Whaley Rumeal D, Sill Daniel R, Tekin Burak, McCarthy Micheal R, Cheville John C, Ebare Kingsley, Stanton Melissa L, Reynolds Jordan P, Raghunathan Aditya, Herrera Hernandez Loren P, Jimenez Rafael E, Sharma Vidit, Boorjian Stephen A, Leibovich Bradley C, Hofich Christopher D, Alvand Saba, Pujari Ganesh P, Kipp Benjamin R, Ketterling Rhett P, Geiersbach Katherine B, Greipp Patricia T, Sukov William R, Halling Kevin C, Gupta Sounak
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
The Department of Laboratory Medicine and Pathology, Mayo Clinic, Phoenix, AZ, USA.
Hum Pathol. 2025 May;159:105797. doi: 10.1016/j.humpath.2025.105797. Epub 2025 May 15.
Molecularly defined renal cell carcinomas include TFE3-rearranged renal cell carcinoma (TFE3-RCC) and TFEB-altered renal cell carcinoma (TFEB-RCC). There is significant morphologic and immunophenotypic overlap between these entities and common renal tumors, such that molecular testing is often required to make the diagnosis. Herein, we reviewed our reference laboratory experience pertaining to TFE3 and TFEB FISH testing, targeted next generation RNA sequencing (NGS), and GPNMB immunohistochemistry (IHC). Most FISH testing (2963/3543, 83.6%) was performed on renal tumors. TFE3 FISH showed rearrangements in 449 of 2467 specimens (18.2%), including 281 (of 1887, 14.9%) renal tumors. TFEB FISH identified an abnormality in 107 of 1076 (9.9%) renal tumors, including 52 (of 107, 48.6%) rearrangements, 41 (of 107, 38.3%) amplifications, or 14 (of 107, 13.1%) with both rearrangements and amplifications. More specifically, TFE3-rearranged, TFEB-rearranged, TFEB-amplified, and TFEB-rearranged/amplified renal tumors occurred in females in 54%, 69.6%, 39.1%, and 40% of cases, respectively. The pediatric and young adult population (aged ≤21 years) included 44 (of 121, 36.3%) TFE3-RCC and 9 (of 50, 18%) TFEB-rearranged RCC. TFE3-RCC fusion partners included RBM10, NONO, ASPSCR1, FUBP1, SFPQ, MAPK1IP1L, and PRCC. TFEB-rearranged RCC fusion partners SYNRG and BYSL were identified. Diffuse GPNMB expression was seen in 92% of TFE3-RCC (24/26; median H-score 275), 100% of TFEB-rearranged RCC (19/19; median H-score 300), and 100% of TFEB-amplified RCC (17/17; 240). Finally, our cohort included 5 eosinophilic TFEB-amplified RCCs with non-focal keratin 20 expression. This large series of TFE3-RCC and TFEB-RCC provides population data regarding these rare tumors and demonstrates the clinical value of targeted FISH strategies. Our results suggest that GPNMB IHC is an effective screen for TFE3-RCC and TFEB-RCC. Additionally, we report a RCC harboring a novel SYNRG::TFEB fusion.
分子定义的肾细胞癌包括TFE3重排肾细胞癌（TFE3-RCC）和TFEB改变肾细胞癌（TFEB-RCC）。这些实体与常见肾肿瘤之间存在显著的形态学和免疫表型重叠，因此通常需要进行分子检测以做出诊断。在此，我们回顾了我们参考实验室在TFE3和TFEB荧光原位杂交（FISH）检测、靶向新一代RNA测序（NGS）以及GPNMB免疫组织化学（IHC）方面的经验。大多数FISH检测（2963/3543，83.6%）是针对肾肿瘤进行的。TFE3 FISH在2467个标本中的449个（18.2%）显示重排，其中包括1887个肾肿瘤中的281个（14.9%）。TFEB FISH在1076个肾肿瘤中的107个（9.9%）检测到异常，包括107个中的52个（48.6%）重排、107个中的41个（38.3%）扩增，或107个中的14个（13.1%）同时存在重排和扩增。更具体地说，TFE3重排、TFEB重排、TFEB扩增以及TFEB重排/扩增的肾肿瘤分别在54%、69.6%、39.1%和40%的病例中发生于女性。儿童和年轻成人（年龄≤21岁）包括44例（121例中的36.3%）TFE3-RCC和9例（50例中的18%）TFEB重排RCC。TFE3-RCC融合伙伴包括RBM10、NONO、ASPSCR1、FUBP1、SFPQ、MAPK1IP1L和PRCC。鉴定出TFEB重排RCC融合伙伴SYNRG和BYSL。在92%的TFE3-RCC（24/26；中位H评分275）、100%的TFEB重排RCC（19/19；中位H评分300）和100%的TFEB扩增RCC（17/17；240）中观察到弥漫性GPNMB表达。最后，我们的队列包括5例嗜酸性TFEB扩增RCC，其具有非局灶性角蛋白20表达。这一大系列的TFE3-RCC和TFEB-RCC提供了关于这些罕见肿瘤的人群数据，并证明了靶向FISH策略具有临床价值。我们的结果表明，GPNMB IHC是TFE3-RCC和TFEB-RCC的有效筛查方法。此外，我们报告了1例携带新型SYNRG::TFEB融合的RCC。
