Primary Renal Neoplasms with the ASPL-TFE3 Gene Fusion of Alveolar Soft Part Sarcoma

Abstract

The unbalanced translocation, der(17)t(X;17)(p11.2;q25), is characteristic of alveolar soft part sarcoma (ASPS). We have recently shown that this translocation fuses the TFE3 transcription factor gene at Xp11.2 to ASPL, a novel gene at 17q25. We describe herein eight morphologically distinctive renal tumors occurring in young people that bear the identical ASPL-TFE3 fusion transcript as ASPS, with the distinction that the t(X;17) translocation is cytogenetically balanced in these renal tumors. A relationship between these renal tumors and ASPS was initially suggested by the cytogenetic finding of a balanced t(X;17)(p11.2;q25) in two of the cases, and the ASPL-TFE3 fusion transcripts were then confirmed by reverse transcriptase-polymerase chain reaction. The morphology of these eight ASPL-TFE3 fusion-positive renal tumors, although overlapping in some aspects that of classic ASPS, more closely resembles renal cell carcinoma (RCC), which was the a priori diagnosis in all cases. These tumors demonstrate nested and pseudopapillary patterns of growth, psammomatous calcifications, and epithelioid cells with abundant clear cytoplasm and well-defined cell borders. By immunohistochemistry, four tumors were negative for all epithelial markers tested, whereas four were focally positive for cytokeratin and two were reactive for epithelial membrane antigen (EMA) (one diffusely, one focally). Electron microscopy of six tumors demonstrated a combination of ASPS-like features (dense granules in four cases, rhomboid crystals in two cases) and epithelial features (cell junctions in six cases, microvilli and true glandular lumens in three cases). Overall, although seven of eight tumors demonstrated at least focal epithelial features by electron microscopy or immunohistochemistry, the degree and extent of epithelial differentiation was notably less than expected for typical RCC. We confirmed the balanced nature of the t(X;17) translocation by fluorescence in situ hybridization in all seven renal tumors thus analyzed, which contrasts sharply with the unbalanced nature of the translocation in ASPS. In summary, a subset of tumors previously considered to be RCC in young people are in fact genetically related to ASPS, although their distinctive morphological and genetic features justify their classification as a distinctive neoplastic entity. Finally, the finding of distinctive tumors being associated with balanced and unbalanced forms of the same translocation is to our knowledge, unprecedented.

Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation

“…Clinicopathologic features of other renal neoplasms with recurrent translocations involving TFE3 have been described (19,34). These tumors include the ''ASPL-TFE3 renal carcinomas'' showing t(X;17)(p11.2;q25) (19), and ''PRCC-TFE3 renal carcinoma'' showing t(X;1)(p11.2;q21) (34).…”

“…These tumors include the ''ASPL-TFE3 renal carcinomas'' showing t(X;17)(p11.2;q25) (19), and ''PRCC-TFE3 renal carcinoma'' showing t(X;1)(p11.2;q21) (34). Like the t(6;11) tumors, these neoplasms seem primarily to affect children and young adults.…”

“…TFE3 translocations occur in distinctive renal carcinomas of childhood and young adults and in alveolar soft part sarcoma. In these translocations, the DNA binding domain of TFE3 is fused to various N-terminal partners, including PRCC, NonO (p54 nrb ), PSF, or ASPL (15)(16)(17)(18)(19)(20). Although the mechanism through which these fusions contribute to oncogenesis remains unclear, several studies suggest that the PRCC-TFE3 (21,22) and ASPL-TFE3 fusion proteins (M.L., unpublished observations) are transcriptional activators.…”

A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23)

“…We and others have recently characterized an additional subset of RCCs characterized by a balanced t(X;17)(p11.2;q25), which results in a fusion of the ASPL (a.k.a. ASPSCR1 or PRCC2) and TFE3 genes (Argani et al, 2001b(Argani et al, , 2002Heimann et al, 2001). Notably, the ASPL-TFE3 gene fusion, arising from an unbalanced der(17) t(X;17)(p11;q25), was originally identified as the recurrent genetic aberration of alveolar soft part sarcoma (ASPS) .…”

“…Notably, the ASPL-TFE3 gene fusion, arising from an unbalanced der(17) t(X;17)(p11;q25), was originally identified as the recurrent genetic aberration of alveolar soft part sarcoma (ASPS) . We have recently found that RCCs associated with PRCC-TFE3 or ASPL-TFE3 can be distinguished from each other by careful morphologic analysis, suggesting that differences in the TFE3 fusion partner can result in subtle but consistent phenotypic differences (Argani et al, 2001b(Argani et al, , 2002. Nonetheless, it is likely that some common features of all TFE3 fusion proteins underlie a common molecular pathogenesis of these cancers.…”