PEComa With MITF Overexpression: Clinicopathologic and Molecular Analysis of a Series of 36 Cases.

IF 4.5 1区 医学 Q1 PATHOLOGY
American Journal of Surgical Pathology Pub Date : 2024-11-01 Epub Date: 2024-06-27 DOI:10.1097/PAS.0000000000002276
John Hanna, Eleanor Russell-Goldman, Esther Baranov, Daniel Pissaloux, Yvonne Y Li, Franck Tirode, Arnaud de la Fouchardiere, Christopher D M Fletcher
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Abstract

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.

MITF 过度表达的 PEComa:36 例系列病例的临床病理学和分子分析
血管周上皮样细胞瘤(PEComas)是一种细胞系不确定的肿瘤,发生在不同年龄段、不同解剖部位,女性占多数。大多数 PEComas 与 mTOR 通路失调有关,最常见的原因是 TSC2 或 TSC1 发生了失活突变。不过,也有一小部分 PEComas 与 TFE3 基因融合有关。MITF 与 TFE3 关系密切,经常在 PEC 瘤中过表达,而且往往与 TFE3 以互斥的方式表达。在此,我们报告了一系列 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 相似,但免疫组化特征的显著特点是黑色素细胞标志物的表达相对有限,鉴于 MITF 是黑色素细胞分化的主要调节因子,这一发现令人惊讶。在分子水平上,20 个病例(56%)显示出 MITF 基因的超数拷贝,这表明 MITF 基因过表达的潜在原因。在通过DNA或RNA测序分析的15个病例中,有11个病例(73%)确定了mTOR通路中的潜在遗传驱动因子。有趣的是,恶性 PEComas 表现出两个显著的分子特征:它们与复杂的染色体拷贝数特征有关,而且往往会出现额外的基因变化,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 的主要特征,开始解释一些 PEComa 中 MITF 过表达的分子基础,并确定了可能适用于更广泛的 PEComa 家族的潜在恶性肿瘤分子相关性。
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来源期刊
CiteScore
10.30
自引率
5.40%
发文量
295
审稿时长
1 months
期刊介绍: The American Journal of Surgical Pathology has achieved worldwide recognition for its outstanding coverage of the state of the art in human surgical pathology. In each monthly issue, experts present original articles, review articles, detailed case reports, and special features, enhanced by superb illustrations. Coverage encompasses technical methods, diagnostic aids, and frozen-section diagnosis, in addition to detailed pathologic studies of a wide range of disease entities. Official Journal of The Arthur Purdy Stout Society of Surgical Pathologists and The Gastrointestinal Pathology Society.
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