Molecular characterization of localized pleural mesothelioma

Abstract

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.

Fig. 1

Clinicopathologic and molecular features of the six localized pleural mesotheliomas. B biphasic, E epithelioid, F female, M male, VUS, variant of uncertain significance

Fig. 2

BAP1-mutant localized pleural mesothelioma (Case 1). a Computed tomography demonstrated a circumscribed pleural mass in the right upper lobe. b Grossly, the tumor was solitary with no evidence of serosal spread. c The tumor showed biphasic histology with both epithelioid and sarcomatoid components, histologically indistinguishable from diffuse malignant pleural mesothelioma (hematoxylin and eosin, 200×). By immunohistochemistry, tumor cells expressed calretinin (d) and WT1 (e) and showed complete loss of nuclear BAP1 expression (f), with positive control BAP1 staining in the background stromal and inflammatory cells. g Single nucleotide polymorphism array analysis (top) showed homozygous deletion of CDKN2A at 9p (close-up: bottom left) and hemizygous deletion of NF2 at 22q (close-up: bottom right)

Fig. 3

Localized pleural mesothelioma with trisomies of chromosomes 3, 5, 7, and X (Case 4). a A scanning photomicrograph demonstrated a circumscribed solitary tumor (hematoxylin and eosin). b The tumor showed epithelioid histology, characterized by a tubular and nested pattern (100×) and c occasional vacuoles (400×). Tumor cells demonstrated calretinin (d) and WT1 (e) immunoreactivity. Mucicarmine stains, without (f) and with (g) hyaluronidase treatment, confirmed the presence of hyaluronic acid. h Single nucleotide polymorphism array analysis showed select gains of chromosomes 3, 5, 7, and X (arrows), with karyotypic analysis (i) confirming trisomies of chromosomes 3, 5, 7, and X (arrows)

Fig. 4

BAP1-wild-type TRAF7-wild-type localized pleural mesothelioma with genomic near-haploidization sparing chromosomes 5 and 7 (Case 5). a A low power image (hematoxylin and eosin, 40×) demonstrated a circumscribed pleural mass adjacent to the lung. Histologically, tumor cells showed both epithelioid component (b), characterized by epithelioid cells in a tubular and solid pattern, and sarcomatoid component (c), with intermixed hyperchromatic spindle tumor cells and chronic inflammation (400×). Tumor cells demonstrated diffuse calretinin (d), patchy WT1 (predominantly in a nucleolar pattern) (e), and patchy D2-40 (f) immunoreactivity. g Copy number VisCap plot and h a plot of variant allele fraction in the targeted genome demonstrated extensive loss of heterozygosity in all chromosomes except 5 and 7 (arrows)