TFE3-Rearranged Tumors of the Kidney: An Emerging Conundrum

Abstract

Background: Identical translocations involving the TFE3 gene and various partners have been found in both renal and soft tissue tumors, like alveolar soft part sarcoma (ASPSCR1), ossifying fibromyxoid tumor (PHF1), epithelioid hemangioendothelioma, and the clear cell stromal tumor of the lung (YAP1). Methods: Herein, we review in detail the clinicopathologic and molecular data of TFE3-rearranged renal tumors and propose our perspective, which may shed light on this emerging conundrum. Results: Among the kidney tumors carrying TFE3 translocations, most are morphologically heterogeneous carcinomas labeling for the tubular marker PAX8. The others are mesenchymal neoplasms known as PEComas, characterized by epithelioid cells co-expressing smooth muscle actin, cathepsin-K, melanogenesis markers, and sometimes melanin pigment deposition. Over the past 30 years, numerous TFE3 fusion partners have been identified, with ASPL/ASPSCR1, PRCC, SFPQ/PSF, and NONO being the most frequent. Conclusions: It is not well understood why similar gene fusions can give rise to renal tumors with different morpho-immunophenotypes, which may contribute to the recent disagreement regarding their classification. However, as these two entities, respectively, epithelial and mesenchymal in nature, are widely recognized by the pathology community and their clinicopathologic features well established, we overall believe it is still better to retain the names TFE3-rearranged renal cell carcinoma and TFE3-rearranged PEComa.

Keywords: TFE3 gene; genetic fusions; renal PEComa; renal cell carcinoma; tumor classification.

Figure 1

Structure of the TFE3 gene (A). Physiologically, the TFE3 transcriptional factor works as a dimer with other MiTF/TFE family proteins. In nutrient-replete settings, these complexes are recruited to the lysosomal membranes by amino acids and RagGTases such as RagA and RagC, which allow MTORC1-mediated phosphorylation and, consequently, ubiquitination by CUL1^β-TrCP1/2 and proteasomal degradation. On the other hand, the lack of nutrients in starvation/hypoxic conditions lets TFE3 translocate to the cell nucleus, where it can modulate the transcription of key downstream genes involved in lysosomal activity, autophagy, and other catabolic processes (B). AD: activation domain; bHLH: basic helix–loop–helix domain; LZ: leucine zipper domain.

Figure 2

Schematic representation of a TFE3::SFPQ fusion, with the breakpoints occurring at exon 5 of the TFE3 gene (mapped at chromosome 1) and exon 9 of the SFPQ gene (located at chromosome 1), respectively.

Figure 3

TFE3-rearranged renal cell carcinoma morphological variability, immunohistochemical and molecular findings. A case showing solid–trabecular neoplasms made up of large eosinophilic cells intermingled with several psammoma bodies (A). Another one revealed a papillary architecture (B), strongly and diffusely labeling for cathepsin K (C) and PAX8 (D).

Figure 4

Positive TFE3 immunohistochemical staining in an example of TFE3-rearranged renal cell carcinoma (A). FISH in TFE3-rearranged renal cell carcinoma. The distant red and green signals demonstrate the TFE3 gene translocation using a break-apart probe (B).

Figure 5

Genetic fusion pattern distribution among TFE3-rearranged PEComas from different sites, highlighting the higher frequency of kidney tumors [39,42,76,77,78,79,80,81,82,83,84] compared to the other organs (A). Break-point distribution in SFPQ/PFS-TFE3-rearranged PEComas and renal cell carcinomas (B).

Figure 6

Conventional PEComa composed of spindle cells arranged in a fascicular pattern (A). TFE3-rearranged PEComa made up of clear to eosinophilic cells displaying a nested to solid carcinoma architecture, not uncommonly with melanin pigment deposition (B). FISH images from conventional PEComa (C) and TFE3-rearranged PEComa (D), the latter revealing multiple breaks of the investigated probes witnessing an underlying genetic fusion. As for immunohistochemistry, TFE3-rearranged PEComas usually stain positive for melanocytic markers, like HMB45 (E), and cathepsin K (F).