Department of Pathology, Nanjing Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, China.
Department of Pathology, Linyi People's Hospital, Linyi, Shandong, China.
Mod Pathol. 2018 Sep;31(9):1346-1360. doi: 10.1038/s41379-018-0051-5. Epub 2018 Apr 30.
Both Xp11 translocation renal cell carcinomas and the corresponding mesenchymal neoplasms are characterized by a variety of gene fusions involving TFE3. It has been known that tumors with different gene fusions may have different clinicopathologic features; however, further in-depth investigations of subtyping Xp11 translocation-associated cancers are needed in order to explore more meaningful clinicopathologic correlations. A total of 22 unusual cases of Xp11 translocation-associated cancers were selected for the current study; 20 cases were further analyzed by RNA sequencing to explore their TFE3 gene fusion partners. RNA sequencing identified 17 of 20 cases (85%) with TFE3-associated gene fusions, including 4 ASPSCR1/ASPL-TFE3, 3 PRCC-TFE3, 3 SFPQ/PSF-TFE3, 1 NONO-TFE3, 4 MED15-TFE3, 1 MATR3-TFE3, and 1 FUBP1-TFE3. The results have been verified by fusion fluorescence in situ hybridization (FISH) assays or reverse transcriptase polymerase chain reaction (RT-PCR). The remaining 2 cases with specific pathologic features highly suggestive of MED15-TFE3 renal cell carcinoma were identified by fusion FISH assay. We provide the detailed morphologic and immunophenotypic description of the MED15-TFE3 renal cell carcinomas, which frequently demonstrate extensively cystic architecture, similar to multilocular cystic renal neoplasm of low malignant potential, and expressed cathepsin K and melanotic biomarker Melan A. This is the first time to correlate the MED15-TFE3 renal cell carcinoma with specific clinicopathologic features. We also report the first case of the corresponding mesenchymal neoplasm with MED15-TFE3 gene fusion. Additional novel TFE3 gene fusion partners, MATR3 and FUBP1, were identified. Cases with ASPSCR1-TFE3, SFPQ-TFE3, PRCC-TFE3, and NONO-TFE3 gene fusion showed a wide variability in morphologic features, including invasive tubulopapillary pattern simulating collecting duct carcinoma, extensive calcification and ossification, and overlapping and high columnar cells with nuclear grooves mimicking tall cell variant of papillary thyroid carcinoma. Furthermore, we respectively evaluated the ability of TFE3 immunohistochemistry, TFE3 FISH, RT-PCR, and RNA sequencing to subclassify Xp11 translocation-associated cancers. In summary, our study expands the list of TFE3 gene fusion partners and the clinicopathologic features of Xp11 translocation-associated cancers, and highlights the importance of subtyping Xp11 translocation-associated cancers combining morphology, immunohistochemistry, and multiple molecular techniques.
Xp11 易位性肾细胞癌和相应的间叶性肿瘤均表现为涉及 TFE3 的多种基因融合。已知不同基因融合的肿瘤可能具有不同的临床病理特征；然而，为了探索更有意义的临床病理相关性，需要对 Xp11 易位相关癌症进行更深入的亚型分类研究。本研究共选择了 22 例不典型的 Xp11 易位相关癌症病例；其中 20 例进一步通过 RNA 测序分析以探索其 TFE3 基因融合伙伴。RNA 测序鉴定出 20 例中的 17 例（85%）存在 TFE3 相关基因融合，包括 4 例 ASPSCR1/ASPL-TFE3、3 例 PRCC-TFE3、3 例 SFPQ/PSF-TFE3、1 例 NONO-TFE3、4 例 MED15-TFE3、1 例 MATR3-TFE3 和 1 例 FUBP1-TFE3。这些结果通过融合荧光原位杂交（FISH）检测或逆转录聚合酶链反应（RT-PCR）得到验证。另外 2 例具有高度提示 MED15-TFE3 肾细胞癌的特定病理特征的病例通过融合 FISH 检测得到鉴定。我们提供了 MED15-TFE3 肾细胞癌的详细形态学和免疫表型描述，其常表现为广泛的囊性结构，类似于低度恶性潜能的多房囊性肾肿瘤，并表达组织蛋白酶 K 和黑色素标志物 Melan A。这是首次将 MED15-TFE3 肾细胞癌与特定的临床病理特征相关联。我们还报告了首例具有 MED15-TFE3 基因融合的相应间叶性肿瘤。此外，还鉴定了其他新型 TFE3 基因融合伙伴 MATR3 和 FUBP1。ASPSCR1-TFE3、SFPQ-TFE3、PRCC-TFE3 和 NONO-TFE3 基因融合病例的形态特征具有广泛的变异性，包括模拟集合管癌的侵袭性管状乳头模式、广泛的钙化和骨化以及重叠和高柱状细胞，核沟类似甲状腺乳头状癌的高柱状细胞变体。此外，我们分别评估了 TFE3 免疫组化、TFE3 FISH、RT-PCR 和 RNA 测序对 Xp11 易位相关癌症进行分类的能力。总之，本研究扩展了 TFE3 基因融合伙伴和 Xp11 易位相关癌症的临床病理特征列表，并强调了结合形态学、免疫组化和多种分子技术对 Xp11 易位相关癌症进行亚型分类的重要性。
