PEComa (Perivascular Epithelioid Tumour)

Not clinically relevant

Loss of heterozygosity involving the TSC2 locus has been found. Deletion of 16p, the location of the TSC2 gene, indicates the oncogenetic relationship of PEComas and angiomyolipomas as TSC2-linked neoplasms. TP53 mutations have been identified in 63% of TSC2-mutated PEComas. A small subset of PEComas harbor TFE3 gene fusions, which correlate with strong nuclear immunoreactivity for TFE3. The most common fusion partner with TFE3 is SFPQ (PSF). DVL2-TFE3 and NONO-TFE3 gene fusions have also been identified in PEComa arising in soft tissue. TFE3-rearranged PEComa lacks TSC2 mutations/loss of heterozygosity and thus appears to be pathogenetically distinct.

PEComas are grossly well circumscribed, with a firm and fibrous or fleshy cut surface. Tumors show a wide size range (mean: 5–8 cm); cutaneous tumors are usually smaller than those arising at deep locations.

PEComas typically show a nested architecture and are composed of epithelioid cells with abundant granular eosinophilic or clear cytoplasm and round nuclei with small nucleoli. The nests or trabeculae are typically surrounded by thin-walled capillary vessels. A small subset of tumors have predominantly spindle cell morphology. PEComa usually shows a distinctive perivascular pattern of growth, with tumor cells radially arranged around vessels, replacing the vessel wall and approaching the endothelium. The sclerosing subtype of PEComa is composed of cords and trabeculae of epithelioid cells in a densely collagenous stroma. Epithelioid angiomyolipoma is synonymous with PEComa. Typical PEComa may contain occasional multinucleated cells and show limited pleomorphism (symplastic change), but mitotic figures are usually scarce or absent. Malignant PEComas are characterized by a variable combination of mitotic activity, necrosis, and pleomorphism.

PEComas characteristically express both melanocytic markers, such as HMB45 (the most sensitive immunomarker), melan-A, and MITF, and muscle markers, such as SMA, desmin, and caldesmon. Expression of melanocytic markers is more common in epithelioid than spindled tumor cells. Desmin and h-caldesmon are often less extensively positive than SMA. Some tumors lack expression of muscle markers. Nuclear expression of S100 is generally not observed in PEComas. Approximately 15% of cases show strong nuclear staining for TFE3. PEComas with TFE3 rearrangement tend to occur in younger patients, have a prominent alveolar growth pattern and epithelioid morphology, and often lack expression of smooth muscle markers. Occasional TFE3-rearranged epithelioid but non-epithelial neoplasms contain melanin pigment; these were initially described in the kidney as melanotic Xp11 translocation renal cancer, but they have also been described in soft tissue and most closely fit into the category of TFE3-rearranged PEComa.

Not clinically relevant

Clinically malignant tumors are typically large; show marked nuclear atypia and pleomorphism, conspicuous mitoses, necrosis, and infiltrative margins; and tend to pursue an aggressive clinical course. Tumor size > 5 cm has also been significantly associated with recurrence. The most common metastatic sites are the liver, lymph nodes, lungs, and bone.

For cases with strong TFE3 protein expression, identification of TFE3 gene rearrangement or a corresponding fusion gene can help confirm the diagnosis.

Essential: epithelioid and/or spindle cells with granular eosinophilic to clear cytoplasm; nested, trabecular, or sheet-like architecture with frequent perivascular orientation; variable coexpression of melanocytic and smooth muscle markers.

Desirable: TFE3 expression if smooth muscle markers are negative.