Department of Pathology, Indiana University School of Medicine, 305 W 11 Street, Room 4080, Indianapolis, IN, USA.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
Virchows Arch. 2024 Sep;485(3):471-478. doi: 10.1007/s00428-024-03855-z. Epub 2024 Jul 7.
Angiomyolipoma (AML) is a neoplasm within the perivascular epithelioid cell tumor family that occurs somewhat frequently in the kidney. Most are indolent and discovered incidentally, with rare tumors demonstrating malignant clinical behavior. A small subset of renal AMLs with epithelioid features are associated with aggressive behavior, and may demonstrate morphologic overlap with renal cell carcinomas (e.g., clear cell renal cell carcinoma (RCC), TFE3-rearranged RCC). Prior studies of spindle cell and epithelioid AMLs have identified rare examples with underlying TFE3 gene fusions. TFE3 protein expression (demonstrated by immunohistochemistry) with no evidence of concurrent TFE3 rearrangements has been reported previously in 4/24 AMLs (17%) (Argani et al. Am J Surg Pathol 34:1395-1406, 2010). Currently, the relationship between TFE3 protein expression, TFE3 fusions, and expression of TFE3-mediated genes remains incompletely understood in renal epithelioid AMLs. We sought to explore these relationships using TFE3 break-apart fluorescence in situ hybridization (FISH) and TRIM63 RNA in situ hybridization (ISH) on epithelioid AMLs with moderate to strong TFE3 expression by immunohistochemistry. RNA sequencing (fusion panel) was performed on two cases with negative FISH results to assess for FISH-cryptic gene fusions. The series comprised five epithelioid AMLs from four patients (three women, one man) aged 13 to 76 years. All were considered positive for TFE3 by immunohistochemistry (2 + /3 + expression). TRIM63 ISH was performed on four specimens from three patients, yielding positive results in 3/3 tumors (100%) that were successfully analyzed. TFE3 break-apart FISH was performed on all samples, demonstrating a TFE3 rearrangement in only 1/4 tumors (25%). RNA sequencing demonstrated the absence of productive TFE3 gene fusions in three tumors with negative break-apart TFE3 FISH results. This study demonstrates that renal epithelioid AMLs overexpress TFE3 and TFE3-mediated genes (TRIM63) even in the absence of TFE3 rearrangements. This finding could be explained by functional upregulation of TFE3 secondary to activation of the mammalian target of rapamycin complex 1 (mTORC1). Expression of TFE3 and TRIM63 in this tumor type represents a potential pitfall, given the morphologic and immunophenotypic overlap between epithelioid AML and TFE3-altered renal cell carcinoma.
血管平滑肌脂肪瘤 (AML) 是一种发生于血管周上皮样细胞肿瘤家族的肿瘤，在肾脏中较为常见。大多数肿瘤生长缓慢，为偶然发现，极少数肿瘤具有恶性临床行为。一小部分具有上皮样特征的肾 AML 与侵袭性行为相关，并且可能与肾细胞癌 (例如透明细胞肾细胞癌 (RCC)、TFE3 重排的 RCC) 具有形态学重叠。先前对梭形细胞和上皮样 AML 的研究已经发现了少数具有潜在 TFE3 基因融合的病例。先前已经报道过在 24 例 AML 中有 4 例（17%）存在 TFE3 蛋白表达（通过免疫组化证实）而没有同时存在 TFE3 重排的情况（Argani 等人，Am J Surg Pathol 34:1395-1406, 2010）。目前，在肾上皮样 AML 中，TFE3 蛋白表达、TFE3 融合与 TFE3 介导的基因表达之间的关系仍不完全清楚。我们试图使用免疫组化中 TFE3 表达强阳性的上皮样 AML 进行 TFE3 断裂分离荧光原位杂交 (FISH) 和 TRIM63 RNA 原位杂交 (ISH) 来探索这些关系。对两个 FISH 结果阴性的病例进行 RNA 测序 (融合面板)，以评估是否存在 FISH 隐匿性基因融合。该系列包括来自 4 名患者（3 名女性，1 名男性）的 5 例上皮样 AML，年龄为 13 至 76 岁。所有患者的 TFE3 免疫组化结果均为阳性（2+/3+表达）。对来自 3 名患者的 4 个标本进行了 TRIM63 ISH，在 3/3 成功分析的肿瘤中均得到阳性结果（100%）。对所有样本均进行了 TFE3 断裂分离 FISH，仅在 4 例肿瘤中有 1 例（25%）显示 TFE3 重排。RNA 测序显示，在 3 例 TFE3 断裂分离 FISH 结果阴性的肿瘤中均不存在有活性的 TFE3 基因融合。这项研究表明，即使没有 TFE3 重排，肾上皮样 AML 也会过度表达 TFE3 和 TFE3 介导的基因 (TRIM63)。这一发现可以通过哺乳动物雷帕霉素靶蛋白复合物 1 (mTORC1) 的激活导致 TFE3 的功能上调来解释。在具有上皮样 AML 和 TFE3 改变的肾细胞癌之间存在形态学和免疫表型重叠的情况下，这种肿瘤类型中 TFE3 和 TRIM63 的表达代表了一个潜在的陷阱。
