TFE3-Fusion Variant Analysis Defines Specific Clinicopathologic Associations Among Xp11 Translocation Cancers

Abstract

Xp11 translocation cancers include Xp11 translocation renal cell carcinoma (RCC), Xp11 translocation perivascular epithelioid cell tumor (PEComa), and melanotic Xp11 translocation renal cancer. In Xp11 translocation cancers, oncogenic activation of TFE3 is driven by the fusion of TFE3 with a number of different gene partners; however, the impact of individual fusion variant on specific clinicopathologic features of Xp11 translocation cancers has not been well defined. In this study, we analyze 60 Xp11 translocation cancers by fluorescence in situ hybridization using custom bacterial artificial chromosome probes to establish their TFE3 fusion gene partner. In 5 cases RNA sequencing was also used to further characterize the fusion transcripts. The 60 Xp11 translocation cancers included 47 Xp11 translocation RCC, 8 Xp11 translocation PEComas, and 5 melanotic Xp11 translocation renal cancers. A fusion partner was identified in 53/60 (88%) cases, including 18 SFPQ (PSF), 16 PRCC, 12 ASPSCR1 (ASPL), 6 NONO, and 1 DVL2. We provide the first morphologic description of the NONO-TFE3 RCC, which frequently demonstrates subnuclear vacuoles leading to distinctive suprabasal nuclear palisading. Similar subnuclear vacuolization was also characteristic of SFPQ-TFE3 RCC, creating overlapping features with clear cell papillary RCC. We also describe the first RCC with a DVL2-TFE3 gene fusion, in addition to an extrarenal pigmented PEComa with a NONO-TFE3 gene fusion. Furthermore, among neoplasms with the SFPQ-TFE3, NONO-TFE3, DVL2-TFE3, and ASPL-TFE3 gene fusions, the RCCs are almost always PAX8 positive, cathepsin K negative by immunohistochemistry, whereas the mesenchymal counterparts (Xp11 translocation PEComas, melanotic Xp11 translocation renal cancers, and alveolar soft part sarcoma) are PAX8 negative, cathepsin K positive. These findings support the concept that despite an identical gene fusion, the RCCs are distinct from the corresponding mesenchymal neoplasms, perhaps due to the cellular context in which the translocation occurs. We corroborate prior data showing that the PRCC-TFE3 RCCs are the only known Xp11 translocation RCC molecular subtype that are consistently cathepsin K positive. In summary, our data expand further the clinicopathologic features of cancers with specific TFE3 gene fusions and should allow for more meaningful clinicopathologic associations to be drawn.

Figure 1

FISH analysis of TFE3 fusion partner genes. All four neoplasms (A–D) in this composite image demonstrated TFE3 gene rearrangements by FISH. A. RCC with NONO-TFE3 fusion (Table 1, case 3): 3-color FISH fusion assay shows the 5′ NONO (red, centromeric) signal is fused to the 3′TFE3 probes (green, telomeric); while the 5′TFE3 probe (orange, centromeric) is split apart. B. DVL2-TFE3 fusion positive RCC: arrows show 3 cells with DVL2 break-apart signals (red, centromeric; green, telomeric); C. RCC with SFPQ-TFE3 fusion (Table 4, case 4): arrows show 3 cells demonstrating split SFPQ signals (red, centromeric; green, telomeric). D. RCC with PRCC-TFE3 fusion (Table 4, case 4): arrows show 3 cells with break-apart PRCC signals (red, centromeric; green, telomeric).

Figure 2

NONO-TFE3 RCC (Table 1, case 1). A and B, this neoplasm demonstrated nested to papillary architecture. The neoplastic cells have predominantly clear cytoplasm and demonstrate sub-nuclear vacuolization, leading to apical palisading of nuclei. The neoplastic cells demonstrate nuclear labeling for PAX8 (C) but not for cathepsin K (D). Note the intact labeling of endothelial cells as an internal control for cathepsin K labeling.

Figure 3

NONO-TFE3 RCC (Table 1, case 4). A and B, this neoplasm demonstrated nested to papillary architecture. The neoplastic cells have predominantly clear cytoplasm and demonstrate sub-nuclear vacuolization, leading to apical palisading of nuclei. The neoplastic cells demonstrate nuclear labeling for PAX8 (C) but not for cathepsin K (D). Note the intact labeling of endothelial cells as an internal control for cathepsin K labeling.

Figure 4

NONO-TFE3 melanotic PEComa (Table 1, case 6). A and B, this is a neoplasm with nested to alveolar architecture, which features epithelioid cells with clear to finely granular eosinophilic cytoplasm. Fine pigment which proves to be melanin is present in the cytoplasm. The neoplasm was immunoreactive for melan A (not shown). The neoplasm does not label for PAX8 (C) but shows diffuse immunoreactivity for cathepsin K (D).

Figure 5

DVL2-TFE3 RCC. This neoplasm demonstrates a variety of morphologic patterns. Much of the neoplasm has basophilic to pale cytoplasm, and demonstrates tubular and papillary architecture (A) each merges with sarcomatoid areas (B, C). Other areas on the same slides demonstrated more oncocytic cytoplasm (D). The neoplasm demonstrated nuclear immunoreactivity for PAX8 (E) but did not label for cathepsin K (F). Note the intact labeling of capillaries and associated macrophages as an internal control for cathepsin K labeling.

Figure 6

SFPQ-TFE3 renal cell carcinoma (Table 2, case 5). This neoplasm demonstrated solid nested architecture (A and B), and demonstrated abundant clear cytoplasm with prominent sub-nuclear vacuoles leading to apical palisading of nuclei. This case was originally classified as a clear cell RCC. The neoplasm demonstrated nuclear labeling for PAX8 (C) but was negative for cathepsin K (D). Note the intact staining of endothelial cells as an internal control for cathepsin K labeling.

Figure 7

SFPQ-TFE3 renal cell carcinoma (Table 2, case 4). A and B, this neoplasm demonstrated solid nested to papillary architecture, and striking sub-nuclear vacuoles leading to apical palisading of nuclei. The neoplasm was diffusely immunoreactive for PAX8 but not for cathepsin K. Note the intact staining of endothelial cells as an internal control for cathepsin K labeling.

Figure 8

SPFQ-TFE3 PEComa. (Table 2, case 9). This neoplasm was centered in the renal pelvis (A). The neoplasm was highly vascular, and had a nested to an alveolar architecture (B). The neoplastic cells had abundant clear to finely granular eosinophilic cytoplasm (C). The neoplasm was negative for cytokeratins, but showed labeling for HMB45 (D). The neoplasm was negative for PAX8 (E) but demonstrated diffuse labeling for cathepsin K (F).