Epithelioid sarcoma: New insights based on an extended immunohistochemical analysis

Archives of Pathology & Laboratory Medicine, Sep 2003 by Laskin, William B, Miettinen, Markku

* Context.-Epithelioid sarcoma has a distinctive epithelioid phenotype and characteristically exhibits immunohistochemical reactivity for epithelial markers (keratins and epithelial membrane antigen) and mesenchymal markers (most notably vimentin and CD34). Antibodies to certain keratin subunits and other novel antigens now available to surgical pathologists have not been tested on a large number of cases.

Objective.-To assist in the differential diagnosis of epithelioid sarcoma and to help elucidate its histogenesis through an expanded immunohistochemical profile.

Design.-Immunohistochemical testing with diverse antibodies was performed on 95 archived epithelioid sarcomas including 73 classic and 22 histologically variant subtypes retrieved from the files of the Armed Forces Institute of Pathology.

Results.-Immunohistochemical reactivity (number positive/number of cases tested [percent positive], frequency of staining) included keratin 14 (31/64 [48%], variable), gamma-catenin (35/74 [47%], variable), keratin 5/6 (10/33 [30%], focal), calretinin (8/40 [20%], focal), keratin 20 (11/71 [15%], focal), p63 (3/20 [15%], focal), whereas 9 invasive cutaneous squamous cell carcinomas showed strong p63 positivity, epithelial-specific antigen (10/74 [14%], variable), CD117/Kit (5/37 [14%], focal), keratin 15 (3/23 [13%], rare cell), mesothelin (2/64 [3%], rare cell), and CD10 (1/41 [2%], rare cell). No reactivity was observed for keratins 2, 5, and 10.

Conclusions.-Diagnostically, p63 and keratin 5/6 distinguish cutaneous squamous cell carcinoma (positive) from epithelioid sarcoma (usually negative). No single immunomarker was able to distinguish the main 4 histologic subtypes of epithelioid sarcoma, indicating that they are all histogenetically related lesions. The limited expression of specific keratin subtypes used in our study supports the notion that epithelioid sarcoma is a mesenchymal neoplasm capable of partial epithelial transformation.

Although tumors with the histologic appearance of epithelioid sarcoma (ES) were first reported in series by Laskowski in 1961,1-2 it was not until 1970 when Enzinger3 fully elucidated the clinicopathological features of the neoplasm and coined the term "epithelioid sarcoma" that the tumor was firmly established as a distinct clinicopathological entity. In general, ES is a relatively rare sarcoma but does represent the most common primary sarcoma of the hand and wrist in large series.2-8 The neoplasm typically manifests clinically as a painless, slow-growing nodule arising within dermis or subcutis or, less commonly, in deep fascial or tenosynovial tissue. Sometimes this innocuous presentation leads to delay in correct pathologic diagnosis and treatment until continued growth or local spread prompts intervention. The clinical course of ES is usually characterized by local recurrence and the potential for metastatic spread mostly to lymph nodes and lung.24-9 Histologically, the classic form of ES consists of mild to moderately pleomorphic epithelioid and plump spindled cells arranged in nodular aggregates that commonly exhibit central necrosis.1 The microscopic resemblance of some examples of classic ES to a benign granulomatous process is a well-recognized phenomenon. More recently, other less commonly encountered morphologic variants of the tumor have been described. These subtypes include the "proximal type" or large cell/rhabdoid ES, which more often arises in deep soft tissue and consists of larger, more pleomorphic-appearing epithelioid cells, some with "rhabdoid" features, arranged in bulky nodules10; the "fibroma-like" variant composed chiefly of relatively bland spindled cells arranged in a storiform and fascicular growth pattern"; and the "angiomatoid" ES that features cyst formation and hemorrhage within tumor nodules.12

The cells of ES immunohistochemically react with a wide array of antibodies. Early studies documented reactivity of the tumor cells for mixed polyclonal13-16 and monoclonal antibodies directed against keratin (K),17-21 antiepithelial membrane antigen.14-16,18,19,21 and anticarcinoembryonic antigen.4,19 These findings together with ultrastructural features of epithelial differentiation15,16,22 supported the light-microscopic impression that ES is a soft-tissue neoplasm that exhibits an epithelial phenotype.8,15-17,19,22 A small number of investigators have reported reactivity for monoclonal antibodies directed against specific keratin subunits, including the "simple" epithelial keratins, K 7, 8, 18, and 19(8,18,23-25); "complex" epithelial keratins, K 5, 14, and 17(8,24,25); and the intermediateto high-molecular-weight keratins, K 4, 6, 10, 13, and 16,(14,18,22,24,25) which are usually found in suprabasal cells of squamous epithelia.

Coexpression of antigens related to mesenchymal lines of differentiation is a nearly consistent feature of ES. Vimentin expression in both epithelioid and spindled cells of ES is observed in virtually every case, and CD34 expression has been documented in approximately 50% of tumors examined.8,26,27 Expression of other mesenchymal antigens in ES has been reported less often. In the largest series evaluating the immunohistochemical profile of ES published to date, muscle-specific actin expression was noted in 41% of examples of classic ES.8 Sporadic and typically focal expression of desmin,10,19 CD31,28,29 S100 protein,8,14 neurofilament protein,23 and neuron-specific enolase14 has been reported in a handful of cases. A few recent studies have focused on the presence of surface adhesion molecules in soft-tissue neoplasms, including ES. One study found neural-type and epithelial-type cadherin expression in 38% and 8% of the 63 examples of ES evaluated, respectively.30 Another group reported expression of vascular-endothelial cadherin expression in 5 of 7 examples of ES but no expression of epithelial-type cadherin.29 Saito et al31 reported membrane expression of betacatenin, a component of the epithelial-type cadherin cell adhesion complex and a mediator of the Wnt signal pathway, in 73% of ESs studied, whereas Kuhnen et al32 found membranous and cytoplasmic expression of the molecule in 2 examples of ES evaluated.