血管平滑肌脂肪瘤（AML）是血管周围上皮样细胞肿瘤家族中的一种肿瘤，在肾脏中经常发生。大多数是惰性的并且是偶然发现的，罕见的肿瘤表现出恶性的临床行为。一小部分具有上皮样特征的肾 AML 与攻击行为相关，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）表现出形态学重叠。先前对梭形细胞和上皮样 AML 的研究已经发现了具有潜在 TFE3 基因融合的罕见例子。先前在 4/24 AML (17%) 中报道过 TFE3 蛋白表达（通过免疫组织化学证明），但没有并发 TFE3 重排的证据（Argani 等人，Am J Surg Pathol 34:1395-1406, 2010）。目前，肾上皮样 AML 中 TFE3 蛋白表达、TFE3 融合和 TFE3 介导基因表达之间的关系仍不完全清楚。我们试图通过免疫组织化学方法，对具有中度至强 TFE3 表达的上皮样 AML 使用 TFE3 断裂荧光原位杂交 (FISH) 和 TRIM63 RNA 原位杂交 (ISH) 来探索这些关系。对两例 FISH 结果呈阴性的病例进行 RNA 测序（融合组），以评估 FISH 隐性基因融合情况。该系列包括来自 4 名年龄在 13 岁至 76 岁之间的患者（三名女性，一名男性）的 5 例上皮样 AML。免疫组织化学结果显示，所有样本均呈 TFE3 阳性（2  /3  表达）。 TRIM63 ISH 对三名患者的四份标本进行了检测，在成功分析的 3/3 肿瘤（100%）中产生了阳性结果。对所有样本进行 TFE3 断裂 FISH，证明仅 1/4 肿瘤 (25%) 中存在 TFE3 重排。 RNA 测序表明，三个肿瘤中不存在有效的 TFE3 基因融合，且断裂 TFE3 FISH 结果为阴性。这项研究表明，即使在没有 TFE3 重排的情况下，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复合物靶标 1 (mTORC1) 激活继发的 TFE3 功能上调来解释。鉴于上皮样 AML 和 TFE3 改变的肾细胞癌之间的形态学和免疫表型重叠，TFE3 和 TRIM63 在这种肿瘤类型中的表达代表了一个潜在的陷阱。© 2024。作者获得 Springer-Verlag GmbH 德国的独家许可，施普林格自然的一部分。

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.© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.