Epithelioid Tumors of Soft Tissue

INTRODUCTION

Many spindle cell or pleomorphic tumors of soft tissue can assume at least focally an epithelioid appearance, in which the cells become rounded with discernible, often with abundant cytoplasm, and additional clear cell or granular cell variation in some cases. These include tumors of nerve sheath, endothelium and smooth muscle, gastrointestinal stromal tumor, myxofibrosarcoma, and pleomorphic liposarcoma. Diagnosis is relatively easy when this component is small, although it may be more of a challenge when it is predominant in a core biopsy.

Soft tissue tumors composed primarily of epithelioid cells include epithelioid sarcoma, extraskeletal myxoid chondrosarcoma, epithelioid mesothelial proliferations, and sclerosing epithelioid fibrosarcoma, as well as carcinoma, melanoma, plasmacytoma, and chordoma involving soft tissue. Rhabdoid cells are epithelioid cells with prominent cytoplasm displacing the nucleus. They can be seen in malignant rhabdoid tumor (MRT), as well as on occasion in epithelioid sarcoma, extraskeletal myxoid chondrosarcoma, mesothelioma, synovial sarcoma, myoepithelial tumors, angiomatoid fibrous histiocytoma, and melanoma.

Those sarcomas in which other features such as spindle cells or myxoid stroma are generally prominent are dealt with principally in other chapters. This chapter concerns those in which epithelioid cell morphology is the dominant feature. The differential diagnosis is summarized in Tables 11.1 and 11.2.

EPITHELIOID SARCOMA

Epithelioid sarcoma is a mesenchymal tumor that has prominent epithelial differentiation as well as demonstrating myofibroblastic and other lineages.¹ It can mimic carcinoma, epithelioid angiosarcoma, synovial sarcoma, and mesothelioma, and also resemble melanoma and rhabdomyosarcoma. The principal subtypes are the classic and proximal variants, although each can occur in both proximal and distal sites and both patterns can, rarely, coexist in the same tumor.

TABLE 11.1 Differential Diagnosis of Epithelioid Soft Tissue Tumors

	Typical Clinical Features	Microscopic Features	Ancillary Investigations
Epithelioid sarcoma	Nonhealing ulcerated nodules, typically on hand or forearm, mainly first two decades Proximal variant in young adults, in limb girdles, or axial in perineum, chest wall, pelvis, mediastinum	Centrally necrotic granuloma-like lesions, mainly polygonal cells with mildly pleomorphic nuclei and abundant eosinophilic cytoplasm Proximal variant has large cells with vesicular nuclei and prominent nucleoli, focal rhabdoid appearance	CK+, EMA+, CD34+ (50%), SMA focal, INI1−, ERG±, S100 protein−, desmin−
Extrarenal malignant rhabdoid tumor	Children, young adults, head and neck, mediastinum, paraspinal, vulva, perineum	Multinodular, central necrosis, sheets or cords of polygonal cells, vesicular nucleoli, large nucleoli, eccentric cytoplasm Occasional fibrosis or myxoid stroma	CK+, EMA+, CD34−, INI1−
Epithelioid angiosarcoma	Usually deep, mostly adults Can arise in immunosuppression, or in course of other tumor (e.g., hemangioma, schwannoma, malignant peripheral nerve sheath tumor)	Sheets of polygonal cells, rounded vesicular nuclei, prominent nucleoli Focal vasoformation, intracytoplasmic lumina Geographic necrosis, old and recent hemorrhage	CD31+, CD34+, ERG+, FLI-1+, CK±, EMA±, D240±, S100 protein−, desmin−, nuclear INI1+
Epithelioid hemangioendothelioma	Deep lesions of soft tissues, lungs, and liver of adults	Epithelioid cells in a chondromyxoid background, sometimes associated with a vessel The cells infiltrate singly, in cords or small nests and do not form vascular channels, but individual cells can have intracytoplasmic lumina	CD34+, CD31+, FLI-1+, CK±, VEGFR-3−, nuclear INI1+ t(1;3)(p36.3;q25), WWTR1-CAMTA1 fusion, t(X;11)(p11.22;q13), YAP1-TFE3 fusion
Epithelioid hemangioma	Adults (20-40 y), head-neck region, single or multiple smooth papules or plaques (superficial) Benign but can locally recur	Lobular vascular proliferation surrounded by lymphoid cuff, often associated with damaged artery Vessels lined by epithelioid endothelial cells, background eosinophils	CD34+, CD31+, ERG+ in epithelioid cells
Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma	Rare tumors of young adults Extremities or trunk, in subcutis or deep soft tissue Indolent behavior with local or regional recurrence	Sheets, ill-defined nodules, fascicles of deeply eosinophilic cells in desmoplastic stroma but no overt vascular channel formation Occasional cells with intracytoplasmic vacuoles suggesting vascular lumen formation	CK+, CD31+, FLI-1+, CD34−, nuclear INI1+ t(7;19)(q22;q13), SERPINE1-FOSB fusion
Epithelioid malignant peripheral nerve sheath tumor	Adults, F > M Subcutaneous or deep, the latter usually associated with a nerve	No capsule, nodules of cells in cords, nests or sheets Cells have large nucleoli, eosinophilic cytoplasm, with occasional rhabdoid or clear cell change Pleomorphism is rare Spindle cell component is common	S100 protein+, CD34±, INI1− (in about 50%). HMB45−, melan-A−, desmin−
Epithelioid schwannoma	Adults, superficial soft tissue of digits, ear, thigh, and on VIII cranial nerve	Circumscribed, encapsulated Cords of rounded cells, focal hyperchromatic nuclei, rare mitoses, thick-walled vessels Epithelioid change can be focal in regular schwannoma	S100 protein+ (diffuse), GFAP+, CK+ in some. Rim of EMA+ perineurial cells
Epithelioid neurofibroma	Very rare focal feature in typical neurofibroma in neurofibromatosis type 1	Clusters and cords of plump epithelioid Schwann cells	S100 protein+, CK−
Sclerosing perineurioma	M > F, affects fingers, thumb, palm	Cords and whorls of rounded or epithelioid cells in dense stroma, without atypia	EMA+, claudin-1+, CD34±, CK−, betacatenin−, INI1+
Epithelioid inflammatory myofibroblastic sarcoma	M > F, adults, intraabdominal (omentum or mesentery), recur and metastasize	Atypical polygonal cells with prominent nucleoli in myxoid and inflammatory stroma including neutrophils, necrosis	ALK+ (nuclear membrane), CD30+, desmin + t(2;2)(p23;q13), RANBP2-ALK fusion
Epithelioid smooth muscle tumor	Female genital tract, skin, subcutis especially head and neck, usually <2.5 cm	Sheets of cells with distinct cell membranes, rounded nuclei, and eosinophilic, granular, or clear cytoplasm Atypia, mitoses, necrosis, vascular invasion in epithelioid leiomyosarcoma	SMA+, desmin+, h-caldesmon+, occasional CK+ (dot)
Epithelioid gastrointestinal stromal tumor	Related to wall of any part of alimentary tract (most commonly stomach, small intestine) Also, in retroperitoneum, omentum	Sheets of epithelioid or clear cells often a spindle component Organoid pattern, occasional plasmacytoid, or rhabdoid change	CD117+, DOG1+, CD34+, h-caldesmon +, SMA variable, desmin+ rarely, S100 protein+ rarely. CK+ in some after therapy KIT or PDGFRA mutations
Epithelioid pleomorphic liposarcoma	Deep soft tissue, extremities, rarely retroperitoneum, rarely subcutis	Sheets of clear or granular cells, admixed with pleomorphic lipoblasts Usually focal, more typical tumor elsewhere	S100 protein+, AE1/3+, melan-A+, SMA+
Angiomatoid fibrous histiocytoma	Children, young adults, deep dermis or subcutis of upper limb, antecubital fossa, axilla, head and neck, trunk, groin	Circumscribed, fibrous, and lymphoplasmacytoid cuff with germinal centers Sheets of bland ovoid cells with scanty cytoplasm Variable cystic blood-filled spaces without endothelial lining	Desmin+ (60%), h-caldesmon+, EMA+, CD99+, CD68+, S100 protein− t(2;22)(q33;q12), EWSCREB1 fusion, t(12;22)(q13;q12) EWSATF1 fusion or t(12;16)(q13;p11), FUSATF1 fusion
Epithelioid myxofibrosarcoma	Most subcutaneous, some subfascial Extremities, M = F	Epithelioid cells with prominent nucleoli in myxoid stroma, pattern of short curved vessels	CK−, EMA−, desmin−, S100 protein−
Extraskeletal myxoid chondrosarcoma	Deep soft tissues of extremities, slight male predominance	Cords, sheets, and reticular pattern of uniform rounded cells with eosinophilic cytoplasm in hypovascular myxoid background	S100 protein+, neuroendocrine markers+ in a subset t(9;22)(q22;q12), EWSR1-NR4A3 fusion, t(9;17) (q22;q11), TAF1168-NR4A3 fusion, or t(9;15)(q22;q21), TCF12-R4A3 fusion
Sclerosing epithelioid fibrosarcoma	Deep soft tissue, limbs/girdles, head and neck Can involve or arise in bone	Multinodular, focal calcification Cellular islands in dense fibrosis Nests of ovoid cells, clear cytoplasm, or single files simulating carcinoma Fibrosarcoma-like spindle cell areas in many cases	Occasional and variable expression of bcl-2, EMA, CK, S100 protein No specific immunophenotype Some have genetic features of lowgrade fibromyxoid sarcoma including FUS-CREB3L2 and EWSR1-CREB3L1 fusions
Carcinoma	Usually metastatic deposit in skin or subcutis	Cords and sheets of epithelioid cells with variable pleomorphism, sometimes with focal glandular formation	CK+, EMA+, nuclear INI1+, CD34− Other markers as indicated: PSA, thyroglobulin, calcitonin, hepar-1, CD56, chromogranin, WT1, GCDFP15, TTF-1, ER, PgR, etc.
Epithelioid mesothelioma	Pleural, peritoneal, paratesticular solitary or multiple masses or sheet-like proliferation Can infiltrate organs	Sheets of epithelioid cells, adenopapillary formations, necrosis	CK5/6+, calretinin+, thrombomodulin+, D2-40+, desmin+ in some, CD34 and bcl-2−, BerEP4 and CEA−, nuclear INI1+
Melanoma	Primary or metastatic	Plump epithelioid cells in sheets, often with prominent nucleoli Cytoplasm eosinophilic, sometimes rhabdoid Anisocytosis and nuclear pleomorphism can be prominent, unlike in most epithelioid soft tissue tumors	S100 protein+, melan-A+, HMB45+, INI1+, CK+ rarely
Perivascular epithelioid cell tumor	Intra-abdominal, soft tissue, or gynecologic locations	Monotypic epithelioid type has sheets of granular or epithelioid cells Malignant variants also have pleomorphism, multinucleation, and abnormal	SMA+, HMB45+, melan-A+, desmin+ in some, CD117+ in some, S100 protein+ rarely, TFE3+ in some
Anaplastic large cell lymphoma	Skin or soft tissue involvement, the latter usually associated with advanced nodal disease	Sheets of polygonal cells, prominent nucleoli, multinucleated forms Can be spindled	CD30+, ALK+ (or −), CD43+, CD45+, CD3+, TIA1+, t(2;5) (p23;q35), TMP3-ALK fusion
Histiocytic sarcoma	Very rare tumor occurring in skin, lymph nodes, gastrointestinal tract	Sheets of epithelioid cells with eosinophilic cytoplasm and prominent nucleoli, binucleated or giant cells, necrosis Marked neutrophilic or lymphocytic infiltrate	CD45+, CD45RO+, CD68+, CD4+, lysozyme+, CD31+
Rhabdomyoma	Extracardiac lesions occur in larynx, oral cavity, neck, female genital tract	Adult type has large polygonal cells with voluminous granular cytoplasm, some with cross-striations. Fetal type is myxoid or cellular with spindle cells and variable myotube formation, and some with cross-striation.	Desmin+, myogenin+ (nuclear), MyoD1+ (nuclear)
Granular cell tumor	Skin, head and neck sites (tongue), viscera	Infiltrative, cords and nests of cells with small nuclei, large amounts of coarsely granular cytoplasm, and distinct cell margins	S100 protein+, CEA+, melanocytic and myoid markers negative

TABLE 11.2 Immunohistochemistry of Selected Malignant Epithelioid Tumors

	Epithelioid Sarcoma	Epithelioid Angiosarcoma	Epithelioid Malignant Peripheral Nerve Sheath Tumor	Pleomorphic Rhabdomyosarcoma	Carcinoma	Melanoma	Anaplastic Large Cell Lymphoma
CK (pan)	+	+^a	−^a	+^a	+	+^b	+^a
EMA	+	+^a	−^a	−	+	−	+
S100	−	−	+	−	±	+	−
CD34	+	+	−	−	−	−	−
CD31	−	+	−	−	−	−	−
Desmin	−	−	−	+	−	+^a	−
SMA	+	−	−	−	−	−	−
INI1 (n)	−	+	±	+	+	+	+
Myogenin (n)	−	−	−	+	−	−	−
p63 (n)	−	−	−	−	+	−	−
CD30	−	−	−	−	+^b	−	+
CD45	−	−	−	−	−	−	+
^aRarely.^b+ in some germ cell tumors (embryonal carcinoma).
n, nuclear.

Clinical Features

This tumor arises at any age but mostly in the second and the third decades and more often in males than females. The most common site is the forearm and hand, but any site can be affected. The proximal variant (see below) predilects for the midline of trunk and the proximal limbs and limb girdles. Usual epithelioid sarcoma typically arises in dermis and subcutis but can also involve and extend along tendon sheaths and, rarely, bone. It often presents as a slowly growing nodule, which forms a nonhealing ulcer. Multiple lesions can appear, extending proximally, during the course of the disease. The recurrence rate is very high at over 70%, and over 40% metastasize, to lymph nodes (in 34%) and remote sites, including scalp (22%) and lungs (51%).² Epithelioid sarcoma is an aggressive neoplasm that can have a protracted course, with a 5-year survival of about 70% and a 10-year survival of 42% to 62%.²,³ Treatment is essentially surgical, with excision of lesions which sometimes requires amputation, although isolated limb perfusion might have a role.⁴

Pathologic Features

The classic lesion of epithelioid sarcoma is an ulcerating dermal or subcutaneous nodule with central necrosis, surrounded by plump epithelioid cells with relatively uniform nuclei and abundant, markedly eosinophilic cytoplasm (Figs. 11.1 and 11.2, e-Figs. 11.1 to 11.3). The cells are sometimes rhabdoid, although this is more common in the proximal variant. At the periphery of the nodules, the neoplastic cells can assume a spindled shape, by gradual transition; the tumor is not truly biphasic. Mitoses are variable, but abnormal forms are rare. The stroma can be fibrous, with neoplastic cells in carcinoma-like files (e-Figs. 11.4 and 11.5) or forming spindle cells with storiform pattern (fibroma-like variant) (e-Fig. 11.6), or modified by hemorrhage (angiomatoid or angiosarcoma-like variant) (e-Fig. 11.7) or, very rarely, myxoid change (e-Fig. 11.8).⁵ There is often increased desmoplasia in recurrent lesions. Multinucleated giant cells, calcification, and osteochondroid metaplasia are occasionally seen.

FIGURE 11.1 Epithelioid sarcoma. This is the typical appearance of a dermal lesion of epithelioid sarcoma with ulceration and central necrosis within a peripheral ring of eosinophilic tumor cells. The margins of the lesion are indistinct. Note the epidermal hyperplasia adjacent to the ulcer.

FIGURE 11.2 Epithelioid sarcoma. The tumor cells have markedly eosinophilic cytoplasm and mildly pleomorphic, ovoid vesicular nuclei.

Ancillary Investigations

Almost all epithelioid sarcomas express cytokeratins (Fig. 11.3, e-Fig. 11.9), with diffuse cytoplasmic distribution, and EMA, mostly on cell membranes. Among cytokeratin subtypes, CK8, CK19, and CK14 are demonstrable in the majority of cases, whereas CK7, CK20, and (in contrast to cutaneous carcinomas⁶) CK5/6 are infrequently expressed. About half of epithelioid sarcomas are positive for CD34 (e-Fig. 11.10); this is useful in excluding carcinomas, which almost always lack this marker. Claudin-1 is also positive,⁷ and reactivity for SMA is found in about 40% of cases, especially in the spindle cells. INI1 has been shown to be lost (immunohistochemically negative) in up to 93% of epithelioid sarcomas, which is of diagnostic use since almost all carcinomas and epithelioid endothelial neoplasms, and 50% of malignant epithelioid schwannomas display nuclear immunoreactivity for this otherwise ubiquitous antigen.⁸

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