroma, no spindle cells or rhabdomyoblasts, no necrosis, no nuclear pleomorphism
Micro images: submucosal proliferation of haphazard skeletal muscle cells with prominent cross striations and fibromyxoid stroma #1; #2; #3
Positive stains: muscle specific actin and desmin highlight rod-like structures, myoglobin (100%)
Negative stains: keratin, EMA, CD68
DD: vaginal polyp (may have atypical cells, no cross striations), botyroid variant of embryonal rhabdomyosarcoma (usually <25 years old with rapidly growing mass, cambium layer, atypia, mitotic activity)
Rhabdomyosarcoma of soft tissue-general
Definition: primitive malignant soft tissue sarcoma with skeletal muscle phenotype by H&E, immunohistochemistry or EM
Most common soft tissue sarcoma of childhood/adolescence (5-8% of solid pediatric tumors)
Usually aneuploid
Children 2-6 years usually have head, neck or GU tumors; teenagers usually have paratesticular, trunk or abdominal tumors
Relatively rare in adults
Intergroup Rhabdomyosarcoma Study Group classifies tumors as favorable (botryoid, well differentiated, spindle cell, most embryonal, 89% disease free survival at 2 years) or unfavorable (anaplastic features, alveolar, poorly differentiated with monomorphous round cells - 20%, 72% disease free survival at 2 years)
Should compare post-treatment to pre-treatment specimens (AJCP 2005;123:75)
Rhabdomyoblast: cell of origin; eccentric eosinophilic granular cytoplasm rich in thick and thin filaments; if round and elongate, are called strap cells or tadpole cells
Subtypes: alveolar, anaplastic, embryonal, pleomorphic, sclerosing (Mod Path 2001;14:506)
Note: subtypes overlap and mixtures are common
Positive stains: recommended panel contains myogenin, sarcomeric actin (90%) and desmin (95%)
positive stains are common muscle or sarcomeric actin (good marker for this tumor), desmin (reliable for solid variant of alveolar rhabdomyosarcoma, positive in tumors with round or strap cell rhabdomyoblasts, also smooth muscle tumors), myoglobin (specific, but only found in better differentiated tumors, may be non-specific due to diffusion from adjacent injured skeletal muscle cells), vimentin (not specific), myogenin (sensitive and specific, particularly useful for alveolar subtype, Mod Path 2000;13:988); also MyoD1, myosin
Negative stains: FLI-1
EM: rhabdomyoblasts contain sarcomeres (thick and thin filaments) and Z bands
References: Archives 2006;130:1454, Archives 2003;127:1290 (reporting protocol)
Alveolar rhabdomyosarcoma of soft tissue
Definition: high grade round cell malignancy with solid and alveolar growth and partial skeletal muscle differentiation
More common in early to mid-teens but all ages affected; in deep muscles of extremities, axial muscles or perineum
20% of all rhabdomyosarcomas
Rapidly growing, often high stage at presentation
Overall poorer prognosis than embryonal subtype
Intergroup Rhabdomyosarcoma Study grouping is predictive of outcome
Poor prognostic factors: N-myc amplification, PAX3 fusion transcripts
Mixed forms with alveolar component are classified as alveolar for staging and diagnosis
Case reports: primary cutaneous tumor (AJSP 2002;26:938), perineal skin tumor in infant (Archives 2002;126:982), 2 year old girl with pleural effusion and ovarian mass (Archives 2003;127:e56
Gross: fleshy, tan-gray, mean 5 cm
Micro: thin fibrous septae lined by small round blue cells (resembling lymphoma) in an alveolar growth pattern (resembles pulmonary alveoli); loss of cellular cohesion so cells appear to float in alveolar spaces; also peripheral cracking artifact at borders of cell clusters; amount of alveolar tissue present is NOT significant (i.e. diagnose as alveolar even if only focal alveolar pattern); deep eosinophilic cytoplasm and presence of occasional multinucleated giant cells are important diagnostic features; often foci of coagulative tumor cell necrosis, rhabdomyoblasts with cytoplasmic cross striations in 1/3; rarely rhabdoid features (pink, ground-glass or fibrillar round to oval cytoplasmic bodies, large eosinophilic nucleoli)
Micro images: primitive round cells appear to float within nests lined by fibrous septa; tumor cells grow in nests or clusters separated by fibrous septa #1; #2; #3; fig B: nuclei are large and uniform; solid growth #1; #2 (with giant cells); #3; #4; alveolar type spaces contain desquamated small, round and poorly differentiated skeletal muscle cells, fibrovascular stroma is lined by undifferentiated round cells and differentiating cells with abundant eosinophilic cytoplasm, but only rare cross striations #1; #2; desquamated multinuclear giant cells; tumor cells may resemble embryonal rhabdomyosarcoma cells, including small round and spindle cells with hyperchromatic nuclei and vacuolated spider cells; predominantly solid areas with only focal alveolar pattern resembles embryonal rhabdomyosarcoma; some cells may resemble lipoblasts; focal rhabdoid cells; various images-perineal skin of infant; H&E, ALK1 and p80 staining; desmin staining; myogenin #1; #2
Alveolar rhabdomyosarcoma of soft tissue (continued)
Positive
stains: muscle specific actin,
desmin, myogenin (strong nuclear staining, AJSP
2001;25:1150), Myo-D1 (AJSP 2006;30:962); also ALK1 and p80 (25%, cytoplasmic dot-like pattern, Mod Path 2002;15:931)
EM: skeletal muscle differentiation
Molecular/cytogenetics: t(2;13)(q35;q14) [PAX3-FKHR] in 60-85%, t(1;13)(p36;q14) [PAX7-FKHR] in 15%; solid types are more likely to be fusion gene negative (AJSP 2007;31:895); N-myc amplification in 50%
DD: Merkel cell carcinoma (negative for muscle specific actin, desmin, myogenin and Myo-D1), metastatic neuroendocrine carcinoma (keratin+, EMA+, desmin-, muscle specific actin-), alveolar soft parts sarcoma (negative for muscle specific actin and myoglobin, PAS+ intracytoplasmic crystalline rods and granules, no pleomorphism, no giant cells, no fibrous septa)
Anaplastic variant of alveolar rhabdomyosarcoma of soft tissue
Prognosis may be worse than typical alveolar rhabdomyosarcoma
Micro: anaplastic nuclei are 3x larger than surrounding nuclei
Micro images: foci of anaplastic cells (nuclei are hyperchromatic and 3x larger than surrounding cells)
Solid variant of alveolar rhabdomyosarcoma of soft tissue
Micro: poorly developed alveolar pattern, lacks fibrovascular septa; alveolar pattern may be missed on small biopsies
Micro images: solid variant
Positive stains: desmin and muscle specific actin are most helpful
Anaplastic rhabdomyosarcoma of soft tissue
Not a WHO diagnosis
See also anaplastic variant of embryonal rhabdomyosarcoma
Poor prognosis
Micro: cells have enlarged, pleomorphic, hyperchromatic nuclei, also atypical polar mitotic figures
Micro images: cluster of cells with enlarged, pleomorphic, hyperchromatic nuclei
References: Mod Path 2001;14:506
Embryonal rhabdomyosarcoma of soft tissue
Definition: primitive soft tissue sarcoma with small blue cells resembling embryonic skeletal muscle
Most common rhabdomyosarcoma subtype (65%)
Usually children ages 3-10 years, in nasal and oral cavities, orbit, middle ear, prostate, paratesticular region; rare in skin, thoracic cavity
Extremity involvement uncommon, associated with more relapses, lower survival
May be associated with hypercalcemia thorough increased parathormone production
Metastasizes to soft tissue, serosa, lung, lymph nodes and bone marrow
Favorable prognostic factors: younger patients, spindle and botyroid variants in young patients, GU location (survival of 90%+ after excision and chemotherapy), localized tumor (survival of 80%)
Treatment: excision, chemotherapy, radiation therapy
Gross: poorly circumscribed mass, white, soft or firm, infiltrative
Gross images: intramuscular white tumor with central necrosis
Micro: sheets of small, spindled or moderate to poorly differentiated round cells with scant or deeply eosinophilic cytoplasm and eccentric, small oval nuclei; highly cellular areas around blood vessels alternate with parvicellular mucoid regions (resembles normal embryonal myogenesis); cross striations in 50%s; rarely has anaplastic features, clear cell changes, rhabdoid features, neuronal, melanocytic or schwannian differentiation (ectomesenchymoma); more differentiation typically occurs post-chemotherapy or radiotherapy
Subtypes: embryonal NOS, anaplastic, botyroid, spindle cell
Positive stains: vimentin in all cells (even most primitive); some cells should stain for desmin, MyoD1 or myogenin; actin and desmin in more differentiated cells; PAS highlights glycogen in most tumors; c-kit (15%), myogenin (rare to 25% of tumor cells, Mod Path 2000;13:988), MyoD1
EM: developing striated muscle, thick and thin filaments
Molecular/cytogenetics: -11p15; also +2q, +8, +12, +13, +20; no N-myc amplification; no diagnostic translocation found to date
DD: Ewing’s / PNET (often rosettes, nuclei are uniform and pale, not dense and hyperchromatic; CD99+, desmin-, muscle specific actin-, t(11;22)+), large cell lymphoma (CD45+, B/T cell markers, desmin-, muscle specific actin-), desmoplastic small round cell tumor (presents with tumor nodules on serosal surfaces, may be desmin+, but strongly keratin+ and EMA+, muscle specific actin-), undifferentiated sarcoma (negative for muscle markers), neuroblastoma (elevated urinary catecholamines, rosettes, granular chromatin, S100+ (often), chromogranin+, GFAP+), rhabdomyoma
Variants of embryonal rhabdomyosarcoma:
Anaplastic variant of embryonal rhabdomyosarcoma of soft tissue
4% of embryonal rhabdomyosarcoma
Mean age 6 years, 2/3 male, various sites
Micro: enlarged atypical cells with hyperchromatic nuclei (3x larger than nuclei in neighboring tumor cells), often with atypical mitotic figures; may be focal or diffuse
Micro images: extremely hyperchromatic nuclei that are 3x larger than nuclei of adjacent tumor cells, mixed with smaller, undifferentiated, round and spindle cells #1; #2; #3; bizarre mitotic figure (left side); rare cells suggest skeletal muscle differentiation
Positive stains: muscle specific actin (80%), desmin (60%)
Botyroid variant of embryonal rhabdomyosarcoma of soft tissue
Named due to distinctive gross features (resembles a bunch of grapes)
25% of rhabdomyosarcoma, 10% of embryonal subtype
Associated with tumors beneath mucosal membrane in walls of hollow structures (bladder, vagina, nasal cavity), extrahepatic bile ducts or near a space; rarely in eyelid or anal region
Very good prognosis
Gross: resembles cluster of grapes or allergic nasal polyp, fleshy nodular polypoid projections of variable size into lumen
Gross images: clusters of edematous, grape-like masses that protrude into lumen of hollow organs
Micro: hypercellular zone immediately beneath epithelium (Nicholson’s cambium layer - resembles hypercellular zones that produce growth rings in trees); cells are undifferentiated, round or spindled with minimal cytoplasm, frequent mitotic figures; less cellular in deeper layers, composed of differentiating and undifferentiated cells resembling embryonal NOS
Micro images: condensation of tumor cells in subepithelial zone; polypoid or lobulated masses of cells covered by mucosa, with underlying hypercellular zone of poorly differentiated cells (cambium layer) #1; #2; tumor may have only focal cambium layer, and consist primarily of paucicellular edematous tissue with scattered undifferentiated or atypical large cells; tumor with sheets of round or spindle cells resembling benign polyp or fibroinflammatory lesion; deep foci of hypercellularity is common with round or spindled undifferentiated cells mixed with differentiating rhabdomyoblasts #1; #2
Embryonal rhabdomyosarcoma not otherwise specified (NOS) of soft tissue
Most common subtype (75%)
Mean age 7 years, 2/3 male
Usually head and neck, GU, extremities
Micro: dense zone of undifferentiated, differentiating and well differentiating cells; cells are immediate beneath epithelium (Nicholson’s cambium layer - resembles hypercellular zones that produce growth rings in trees); undifferentiated cells are blue cells with minimal wispy cytoplasm but no skeletal differentiation, and central nuclei; differentiating cells have moderate amphophilic or eosinophilic cytoplasm, often fibrillar, may have tadpole shape (tapering bipolar cytoplasm), often with nuclei arranged in tandem; well differentiated cells have cytoplasmic cross-striations; matrix is collagenous or myxoid; nuclei usually are dense and smooth with indistinct nucleolus, moderate nuclear pleomorphism but no anaplasia; more mitotic figures associated with less differentiated cells; rarely rhabdoid features (abundant eosinophilic cytoplasm, round/oval cytoplasmic inclusions)
Cytology: noncohesive undifferentiated cells with minimal cytoplasm, variable cytoplasm in differentiating cells; cross striations only in well differentiated cells; nuclei are dense with indistinct nucleoli
Micro images: dense condensations of rhabdomyoblasts with myxoid stroma; cells in sheets; cells in anastomosing fascicles; individually dispersed cells; cells in abundant fibromyxoid stroma; paucicellular tumor due to markedly edematous or myxoid stroma; most tumors contain undifferentiated round or oval cells with sparse clear or amphophilic wispy cytoplasm, dense chromatin and irregular nuclear membranes #1; #2; #3; diagnostic cells have increased eosinophilic or basophilic cytoplasm that displace the dense hyperchromatic nucleus #1; #2; differentiating cells have tapered, bipolar cytoplasm or a tadpole shape with the nuclei at one end, nuclei may be arranged in tandem (like cars on a train) #1; #2; #3; well differentiated rhabdomyoblasts (found in 1/3) have eosinophilic cytoplasm with cross striations; cells may have abundant amphophilic or clear cytoplasm, fine chromatin and small nucleoli, resembling lymphoma; cells often have clear cytoplasm due to glycogen, rarely causing a spiderweb appearance; rarely consists primarily of cells with circumscribed, pink, ground glass or fibrillar cytoplasmic inclusions but no cross striations, nuclei may be more vesicular than usual with prominent nucleoli #1; #2; #3; #4; part A: nuclei are small with pleomorphism; myogenin
desmin staining - cross striations; muscle differentiation in rhabdoid cells; spindle cells; anaplastic cells
Cytology images: noncohesive, poorly differentiated cells with no/minimal cytoplasm or differentiating cells with variable eosinophilic cytoplasm
Positive stains: HHF35 (90%), S100 (scattered in 20%), CAM5.2 (6%)
Spindle-cell variant of embryonal rhabdomyosarcoma of soft tissue
Usually boys in paratesticular, head or neck regions or adults in non-paratesticular regions
6% of embryonal rhabdomyosarcoma
Favorable prognosis in children, more aggressive in adults (AJSP 2005;29:1106)
Gross: firm, fibrous tumor with tan-yellow, whorled cut surface resembling leiomyoma
Micro: low grade, whorls of relatively differentiated elongated spindle cells with fascicular or storiform pattern; cytologic features similar to smooth muscle tumors with blunted central nuclei and tapered ends, but with pale indistinct cytoplasm; cross-striations are rare; low mitotic activity; 50% of more of tumor cells should be spindled for this diagnosis
Micro images: relatively differentiated spindle cells; spindle cells resemble leiomyosarcoma; spindle cells resemble MFH #1; #2; somewhat bland spindle cells are characteristic; may be paucicellular with fibrotic stroma containing undifferentiated round and spindle cells mixed with differentiating rhabdomyoblasts with abundant eosinophilic cytoplasm; desmin+ rhabdomyoblasts are usually present, but often sparse
Positive stains: desmin, muscle specific actin, smooth muscle actin; also vimentin and titin (marker of terminal differentiation)
Negative stains: caldesmon, S100
DD: fibrosarcoma, leiomyosarcoma
Pleomorphic rhabdomyosarcoma of soft tissue
Definition: high grade sarcoma of adults with bizarre polygonal, round or spindle cells, with skeletal muscle differentiation and no alveolar or embryonal component
Usually age 50+ in deep soft tissue
Common rhabdomyosarcoma subtype in adults, 70% male
Rapidly growing painful mass, most commonly of lower extremity, abdomen/retroperitoneum, chest/abdominal wall or spermatic cord/testes
Similar behavior to other pleomorphic sarcomas
Poor prognosis; 70% die of disease after mean followup of 20 months (Mod Path 2001;14:595)
Requirements for diagnosis: cross striations or skeletal muscle marker immunoreactivity (i.e. must prove skeletal muscle differentiation); common errors are overdiagnosing entrapped normal skeletal muscle, non-specific myoglobin immunoreactivity or skeletal muscle differentiation of other tumors
Case reports: 71 year old woman with retroperitoneal tumor with osteoclast-like giant cells (Archives 2005;129:703)
Gross: mean 7 cm, up to 30 cm, may be confined to fascial compartment and assume shape of muscle from which it arises; white and firm cut surface with variable hemorrhage and necrosis
Micro: well circumscribed; large, multinucleated, bizarre, eosinophilic tumor cells; should see cross striations or have immunohistochemical evidence of skeletal muscle differentiation
(a) classic type: predominantly atypical rhabdomyoblasts in sheets
(b) round cell type: clusters of rhabdomyoblasts in background of slightly atypical, medium sized, round blue rhabdomyoblasts
(c) spindle cell type: scattered rhabdomyoblasts with predominantly atypical spindled rhabdomyoblasts in storiform pattern
Note: multinucleated cases may be considered variants of embryonal type
Pleomorphic rhabdomyosarcoma of soft tissue (continued)
Micro images: classic type with sheets of atypical rhabdomyoblasts; round cell type with pleomorphic rhabdomyoblasts; spindle cell type; fascicular pattern; storiform pattern; hemangiopericytoma-like pattern; patternless pattern; spindle cells; pleomorphic and polygonal cells; epithelioid with abundant eosinophilic cytoplasm; clear cytoplasm due to washing out of glycogen; fig B: rhabdomyoblasts have muscle filaments and cross striations; tumor of psoas muscle with tumor cells exhibiting abundant eosinophilic cytoplasm with hyaline like inclusions (fig 3) and osteoclast-like giant cells (fig 4); H&E and various stains
Positive stains: myoglobin (>90%), desmin (>90%), muscle specific actin (70%), MyoD1 (50%), skeletal muscle myogenin (50%), smooth muscle actin (50%)
EM: skeletal muscle differentiation with rudimentary sarcomeres containing Z bands or Z band material with thick and thin filaments
EM images: thick and thin filaments form primitive Z bands
Molecular/cytogenetics: complex karyotypes
DD: embryonal or alveolar rhabdomyosarcoma with pleomorphism, pleomorphic liposarcoma, MFH-pleomorphic, sarcoma with heterologous rhabdomyosarcomatous differentiation (differentiated features are characteristic of primary tumor)
Sclerosing rhabdomyosarcoma of soft tissue
Definition: rhabdomyosarcoma with extensive matrix production
Not a WHO diagnosis
Case reports: tumors of forearm, hand, orbit and nasopharynx of 40-year-old woman, 50-year-old man, 18-year-old man, 21-year-old man, respectively (AJSP 2002;26:1175)
Gross: 4 to 8 cm
Micro: lobules and infiltrating cords of small round malignant cells embedded in densely hyalinized matrix with chondroid and osteoid-like appearance; no definite lacunae or matrix calcification present; alveolar pattern present only focally; no tumor giant cells; one case with single focus of rhabdomyoblastic differentiation with strap cells; extensive mitotic activity (>20 mitotic figures/20 high power fields) in 3 of 4 cases
Positive stains: MyoD1 (100%, almost every cell), desmin (strong in 1 case, focal in 3 of 4 cases); myogenin focal
Negative stains: cytokeratin, S100
Molecular: no t(2;13)
DD: osteosarcoma, chondrosarcoma, sclerosing epithelioid fibrosarcoma
Tumors of Smooth Muscle - soft tissue chapter
Tumor cells resemble smooth muscle with easily visible, often fibrillar and eosinophilic cytoplasm, usually in long bundles or fascicles, nucleus is long, oval and round at both ends, often with cytoplasmic vacuole at one end, nucleoli are indistinct
Minimal collagen present between smooth muscle cells
Smooth muscle cells may resemble myofibroblasts with less cytoplasm, thinner nuclei, denser chromatin
Trichrome stains smooth muscle cytoplasm red and collagen blue or green
Positive stains: actin, desmin (but also seen in myofibroblasts and myofibroblasts)
Definition: benign, painful, subcutaneous or deep dermal tumor of smooth muscle and vessels
Part of morphologic spectrum with myopericytoma and myofibroma
Also called angiomyoma, vascular leiomyoma; do NOT diagnose as “superficial angiomyolipoma” even if contains some fat
Arises from smooth muscle of blood vessels without elastic fibers
Relatively common, usually females, ages 30-60 years, solitary, often in soft tissue of lower limbs
Tumors in males are more common in upper extremity, head and neck
Other painful nodules are glomus tumor, traumatic neuroma, eccrine spiradenoma and angiolipoma
Pain is due to stretching of nerves in tumor or capsule or release of mediators from mast cells, may be exacerbated by wind, cold, pressure, menses
Treatment: excision, does not recur
Gross: firm, sharply circumscribed, gray-white-brown nodules, usually 2 cm or less
Micro: well circumscribed lesion of fascicles of mature smooth muscle cells surrounding vascular lumina lined by normal appearing endothelium but with no elastic lamina present; subtypes are solid (closely compacted smooth muscle bundles), venous (vessels have thick muscular walls that merge with smooth muscle bundles) and cavernous (dilated vascular channels with minimal smooth muscle that merges with smooth muscle bundles); may have foci of cartilaginous or adipose metaplasia; may have bizarre degenerative type cells similar to symplastic leiomyoma of uterus; no hemorrhage, no necrosis, no mitotic activity
Micro images: smooth muscle plus numerous vessels, often thick walled; smooth muscle in vessel walls merges into smooth muscle of lesion
Positive stains: alpha smooth muscle actin, desmin, vimentin, type IV collagen; S100 in small nerve fibers
Negative stains: HMB45
Not a WHO diagnosis
Definition: bland smooth muscle tumor without mitotic figures
Cases not in deep soft tissue are usually in uterus (most common neoplasm in women); also skin, subcutis
Patients with multiple leiomyomas may have autosomal dominant disorder
Some tumors previously considered to be leiomyomas are actually GIST tumors
Micro: bundles or fascicles of spindled cells with eosinophilic, possibly fibrillary cytoplasm, blunt ended and elongated nuclei with fine chromatin and indistinct nucleolus and variable cytoplasmic vacuole at one end, minimal atypia, few mitotic figures, no coagulative tumor necrosis
Micro images: bundles of elongate cells with eosinophilic cytoplasm and oblong nuclei; oblong nuclei have rounded ends; calcified leiomyoma #1; #2; #3; #4
Molecular/cytogenetics: structural and numerical changes in #6, 7, 12, 14
Bizarre leiomyoma of soft tissue
Also called symplastic, atypical, apoplectic leiomyoma
Usually found in uterus
Benign behavior
Micro: large, atypical nuclei in otherwise normal appearing leiomyoma, no/rare mitotic figures
Cutaneous leiomyoma - soft tissue chapter
Arises from arrector pili muscles
Superficial, small, multiple, painful
Epithelioid leiomyoma of soft tissue
Micro: polygonal cells; may have vacuolated cytoplasm (artifact of fixation)
Genital leiomyoma - soft tissue chapter
Arises from smooth muscle bundles in superficial subcutaneous tissue or related structures (nipple, areola, axilla, scrotum, penis, labia and anal skin)
Solitary
Retroperitoneal leiomyoma - soft tissue chapter
Well differentiated smooth muscle tumor resembling uterine tumor with trabecular pattern and hyaline change
Smooth muscle tumors usually occur in women, mean 45 years (range 25-79 years)
Rare local recurrence, no metastases (AJSP 2001;25:1355)
Leiomyoma: 4 cm or less, bland smooth muscle tumor, no mitotic figures; considered to be very rare at this site
Smooth muscle tumor of uncertain malignant potential: bland smooth muscle tumor, either 4 cm or less and 1-4 MF/10 HPF or 5 cm or more and no mitotic figures
Leiomyosarcoma: pleomorphism, nuclear atypia or tumor cell necrosis, regardless of size or mitotic activity
Treatment: excision for leiomyomas
Positive stains: smooth muscle actin, desmin; also ER, PgR in women; trichrome stains cytoplasm red
DD: GIST tumors (CD117+), parasitic leiomyoma (if clearly attached to non-retroperitoneal structures)
Definition: very rare tumor of deep subcutis or skeletal muscle of extremities or retroperitoneum; by definition is distinct from uterus
Tumors of deep somatic soft tissue affect males and females equally; tumors of retroperitoneum almost always occur in women
May have dystrophic calcification, degenerative nuclear changes or necrobiotic nodules resembling giant rosettes
Treatment: excision, rarely recurs
Gross: well circumscribed, gray-white, up to 15 cm; may have myxoid change
Micro: fascicles of normal appearing smooth muscle with eosinophilic cytoplasm, bland and uniform blunt ended, cigar shaped nuclei; no/minimal atypia, no/rare mitotic figures (up to 5 per 50 HPF in retroperitoneum), no necrosis
Positive stains: actin, desmin, h-caldesmon, ER and PgR in retroperitoneal tumors
Negative stains: S100
DD: myolipoma (prominent fatty change)
Definition: smooth muscle tumor with atypia plus either mitotic activity, tumor cell necrosis or size > 10 cm
10% of adult soft tissue sarcomas
Usually in extremities, arises from large vessels (AJSP 2002;26:14), most commonly inferior vena cava, saphenous vein, femoral vein, pulmonary artery, femoral artery; also in retroperitoneum, superficial or deep soft tissues
Often recurs locally or metastasizes; lung is common site of metastasis, lymph nodes are uncommon
Skin/subcutis: usually male, may have low mitotic rates, epithelioid or granular cell morphology, better survival than retroperitoneum
Retroperitoneum: #3 most common sarcoma after liposarcoma and MFH; usually women, 5 year survival is only 29%
Immunocompromised patients: associated with EBV in HIV patients; may be multifocal
Poor prognostic factors: retroperitoneum, mesenteric or other deep location, > 5 cm, age > 62 years, high grade, tumor disruption by prior incisional biopsy or incomplete excision, intramuscular location or smooth muscle differentiation
Case reports: EBV+ tumor after heart transplantation (AJSP 2000;24:614), tumor of inferior vena cava (Archives 2003;127:e423)
Treatment: excision with clear margins (enucleation is inadequate treatment)
Gross: large, soft, with necrosis, hemorrhage and cystic degeneration; may project into lumen of major vessels or be intramural
Gross images: leg tumor #1; #2; retroperitoneal tumor; thigh tumor
Micro: fascicular growth pattern (bundles intersect at right angles), tumor cells merge with blood vessel walls, palisading of spindle cells with eosinophilic fibrillary cytoplasm with focal granularity and cigar-shaped, blunt-ended nuclei with variable atypia, often with cytoplasmic vacuoles at both ends of nuclei (unlike neural lesions); mitotic figures common; may have hemangiopericytoma-like vasculature, nuclear palisading, myxoid change, osteoclast-like multinucleated giant cells; often infiltrates into adjacent tissue; see also variants below
Leiomyosarcoma of soft tissue (continued)
Malignant criteria by site:
Soft tissue: 1-2 MF/10 HPF and deep
Skin/subcutaneous: 2 MF/10 HPF is definitive, 1 MF/10 HPF if consistent in all fields
Retroperitoneum: 5 MF/10 HPF is definitive, or 1-4 MF/10 HPF and necrosis and size > 7.5 cm
Vascular: 1-4 MF/10 HPF and large size and necrosis
Call uncertain malignant potential (UMP) if mitotic figures are fewer than above or focal
Micro images: well defined fascicular structure with anaplastic foci; malignant based on low power pleomorphism; pleomorphism and smooth muscle differentiation are evident at high power; markedly pleomorphic tumor with little evidence of smooth muscle differentiation; multinucleated giant cells; tumor of inferior vena cava - cytology, H&E and smooth muscle actin
retroperitoneum - smooth muscle differentiation; marked pleomorphism and no readily identifiable smooth muscle
uncertain malignant potential - 8 cm retroperitoneal tumor with bland cells and < 1 MF/10 HPF - image #1; #2
Positive stains: HHF-35 (90%), alpha-smooth muscle actin (90%), vimentin, desmin (75%), h-caldesmon; also PTAH (stains myofibrils), keratin (30%), ER (some), S100 (occasionally weak staining), EMA (may be focal)
Negative stains: CD117
EM: some smooth muscle features, including cytoplasmic filaments with focal densities (also present in myofibroblasts), pinocytotic vesicles, thick basal lamina
Molecular/cytogenetics: often complex karyotypes with no consistent aberrations
DD: leiomyoma (no/rare mitotic activity, small, no hemorrhage, no necrosis), dedifferentiated liposarcoma (usually trunk, better prognosis, well differentiated component present, MDM2 and CDK4 amplification AJSP 2007;31:1557)
Cutaneous leiomyosarcoma - soft tissue chapter
May recur but typically doesn’t metastasize unless involves subcutis
Usually arises from pilar arrecti but can extend into subcutaneous tissues
Micro: intersecting fascicles of brightly eosinophilic spindle cells with ovoid to cigar-shaped nuclei; usually no marked pleomorphism
Positive stains: desmin
Epithelioid leiomyosarcoma of soft tissue
Usually in uterus; rarely in bone or soft tissue
Rare; occurs in children < 10 years old
Case reports: 78 year old man with thigh tumor (Archives 2002;126:468), intraabdominal mass in infant (Mod Path 2000;13:1156)
MRI image: 18 month girl with intraabdominal mass
Micro: round/polygonal cells with eosinophilic and vacuolated cytoplasm, vesicular nuclei, arranged in sheets with focal spindle cells
Micro images: various images #1; #2; large anaplastic type cells with cytoplasmic inclusions
Positive stains: alpha-smooth muscle actin, alpha-sarcomeric actin, vimentin, CD99/MIC2; reticulin stain outlines individual tumor cells
Negative stains: CAM 5.2, CD34, CD45, desmin, EMA, Factor VIII, glial fibrillary acidic protein, HMB45, S100
EM: abundant actin-type filaments in cytoplasm of some cells, glycogen
EM images: image1
DD: metastatic uterine tumor, metastatic carcinoma, epithelioid sarcoma, melanoma
References: Mod Path 2000;13:1211
Myxoid leiomyosarcoma of soft tissue
Rare
Defined as 50%+ myxoid stroma
75% women, median 58 years old, range 22-84
Limbs, female genitalia, head and neck, chest
40% recur, 15% metastasize, 17% have tumor related deaths (AJSP 2000;24:927)
Gross: gelatinous, well circumscribed
Micro: fascicular, reticular, microcystic or resembling myxofibrosarcoma; spindled with smooth muscle features; may have focal epithelioid cells; usually low grade
Positive stains: smooth muscle actin, desmin (50%), CAM5.2 (25%), EMA (15%)
Pleomorphic leiomyosarcoma of soft tissue
Pleomorphic areas should be at least 2/3 of tumor
~10% of all leiomyosarcomas
Mean age 58 years, range 31-89 years
Usually extremities, also retroperitoneum/abdominal cavity, chest/abdominal wall, occasionally scalp
May be more aggressive than ordinary leiomyosarcoma, as 65% die of disease
Micro: focally fascicular with smooth muscle tumor cells; pleomorphic areas mimic MFH-pleomorphic; storiform pattern common; also stromal hyalinization, chronic inflammatory infiltrate; usually high grade; occasionally rhabdoid features
Positive stains: at least one smooth muscle marker (desmin, muscle-specific actin or alpha-smooth muscle actin) in the leiomyosarcomatous fascicular areas.
DD: inflammatory MFH, myofibrosarcoma (usually low grade)
References: AJSP 2001;25:1030
Rhabdoid features in leiomyosarcoma of soft tissue
Poorer prognosis for external soft tissue cases, but not for retroperitoneal cases (Mod Path 2000;13:1211)
Gross: 3-22 cm
Micro: pleomorphic or epithelioid subtypes in small case study; rhabdoid cells are large and polygonal with eosinophilic cytoplasm, eosinophilic globular perinuclear inclusions, eccentric nuclei and prominent nucleoli
Micro images: various images #1; #2
Positive stains (rhabdoid cells): vimentin, desmin, muscle actin
Vascular Tumors
Normal vessels
Contain endothelial cells towards lumen and pericytes, smooth muscle cells and glomus cells (towards outside of vessel)
Endothelial cells: EM shows numerous pinocytotic vesicles, cytoplasmic microfilaments, specialized cell junctions, microvilli, continuous basal lamina, Weibel-Palade bodies (membrane bound organelle which contains von Willebrand factor)
Positive stains: CD34, CD31, Factor 8-related antigen, vimentin, Ulex europaeus I lectin, endothelin, basal lamina, von Willebrand factor, FLI-1 (nuclear stain, AJSP 2001;25:1061)
Note: lymphatic vessels compared to blood vessels stain weaker for Factor 8 related antigen, similar for Ulex
Pericyte-smooth muscle-glomus family: EM shows cytoplasmic microfilaments with focal condensations, numerous pinocytotic vesicles, thick continuous basal lamina
Positive stains: actin, vimentin, myosin, desmin in smooth muscle cells only;
Benign vascular tumors
Hemangioma
Common benign tumor, particularly in childhood; many may actually be hamartomas
Usually superficial (head/neck), may occur internally (1/3 in liver), malignant transformation rare
Usually localized, but may involve large segments of body (termed angiomatosis)
Most pediatric angiomas are present at birth and expand with growth of child, may regress at puberty
Micro: increased number of vessels (normal/abnormal); readily recognizable vascular structures with red blood cells or transudate; lined by monolayer of non-atypical endothelial cells
Capillary hemangioma
Blood vessels resemble capillaries
Present in skin, subcutaneous tissue, mucous membranes of lips, mouth, internal viscera
Strawberry type is seen in juveniles in 1/200 births, may be multiple, grow in first year, fade at ages 1-3, regress by age 7 in 75%
Micro: closely packed spindle cells with spaces containing little blood; lumens may be thrombosed or organized, hemosiderin present due to rupture; scant fibrous stroma
Micro images: figures 1A, 1B
References: Mod Path 2000;13:180
Cavernous hemangioma
In skin, called port-wine nevus or nevus flammeus
Present at birth, grows slowly with patient; does not regress
In deep locations may thrombose, ulcerate, become infected; associated with thrombocytopenia, intravascular coagulation
Associated with von Hippel Lindau disease, which has cavernous hemangiomas in cerebellum, brain stem, eye grounds
Sinusoidal hemangiomas: cavernous hemangiomas with dilated, interconnected, thin-walled channels with occasional pseudopapillary projections
Gross: 1-2 cm (larger than capillary), sharply defined
Micro: large cystically dilated vessels with thin walls; intravascular thrombosis or calcification is common
Intramuscular hemangioma
Resemble cavernous hemangiomas
May resemble angiosarcoma due to high cellularity with mitotic figures, intraluminal papillary projections, plump endothelial cells, perineurial infiltration, but no atypia
Also, angiosarcomas extremely uncommon in skeletal muscle
Large vessel hemangioma
Veins, arteries or a mixture
May have abnormal vascular wall structure that defies classification
Back, gluteal region, thigh; occasionally entire extremity
Thrombosis and calcification common
Klippel-Trenaunay syndrome: varicose veins, dysplastic cutaneous hemangiomas and soft tissue and bone hypertrophy
Microvenular hemangioma
First described in 1991 (J Cutan Pathol 1991;18:235)
Rare, <50 cases reported
Presents as slow growing, solitary, asymptomatic, purple-red papule or plaque in young to middle-aged adults
Sites: often trunk or limbs
Case reports: Case of the Week #80, 40 year old woman (Dermatology 2003;206:161), 23 year old Japanese woman (Pathol Int 1998;48:237), HHV8+ microvenular hemangioma in case of POEMS syndrome (Archives 2003;127:1034)
Treatment: excision is curative
Micro: dermal proliferation of small, irregular branching capillaries and venules with inconspicuous lumina; endothelial cells may be plump, but no atypia; stroma is collagenous; no spindle cells
Micro images: image #1; #2; #3; HHV8+ tumor
Positive stains: endothelial cells - CD34 and Factor VIII related antigen; pericytes - smooth muscle actin
DD: patch stage Kaposi's sarcoma (has irregular vascular spaces, but they are anastomosing and not collapsed, and are accompanied by atypical endothelial cells, eosinophilic hyaline globules, plasma cells and fascicles of spindle cells; may be irregular dissection of collagen bundles by vessels; spindle cells are HHV8+, patients are HIV+, AJCP 2004;121:335); kaposiform hemangioendothelioma (also has slit-like lumina, but they are due to nodules and sheets of compact spindle cells; affects the skin or retroperitoneum of infants and children, may be associated with severe coagulopathy)
Pyogenic granuloma
Aka lobular capillary hemangioma
Rapidly growing, exophytic red nodule, attached by a stalk to skin or gingival mucosa
Bleeds easily, ulcerates
1/3 due to trauma (1-2 cm after 1-2 weeks)
Pregnancy tumor: aka granuloma gravidarum, a pyogenic granuloma found in 1% of pregnant women, regresses after delivery
Micro: vessels, edema, acute and chronic inflammation; resembles granulation tissue
Symplastic hemangioma
Bizarre stromal cells in fibrinous material around vessels
Intravascular papillary endothelial hyperplasia
Aka Masson’s tumor
Reactive, not neoplastic, representing exuberant organization and recanalization of thrombus
In normal vessels but also varices, hemorrhoids, pyogenic granulomas, hematomas, angiosarcomas
Dermis and subcutis of head and neck, lip, tongue, buccal mucosa
Case history of paranasal sinus lesion with erosion of surrounding bony structures , Archives 2000;124:1224
Pure type: within a dilated vascular space
Mixed type: with preexisting vascular disorder or in a hematoma
Gross: small, firm, red-blue superficial masses in skin
Micro: papillary formations with hyaline or fibrous stalks, anastomosing vascular channels, plump endothelial cells; residual organizing thrombi; intravascular lesion only; no necrosis, no atypia, no atypical mitotic figures
Micro images: image1, image2, image3
DD: angiosarcoma
Lymphangioma
May represent malformations due to failure of lymphatics to communicate with venous system
Large lymphatic channels in loose connective tissue stroma; focal disorganized smooth muscle in wall of larger channels; focal papillary endothelial proliferations; peripheral lymphoid aggregates
Benign
Capillary (simple)
Subcutaneous tissue of head, neck, axilla
1-2 cm; resembles capillary channels but no red blood cells
Cavernous (cystic hydroma)
Deep soft tissue
In children in neck, axilla; may extend into mediastinum
Up to 15 cm
Stroma may contain lymphocytes
Not encapsulated, so removal can be difficult
May cause fetal death due to hydrops
Associated with Turner’s syndrome or other chromosomal abnormalities
Lymphangiomatosis
Diffuse / multicentric lymphangiomas, often in thoracic cavity, also extremities, bone, viscera
Lymphangiomatous papules/plaques, post-radiation
Lymphatic counterpart of telangiectasias
Secondary to obstruction/destruction of lymphatic drainage, post-radiation therapy or idiopathic in elderly
In women, age 33-72
3-20 years after radiation therapy for breast (93%) or ovarian (7%) carcinoma
Clinical: multiple papules, small vesicles, or erythematous plaques in irradiated field
Benign behavior
Micro: irregular dilated vascular spaces with branching and anastomosing pattern in superficial dermis; thin walls, lymphatic appearance; vascular channels lined by single discontinuous layer of endothelial cells with flattened nuclei with numerous small stromal papillary formations also lined by endothelial cells projecting into lumina (lymphatic counterpart of intravascular papillary endothelial hyperplasia/Masson’s tumor)
May have poorly circumscribed and focally infiltrating irregular jagged vascular spaces involving the entire dermis, lined by inconspicuous endothelial cells, dissecting collagen bundles of the dermis, and mimicking Kaposi's sarcoma, AJSP 2002;26:328
Positive stains: CD31
Negative stains: CD34 (or focally positive), smooth muscle actin (no peripheral ring of stain characteristic of pericytes), Ki-67
Lymphangioendothelioma
Benign
Aka acquired progressive lymphangioma
No gender preference, median age 54 years, range 17-90 years
Occasional local recurrence
Clinical: solitary red or bruise-like slow growing plaque present for median 5.5 years; often in head and neck, but variable sites
Gross: median 1.5 cm, range 0.3 cm to 10 cm
Micro: delicate, thin-walled, endothelium-lined dilated vascular spaces involving the superficial dermis; intravascular papillary stromal projections resembles papillary endothelial hyperplasia; deeper portion of lesions have vascular space collapse and dissect collagen bundles, mimicking patch-stage Kaposi's sarcoma; preexisting vessels and adnexal structures of the dermis also appear dissected by newly formed vascular channels; vascular spaces lack erythrocytes and hemosiderin deposits; crowding of endothelial cells present, but no endothelial atypia; no mitotic figures
Positive stains: CD31, CD34, Factor 8
DD: Kaposi sarcoma (patch stage), well differentiated angiosarcoma
References: AJSP 2000;24:1047
Lymphangiomyoma
Benign, women only
Fka lymphangiopericytoma
Localized form present in mediastinum and retroperitoneum, associated with thoracic duct, causes chylothorax, chylous ascities and chyluria
Diffuse form is lymphangioleiomyomatosis (see lung)
Treatment: progesterone, oophorectomy
Micro: proliferation of intermingled blood vessels and smooth muscle; tumor cells plumper and paler than leiomyoma
Positive stains: actin, desmin, HMB45
DD: angioleiomyoma
Lymphangiosarcoma
Typically ~10 years post-axillary nodal dissection or radiation therapy for breast cancer with long-standing massive lymphedema
Also after chronic lymphedema of lower leg
5 year survival < 10%
Gross: blue/purple papules in edematous skin, often multiple
Micro: angiosarcoma-like areas and endothelium-lined spaces without red blood cells; early - resembles benign collection of vessels, call “atypical vascular proliferation”
later - freely anastomosing vascular channels lined by atypical endothelial cells, often with solid areas resembling breast carcinoma
Glomus tumor
Usually benign; excision curative
Subungual tumors are exquisitely painful due to abundant nerve fibers
Arises from modified smooth muscle cells of glomus body, a specialized arteriovenous anastomosis involved in thermoregulation
Usually under fingernails; also skin, flexor arm/knee, GI tract
Glomangioma: glomus tumors that resemble cavernous hemangiomas
Glomangiomatosis: diffuse angiomatosis resembling angiomatosis with excess glomus cells; often associated with considerable fat and pain; probably represents vascular malformations
Gross: less than 1 cm, rounded, red-blue, firm; resembles fresh hemorrhage under the nail
Micro: branching vascular channels separated by stroma containing glomus cells in nests, aggregates; glomus cells are arranged around vessels; have small, regular, round, indistinct nucleoli; more infiltrative in children; may have secondary myxoid change
Positive stains: smooth muscle actin, type 4 collagen, vimentin; CD34 in 20% only
Negative stains: cytokeratin, desmin
EM: resemble smooth muscle cells
Grading scheme for glomus tumors
All should have areas of typical glomus tumor, usually at periphery
References: AJSP 2001;25:1
Malignant glomus tumor (glomangiosarcoma)
Deep (to muscular fascia) and 2 cm or larger
OR atypical mitotic figures
OR moderate/high nuclear grade and 5+ MF/50 HPF
38% had metastases in one series, no metastases in symplastic, uncertain, glomangiomatosis
Symplastic glomus tumor
High nuclear grade only, may be degenerative
Glomus tumor of uncertain malignant potential
High (5+/50 HPF) mitotic activity and superficial
OR 2 cm+ only
OR deep only
Vascular ectasias
Localized dilation of preformed vessels
Hereditary hemorrhagic telangiectasia: aka Osler-Rendu-Weber syndrome; autosomal dominant disorder in which localized capillary dilation causes arterial blood to be shunted directly into postcapillary venules
from birth; dilated capillaries and veins are present over skin and mucous membranes of oral cavity, lips, respiratory, GI, GU; may bleed into gut, urine, nose; patients have mutations in two transforming growth factor -beta binding proteins including endoglin
Nevus flammeus: aka salmon patch; ordinary birthmark, usually on head and neck, represents dilated dermal vessels; usually regress
Port-wine stain: type of nevus flammeus; may grow proportionately with the child and thicken the skin surface; those in distribution of trigeminal nerve are associated with Sturge-Weber syndrome (encephalotrigeminal angiomatosis), a rare congenital disorder with venous angiomatous masses in leptomeninges over cortex, ipsilateral port-wine nevi, mental retardation, seizures, hemiplegia, skull radiopacities; attributed to faulty development of mesodermal and ectodermal elements
Spider telangiectasia: non-neoplastic vascular lesion, composed of radial, pulsatile array of dilated subcutaneous arteries or arterioles around a central core that blanches with pressure applied to its center
Usually on face, neck, upper chest of pregnant women and patients with cirrhosis; may be associated with hyperestrinism
Telangiectasias: group of abnormally prominent capillaries, venules and arterioles that creates a small focal red lesion, usually in skin or mucous membranes; congenital anomalies or exaggerations of preexisting vessels; not true neoplasms
Bacillary angiomatosis
First described in AIDS
Opportunistic infection of immunocompromised, manifesting as vascular proliferations in skin, bone, brains, other organs
Caused by infection with Bartonella species (gram negative rods), either Bartonella henselae (causes cat-scratch disease, reservoir in cats, vector is cat flea), B. quintana (cause of trench fever during WW I, reservoir is humans, vector is human body louse) or other species; transmitted via traumatic inoculation of skin
Bacillary peliosis: related vascular lesion of liver and spleen
Treatment: erythromycin
Gross: moist, eruptive, cutaneous lesion
Micro: acute neutrophilic inflammation with vascular proliferation and prominent endothelial cells with nuclear atypia and mitotic figures; nuclear dust and granular material (bacteria) present; bacteria highlighted by silver stain
DD: pyogenic granuloma, Kaposi sarcoma, angiosarcoma
Myopericytoma
Aka perivascular myoid tumor
Usually adults, youngest case was age 10
Cells with pericytic / myofibroblastic differentiation in a concentric arrangement around vascular lumens
May have hemangiopericytoma-like areas; rarely infiltrative
No giant cells
Low/intermediate grade vascular tumors
Giant cell angioblastoma
Rare, congenital/neonatal soft-tissue tumor, infiltrative but slow growing; appears to be benign
Hand, palate, scalp
Treatment: surgery, interferon-alpha
Gross: ulcerated tumors infiltrating soft tissue and bone
Micro: solid, nodular, and plexiform proliferation of oval-to-spindle cells with striking, concentric aggregation around small vascular channels; cells resemble undifferentiated mesenchymal cells, fibroblasts, myofibroblasts, pericytes; also large mononuclear and multinucleate giant cells with histiocytic features
Positive stains: CD68 (large mononuclear and multinucleate giant cells)
DD: giant cell fibroblastoma (CD34+, molecular rearrangements of #17 and #22), epithelioid hemangioendothelioma with osteoclast-like giant cells (Factor 8+ cells that don’t resemble oval-spindle cells of giant cell angioblastoma, no concentric aggregation around vessels), plexiform fibrohistiocytic tumor (children/young adults, no onion-skin layering of tumor cells around vessels), myopericytoma (older age group, no giant cells), bacillary angiomatosis (positive special stains for organisms, patients usually immunosuppressed)
References: AJSP 2001;25:185
Hemangioendothelioma
Intermediate grade vascular tumor with variable histologic features and clinical behavior
40% recur, 20% metastasize, 15% die of tumors
Positive stains: FLI-1 (nuclear stain, AJSP 2001;25:1061)
Composite hemangioendothelioma
Mixtures of various subtypes below, as well as angiosarcoma-like areas
Usually superficial dermis or subcutaneous in hands or feet
Median age 40 years, range 21-71 years
Recur locally, may metastasize, no deaths after median follow-up of 5 years
Must sample extensively to obtain correct diagnosis
References: AJSP 2000;24:352
Epithelioid/histiocytic hemangioendothelioma
Intermediate grade vascular malignancies that are closely associated with or arise from a vein in 50% of cases
Various organs and soft tissue including skin, lung (fka intravascular bronchioloalveolar tumor), liver, bone, stomach, lymph nodes, CNS, mediastinum
Unpredictable clinical course, but less aggressive than angiosarcoma
13% recur, 20-30% metastasize, 13% die of disease (AJSP 1997;21:363); for lung, mortality is 65%
Case reports: Case of the Week #77
Treatment: low grade tumors - wide local excision; high grade tumors - radical local excision with possible neck dissection
Micro: cords or small nests of round endothelial cells with abundant eosinophilic cytoplasm; tumors arising from vessels extend outward from the lumen towards soft tissue; tumor cells often have intracytoplasmic vacuoles representing small vascular lumina, which may resemble mucin; nuclei are round and may be indented; usually minimal mitotic activity, atypia or necrosis, but 25% of cases exhibit frank malignant features of prominent nuclear pleomorphism, mitotic activity, focal spindling or necrosis; stroma may be scanty or myxoid; may have peripheral inflammatory infiltrate with germinal centers and eosinophils, multi-nucleated giant cells
Micro images: low power - #1; #2; #3; #4; #5; CD31
Positive stains: vimentin, CD31, von Willebrand factor, keratin (30%, focal), reticulin (nests and cords of cells are invested by a reticulin sheath)
Molecular: occasional tumors may demonstrate t(1;3)(p36.3;q25) (AJSP 2001;25:684).
DD: metastatic carcinoma (more marked atypia, mitotic activity, usually not angiocentric, keratin+, CD31-), melanoma (S100+, HMB45+, CD31-), epithelioid sarcoma (distal extremities of young adults, tumor cells merge with collagenous stroma, keratin+ (strong), CD31-), epithelioid angiosarcoma (irregular sinusoidal vascular channels, solid sheets of cells with marked atypia and prominent mitotic activity, necrosis)
Endovascular papillary hemangioendothelioma
Aka Dabska’s tumor
Very rare tumor of children in skin or soft tissue
Good prognosis, with only rare nodal metastases
Micro: papillary tufts lined by plump endothelial cells (epithelioid- or histiocytic-like) within dilated vascular lumina; may have glomeruloid appearance
Micro images: figure 4A, 4B
Positive stains: vascular endothelial growth factor receptor-3
References: Mod Path 2000;13:180, AJSP 2001;25:1061
Kaposiform hemangioendothelioma
Rare, locally aggressive; tumor of infants and children; affects skin (75%), retroperitoneum (18%), bone
Death due to extensive disease and severe coagulopathy (Kasabach-Merritt syndrome), although no metastatic potential
Usually initial tumor is cutaneous
Micro: infiltrating nodules and sheets of compact spindle cells with formation of slit-like lumen
Micro images: figure 4C, 4D
Micro images: image1, image2, image3, image4
Positive stains: vascular endothelial growth factor receptor-3
DD: Kaposi's sarcoma
References: Mod Path 2001;14:1087, Mod Path 2000;13:180
Polymorphous hemangioendothelioma
<10 cases reported
Lymph nodes and soft tissue
Recurs locally, rare metastases
Micro: combinations of solid, primitive vascular and angiomatous patterns; uniform cytologic features; no epithelioid, spindle cell or angiosarcoma-like areas
Retiform hemangioendothelioma
Low grade variant of angiosarcoma
Usually distal extremities of young individuals
Weiss and Goldblum use term “hobnail hemangioendothelioma” for retiform and Dabska-type tumors, which they believe to be closely related
Rarely multiple (Am J Dermatopathol 1996;18:606)
2/3 recur, particularly without wide local excision; low rate of metastases, no tumor related deaths
Case reports: Case of the Week #107
Treatment: wide local excision;
Gross: lesion of reticular dermis and subcutaneous tissue
Micro: retiform (net-like, similar to rete testis) pattern of blood vessels that disperse through reticular dermis and subcutis; vessels lined by monomorphic hobnail endothelial cells with scant cytoplasm and rounded, naked-type nuclei; often prominent lymphocytic infiltrate; no epithelioid areas or cytoplasmic vacuoles (AJSP 1994;18:115)
Micro images: #1; #2; #3; #4; #5; CD31 #1; #2
Positive stains: endothelial cells - CD34 (strong), CD31, vWF
Negative stains: endothelial cells - keratin.
DD: angiosarcoma (may focally have low grade features, but also exhibits areas of marked atypia and pleomorphism; also dissects between individual collagen bundles and has mitotic activity), hobnail hemangioma (smaller, more superficial and more localized, with papillary dermal vessels that disappear into reticular dermis)
Spindle cell hemangioendothelioma
Any age, usually males, usually distal extremities
Low grade lesion: recur commonly and may be multicentric, but only one reported “metastases” after repeated recurrence and radiation therapy
May be a hamartoma due to aberrations in local blood blow; perhaps should be called spindle cell hemangioma
Associated with Mafucci’s syndrome
Gross: dermal or subcutaneous tumor
Micro: cavernous hemangioma and Kaposi sarcoma like features; cavernous spaces with solid areas composed predominantly of bland spindle cells, with a minor component of epithelioid, often vacuolated, endothelial cells, usually associated with irregular fascicles of smooth muscle fibers and adjacent malformed vessels
Positive stains: endothelial markers
Kaposi sarcoma
Subtypes: chronic, lymphadenopathic, transplant-associated, AIDS-associated
Vascular proliferative disorder mediated by inflammatory cytokines and angiogenic growth factors in patients with HHV-8 / Kaposi sarcoma associated herpesvirus infection, influenced by immune status
May originate from cell type capable of undergoing lymphatic differentiation based on D2-40 staining, a lymphatic specific marker (Mod Path 2002;15:434)
Usually limited to skin; may involve mucus membranes, visceral organs, lymph nodes
HHV-8 also positive in multicentric Castleman’s disease, primary effusion lymphoma, some multiple myeloma
Micro images: figures 1C, 1D; H&E and D2-40
Positive stains: FLI-1 (nuclear stain, AJSP 2001;25:1061), vascular endothelial growth factor receptor-3
DD: angiosarcoma (may have Kaposi-like features but is HHV-8 negative (Archives 2002; 126:191)
References: Mod Path 2000;13:180
Chronic/classic
Classic type seen in Europeans
Described by Kaposi in 1872
90% occur in older men from Eastern Europe, often Ashkenazic Jews; rare in US
Associated with second malignant tumor or altered immune state, but not with HIV
Multiple red-purple skin plaques or nodules in distal lower extremity, slowing increasing in size and spreading proximally
Locally persistent with remission and relapses, but usually stay localized to skin
Lymphadenopathic
Aka African endemic
Occurs in young Bantu children in South Africa (same population gets Burkitt lymphoma)
Presents with localized or systemic lymphadenopathy
Extremely aggressive disease; rarely is restricted just to lymph nodes; skin involvement is unusual
Transplant-associated
Occurs months to years after high-dose immunosuppressive therapy; 0.2-1.0% of kidney transplants
Skin or metastatic lesions present
Skin lesions may regress if immunosuppression is stopped
Usually fatal if spreads to viscera
AIDS associated (epidemic)
Historically, 40% of homosexual men with AIDS got Kaposi vs. 5% of others with AIDS
Incidence of Kaposi has been decreasing over time, Archives 2002;126:182
Early involvement of lymph nodes and gut and wide dissemination
Usually not a direct cause of death, although 1/3 develop lymphoma or another second malignancy
Gross: indolent disease has 3 stages: early - macule/patch, intermediate - plaque, late - nodule/tumor
Macule/patch: pink-purple macules of lower extremity or feet
Micro: dilated irregular blood vessels in background of lymphocytes, plasma cells, macrophages; resembles granulation tissue; disease spreads proximally, converts to raised
Micro images: image1
Macule/patch: superficial or mid-dermal proliferation of collagen-dissecting jagged capillary vessels with inconspicuous spindle cell component; may be confluence of vessels
Plaque: dermal, dilated, jagged vascular channels that dissect collagen fibers and contain isolated or small groups of spindle cells; red blood cell extravasation prominent; also hemosiderin laden macrophages, pink hyaline globules
Nodule/tumor: more distinctly neoplastic, most of lesion composed of spindle cells with intersecting fascicle like pattern in a background of inflammatory cells and red blood cells; small vessels and slitlike spaces with hyaline droplets and rows of red blood cells; mitotic figures common; may involve lymph nodes and viscera (African and AIDS variants)
Positive stains: smooth muscle actin
Negative stains: Factor 8
Molecular: detect HHV8 by PCR or in-situ hybridization
References: Mod Path 2002;15:434
High grade vascular lesions
Angiosarcoma
Well differentiated (hemangiosarcoma) to anaplastic tumor resembling melanoma or carcinoma
Older adults, skin (scalp, face), soft tissue, breast, liver, bone, spleen
May arise from inferior vena cava, pulmonary artery, aorta (usually undifferentiated, solid, difficult to identify as endothelial)
Arises from endothelial cells of blood vessels
Treatment: early surgery, but survival >5 years is rare
Risk factors: chronic lymphedema, sun exposure, radiation, Thorotrast, PVC
Nodal metastases in 14% of cases (high rate for sarcomas); also metastases to lungs, liver, bone
Breast: 3-12 years after radiation therapy for carcinoma; incidence is 1 per 1000-2000; usually in women age 60+ with low grade, low stage lesions; poor prognosis with 41% 3 year survival
Extremities: associated with lymphedema ~ 10 years after radical mastectomy for breast cancer, arising from dilated lymphatics (lymphangiosarcomas, aka Stewart-Treves syndrome), not associated with radiation therapy
Kidney: case report of renal angiosarcoma, Archives 2002;126:478
Liver: associated with arsenic, Thorotrast, PVC; latent period of years
Also associated with radiation to other sites, introduction of foreign material
Lung: rarely presents as diffuse pulmonary hemorrhage due to metastases in young adults, Archives 2001;125:1562; lung metastases often multiple peripheral nodules accompanied by infiltrates, primary tumor usually not identified at presentation; tumor cells may have minimal atypia, may be keratin positive, primary site of lung metastases is often the heart, Mod Path 2001;14:1216;
Skin: Cases related to chronic lymphedema are usually in extremities; lymphedema due to radical mastectomy, postfilarial, congenital; cases unrelated to lymphedema are often in head and face
Case report associated with chronic lymphedema due to morbid obesity, Archives 2001;125:531
Gross: early - small, sharply demarcated, asymptomatic, multiple red nodules
late - fleshy, gray-white with hemorrhage, necrosis, deeply invasive
Gross image: Figure 1A
Micro: atypical vascular spaces lined by endothelial cells with cytologic atypia, multilayering; in more solid areas are intracytoplasmic lumina containing red blood cells; involves subcutaneous tissue; variable grade; multinucleated cells may have prominent hyaline globules containing alpha-1-antitrypsin and alpha-1-antichymotrypsin; post-radiation lesions usually high grade
Micro images: image1, image2, image3, image4, image5
Micro images: lung metastases - image1, image2, image3, image4, image5, image6
FNA images: image1
Positive stains: Factor 8 related protein, CD31, Ki-67, FLI-1 (nuclear stain, AJSP 2001;25:1061), thrombomodulin, CD34 (not specific), c-kit (50%)
DD: atypical vascular lesions (circumscribed, no atypia, no mitotic figures), hemangiomas (usually < 2 cm, well circumscribed, contain fibrous septa and thick-walled vessels, not invasive), MFH (intratumoral macrophages from non-vascular tumors may be CD31+, AJSP 2001;25:1167, image), florid vascular proliferation of colon due to intussusception, Mod Path 2001;14:1114
References: Mod Path 2000;13:180
Epithelioid angiosarcoma
Positive stains: CD34, keratin
References: AJSP 2001;25:1061
Hemangiopericytoma (HPC)
Adult tumor, usually deep-seated, often in thigh, pelvic retroperitoneum, orbit
Derived from pericytes, cells normally arranged around capillaries and venules
Slowly enlarging, painless mass, usually thigh, lower extremity, retroperitoneum
20-50% metastasize to lungs, liver, bone
Gross: 4-8 cm, solitary, solid, gray/white to red/brown; hemorrhage, necrosis, cystic degeneration common; usually well-circumscribed or encapsulated
Micro: branching capillary channels, large gaping sinusoidal spaces (“staghorn” configuration) surrounded by spindle shaped cells; may have extensive fibrosis, hyalinization, myxoid change
Positive stains: with silver stain, spindle cells are outside the endothelial basement membrane and hence are pericytes, not endothelial cells; vimentin
Negative stains: trichrome (no myofibrils), desmin, actin
EM: pericytic features (cytoplasmic filaments and processes, pinocytotic vesicles, basal lamina, poorly formed intercellular junctions)
Molecular: 12q13-15 alterations in some cases
DD (HPC vascular pattern): mesenchymal chondrosarcoma (islands of mature cartilage), synovial sarcoma, infantile fibrosarcoma, MFH, solitary fibrous tumor, MPNST, thymoma (epithelial foci)
Variants:
Infantile/congenital hemangiopericytoma
Typically superficial, multilobulated
Benign behavior
Micro: immature cytology, frequent mitotic figures, necrosis, possibly neoplastic endothelial cells
Lipomatous hemangiopericytoma
HPC with myxoid and sclerotic areas and islands of mature adipose tissue
Phosphaturic mesenchymal tumor
HPC areas associated with osteoclast-like cells, cartilage
Peripheral Nerve Tumors
Nerve - normal
Composed of axons, Schwann cells, perineurial cells and fibroblasts in epineurium (outer sheath)
Perineurium: surrounds each nerve fascicle, is continuous with pia mater of CNS
Perineurial cells: derived from fibroblasts; EMA+, S100-
Schwann cells: neuroectodermally derived cells that resemble fibroblasts, but strongly S100+, intimately related to axons (by EM), have continuous basal lamina that coats the cell facing the endoneurium
Malignant peripheral nerve sheath tumor (MPNST)
Aka malignant schwannoma, MPNST
Bulky deep-seated tumor usually arising from major nerves in neck, forearm, lower leg, buttock
50% associated with neurofibromatosis (NF), 50% arise de novo
May be due to radiation; rarely arise from ganglioneuromas
Usually adults, also children
High clinical suspicion for MPNST if NF1 patient or tumor arising within anatomic component of a major nerve or contiguous with neurofibroma
Recur locally, distant metastases frequent
Plexiform variant in children has better prognosis, otherwise cannot predict prognosis
Gross: large mass producing a fusiform enlargement of a major nerve (often sciatic)
Micro: monomorphic serpentine cells, palisading, large gaping vascular spaces, perivascular plump tumor cells, geographic necrosis with tumor palisading at the edges (resembles glioblastoma multiforme)
frequent mitotic figures; may have bizarre cells; 15% have metaplastic cartilage, bone, muscle
May have glandular differentiation (positive for keratin, EMA, CEA, chromogranin); if so, presume malignant
May have melanin in tumor cells, particularly if arise from spinal nerve roots (overlaps with primary melanoma of nerves)
Note: some have no discernable Schwannian features at any level
Micro images: image1
Micro images: post-implant
Positive stains: S100 (62%), Leu7/CD57 (in neurofibroma-like areas), p53, CD57 (55%), collagen IV, CD99/O13 (86%), protein gene product 9.5 (Archives 2001;125:1321, but PGP9.5 not specific)
Negative stains: EMA (usually), keratin (usually), CD19
Molecular: t(X;18) negative, Mod Path 2002;15:589
EM: infoldings of cell membrane with lamellar configuration, discontinuous basal lamina, conspicuous intercellular junctions, occasional dense-core granules
DD: pleomorphic liposarcoma, MFH, synovial sarcoma
Epithelioid MPNST
5% of MPNST
Plump epithelioid cells with acidophilic cytoplasm
Most neurofibromas with malignant transformation are epithelioid, but most epithelioid MPNST are NOT associated with NF1
Positive stains: HMB45 (DD: desmoplastic melanoma), protein gene product 9.5 (Archives 2001;125:1321, but PGP9.5 not specific)
Negative stains: S100 (often)
DD: epithelioid angiosarcoma (CD31+, CD34+, vWF+, S100-), melanoma
Malignant triton tumor
MPNST with well developed skeletal muscle
Myxopapillary ependymoma
Usually spinal cord tumor, may arise is soft tissue in sacrococcygeal area separate from cord
Resembles pilonidal cyst clinically, but 20% metastasize
Gross: well circumscribed , easily enucleated
Micro: resembles CNS tumor; small blue cells forming well defined perivascular structures, surrounded by dense fibrous tissue
DD: ependymal rests (clusters of cells < 0.5 cm in dermis/subcutaneous tissue near pilonidal sinuses)
Nerve sheath myxoma
Controversial tumor
Skin, soft tissue, intraspinal
Resembles myxoma but plumper, epithelial-like cells; fascicular or plexiform arrangement
May be similar to neurothekeoma
DD: perineurioma, myxoid neurofibroma (S100+)
Neurofibroma
Solitary tumor suggests patient does NOT have neurofibromatosis type 1
Malignant transformation rare in sporadic neurofibromas
Gross: not encapsulated, softer (more gelatinous) than schwannoma
Superficial tumors are small, pedunculated nodules protruding from skin (molluscum pendulum)
Deeper tumors are larger, may cause tortuous enlargement of peripheral nerves (plexiform neurofibromas)
Micro: Non-encapsulated; proliferation of all elements of peripheral nerves; Schwann cells with wire like collagen fibrils (wavy serpentine nuclei, pointed ends), stromal mucosubstances, mast cells, Wagner-Meissner corpuscles, Pacinian corpuscles, axons (highlight with silver or acetylcholinesterase stain, NSE, neurofilament), fibroblasts and collagen; perineurial cells in plexiform types, mitotic figures are rare; may be infiltrative; less of a fascicular pattern than fibromatosis
May have myxoid areas; no Verocay bodies, no nuclear palisading, no hyalinized thickening of vessel walls
Rarely has skeletal differentiation (neuromuscular hamartoma)
Positive stains: S100, CD34+ (focal), Factor 13a (focal)
Negative stains: EMA (except in plexiform neurofibromas)
EM: Schwann cells enclose axons in plasmalemmal invaginations (mesaxons)
DD (myxoid areas): myxoma, myxoid liposarcoma
Diffuse cutaneous
Traps adnexa, infiltrates into fat
Focal cutaneous
Intraneural
Pacinian
Prominent Pacinian corpuscles
Pigmented
DD: blue nevi, melanoma
Plexiform
Twisted, complex, large if deep
May be too big to resect
5% transform to MPNST, higher rate than classic neurofibromas, usually large tumors attached to major nerve trunks in neck or extremities
Sites: orbit, neck, back, inguinal
Positive stains: EMA (perineurial cells, not in ordinary neurofibromas)
Neurofibromatosis type 1
von Recklinghausen disease, NF1
Defect in neurofibromin gene at 17q11.2; protein is a widely expressed tumor suppressor gene with highest levels in neural tissue that downregulates p21 ras oncoprotein; numerous sites of mutation in the gene; variable phenotypic expression
1/3000 individuals, 50% from autosomal dominant inheritance, 50% are new mutations
2-4x increased risk of other tumors (ganglioneuromas, pheochromocytomas, meningiomas, rhabdomyosarcoma, childhood CML)
5-13% develop MPNST
Clinical: (1) multiple neurofibromas (plexiform, solitary), (2) 6 or more cafe au lait spots over nerve trunks, 1.5 cm or larger; (3) Lisch nodules (pigmented iris hamartomas, 94% by age 6); (4) unilateral acoustic neuromas (schwannomas), optic nerve gliomas, plexiform neurofibromas (relatively specific), skeletal lesions (30%-spinal deformities [kyphoscoliosis], bone cysts); also congenital malformations, megacolon, fibrosing alveolitis, lipoma, carcinoid tumor, GIST, Wilm’s tumor; increased nerve growth factor
Cafe au lait spot: increase in melanin in epidermal basal layer, may overlie a neurofibroma, smooth delicate margins; solitary café au lait spots are normal
DD of cafe au lait spots: Albright’s syndrome (polyostotic fibrous dysplasia of bone, patchy dermal pigmentation, endocrine dysfunction)
Neurofibromatosis type 2
Aka NF2, aka acoustic neurofibromatosis
Autosomal dominant, 1/40K incidence
Mutation in merlin gene at 22q12; similar to cytoskeletal protein; function unknown but protein widely distributed
Nonsense mutations usually more severe than missense mutations
Signs/symptoms: bilateral acoustic neuromas or multiple meningiomas, spinal cord ependymomas; also schwannosis (ingrowth of Schwann cells into cord), meningioangiomatosis (meningeal cells and blood vessel proliferation into the brain), glial hamartia (microscopic nodular collections of glial cells in cerebral cortex); cafe au lait spots, but no Lisch nodules
Neuroma
Benign nonneoplastic overgrowth of nerve fibers and Schwann cells
Usually post-traumatic; proximal nerve regenerates and if it fails to meet the distal end, a tangled mass of nerve fibers results
Painful
Micro: axons, Schwann cells, perineurial fibroblasts, also scar
Positive stains: CD68 (Schwann cells-become phagocytic)
Amputation neuroma
Due to partial/total amputation
Granular cell traumatic neuroma
Case report of 2 lesions in mastectomy scars with features of both granular cell tumor and traumatic neuroma at Archives 2000;124:709
Micro: nests of large granular cells, in background of fibrous tissue with sparse inflammatory infiltrates; several tortuous hypertrophic nerve bundles were embedded in fibrous tissue, some with degenerative changes and containing granular cells
Micro images: image1
Positive stains (granular cells): S100, NSE, vimentin, CD68
Morton’s neuroma
Aka Morton’s metatarsalgia
More common in adult women
Due to repeated mild trauma to interdigital plantar nerve, usually between toes 3 and 4
Gross: affected nerve is markedly distorted
Micro: extensive concentric perineurial fibrosis, thickened arterioles with thrombi
Palisaded encapsulated neuroma
Aka solitary circumscribed neuroma
Small, solitary, asymptomatic skin papule, in face of middle-aged
Micro: dermal lesion with proliferation of Schwann cells (S100+) and axons (neurofilament+), encapsulated by perineurium (EMA+)
Perineurioma
Uncommon, benign tumor of peripheral nerve composed primarily of perineurial cells, first described in 1978
Adults, more common in females
Extremities and trunk most common sites
Gross: well circumscribed, variable size, usually NOT associated with a nerve
Micro: bland, elongated cells in parallel bundles, resembles neurofibroma or pacinian neurofibroma; may have storiform growth; no atypia, rare mitotic figures; suspect if myxoid lesion of soft tissue with storiform or fascicular growth pattern; may have collagenous stroma with pericellular cracking / clefting
Positive stains: EMA, CD34 (33%)
Negative stains: S100
EM: non-branching, thin cytoplasmic processes, coated by external lamina, joined at ends by tight junctions, few organelles, actin and vimentin filaments, numerous pinocytotic vesicles
Molecular: monosomy 22, deletion of 22q11-13.1
Reticular variant
Median age 43, range 34-61, 2/3 women in small study
Upper extremity, gingiva, inguinal region
Appears to have benign behavior
Gross: median 4 cm, range 1.5 to 10 cm
Micro: lace-like or reticular (“net-like”) growth pattern of anastomosing cords of fusiform cells with bipolar cytoplasmic processes and palely eosinophilic cytoplasm; central nuclei; all cases had transitions to more cellular areas; collagenous to myxoid stroma; cystic areas common; no mitotic figures; mild/moderate nuclear atypia (may be degenerative)
Positive stains: EMA, alcian blue (myxoid stroma)
Negative stains: S100
DD: myoepithelial tumors (variable S100+, keratin; acinar or ductal component), extraskeletal myxoid chondrosarcoma (deep seated tumor, subfascial or intramuscular, cord/lace like architecture, larger cells with abundant eosinophilic cytoplasm, no microcystic change, typical t(9;22)), myxoid synovial sarcoma (deep soft tissue, younger age group, more nuclear atypia, EMA+, CK+, CD99+, bcl2+)
References: AJSP 2001;25:485
Sclerosing perineurioma
Usually small tumors in dermis of hands
Pigmented neuroectodermal tumor of infancy
Aka melanotic progonoma, retinal anlage tumor
Maxilla, also mandible, skull, other bones, mediastinum, soft tissues, epididymis
Usually benign, rare recurrent and metastatic tumors
Micro: small round tumor cells resembling neuroblasts in pseudoglandular or alveolar patterns, lined by larger cells with cytoplasmic spiculated melanin
Positive stains: large cells - keratin, HMB45; small cells - NSE
Negative stains: S100 (despite neural origin)
EM: melanosomes in large cells, neurosecretory granules and cytoplasmic processes in small cells
DD: neuroblastoma
Schwannoma
Aka neurilemoma
Encapsulated biphasic nerve sheath tumor derived from Schwann cells with highly ordered cellular component (Antoni A) that palisades (Verocay bodies), plus myxoid component (Antoni B)
Small tumors may be all Antoni A
Recurrence rare, so attempt to preserve the nerve if clinically significant
Ages 20-50; M=F
Head, neck, flexor upper and lower extremities, retroperitoneum, posterior spinal roots, cerebellopontine angle
May be due to alteration/loss of NF2 gene product
Slow growing; no symptoms until becomes large; may wax and wane in size
Pain or rapid enlargement of preexisting lesion are suggestive of malignant change
Dumbbell tumor – in posterior mediastinum, originates from or extends into vertebral canal
Gross: usually solitary; large tumors may be cystic; nerve of origin present in periphery - does not penetrate substance of tumor
Micro: large irregularly spaced vessels are most prominent in Antoni B areas; gaping tortuous lumina have thickened hyalinized walls and may have thrombus; tumor cells have dense chromatin, ill defined cytoplasm; rare mitotic figures, no axons except where nerve is attached; may have foamy macrophages; often displays degenerative nuclear atypia (ancient change); rarely have plexiform, glandular (may be entrapped sweat glands), pigmented, epithelioid areas or rosettes; amianthoid fibers or collagenous spherules: large nodular masses of collagen with radiating edges
Positive stains: EMA (capsule), S100 (Schwann cells), calcinurin, laminin, type 4 collagen, vimentin, CD68, GFAP
Negative stains: keratin, neurofilament, desmin
EM: elongated cells with continuous basal lamina, thin cytoplasmic processes, aggregates of intracytoplasmic microfibrils, peculiar intracytoplasmic lamellar bodies, extracellular long-spacing collagen; contains lipid
DD palisading patterns: leiomyoma, leiomyosarcoma, fibrous histiocytoma, calcifying aponeurotic fibroma, appendiceal smooth muscle
Ancient Schwannoma
Degenerative change to tumors, usually large and of long duration, deep within retroperitoneum
Cyst formation, calcification, hemorrhage (stromal hemosiderin), hyalinization, histiocytic infiltration, severe nuclear atypia (nuclear hyperchromasia, irregular nuclear shapes)
No mitotic figures
Cellular schwannoma
Primarily Antoni A areas without Verocay bodies; usually in retroperitoneum, pelvis, mediastinum;
May have nuclear atypia and focal necrosis
0-3 mitotic figures/10HPF; 5% recur, no metastases
Malignant transformation
Occurs even without neurofibromatosis, tumors usually have epithelioid features
Sites: limb, limb girdles or head/neck; contain areas of benign schwannoma
Transform to MPNST, angiosarcoma or epithelioid malignant change (EMC)
References: AJSP 2001;25:13
Epithelioid malignant change large epithelioid cells with abundant eosinophilic cytoplasm, vesicular chromatin, prominent nucleoli, resembles epithelioid MPNST; strongly S100+
May recur locally, may be a precursor lesion to MPNST since younger age than MPNST
Suggest sign out as “atypical schwannoma with epithelioid cells”
References: AJSP 2001;25:13
Criteria for MPNST in schwannoma: benign schwannoma present, no primary tumor that may have metastasized to schwannoma, histologically malignant cells resembling epithelioid MPNST; 5 year survival < 20%
References: AJSP 2001;25:13
Criteria for angiosarcoma in schwannoma: benign schwannoma present, transition to angiosarcoma (irregular vasoformative structures lined by multilayered cells with nuclear atypia or atypical endothelial cells with a solid growth pattern); cytoplasmic staining for CD31, CD34 or vWF
DD: pleomorphic hyalinizing angiectatic tumor (PHAT)
References: AJSP 2001;25:13
Pigmented schwannoma
Pigmented tumor cells have widely scattered, coarse pigment, reactive with Fontana Masson stain (melanin stain), nonreactive with Prussian blue (iron stain)
Positive stains: S100 (strong), vimentin, Fontana Masson
Negative stains: Prussian blue, tyrosinase, HMB45
References: Archives 2002;126:816
Plexiform schwannoma
Only 5% of schwannomas
Pattern not strongly associated with neurofibromatosis 1 or 2
Usually superficial, in dermis or subcutaneous tissue
Case reports: Case of the Week #50
Micro: plexiform architecture with nuclear palisading; biphasic pattern may not be prominent; often cellular with hyperchromatic nuclei and mitotic activity; no necrosis, no myxoid change
Micro images: plexiform architecture; nuclear palisading; cellular areas
Positive stains: S100 (strong staining of nodules but not intervening stroma)
DD: plexiform neurofibroma (early childhood, associated with neurofibromatosis type 1; found with grossly enlarged and tortuous nerves; hypocellular with myxoid background; no biphasic pattern; may occasionally show nuclear palisading; S100+ but only scattered cells); MPNST (may be multinodular, S100 weak/negative, should be sampled extensively to rule out a plexiform schwannoma, AJSP 2005;29:1042)
Psammomatous melanotic schwannoma
Part of Carney’s syndrome of functioning extra-adrenal paraganglioma, gastric epithelioid leiomyosarcomas, lung hamartoma
Arises from spinal nerve roots
Low grade malignancy: recurs locally, rarely metastasizes
Tumors of Uncertain Histogenesis
Alveolar soft parts sarcoma
0.5-1.0 % of all soft tissue tumors
Tumor of deep soft tissues of thigh/leg, oral cavity, pharynx, mediastinum, elsewhere
Usually young females
Highly malignant, although clinical course is slow/indolent
Metastases up to 30 years later to veins, lungs, other
Lung metastases may be presenting feature
Prognostic variables: size, presence of 17q25 abnormality
Gross: well circumscribed, large, gray-yellow, hemorrhage, necrosis
Micro: well defined nests of cells separated by fibrous stroma; alveolar pattern if cells discohesive; composed of large polygonal cells with granular eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli; no/rare mitotic figures, minimal pleomorphism; also characteristic rod-shaped crystalloids
Micro images: figure 6
Positive stains: PAS positive, diastase resistant needle-like structures, MyoD1 (cytoplasmic only)
Molecular: changes in #1, 5, 13, 17
EM: membrane-bound crystals with periodicity of 58-100 nm and cross grid pattern; numerous electron dense vesicles near Golgi; smooth tubular aggregates associated with plasmalemmal invaginations; no features of skeletal muscle differentiation
Clear cell sarcoma
Aka melanoma of soft parts
Rare aggressive tumor of adolescents / young adults
Deep location, tends to occur near tendon, fascia or aponeuroses
Slow progression, frequent local recurrences; eventually nodal and distant metastases
Gross: firm, well circumscribed, gray-white, gritty sensation when cutting
Micro: distinctly nested growth pattern with mixed of spindle, epithelioid and tumor giant cells; melanin pigment in 2/3; may have floret-like multinucleated giant cells
Micro images: image1, image2, figure 7
Positive stains: S100, HMB45, microphthalmic transcription factor (75%), melanoma-cell adhesion molecule, MelanA (43%), iron (intra- and extracellular), Leu7/CD57, vimentin, keratin (variable)
Molecular: t(12;22)(q13;q12) - ATF1 and EWS (not seen in melanoma); usually diploid or less aneuploidy than metastatic melanoma to soft tissue
EM: melanosomes
DD: melanoma
References: Mod Path 2001;14:6
Epithelioid sarcoma
Uncommon, usually mass in deep soft tissues of distal extremities of young adults, often hand, M/F = 2:1
“Carcinoma of soft tissue”, like synovial sarcoma and adamantinoma of soft tissue
Typically recur, metastases in 45% of cases; usually to lungs, skin (including scalp), lymph nodes
Frequently underdiagnosed
May derive from mesenchymal cells undergoing epithelial differentiation
Poor prognostic features: proximal/axial tumor, large size, deep tumor, hemorrhage, mitotic figures, necrosis, rhabdoid features, angiolymphatic invasion
Treatment: excision, radiation therapy
Micro: epithelioid tumor cells in granuloma like fashion around areas of necrosis and central hyalinization; striking acidophilic tissue due to cytoplasmic staining and desmoplasia; tumor usually in reticular dermis, sometimes deeper soft tissue around fascial plans, aponeuroses, tendon sheaths
Positive stains: keratin, EMA, vimentin, CD34 (Histopathology 1998;33:425), rarely CD31 (Virchows Arch 2003;443:93)
Negative stains: factor VIII related antigen (Virchows Arch A Pathol Anat Histopathol 1987;410:309)
Molecular: usually DNA copy number changes, gains > losses, including +11q13, 1q21-q23, 6p21.3, 9q31-qter, losses at 9pter-p23, 13q22-q32, others (Mod Path 2000;13:1092)
EM: abundant intermediate filaments, desmosome-like junctions, small intercellular spaces with microvilli
DD: granuloma (due to necrosis)
Cutaneous
Confined to skin or subcutaneous fat, with little/no involvement of deep soft tissues
20% have history of prior trauma
Accurate diagnosis usually established only after repeated biopsies
Gross: ulcerated papule or nodule on distal extremity of young adult
Micro: pseudogranulomatous pattern, bland cytology; monomorphous cell population; hyalinized focally calcified stroma; mummified remnants of necrotic epithelioid cells present
Micro images: image1 (4A-vimentin, 4B-EMA)
Positive stains: keratin, EMA, vimentin
DD: granulomatous inflammation
References: AJSP 2001;25:1061
Proximal type
First described in 1997 (AJSP 1997;21:130)
Arises in soft tissue of proximal limbs or trunks
Frequently with epithelioid features and rhabdoid phenotype
Worse prognosis than “distal” type (Mod Path 2001;14:655, free full text)
May be variant of extrarenal malignant rhabdoid tumor
Aggressive behavior; metastases frequently lead to death
Case reports: Case of the Week #69; scrotum - Eur Urol 2006;49:406, Diagn Cytopathol 2001;24:36
Gross images: pubic tumor with ill defined multinodular masses
Micro: composed primarily of large epithelioid cells with more atypia than classic epithelioid sarcoma; resembles rhabdoid tumor due to intracytoplasmic hyaline inclusions; large areas of necrosis and a multinodular pattern are common, but a granuloma-like pattern is uncommon
Micro images: sheets of large round/polygonal cells with prominent nucleoli (A) and aggregates of rhabdoid cells (B); large areas of necrosis; granuloma-like pattern #1; #2; rhabdoid cells; infiltrative margins; angiomatoid appearance; keratin, CD34, neurofilament and p53; EMA; CD34; PLAP negative
Positive stains: keratin, EMA, vimentin; variable desmin, CD34 and smooth muscle actin
Negative stains: S100
DD: epithelioid MPNST (S100+, rarely EMA+, keratin negative), epithelioid angiosarcoma, melanoma (S100+, usually HMB45+)
Fibrous hamartoma of infancy
Tumorlike condition in newborns to 2 year olds
Usually boys, in shoulder, axilla or upper arm
Benign, although may recur locally
Gross: solitary, poorly circumscribed, gray/white fibrous tissue and adipose tissue
Micro: mixture of well differentiated spindle cells resembling fibroblasts or myofibroblasts surrounded by collagen, mature adipose tissue, primitive mesenchyme in whirls
Positive stains: vimentin (fibrous and mesenchyme areas), actin/desmin (spindle cell areas)
Granular cell tumor
Classic location is tongue, also most other tissues
Blacks may have multiple lesions
Congenital tumors occur in gingiva, but are rare; occasionally congenital tumors are systemic
Usually benign, although malignant tumors also look benign; those that appear malignant may be alveolar soft part sarcomas
May reflect degenerative change that can occur in Schwann cells, smooth muscle cells or tumors
Gross: hard, ill defined margins, usually < 5 cm, may be ulcerated, may appear malignant
Micro: large cells with highly granular cytoplasm, small regular granules plus larger eosinophilic PAS+ round droplets; associated with secondary epithelial hyperplasia when grow near an epithelial surface; may see stromal elastosis
Positive stains: S100 (nuclear and cytoplasmic), acid phosphatase, luxol fast blue, PAS
EM: granules resemble lysosomes, also angulated bodies with Gaucher cell-like appearance, replicated basal lamina around granular cells
Malignant giant cell tumor of soft parts
Rare, adults/elderly, usually in extremities
Usually deep
Deep tumors more likely to recur or metastasize
Micro: nodular at low power; osteoclast-like multinucleated giant cells and neoplastic stromal cells resembling fibroblasts or histiocytes; prominent vasculature; resembles giant cell tumor of bone
Myxoma
Rare, benign mesenchymal tumor, resembles fetal umbilical cord
Usually solitary, multiple myxomas associated with McCune-Albright syndrome (polyostotic fibrous dysplasia) and Carney's syndrome
Usually adults, females > males
Often in skeletal muscle of thigh
Question diagnosis if : not intramuscular or juxta-articular, more than occasional vessels, hypercellular, atypia, mitotic activity
Treatment: excision is curative
Gross: mucoid, poorly circumscribed, may have infiltrative borders
Micro: hypocellular, composed of bland cells, no mitotic activity, no lipoblasts, scantly blood vessels; may have focal histiocytes
Positive stains: vimentin
Negative stains: S100, desmin
EM: fibroblast-like cell with prominent Golgi, endoplasmic reticulum, cytoplasmic filaments
DD: tumors with myxoid features/subtypes (liposarcoma, MFH, chondrosarcoma, leiomyoma, leiomyosarcoma, embryonal rhabdomyosarcoma, neurofibroma, aggressive angiomyxoma [female genital tract, vascular, not associated with skeletal muscle]), focal mucinous degeneration of skin / soft tissues (nodular fasciitis, myxedema, cyst, ganglion, mucinosis)
Cardiac myxoma
Pedunculated masses, usually attached to left atrial wall by a pedicle; more vascular and cellular than other myxomas; may embolize; may arise from endocardial subendothelial cells
Carney complex associated
Carney complex: autosomal dominant disorder with multiple cardiac and skin myxomas, spotty pigmentation of skin, endocrine overactivity (pigmented nodular adrenocortical disease, large cell calcifying Sertoli cell tumor of the testis, pituitary adenoma), blue nevi, psammomatous melanotic schwannoma, bone tumors
Fibromyxomas
Myxomas of bone
Rare; well circumscribed lytic lesions of metaphysis, usually femur, pelvis, tibia
Intramuscular myxoma
Painless, slow growing mass within large muscle groups of thigh, shoulder, pelvis
Usually women 40-60
Cell of origin may be fibroblast incapable of producing mature collagen that produce mucopolysaccharides instead
Micro: stellate or spindle cells with poorly defined cytoplasm, myxoid stroma; minimal pleomorphism or mitotic activity
Jaw myxomas
Odontogenic origin, frequently recur
Mazabraud's syndrome associated
Syndrome rare, associated with soft tissue myxomas (multiple, intramuscular, right side of body), usually polyostotic dysplasia precedes the myxomas; may be associated with McCune-Albright syndrome also
DD: chondrosarcoma (bone or soft tissue tumor that resembles chordoma with rows of cuboidal cells separated by myxoid background; S100+, vimentin+, keratin-); myxoid leiomyosarcoma (rare; gelatinous, well circumscribed; invasive, highly myxomatous; see typical smooth muscle cells alternating with mesenchymal cells), liposarcoma (commonly in thigh / lower extremities; few mitotic figures but see lipoblasts, matrix contains lipopolysaccharides and matrix; prominent vascular component; t(12;1)(q13;p11)), myxoid MFH
DD of large retroperitoneal tumor: liposarcoma, MFH, leiomyosarcoma
Ossifying fibromyxoid tumor
Adults
Small, painless mass in extremities
Usually indolent, local recurrences in 25%, rare malignant behavior
Gross: well circumscribed, subcutaneous tissue or muscle
Micro: nests/cords of round/oval cells in myxoid matrix with fibrosis and osteoid formation; lobulated at low power; surrounded by partial capsule of mature bone; minimal atypia, minimal mitotic figures
Positive stains: S100, vimentin, Leu7/CD57 (focal), GFAP (focal)
EM: complex cell processes, basement membrane deposition
Rhabdoid tumor
Kidney, soft tissues and other sites
Usually infants/children
Probably represents emergence of an aggressive phenotype of various tumors (epithelioid sarcoma, intraabdominal desmoplastic round cell tumor, rhabdomyosarcoma, melanoma, carcinoma)
Early metastases to lung, liver, lymph nodes
Very aggressive, poor response to therapy, usually fatal
Micro: solid sheets of large cells with deep eosinophilic cytoplasm, possible laterally displaced nucleus, prominent nucleoli; myxoid, hyalinized, pseudoalveolar areas
Positive stains: vimentin, keratin, EMA
Negative stains: S100, muscle markers
EM: prominent intermediate filaments
Synovial sarcoma
Usually a deep seated mass present for years around large joints (80% in knee and ankle) in young adults (age 20-40); only 10% actually involve the joint
Represent 10% of adult soft-tissue tumors
5 year survival is 50-70%; 10 year survival 40%; recurs locally, 10-15% metastasize to lung and pleura, bone, regional nodes
M/F = 1.5:1
Tumor cells detected in peripheral blood monocytes in one case by nested PCR (AJSP 2001;25:406)
May be radiation associated, Mod Path 2002;15:998
Poor prognostic factors: high histologic grade based on MIB-1 index and necrosis associated with lung metastases, Hum Path 2001;32:257, SYT-SSX1 vs. SYT-SSX2 gene fusion, Mod Path 2000;13:482
Treatment: wide local excision plus radiation
Gross: well circumscribed, firm, gray-pink; focal calcifications on Xray; rarely within major nerves
Micro: biphasic or monophasic or undifferentiated; biphasic have spindle cells resembling synoviocytes and plump epithelial cells forming glands/cords; monophasic lack the epithelial cells
Spindle cells are arranged in plump fascicles with hyalinization and distinct lobulation accompanied by mast cells, occasional osseous or cartilaginous metaplasia, focal whorling
May have hemangiopericytomatous vascular pattern
Poorly differentiated histology predicts poor outcome
Micro images: image1, figure 8
Micro images: image
Positive stains: mucin in spindle cell areas, PAS positive in epithelium, reticulin highlights biphasic pattern; cytokeratin 7, 8/18, 19 [both components], AE1/AE3 (70% of monophasic fibrous, 46% of poorly differentiated), EMA (epithelial areas, 100% of monophasic fibrous, 92% of poorly differentiated), CD99 / O13 (Ewings/PNET marker, 90-100% of monophasic fibrous or poorly differentiated), vimentin (spindle cells), CEA, bcl-2 (both components, 90% of monophasic fibrous or poorly differentiated), CD57 (neural marker in 72%), E-cadherin (50%), S100 (30-40%), c-kit (children), nuclear beta-catenin
Negative stains: CD34 (94% monophasic fibrous, 100% poorly differentiated), desmin (98% monophasic fibrous, 100% poorly differentiated), h-caldesmon, CD141, WT1, FLI-1
Note: normal synovium is cytokeratin negative
EM: glandular formation of epithelioid tumor cells with sparse luminal microvilli
Molecular: t(X;18)(p11.2; q11) - SYT-SSX1 genes in 90%; can detect via PCR;
also t(X;18)(p11.21;q11) - SYT-SSX2 fusion genes; variants can be detected by optimizing RT-PCR, Mod Path 2002;15:679, Hum Path 2001;32:105
Molecular images: image
DD: MPNST, fibrous variant resembles other sarcomas, metastatic adenocarcinoma (if primarily epithelial component)
References: AJSP 2002;26:1434; AJSP 2002;26:486; Archives 1999;123:1246; AJSP 2001;25:1150
Calcifying synovial sarcoma
Heavy stromal calcification, 5 year survival of 84% is better than classic tumor
Good prognosis: young, distal tumor, < 5 cm, < 15 MF/10 HPF, <50% necrosis, no rhabdoid cells, diploid
Perivascular epithelioid cell family of tumors (PEComas) of soft tissue
Perivascular epithelioid cell tumors-general
Definition: mesenchymal tumor with perivascular clear cell and epithelioid features that coexpresses melanocytic and muscle markers
Concept first proposed by Bonetti (AJSP 1992;16:307)
Tumor family includes angiomyolipoma (renal and extrarenal), clear cell “sugar” tumor (lung and extrapulmonary) and lymphangioleiomyomatosis; these tumors are relatively common and are associated with tuberous sclerosis
Family also includes tumors of falciform ligament / ligamentum teres (see below), skin (Histopathology 2005;46:498), uterus (Mod Path 2005;18:1336) and other viscera and soft tissue; these tumors are rare, and are not associated with tuberous sclerosis
No known normal counterpart to the perivascular epithelioid cell
Epidemiology: 80-90% females (Histopathology 2006;48:75), median age 46 years (range 15-97 years)
Prognosis: usually benign, but some cases have malignant behavior and simulate high grade sarcoma (Pathology 2006;38:415)
Poor prognostic factors: tumor size > 5-8 cm, infiltrative growth pattern, high nuclear grade, >1 mitotic figure/50 HPF or atypical mitotic figures, coagulative cell necrosis (AJSP 2005;29:1558)
Case reports: thigh tumor (AJSP 2002;26:809), uterine tumor with late pulmonary metastases (J Clin Pathol 2003;56:627), uterine leiomyosarcoma that became HMB45+ in metastasis (Ann Diagn Pathol 2005;9:43)
Treatment: excision is usually curative if tumors are benign
Gross images: uterus - polypoid gray-white mass; polypoid mass
Micro: perivascular tumor cells may have radial arrangement around lumen; epithelioid cells (closest to vessel) and spindle cells (remote from vessel) with clear to granular eosinophilic cytoplasm; small, central, round/oval nuclei with small nucleoli; often multinucleated giant cells; may have malignant features with marked atypia, mitotic activity and necrosis
Pecosis: continuous layer of perivascular clear cells remote from tumor, transitioning to invasive nests and PEComa; cells are in apposition to and in direct contact with abluminal surface of capillary basal lamina (Virchows Arch 2007;450:463)
Pecomatosis: nests of perivascular clear to eosinophilic cells (World J Surg Oncol 2004;2:35); may simulate mesothelioma (Ann Diagn Pathol 2006;10:352)
Micro images: bladder - epithelioid tumor cells with abundant eosinophilic cytoplasm; MelanA+; smooth muscle actin+
cervix - mass with central circular core; infiltrative border; spindled to epithelioid areas; degenerative atypia; pecomatosis-nests of cells; HMB45+
kidney - MelanA+ tumor
prostate - epithelioid cells with clear to granular cytoplasm are HMB45+
uterus - malignant case-epithelioid cells with eosinophilic cytoplasm and prominent nucleoli #1; #2; actin+ (red) and HMB45+ (brown); HMB45+ recurrent tumor
Positive stains: melanocytic markers (HMB45 and MelanA; microphthalmia transcription factor-50%; also NKI/C3, tyrosinase, S100-33%), smooth muscle markers (MyoD1 [Appl Immunohistochem Mol Morphol 2003;11:156], smooth muscle actin-80%, desmin-40%, calponin), vimentin (80%)
Negative stains: cytokeratin, CD117/c-kit, CD34
Molecular: gross chromosomal aberrances in most/all cases; most frequent imbalances are 19-, 16p-, 17p-, 1p-, 18p-, X+, 12q+, 3q+, 5+, 2q+; 16p- indicates loss of TSC2 gene (Hum Path 2006;37:606)
EM: abundant cytoplasmic glycogen, premelanosomes, thin filaments with occasional dense bodies, hemidesmosomes, poorly formed cellular junctions
DD: undifferentiated / high grade sarcoma, clear cell / oxyphilic carcinoma (cytokeratin+), melanoma (strong S100+), epithelioid/clear cell smooth muscle tumors (HMB45-)
References: Fletcher: Pathology and Genetics of Tumours of Soft Tissue and Bone (2003, WHO, Volume 5) - Chapter 9
PEComa - abdominopelvic sarcoma
Tumors in 4 women ages 19-41 years (Mod Path 2001;14:563, free full text)
Tumor masses involve serosa of ileum, uterus or pelvic cavity
Nodal and metastatic disease present
One patient had tuberous sclerosis
Case reports: 16 year old girl with abdominopelvic tumor exhibiting extensive necrosis, nodal metastases and tissue invasion (Kaohsiung J Med Sci 2005;21:277)
Micro: sheets of large polygonal cells with glycogen-rich clear or eosinophilic cytoplasm, moderately pleomorphic nuclei, delicate vasculature (resembles clear cell carcinoma); also focal coagulative necrosis and occasional mitotic figures; intracytoplasmic brown pigment present in 2/4 cases; angiolymphatic invasion present; no spindle cells, smooth muscle or fat
Micro images: various images #1; #2; nodal metastasis
Positive stains: HMB45, MART1 (50%)
Negative stains: keratin, EMA, S100, vimentin, muscle specific actin, desmin, chromogranin A
PEComa - falciform ligament / ligamentum teres
Usually in or immediately adjacent to falciform ligament or ligamentum teres (AJSP 2000;24:1239)
Epidemiology: usually females, median age 11 years, range 3-21 years
Case reports: malignant tumor of broad ligament (Virchows Arch 2006;448:867)
Usually indolent behavior
Gross: median 8 cm, range 5-20 cm
Micro: fascicular or nested groups of spindle cells (usually no epithelioid cells) with lightly eosinophilic, fibrillar cytoplasm with cytoplasmic clearing and small but distinct nucleoli in delicate capillary network similar to renal cell carcinoma; rare mitotic figures; no necrosis, no angiolymphatic invasion
Positive stains: HMB45 (100%), MelanA (50%), microphthalmic transcription factor (50%), smooth muscle actin (50%), myosin (50%)
Negative stains: desmin, S100
DD: angiomyolipoma (thick walled blood vessels, lipid distended tumor cells, spindled cells), leiomyoma (distinctly eosinophilic, cigar-shaped nuclei with blunt ends and perinuclear vacuoles; thick walled blood vessels), leiomyosarcoma (large deep seated mass with obvious nuclear pleomorphism and mitotic activity, often with necrosis; negative for HMB45, MelanA, microphthalmic transcription factor, positive for desmin), cellular schwannoma (true capsule, thick-walled hyalinized blood vessels, strong S100 staining), clear cell sarcoma of tendons and aponeuroses (epithelioid and spindled areas with tumor giant cells, S100+, positive for melanocytic markers but negative for smooth muscle actin and myosin; t(12,22) present)
Mesenchymal tumors
Mesenchymoma
Definition: tumors composed of two or more different histological mesenchymal elements
See also description in Bone or Eye chapters
May be benign or malignant
AFIP Third Fascicle and WHO dislike this terminology, and recommend (a) describing as mixed mesenchymal neoplasm and specifying the components or (b) classifying based on predominant mode of differentiation and mentioning the other component(s)
Benign mesenchymoma
Definition: tumors composed of two or more different histological benign mesenchymal elements
See also description in Bone or Eye chapters
Also called hamartoma, but mesenchymal hamartoma of liver (also called mesenchymoma) is a different entity
Most frequent type is angiomyolipoma, which is described separately
May recur if inadequately excised
Case reports: translocation of HMGI-C (HMGA2) gene in chondrolipoangioma (Virchows Arch 2002;440:485), mediastinal tumor of mature adipose tissue separated by fascicular bundles of spindle cells mixed with cartilage and bone (Zhonghua Yi Xue Za Zhi (Taipei) 1996;58:213), stomach tumor (J Clin Pathol 1983;36:504)
Micro: dense fibrous tissue, woven bone and cartilage like areas; loose vascular mesenchyme, smooth muscle and fat; smooth muscle with cytoplasmic fat
Malignant mesenchymoma
Definition: rare tumors with two or more sarcomatous elements, including osteosarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma and liposarcoma; each element must be sufficiently differentiated to clearly recognize its histogenic type; cannot count fibrosarcoma as one of the elements since these areas are present in most sarcomas; excludes dedifferentiated liposarcoma, dedifferentiated chondrosarcoma, malignant Triton tumor and myoblastic differentiation in liposarcoma or chondrosarcoma
First described by Stout in 1948 (Ann Surg 1948;127:278)
According to Harry Evans, do not form a distinct clinicopathologic entity and should be classified in other ways (Fletcher: Pathology and Genetics of Tumours of Soft Tissue and Bone 2003; WHO, Volume 5, page 215)
Sites: frequently in retroperitoneum or chest wall
Prognosis: usually high grade and aggressive (Cancer 1996;77:467); frequently recurs (2/3), metastasizes (1/3) and causes death (50%)
Poor prognostic factors: age < 40 years, rhabdomyosarcomatous component (Oncol Rep 2003;10:803)
Must sample generously to find various components and rule out dedifferentiated tumors
Case reports: 24 year old man with lower leg tumor containing myoblastic sarcoma and chondrosarcoma (J Clin Pathol 2001;54:877), retroperitoneal mass with osteosarcoma, leiomyosarcoma, liposarcoma and fibrosarcoma (Korean J Radiol 2002;3:264), tumor with rhabdomyosarcoma and osteosarcoma components 21 years after breast cancer radiotherapy (Br J Radiol 1997;70:424), with well differentiated liposarcomatous component and ring chromosomes (Cancer Genet Cytogenet 1999;109:119), 15 year old boy with osteosarcoma and liposarcoma in tibia (J Bone Joint Surg Br 1968;50:639)
Treatment: complete resection
Micro images: various sarcomatous components #1; #2; osteosarcoma and liposarcoma
Phosphaturic mesenchymal tumor
Definition: benign tumor of bone or soft tissue associated with rickets and osteomalacia
Epidemiology: extremely rare, median age 53 years, range 9-80 years, slight female predominance
Most cases of tumor associated oncogenic osteomalacia are due to phosphaturic mesenchymal tumor, which produces fibroblast growth factor-2, a protein that inhibits renal tubular phosphate reabsorption (AJSP 2004;28:1) or dentin matrix protein 1 (Mod Path 2004;17:573)
Laboratory: low serum phosphate, renal phosphate wasting, low 1,25-dihydroxy Vitamin D3
Treatment: complete excision causes dramatic reversal of signs and symptoms
Gross: 2-14 cm, arises in soft tissue and bone
Micro: hypocellular tumor of bland spindle cells with small nuclei, indistinct nucleoli; has hemangiopericytoma-like vasculature, osteoclast-like giant cells, distinctive “grungy” calcified matrix, fat, microcysts, hemorrhage, incomplete rim of membranous ossification, metaplastic bone; infiltrative; no/rare mitotic activity, no atypia
Malignant cases: rare cases with nuclear atypia, 5+ mitotic figures/10 HPF, high cellularity, resembles MFH
Positive stains: fibroblast growth factor-23, dentin matrix protein 1
DD: hemangiopericytoma, osteosarcoma, giant cell tumor
References: AJSP 1989;13:588
Extraskeletal “bone” tumors
Extraskeletal aneurysmal bone cyst
Features identical to intraosseous aneurysmal bone cyst
Mean 28 years, range 8-37 years
Deep soft tissue of upper extremities, thigh, groin
Rapidly growing mass without involvement of adjacent bones
May recur locally if incompletely excised
Gross: median 4 cm, range 2.5-9 cm, surrounded by thin rim of bone; hemorrhagic cystic spaces with fibrous septa
Micro: cystic spaces filled with blood; fibrous septa composed of fibroblasts, osteoclast-type giant cells, woven bone
Molecular: 46,XY,t(17;17)(p13;q12), similar to intraosseous aneurysmal bone cyst
DD: extraskeletal osteosarcoma
References: AJSP 2002;26:64
Extraskeletal chondroma
Adults, hands and feet
Benign, but recur locally
Gross: lobulated, hyaline and calcified
Micro: lobulated on low power; plump tumor cells with fine punctate calcification; nuclear hyperchromasia common; may have focal fibrosis; may have osteoclast-like giant cells, histiocyte-like cells, vacuoles resembling lipoblasts
DD: chondrosarcoma (rare in hands and feet), calcifying aponeurotic fibroma
Extraskeletal chondrosarcoma
Less aggressive than bone tumors
Usually adult extremities; also children and trunk
Metastases to lung
Micro: usually myxoid; cords of small cells with acidophilic cytoplasm, occasional vacuoles, usually in myxoid stroma; usually no obvious chondrocytes
Positive stains: S100, Leu7/CD57, lysozyme, glycogen, acid mucins
Negative stains: keratin
Molecular: t(9;22)(q22-31;q11-12) - CHN-EWS fusion gene
EM: well developed endoplasmic reticulum, cytoplasmic filaments, glycogen
Variants:
Embryonal chondrosarcoma
Rare
Primitive appearance
Mesenchymal chondrosarcoma
Orbit, dura, trunk, retroperitoneum, extremities, kidney
Poor prognosis
Micro: clusters of undifferentiated small blue cells often with hemangiopericytoma appearance mixed with islands of mature-appearing hyaline cartilage
Micro images: image1
Molecular: Robertsonian translocation der(13;21)(q10;q10) found in skeletal and extraskeletal cases, Mod Path 2002;15:572
Molecular images: image1, image2
Myxoid chondrosarcoma
Rare, first described in 1972
50-65% males, median age 50-52 years, range 6-89 years
80% in proximal extremities or limb girdles, 20% in trunk
Local recurrence in 48%, metastases in 46%
Survival of 90% at 5 years, 70-78% at 10 years
Adverse prognostic factors: older age, larger tumor size (>10 cm), proximal extremity /limb girdle location, anaplastic cytology
Case report of tumor with neuroendocrine features and t(9;17)(q22;q11.2), representing fusion of CHN and RBP56 genes, AJSP 2000;24:1020
Gross: median 7-10 cm (range 1-25 cm) in deep subcutaneous or deeper soft tissue
Micro: most have low cellularity; may have focal hypercellular areas and > 2 mitotic figures/10 HPF
Positive stains: vimentin (90%), S100 (17-50%), synaptophysin (22-72%), EMA (0-28%)
Negative stains: AE1/AE3, CAM5.2, EMA
Molecular: EWS-CHN or TAF2N-CHN fusion gene transcripts
References: Hum Path 2001;32:1116, Mod Path 2000;13:900, AJSP 1999;23:636
Parachordoma
Rare (<50 cases reported), resembles extraskeletal myxoid chondrosarcoma and chordoma
Develops next to tendon, synovium, osseous structures in extremities
Mean age 35 years, range 7-62 years
Surgical excision usually adequate
Micro: well circumscribed lobules of large, round and eosinophilic cells, focally resembling physaliferous cells or cartilaginous cells in myxoid to densely hyaline matrix; also spindly cells
Positive stains: Alcian blue at pH 2.5 (matrix), abolished with hyaluronidase predigestion; CK 8/18, EMA, S100, vimentin, type 4 collagen around nests of cells
Negative stains: smooth muscle actin, GFAP, CK 1/10
Molecular: trisomy 15 (one case), monosomy 1, 16, 17;
DD: extraskeletal myxoid chondrosarcoma [t(9;22)+, type 4 collagen negative], chordoma [monosomy 3, 4, 10 or 13; type 4 collagen negative]
References: AJSP 1999;23:1059
Extraskeletal Ewing sarcoma/PNET
Rare soft tissue tumor, morphologically indistinguishable from Ewing sarcoma of bone, may represent extension of bone tumor into soft tissue
Usually age 30 or less, occasionally age 50+
Chest wall, lower extremities, and paravertebral region; also pelvis, hip region, retroperitoneum, upper extremities
Aggressive; common metastases to lung, bones
Micro: small round/oval cells with scanty cytoplasm containing glycogen; peritheliomatous pattern (concentration around blood vessels); usually more neuroepithelial features than similar bone tumors
Micro images: image1, figure 1
Positive stains: glycogen, vimentin, CD99 / O13 / mic2, S100, keratin (20%)
Negative stains: CK7, CK19 (usually), AJSP 2000;24:1174
Molecular: t(11;22)(q24;q12) fusion transcript by RT-PCR of FLI1-EWS genes; also
t(21;22)(q12q12) of ERG-EWS genes, t(7;22)(p22;q12) of ETV1-EWS genes
t(17;22)(q12;q12) - E1AF-EWS genes, t (2;22)(q33;q12) - FEV-EWS genes
EM: primitive cells, abundant cytoplasmic glycogen, poorly developed cell junctions, no neural features
DD: rhabdomyosarcoma (solid embryonal), lymphoma, rhabdoid tumor
References: Archives 2001;125:1358; AJSP 2000;24:1657
Extraskeletal osteosarcoma
Adults, extremities
May occur after Xray exposure
60% mortality, worse than chondrosarcoma
Subtypes: osteoblastic, chondroblastic, fibroblastic, MFH-like, telangiectactic, well-differentiated (parosteal)
Micro: osteoid and bone formation produced by tumor cells, without interposition of cartilage
DD: myositis ossificans (no nuclear atypia, zonal), other sarcomas producing metaplastic bone (MFH, synovial sarcoma, fibrosarcoma)
Miscellaneous tumors and staging - Soft Tissue Tumors Part 2
Desmoplastic small round cell tumor
Distinctive neoplastic condition; not strictly a sarcoma
Children and young adults, often adolescent boys
Large mass in abdomen or pelvis, accompanied by widespread peritoneal tumor implants
Other locations include pleura, thorax, scrotum, CNS
Micro: solid nests of round/oval cells surrounded by cellular desmoplastic stroma; also necrosis, cystic degeneration, glandular arrangements, signet ring-like cells, pseudorosette formations, rhabdoid cells, extensive areas of predominantly spindle cell morphology, carcinoid-like differentiation, adenoid cystic-like configuration, no remarkable desmoplasia
Micro images: figure 2
Positive stains: WT (C-19) (also positive in nephroblastomas)
Molecular: t(11;22)(p13;q11.2 or q12) - WT1-EWS, AJSP 2000;24:830;
also t(21;22)(q22;q12) - ERG-EWS
Metastases to soft tissue
Unusual to be presenting feature of carcinomas
Usually from renal, lung, colonic carcinoma
Sinus histiocytosis with massive lymphadenopathy
Aka Rosai-Dorfman disease
May present as soft tissue mass with nodal involvement in 25%
Usually women, mean 46 years, range 24-66 years
Usually extremities (52%), also trunk (26%), head and neck (13%), retroperitoneum (9%)
May recur after surgery
Difficult diagnosis to make due to altered morphology compared to nodal tissue
Case report at Pathology 1998;30:14
Micro: large histiocytic cells, frequently spindled, with less conspicuous emperipolesis than nodal lesions; fibroinflammatory component, AJSP 1992;16:122
Positive stains: S100, CD68, lysozyme
DD: inflammatory pseudotumor
Teratoma
Usually females
Congenital or early childhood
May be associated with twins or malformations
Sacrococcygeal area, head and neck, retroperitoneum, mediastinum, CNS
75% benign
Neck during infancy: massive but benign vs. adult neck: usually malignant
Staging
This staging system applies to soft tissue sarcomas only, excluding Kaposi, DFSP, infantile fibrosarcoma, angiosarcoma
Superficial: does not extend into superficial investing muscular fascia in extremity or trunk lesions
Deep: lesions deep to or involving superficial fascia; all intraperitoneal visceral lesions, retroperitoneal lesions, intrathoracic lesions and most head and neck tumors
Primary tumor (T)
TX - primary tumor cannot be assessed
T0 - no evidence of primary tumor
T1 - tumor 5 cm or less
T1a - superficial tumor
T1b - deep tumor
T2 - tumor more than 5 cm
T2a - superficial tumor
T2b - deep tumor
Regional lymph nodes (N)
NX - regional lymph nodes cannot be assessed
N0 - no regional lymph node metastasis
N1 - regional lymph node metastasis
Distant metastasis (M)
MX - distant metastasis cannot be assessed
M0 - no distant metastasis
M1 - distant metastasis
Stage grouping
1 - T1/T2 N0 M0 low grade
2 - T1 or T2a N0 M0 high grade
3 - T2b N0 M0 high grade
4 - N1 or M1 (other variables irrelevant)
End of Soft Tissue Tumors Part 3 - Muscle, Vascular, Nerve, Other