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 (FISH) using custom BAC probes to establish their TFE3 fusion gene partner. In 5 cases RNA sequencing (RNA-seq) 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 sub-nuclear vacuoles leading to distinctive suprabasal nuclear palisading. Similar sub-nuclear 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 RCC 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 RCC are the only known Xp11 translocation RCC molecular subtype which is 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.

Morphologic, Molecular, and Taxonomic Evolution of Renal Cell Carcinoma: A Conceptual Perspective With Emphasis on Updates to the 2016 World Health Organization Classification

“…The varied morphologic spectrum of t-RCC, however, cannot be understated and includes tumors showing areas of overlap with common RCC subtypes, including CCRCC, RCC with eosinophilic (oncocytic) cytoplasm, and papillary RCC (PRCC). In fact, recent studies describe Xp11-associated t-RCC demonstrating morphologic overlap with CCPRCC 29,30 ( Figure 1, E). Therefore, a high level of suspicion for t-RCC is appropriate in children and younger patients, as well as in older patients who have tumors with unusual or mixed morphologies.…”

RBM10-TFE3 Renal Cell Carcinoma

“…Case 2 had prominent psamomma bodies, while case 3 demonstrated focally a second population of smaller cells as has been described previously in both t(6;11) RCC and Xp11 translocation RCC 12, 23 , especially those with the SFPQ-TFE3 gene fusion 27 . Cases 1 and 3 demonstrated foci of subnuclear cytoplasmic vacuolization as often seen in the SFPQ-TFE3 and NONO-TFE3 RCCs 7. Melanin pigment was not identified in any case.…”

“…Underexpression of cytokeratins is a useful clue to the diagnosis 1,2 , which can be substantiated by aberrant expression of cathepsin k and /or melanocytic markers. Absence of the latter two markers essentially excludes the t(6;11) RCC, but does not exclude Xp11 translocation RCC which will be cathepsin K negative in approximately 50% of cases depending upon fusion type 7,14,15 . As our study shows, even a negative conventional TFE3 break-apart FISH study does not exclude the diagnosis of Xp11 translocation RCC, and such cases require more specialized testing for confirmation…”

“…Known TFE3 fusion partners include ASPSCR1 (ASPL), PRCC, SFPQ1 (PSF), NONO, CLTC, PARP14, LUC7L3, DVL2, and KHSRP 1, 2, 3, 4, 5, 6, 7 . Xp11 translocation RCC comprise the majority of pediatric RCC and approximately 1–4% of adult RCC 8–11 .…”

“…One possibility is that these cases demonstrate subtle cytogenetic alterations involving the TFE3 gene at the Xp11.2 locus which are not detectable by FISH resolution. Along these lines, the NONO-TFE3 gene fusion resulting from the intra-chromosomal X inversion, inv(X) (p11.2;q13.1), can be difficult to detect by TFE3 break-apart FISH, often resulting in small constant gaps between the TFE3 signals 7, 12 .…”