Epithelioid sarcoma (ES) is a rare mesenchymal neoplasm which represents less than 1% of soft tissue sarcomas and is further divided into classic and proximal types. Classic ES typically occurs in distal anatomic sites (extremities, especially hand) in young (10-40 years old) adults, while proximal-type ES occurs in an older patient population (20-65 years old) and, as its name suggests, arises in proximal anatomic locations such as the pelvis, perineum, hip and trunk. In either case, ES arises more frequently in males.

 Classic ES can present as an asymptomatic mass lesion, non-healing wound, or ulcer with raised borders. A high index of suspicion may be required for diagnosis in some cases since the presentation may be similar to alternate non-malignant etiologies such as infection. Proximal-type ES may occur as a soft tissue mass of the subcutis or deeper location and demonstrate more rapid expansion. Due to its often deceptively asymptomatic initial course of disease, ES may be multifocal with distant spread by the time of presentation. ES is clinically aggressive with a high rate of both local recurrence and metastasis (most frequently involving the lung, lymph nodes, and skin). There is evidence that proximal-type epithelioid sarcoma is characterized by worse clinical behavior and outcomes. Surgical excision with a wide margin represents the primary mode of treatment, even after metastasis. Poor prognostic factors include location (proximal, deep soft tissue), male sex, and size (classic type is typically smaller, while proximal-type may grow to a larger size (>5 cm)).

Grossly, ES may be a single or multinodular lesion with firm cut surfaces ranging from tan to grey to white. Histologically, classic ES contains epithelioid cells of small to medium size with irregular nuclei and smaller nucleoli, with a typically low mitotic rate, as well as a component of spindle cells (often more prominent at the periphery of the lesion) whose prevalence varies between tumors. Central zonal necrosis may be seen along with a mixed inflammatory infiltrate. Other features that can be observed include metaplastic bone formation, myxoid stroma (infrequent), sclerosis or stromal hyalinization, and formation of pseudovascular or pseudoglandular structures. Proximal-type ES is comprised of larger cell with abundant eosinophilic cytoplasm, prominent nucleoli, and polygonal to rhabdoid morphology. Necrosis, hemorrhage, and mitoses are more frequent in proximal-type ES compared to classic ES as expected from its typically more aggressive growth pattern.

Immunohistochemical analysis plays a key role in the diagnosis of epithelioid sarcoma, which characteristically demonstrate loss of INI1 (SMARCB1/INI1), a member of the SWI-SNF chromatin remodeling complex. Indeed, Hornick et al demonstrated that 91% of classic ES and 95% of proximal-type ES demonstrated INI1 loss, in contrast to a wide variety of other malignancies. However, INI1 loss was also observed in 50% of malignant peripheral nerve sheath tumors and a minority (2/22) of myoepithelial carcinomas. Conversely, a minority of ES cases may demonstrate some degree of INI1 immunoexpression. However, Kohashi et al found alterations to other members of the SWI-SNF complex in a number of these INI1-retained cases, supporting the role of this epigenetic regulating complex in the pathogenesis of this entity. Therefore, although INI1 immunohistochemistry is a key, specific ancillary study in making this diagnosis, INI1-expressing ES has been previously reported and INI1 loss can occur in a few non-rhabdoid entities, therefore diagnosticians should be aware of these possibilities.

ES is positive for keratin (high and low molecular weight), EMA, and vimentin, with expression of CD34 and GLUT1 in approximately half of cases. Staining for FLI1 and ERG (N-terminus) and D2-40 can occur and potentially point to vascular differentiation, however Stockman et al reported that 0/30 cases were positive for CD31. ES is also negative for S100, CD68, and desmin. The differential diagnosis for ES includes epithelioid malignant peripheral nerve sheath tumor (S100 positive), melanoma and clear cell sarcoma (CCS) (S100 positive, EWSR1 translocation in the case of CCS), myoepithelial carcinoma (S100 positive), undifferentiated carcinoma (expression of epithelial markers), extrarenal malignant rhabdoid tumor, and epithelioid angiosarcoma (retained INI1 expression). Of these, extrarenal malignant rhabdoid tumor has a similar immunophenotype with INI1 loss and can morphologically appear similar to proximal-type ES, however clinically this typically occurs in a younger patient population (infants and children).

In this case, the clinical presentation (young adult male, deep soft tissue location involving base of penis and perineum), morphology, and immunophenotype (keratin positive, negative for Sox10, INI-1 loss) were all consistent with a proximal-type ES. Presentation of this aggressive entity may occur in an otherwise healthy adult after incidental trauma (as in this case) or as a non-healing wound, therefore both clinicians and diagnosticians should be aware of this entity.


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