Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
INSERM 1052, CNRS 5286, Cancer Research Center of Lyon.
Am J Surg Pathol. 2024 Nov 1;48(11):1381-1388. doi: 10.1097/PAS.0000000000002276. Epub 2024 Jun 27.
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.
血管周上皮样细胞瘤（PEComa）是一种细胞来源不确定的肿瘤，发生于广泛的年龄范围，发生于多种解剖部位，且以女性为主。大多数 PEComa 与 mTOR 通路的失调有关，最常见的是 TSC2 或 TSC1 的失活突变。然而，一小部分 PEComa 则与 TFE3 基因融合有关。MITF 与 TFE3 密切相关，在 PEComa 中常过度表达，通常与 TFE3 呈相互排斥的方式表达。在此，我们报告了一组 36 例 MITF 过表达型 PEComa 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 相似，尽管免疫组织化学特征是黑色素细胞标志物的表达相对有限，这一发现令人惊讶，因为 MITF 是黑色素细胞分化的主要调节因子。在分子水平上，20 例（56%）显示 MITF 基因的额外拷贝数，这可能是 MITF 过表达的潜在解释。通过 DNA 或 RNA 测序分析的 15 例中的 11 例（73%）发现了 mTOR 通路中的潜在遗传驱动事件。有趣的是，恶性 PEComa 表现出 2 个区分特征：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 PEComa 的关键特征，开始解释某些 PEComa 中 MITF 过表达的分子基础，并确定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。
