Perivascular epithelioid cell neoplasms (PEComas) are tumors of uncertain cell lineage that occur across a wide age range, at a variety of anatomic sites, and with a female predominance. Most PEComas are associated with dysregulation of the mTOR pathway, most commonly through inactivating mutations of TSC2 or TSC1. However, a small subset of PEComas are instead associated with TFE3 gene fusions. MITF is closely related to TFE3 and is frequently overexpressed in PEComas, often in a mutually exclusive manner with TFE3. Here we report the clinical, histopathologic, and molecular features of MITF-overexpressing PEComas in a series of 36 cases. The clinical and morphologic features were comparable to conventional PEComa, although the immunohistochemical profile was notable for the relatively limited expression of melanocytic markers, a surprising finding given that MITF is the master regulator of melanocytic differentiation. At the molecular level, 20 cases (56%) showed supernumerary copies of the MITF gene, suggesting a potential explanation for MITF overexpression. A putative genetic driver event within the mTOR pathway was identified in 11 of 15 cases (73%) analyzed by DNA or RNA sequencing. Interestingly, the malignant PEComas showed 2 distinguishing molecular features: they were associated with a complex chromosomal copy number profile, and they tended to show additional genetic changes, most commonly inactivating events involving TP53, RB1, and ATRX. These results elucidate key features of PEComas showing MITF overexpression, begin to explain the molecular basis for MITF overexpression in some PEComas and identify potential molecular correlates for malignancy that may be applicable to the broader PEComa family.

中文翻译：

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MITF 过表达的 PEComa：一系列 36 例病例的临床病理学和分子分析。


血管周围上皮样细胞肿瘤 （PEComas） 是细胞谱系不确定的肿瘤，发生年龄范围广，解剖部位多种多样，以女性为主。大多数 PEComa 与 mTOR 通路失调有关，最常见的是 TSC2 或 TSC1 的失活突变。然而，一小部分 PEComas 反而与 TFE3 基因融合相关。MITF 与 TFE3 密切相关，经常在 PEComas 中过表达，通常与 TFE3 互斥。在这里，我们报告了 36 例 MITF 过表达 PEComas 的临床、组织病理学和分子特征。临床和形态学特征与传统的 PEComa 相当，尽管免疫组织化学特征因黑素细胞标志物的表达相对有限而显着，鉴于 MITF 是黑素细胞分化的主要调节因子，这是一个令人惊讶的发现。在分子水平上，20 例 （56%） 显示 MITF 基因的多余拷贝，表明 MITF 过表达的潜在解释。通过 DNA 或 RNA 测序分析的 15 例病例中有 11 例 （73%） 确定了 mTOR 通路内推定的遗传驱动事件。有趣的是，恶性 PEComas 显示出 2 个不同的分子特征：它们与复杂的染色体拷贝数谱相关，并且它们往往表现出额外的遗传变化，最常见的是涉及 TP53、RB1 和 ATRX 的失活事件。这些结果阐明了显示 MITF 过表达的 PEComas 的关键特征，开始解释某些 PEComas 中 MITF 过表达的分子基础，并确定了可能适用于更广泛的 PEComa 家族的恶性肿瘤的潜在分子相关性。