Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231-2410, USA.
Am J Surg Pathol. 2012 Oct;36(10):1516-26. doi: 10.1097/PAS.0b013e3182613d8f.
A subset of renal cell carcinomas (RCCs) is characterized by t(6;11)(p21;q12), which results in fusion of the untranslated Alpha (MALAT1) gene to the TFEB gene. Only 21 genetically confirmed cases of t(6;11) RCCs have been reported. This neoplasm typically demonstrates a distinctive biphasic morphology, comprising larger epithelioid cells and smaller cells clustered around basement membrane material; however, the full spectrum of its morphologic appearances is not known. The t(6;11) RCCs differ from most conventional RCCs in that they consistently express melanocytic immunohistochemical (IHC) markers such as HMB45 and Melan A and the cysteine protease cathepsin K but are often negative for epithelial markers such as cytokeratins. TFEB IHC has been proven to be useful to confirm the diagnosis of t(6;11) RCCs in archival material, because native TFEB is upregulated through promoter substitution by the gene fusion. However, IHC is highly fixation dependent and has been proven to be particularly difficult for TFEB. A validated fluorescence in situ hybridization (FISH) assay for molecular confirmation of the t(6;11) RCC in archival formalin-fixed, paraffin-embedded material has not been previously reported. We report herein the development of a break-apart TFEB FISH assay for the diagnosis of t(6;11)(p21;q12) RCCs. We validated the assay on 4 genetically confirmed cases and 76 relevant expected negative control cases and used the assay to report 8 new cases that expand the clinicopathologic spectrum of t(6;11) RCCs. An additional previously reported TFEB IHC-positive case was confirmed by TFEB FISH in 46-year-old archival material. In conclusion, TFEB FISH is a robust, clinically validated assay that can confirm the diagnosis of t(6;11) RCC in archival material and should allow a more comprehensive clinicopathologic delineation of this recently recognized neoplastic entity.
一部分肾细胞癌（RCC）的特征是 t(6;11)(p21;q12)，这导致未翻译的 Alpha（MALAT1）基因与 TFEB 基因融合。仅有 21 例经基因证实的 t(6;11)RCC 病例被报道。这种肿瘤通常表现出独特的双相形态，包含较大的上皮样细胞和围绕基底膜物质聚集的较小细胞；然而，其完整的形态表现谱尚不清楚。t(6;11)RCC 与大多数传统的 RCC 不同，它们始终表达黑色素细胞免疫组织化学（IHC）标志物，如 HMB45 和 Melan A 和半胱氨酸蛋白酶组织蛋白酶 K，但通常为上皮标志物如细胞角蛋白阴性。TFEB IHC 已被证明可用于在存档材料中确认 t(6;11)RCC 的诊断，因为通过基因融合的启动子替代，天然 TFEB 被上调。然而，IHC 高度依赖于固定，并且已经被证明对于 TFEB 特别困难。以前没有报道过在存档的福尔马林固定、石蜡包埋材料中用于分子确认 t(6;11)RCC 的经过验证的荧光原位杂交（FISH）检测。我们在此报告了用于诊断 t(6;11)(p21;q12)RCC 的 TFEB 断裂分离 FISH 检测的开发。我们在 4 例经基因证实的病例和 76 例相关的预期阴性对照病例中验证了该检测，并使用该检测报告了 8 例新病例，扩大了 t(6;11)RCC 的临床病理谱。另一个以前报道的 TFEB IHC 阳性病例在 46 岁的存档材料中通过 TFEB FISH 得到证实。总之，TFEB FISH 是一种强大的、经过临床验证的检测方法，可以在存档材料中确认 t(6;11)RCC 的诊断，并且应该允许更全面地描绘这种最近被认识到的肿瘤实体的临床病理特征。
