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

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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

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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

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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

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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

Pyogenic granuloma

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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

Lymphangiomyoma

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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

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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

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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)

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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

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High (5+/50 HPF) mitotic activity and superficial

OR 2 cm+ only

OR deep only

Vascular ectasias

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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

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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

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Also called perivascular myoid tumor

Usually adults, 60% male, median age 52 years, youngest case was age 10

Affects skin (dermis or subcutis) or soft tissues of extremities, rarely head or trunk

Treatment: excision; only rarely recurs

Micro: thin walled vessels and concentric, perivascular arrangement of plump spindle to round myoxid cells; may have hemangiopericytoma-like areas; occasional prominent atypia and mitotic activity; rarely infiltrative; no giant cells (Am J Surg Pathol 2006;30:104)

Positive stains: alpha smooth muscle actin, h-caldesmon; rarely focal desmin

DD: angioleiomyoma, myofibroma

Low/intermediate grade vascular tumors

Giant cell angioblastoma

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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

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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

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Definition: mixtures of benign, low-grade malignant and malignant vascular components; predominant components resemble epithelioid and retiform hemangioendothelioma

Very rare

Usually women, median age 43 years, range 22-75 years

Usually superficial dermis or subcutaneous, usually in hands or feet

Recur locally, may metastasize, no deaths after median follow-up of 5 years

Must sample extensively to obtain correct diagnosis

Treatment: excision, may recur locally, but no/rare metastases (Am J Surg Pathol 2007;31:1567)

Positive stains: CD31, CD34, Factor VIII

References: AJSP 2000;24:352

Epithelioid/histiocytic hemangioendothelioma

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Intermediate grade vascular malignancies that are closely associated with or arise from a vein in 50% of cases

Usually adults, 60% women

Most commonly affect extremities (60%); also head and neck, mediastinum, trunk, elsewhere

Unpredictable clinical course, but less aggressive than angiosarcoma

13% recur, 20-30% metastasize (lung, lymph node most common), 13% die of disease (AJSP 1997;21:363); for lung, mortality is 65%

High risk (> 3 MF/50 HPF and size > 3 cm) have 5 year disease specific survival of 59% versus 100% for low risk (Am J Surg Pathol 2008;32:924)

Case reports: Case of the Week #77

Treatment: low grade tumors - wide local excision; high grade tumors - radical local excision with possible neck dissection

Gross: variable size, up to 18 cm

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

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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

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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

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<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

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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

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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

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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; mayinvolve 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

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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

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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

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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)

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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-dermalproliferation 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

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Well differentiated (hemangiosarcoma) to anaplastic tumor resembling melanoma or carcinoma

Rare; older adults, skin (scalp, face), soft tissue, breast, liver, bone, spleen

Very rare in children and young adults, but similar histology and poor prognosis (Am J Surg Pathol 2009;33:264)

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; brisk mitotic activity and necrosis are common; 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

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Positive stains: CD34, keratin

References: AJSP 2001;25:1061

Hemangiopericytoma (HPC)

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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

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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

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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)

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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 (usually positive for CK7 and CK19, Am J Clin Pathol 1999;112:641)

Epithelioid MPNST

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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), INI1 (50%, Am J Surg Pathol 2009;33:542)

DD: epithelioid angiosarcoma (CD31+, CD34+, vWF+, S100-), melanoma

Malignant triton tumor

MPNST with well developed skeletal muscle

Myxopapillary ependymoma

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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

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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

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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

Neurofibromatosis type 1

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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

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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

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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

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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

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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

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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+)

Neurothekeoma

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Superficial tumor, originally of purported nerve sheath derivation

First described in 1980

60% women, mean age 17 years (range 2-85 years), 80% are < age 30 at initial diagnosis

May derive from fibroblasts with ability to differentiate into myofibroblasts and to recruit histiocytes (Am J Surg Pathol 2007;31:1103)

Clinical: solitary, superficial, slow growing mass up to 2 cm

Sites: usually head, upper extremities or shoulder girdle

Treatment: excision, may recur

Micro: cellular, myxoid or mixed subtypes; involves dermis or subcutis; multinodular mass with myxoid matrix and peripheral fibrosis; whorled or focally fascicular patterns of spindled and epithelioid mononuclear cells with abundant cytoplasm, indistinct cell borders; margins usually positive; usually occasional multinucleated giant cells; variable nuclear atypia; median 4 MF/25 HPF, may have 10+ MF/25 HPF, may be atypical

Positive stains: vimentin, NKI/C3, CD10, MiTF

Negative stains: S100, GFAP, MelanA

DD: nerve sheath myxoma

Perineurioma

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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

Case reports: 30 year old man with thigh mass and neurofibromatosis 2 (Am J Surg Pathol 2006;30:1624)

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

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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

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Usually small tumors in dermis of hands

Schwannoma

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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

Treatment: excision; usually do not recur

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

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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

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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

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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

Microcystic-reticular variant

First described in 2008 (Am J Surg Pathol 2008;32:1080)

Median age 63 years, range 11-93 years

Often arises in GI tract submucosa; also other sites

Not associated with neurofibromatosis types 1 or 2

Gross: median 4 cm, range 0.4 to 23 cm

Micro: circumscribed, unencapsulated tissue (encapsulated if in subcutis); infiltrative in visceral locations; microcystic and reticular growth pattern with anastomosing and intersecting spindle cells, distributed around islands of myxoid or collagenous/hyalinized stroma; round/oval nuclei with tapering, indistinct nucleoli; 0-3 MF/50 HPF; no necrosis, no pleomorphism

Positive stains: S100, variable GFAP

Negative stains: muscle markers, keratin, p63

Pigmented schwannoma

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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

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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

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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

Perivascular epithelioid cell family of tumors (PEComas) of soft tissue

Perivascular epithelioid cell tumors-general

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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)

Sclerosing PEComa

Definition: variant with extensive stromal hyalinization

First described in 2008 (Am J Surg Pathol 2008;32:493)

Women, mean age 49 years (range 34-73 years)

77% occur in retroperitoneal, usually pararenal

Treatment: excision; may recur/metastasize if high grade morphology)

Gross: median 10 cm, well circumscribed

Micro: cords and trabeculae of bland, uniform, epithelioid cells with pale eosinophilic, granular to clear cytoplasm and round nuclei with small nucleoli; tumor cells are arranged at least focally around blood vessels; abundant densely sclerotic stroma; often has spindle cell component; no/rare mitotic figures; rarely necrosis

Positive stains: desmin (diffuse), smooth muscle actin, caldesmon, HMB45 (scattered cells)

Negative stains: S100 (usually), EMA, keratin, CD117/c-kit

PEComa - abdominopelvic sarcoma

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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

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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

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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

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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

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Definition: rare tumors with two or more sarcomatous elements, includingosteosarcoma, 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, dedifferentiatedchondrosarcoma, malignant Triton tumor and myoblastic differentiationin 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

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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

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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

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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

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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

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Rare

Primitive appearance

Mesenchymal chondrosarcoma

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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

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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; may have rhabdoid features if INI1 negative

Positive stains: vimentin (90%), S100 (17-50%), synaptophysin (22-72%), EMA (0-28%)

Negative stains: AE1/AE3, CAM5.2, EMA; often INI1 (Am J Surg Pathol 2008;32:1168)

Molecular: EWSR1 translocation in 46% (Am J Surg Pathol 2008;32:8); often involves t(9;22)(q31;q12) EWSR1-NR4A3; EWS-CHN or TAF2N-CHN fusion gene transcripts

References: Hum Path 2001;32:1116, Mod Path 2000;13:900, AJSP 1999;23:636

Parachordoma

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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 chordoma

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Very rare

Positive stains: CK9, S100, brachyury (notochord marker, Am J Surg Pathol 2008;32:572)

Extraskeletal Ewing sarcoma/PNET

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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

Case reports: 29 year old man with neck tumor exhibiting focal squamous differentiation (Am J Surg Pathol 2008;32:1742)

Aggressive; common metastases to lung, bones

Gross image: #1

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

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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)

Other tumors

Alveolar soft parts sarcoma

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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

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Aka melanoma of soft parts

Rare aggressive tumor of adolescents / young adults

Median age 30 years, range 13-73 years; 60% male

Deep soft tissues of extremites, trunk or limb girdles, tends to occur near tendon, fascia or aponeuroses

Slow progression, frequent local recurrences; eventually nodal and distant metastases

5 year overall survival is 63% (Am J Surg Pathol 2008;32:452)

Gross: firm, well circumscribed, gray-white, gritty sensation when cutting; median 4 cm

Micro: distinctly nested growth pattern with mixture of spindle, epithelioid and tumor giant cells; melanin pigment in 2/3; may have floret-like multinucleated giant cells; often rhabdoid cells, bizarre pleomorphic cells; usually necrosis; mean 4 MF/10 HPF

Micro images: image1, image2, figure 7

Cytology: variable cellularity, may form microacinar structures resembling adenocarcinoma (Am J Clin Pathol 2002;117:217)

Positive stains: S100, HMB45, microphthalmic transcription factor (75%), melanoma-cell adhesion molecule, MelanA (43%), iron (intra- and extracellular), Leu7/CD57, vimentin, keratin (variable)

Negative stains: alpha-smooth muscle actin, desmin, CAM 5.2

Molecular: t(12;22)(q13;q12) - ATF1 and EWS (not seen in melanoma); usually diploid or less aneuploidy than metastatic melanoma to soft tissue; tumors in GI tract may have a variant fusion gene EWSR1-CREB1

EM: melanosomes

DD: melanoma

References: Mod Path 2001;14:6

Desmoplastic small round cell tumor

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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

Epithelioid sarcoma

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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

Poor prognosis; death from disease in 31%

Frequently underdiagnose

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); INI1 / hSNF5 / SMARCB1 (86-93%, both proximal and conventional, Am J Clin Pathol 2009;131:222, Am J Surg Pathol 2009;33:542)

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

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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

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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

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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

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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

Metastases to soft tissue

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Unusual to be presenting feature of carcinomas

Usually from renal, lung, colonic carcinoma

Myxoma

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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

Cytology: viscous, gelatinous quality when first applied to glass slide; paucicellular, often finely granular myxoid stroma with few cells, usually macrophages and bland spindle cells (Am J Clin Pathol 2005;123:858)

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

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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

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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

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Myxomas of bone

Rare; well circumscribed lytic lesions of metaphysis, usually femur, pelvis, tibia

Intramuscular myxoma

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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

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Odontogenic origin, frequently recur

Mazabraud's syndrome associated

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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

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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

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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

Sinus histiocytosis with massive lymphadenopathy

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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

Synovial sarcoma

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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

Minute (< 1 cm) tumors of hands and feet: 2/3 female, median age 29 years, 2/3 monophasic, 40% have microcalcifications; EMA+, keratin+; have clinically favorable course if completely excised (Am J Surg Pathol 2006;30:721)

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)

also TLE1 (97%, Am J Surg Pathol 2007;31:240), 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),

p16INK4A gene deletion in 74% (Am J Clin Pathol 2006;126:866)

Molecular images: image

DD: MPNST - usually negative for CK7 and CK19 (Am J Clin Pathol 1999;112:641), negative for SYT-SSX fusion products (Am J Clin Pathol 1999;112:43)

, 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

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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

Teratoma

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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

Staging

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This staging system applies to soft tissue sarcomas, but excludes fibromatosis (desmoid tumor), GIST, infantile fibrosarcoma, inflammatory myofibroblastic tumor, Kaposi’s sarcoma, mesothelioma and sarcomas arising from the dura mater, brain, parenchymatous organs or hollow viscera

References: AJCC Cancer Staging Manual (7th ed)

Primary tumor (T)

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TX: Primary tumor cannot be assessed

T0: No evidence of primary tumor

T1: Tumor 5 cm or less in greatest dimension

T1a: Superficial tumor

T1b: Deep tumor

T2: Tumor more than 5 cm

T2a: Superficial tumor

T2b: Deep tumor

Notes: Superficial tumor is located exclusively above the superficial fascia without invasion of the fascia; deep tumor is located either exclusively beneath the superficial fascia, superficial to the fascia with invasion of or through the fascia, or both superficial yet beneath the fascia.

Regional lymph nodes (N)

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NX: Regional lymph nodes cannot be assessed

N0: No regional lymph node metastasis

N1: Regional lymph node metastasis

Note: the presence of positive nodes (N1) in M0 tumors is considered stage III

Distant metastasis (M)

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M0: No distant metastasis

M1: Distant metastasis

Histologic grade (G)

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GX: Grade cannot be assessed

G1: Grade 1 of 3 (low grade)

G2: Grade 2 of 3

G3: Grade 3 of 3 (high grade)

Stage grouping

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IA: T1a-b N0 M0 G1, GX

IB: T2a-b N0 M0 G1, GX

IIA: T1a-b N0 M0 G2-3

IIB: T2a-b N0 M0 G2

III: T2a-b N0 M0 G3 or Any T N1 M0 Any G

IV: Any T Any N M1 Any G

End of Soft Tissue Tumors Part 3 - Muscle, Vascular, Nerve, Other