Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
Mod Pathol. 2020 Feb;33(2):271-280. doi: 10.1038/s41379-019-0330-9. Epub 2019 Aug 1.
Localized pleural mesothelioma is a rare solitary circumscribed pleural tumor that is microscopically similar to diffuse malignant pleural mesothelioma. However, the molecular characteristics and nosologic relationship with its diffuse counterpart remain unknown. In a consecutive cohort of 1110 patients with pleural mesotheliomas diagnosed in 2005-2018, we identified six (0.5%) patients diagnosed with localized pleural mesotheliomas. We gathered clinical history, evaluated the histopathology, and in select cases performed karyotypic analysis and targeted next-generation sequencing. The cohort included three women and three men (median age 63; range 28-76), often presenting incidentally during radiologic evaluation for unrelated conditions. Neoadjuvant chemotherapy was administered in two patients. All tumors (median size 5.0 cm; range 2.7-13.5 cm) demonstrated gross circumscription (with microscopic invasion into lung, soft tissue, and/or rib in four cases), mesothelioma histology (four biphasic and two epithelioid types), and mesothelial immunophenotype. Of four patients with at least 6-month follow-up, three were alive (up to 8.9 years). Genomic characterization identified several subgroups: (1) BAP1 mutations with deletions of CDKN2A and NF2 in two tumors; (2) TRAF7 mutations in two tumors, including one harboring trisomies of chromosomes 3, 5, 7, and X; and (3) genomic near-haploidization, characterized by extensive loss of heterozygosity sparing chromosomes 5 and 7. Localized pleural mesotheliomas appear genetically heterogeneous and include BAP1-mutated, TRAF7-mutated, and near-haploid subgroups. While the BAP1-mutated subgroup is similar to diffuse malignant pleural mesotheliomas, the TRAF7-mutated subgroup overlaps genetically with adenomatoid tumors and well-differentiated papillary mesotheliomas, in which recurrent TRAF7 mutations have been described. Genomic near-haploidization, identified recently in a subset of diffuse malignant pleural mesotheliomas, suggests a novel mechanism in the pathogenesis of both localized pleural mesothelioma and diffuse malignant pleural mesothelioma. Our findings describe distinctive genetic features of localized pleural mesothelioma, with both similarities to and differences from diffuse malignant pleural mesothelioma.
局限性胸膜间皮瘤是一种罕见的局限性胸膜孤立性肿瘤，其显微镜下表现与弥漫性恶性胸膜间皮瘤相似。然而，其与弥漫性间皮瘤在分子特征和分类学关系上仍不清楚。在 2005 年至 2018 年连续诊断的 1110 例胸膜间皮瘤患者中，我们发现了 6 例（0.5%）局限性胸膜间皮瘤患者。我们收集了临床病史，评估了组织病理学，并在选择的病例中进行了核型分析和靶向下一代测序。该队列包括 3 名女性和 3 名男性（中位年龄 63 岁；范围 28-76 岁），通常是在为其他无关疾病进行放射学评估时偶然发现的。两名患者接受了新辅助化疗。所有肿瘤（中位大小 5.0cm；范围 2.7-13.5cm）均表现出大体界限（在 4 例中，显微镜下侵犯肺、软组织和/或肋骨）、间皮瘤组织学（4 例双相型和 2 例上皮样型）和间皮细胞免疫表型。在至少随访 6 个月的 4 名患者中，有 3 名存活（最长 8.9 年）。基因组特征鉴定出了几个亚组：（1）两个肿瘤存在 BAP1 突变，并伴有 CDKN2A 和 NF2 的缺失；（2）两个肿瘤存在 TRAF7 突变，其中一个存在染色体 3、5、7 和 X 的三体；（3）基因组近单体化，表现为广泛的杂合性缺失，仅保留染色体 5 和 7。局限性胸膜间皮瘤在遗传上表现出异质性，包括 BAP1 突变型、TRAF7 突变型和近单体化亚组。虽然 BAP1 突变亚组与弥漫性恶性胸膜间皮瘤相似，但 TRAF7 突变亚组在遗传上与腺瘤样肿瘤和分化良好的乳头状间皮瘤重叠，在这些肿瘤中已经描述了复发性 TRAF7 突变。最近在一部分弥漫性恶性胸膜间皮瘤中发现的基因组近单体化，提示了局限性胸膜间皮瘤和弥漫性恶性胸膜间皮瘤发病机制中的一个新机制。我们的发现描述了局限性胸膜间皮瘤的独特遗传特征，既有与弥漫性恶性胸膜间皮瘤的相似之处，也有不同之处。
