PEComa-like Neoplasms Characterized by ASPSCR1-TFE3 Fusion: Another Face of TFE3-related Mesenchymal Neoplasia

Abstract

Identical TFE3-related gene fusions may be found in renal cell carcinoma and mesenchymal neoplasms such as alveolar soft part sarcoma and TFE3-rearranged perivascular epithelioid cell tumor (PEComa). Among mesenchymal neoplasms, the ASPSCR1-TFE3 gene fusion has previously been described only in alveolar soft part sarcoma. We report 3 unusual mesenchymal neoplasms harboring the ASPSCR1-TFE3 gene fusion, the morphologic phenotype of which more closely matches PEComa rather than alveolar soft part sarcoma. All 3 neoplasms occurred in females ranging in age from 18 to 34 years and were located in the viscera (kidney, bladder, and uterus). All 3 contained nests of epithelioid cells bounded by fibrovascular septa. However, all were associated with hyalinized stroma, tight nested architecture, mixed spindle cell and epithelioid pattern, clear cytoplasm, and lacked significant discohesion. Overall, morphologic features closely resembled PEComa, being distinct from the typical alveolar soft part sarcoma phenotype. While none of the neoplasms labeled for HMB45, cytokeratin, or PAX8 all showed positivity for TFE3 and cathepsin K, and all except 1 were positive for smooth muscle actin. One patient developed a liver metastasis 7 years after nephrectomy. These cases bridge the gap between 2 TFE3-rearranged neoplasms, specifically alveolar soft part sarcoma and Xp11 translocation PEComa, highlighting the relatedness and overlap among Xp11 translocation neoplasms. While most TFE3-rearranged neoplasms can be confidently placed into a specific diagnostic category such as alveolar soft part sarcoma, PEComa, or Xp11 translocation renal cell carcinoma, occasional cases have overlapping features, highlighting the potential role that the cell of origin and the specific gene fusion play in the phenotype of these neoplasms.

Figure 1

(case 1): This primary renal neoplasm has a multinodular appearance as it abuts the native kidney to the right (A). Areas of gross calcification correspond to extensive hyalinization and ossification, associated with compacted clusters of epithelioid cells with clear cytoplasm (B). Perivascular hyalinization separates arterioles from clusters of spindled to epithelioid neoplastic cells (C). The majority of the neoplasm consists of spindle cells with rectangular-shaped nuclei (D). Focal marked nuclear atypia is present (E). The neoplastic cells demonstrate cytoplasmic labeling for smooth muscle actin (F) and cathepsin K (G). They demonstrate nuclear positivity with TFE3: note the adjacent renal tubule which does not label at the top of the image (H).

Figure 2

(case 2): This spindled to epithelioid bladder neoplasm undermines the uninvolved urothelium of the bladder at the left (A). The neoplastic cells have predominantly eosinophilic cytoplasm, and have both epithelioid (right) and spindled (left) morphology (B). The neoplastic cells demonstrate cytoplasmic labeling for smooth muscle actin, similar to that of the pericytes of the entrapped blood vessel (C). The neoplastic cells demonstrate diffuse cytoplasmic labeling for cathepsin K (D).

Figure 3

(case 3): This neoplasm is centered in the uterine myometrium (bottom of image) (A). The neoplastic cells are both spindled and epithelioid, and demonstrate prominent cytologic atypia as well as stromal hyalinization (B). The neoplastic cells surround and infiltrate the wall of an intratumoral blood vessel, a common finding in PEComa (C). In this epithelioid area, the neoplastic cells have eosinophilic or clear cytoplasm, and form compact nests without significant discohesion (D). This spindled cell area demonstrates poorly formed fascicles and cytologic atypia (E). The neoplastic cells demonstrate diffuse cytoplasmic labeling for cathepsin K (F).

Figure 4:

FISH analysis of ASPSCR1-TFE3 fusion positive PEComa-like Neoplasm (Case 3): Cells with ASPSCR1 break-apart signals (red, centromeric; green, telomeric) (A); and TFE3 break-apart signals (red, centromeric; green, telomeric) (B).