Epithelioid Sarcoma

The American Joint Committee on Cancer (AJCC) or Union for International Cancer Control (UICC) TNM system may be used.

Both classic and proximal-type ESs are associated with almost complete loss of SMARCB1 (INI1) nuclear protein expression, except for extremely rare SMARCB1-retained tumors. The SMARCB1 gene (also called BAF47, INI1, or SNF5), located on 22q11.23, encodes a protein that is part of the SWI/SNF chromatin-remodeling complex present in normal cells. SWI/SNF has ATPase activity and functions to shift the position of nucleosomes, thereby modulating transcription of a large class of genes involved in stem cell biology and differentiation. By immunohistochemistry, recurrent loss of SMARCB1 (INI1) is seen in a limited variety of tumor types, within which the mechanisms of protein loss can be distinct. In ES, SMARCB1 biallelic deletions have been demonstrated by FISH analysis; less frequently, monoallelic deletions and heterogeneous FISH patterns have also been detected. In some cases, decreased SMARCB1 (INI1) protein expression has been associated with negative regulation of SMARCB1 transcripts by microRNAs. An extreme minority of ESs retain SMARCB1 (INI1) protein expression, instead exhibiting abnormal expression of other SWI/SNF chromatin-remodeling complex members, such as SMARCA4 (BRG1), SMARCC1 (BAF155), or SMARCC2 (BAF170); such cases have been correlated with rhabdoid morphology and with adverse prognosis, especially among proximal-type ESs. Unlike in many sarcomas that affect younger patients (especially malignant rhabdoid tumors), genomic analysis of ESs by next-generation sequencing has revealed complex copy-number aberrations (with 22q11.2 and 12p13 being the most frequent losses) and a high overall mutation burden, findings that support the differential diagnosis between ES and malignant rhabdoid tumor. SMARCB1 is the most frequently mutated gene, with or without inactivation of its second allele. By RNA sequencing, the transcriptome shows a unique profile that does not cluster with any particular tissue type or with other SWI/SNF-aberrant model systems.

The classic subtype usually presents as one or more indurated, ill-defined, dermal or subcutaneous nodules measuring a few millimeters to 5 cm. Deep-seated tumors are multinodular masses that extend along nerves and fascial planes. The cut surface is glistening, with a greyish-white or greyish-tan color punctuated by yellow and brown foci representing necrosis and hemorrhage, respectively. The proximal-type subtype presents as solitary or multiple whitish nodules ranging from 1 to 20 cm, with areas of hemorrhage and necrosis.

Classic ES consists of cellular nodules of epithelioid and spindled tumor cells with central degeneration and/or necrosis – a growth pattern that imparts a vaguely granulomatous appearance to the process. Fusion of necrotizing nodules results in a serpiginous mass with central geographical necrosis. Deep-situated lesions spread along the fascia as undulating bands of cells punctuated by foci of necrosis. Both types typically have infiltrative margins, and skip lesions are common in the classic type. Tumor nodules are composed of large ovoid or polygonal epithelioid cells and plump spindle-shaped cells with deeply eosinophilic cytoplasm and mildly atypical nuclei possessing vesicular chromatin and small nucleoli. The epithelioid cells, which are generally concentrated towards the center of the nodule, gradually transition with the spindled element. Epithelioid cells may exhibit cytoplasmic vacuoles, mimicking a vascular tumor. Some cases have predominantly spindled morphology. Mitotic activity is usually low. Dystrophic calcification and metaplastic bone formation are detected in 20% of cases, and aggregates of chronic inflammatory cells are usually present at the periphery of the tumor nodules.

The proximal type is characterized by a multinodular and sheet-like growth of large and sometimes pleomorphic epithelioid (carcinoma-like) cells with enlarged vesicular nuclei and prominent nucleoli. Spotty foci of tumor necrosis are frequently encountered, but this feature does not generally result in a pseudogranulomatous pattern typical of classic ES. Cells with rhabdoid features occur in both forms, but they are more frequently observed in the proximal-type subtype, in which differentiation from extrarenal rhabdoid tumor becomes challenging when the rhabdoid cell is the predominant cell type. Occasional cases may have a prominent myxoid stroma. Additionally, rare cases of ES demonstrate hybrid histological features of both the classic and proximal types.

Both classic and proximal-type ESs show immunoreactivity for epithelial markers, including low- and high-molecular-weight cytokeratins and EMA. More specifically, most cases express CK8 and CK19 but are typically negative or only focally positive for CK5/6. Unlike in carcinoma, CD34 is expressed in > 50% of cases. Loss of nuclear expression of SMARCB1 protein occurs in the vast majority of cases of both types. ERG expression is observed in 40–67% of ESs, predominantly in classic-type cases, which can cause confusion with endothelial tumors.

Not clinically relevant

Clinical series of ES patients have reported 5-year and 10-year overall survival rates of 45–70% and 45–66%, respectively. Overall survival rates drop to 24% in patients with metastatic ES, whereas localized ES patients fare better, with an overall survival rate of 62–88% when patients are treated with R0 surgery. On multivariate analysis, deep location correlates with lower overall survival, accounting for the poorer survival associated with proximal-type ES, which is by definition deep-seated. Conversely, location in the hand correlates with good outcome in localized ES patients treated with R0 surgery. The rates of local recurrence, lymph node dissemination, and metastasis for localized ES are 14–25%, 34–52%, and 33%, respectively. A reported 22–30% of cases are metastatic at the time of diagnosis. Multimodal management of localized ES is said to be associated with better local control rates when surgery is combined with isolated limb perfusion chemotherapy or neoadjuvant radiotherapy.

Not clinically relevant

Essential: tumor presenting as a soft tissue mass (so-called distal or proximal presentations); epithelioid to spindled cytomorphology with infiltrative growth; diffuse loss of SMARCB