Molecular characterization of localized pleural mesothelioma

Our plain-English summary of Molecular characterization of localized pleural mesothelioma, by Y.P. Hung, F. Dong, A.M. Dubuc, et al (Modern Pathology, 2020).

The study

• Authors: Y.P. Hung, F. Dong, A.M. Dubuc, P. Dal Cin, R. Bueno, L.R. Chirieac
• Journal: Modern Pathology
• Published: 2020;33(2):271-280
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This study from Brigham and Women's Hospital in Boston described six patients with localized pleural mesothelioma. This is a rare, single, well-defined tumor of the pleura (the lining around the lungs) that looks the same under the microscope as diffuse malignant pleural mesothelioma. The six cases were found among 1110 patients with pleural mesothelioma diagnosed between January 2005 and June 2018 (0.5%). There were three women and three men, with a median age of 63. Two patients, both men, had a documented history of asbestos exposure. No fiber types were named. No ferruginous bodies were seen in lung tissue from the four patients who had lung resections, including those two. Genetic testing of five tumors found three groups. Two tumors, from the two asbestos-exposed men, had BAP1 mutations with CDKN2A and NF2 deletions. Two tumors had TRAF7 mutations. One tumor showed near-haploidization, a widespread loss of one copy of most chromosomes. No patient developed diffuse pleural disease during follow-up. The authors concluded that localized pleural mesotheliomas are genetically varied. They noted that the small number of cases prevented linking genetic features to outcome.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Case series: clinical, pathologic and molecular (genetic) study of six localized pleural mesotheliomas identified from one institution's consecutive cohort
• Who was studied: Six patients with localized pleural mesothelioma (three women, three men; median age 63, range 28 to 76), identified among 1110 patients with pleural mesothelioma diagnosed between January 2005 and June 2018 whose pathology was reviewed at Brigham and Women's Hospital, Boston
• Exposure: The study did not examine exposure as such. Two of the six patients had a documented history of asbestos exposure; no fiber types or exposure details were reported.
• Main results:
  • Six of 1110 patients (0.5%) had localized pleural mesothelioma; the remaining 1104 (99.5%) had diffuse malignant pleural mesothelioma
  • In background lung tissue from the four patients who had lung resection, including the two with documented asbestos exposure, no ferruginous bodies were seen
  • All six tumors were solitary and circumscribed (median size 5.0 cm, range 2.7 to 13.5 cm); four were biphasic and two epithelioid; four showed microscopic invasion into adjacent tissue
  • Of five tumors with enough DNA for sequencing, two had BAP1 mutations with deletions of CDKN2A and NF2, two had TRAF7 mutations (one also with trisomies of chromosomes 3, 5, 7 and X), and one showed genomic near-haploidization sparing chromosomes 5 and 7
  • The two BAP1-mutated tumors were in the two men with documented asbestos exposure, who also received chemotherapy before surgery; the three BAP1-wild-type tumors were in the three women
  • Of four patients with at least 6 months of follow-up, one developed brain metastasis at 0.9 year and died of cardiac complications at 1.0 year; the other three were alive at last follow-up, two with no evidence of disease at 1.1 and 8.9 years. No patient developed diffuse pleural disease.
  • Median tumor mutational burden in the five sequenced tumors was 3.0 (range 0.8 to 3.8) non-synonymous mutations per megabase, with no significant difference between BAP1-mutated and BAP1-wild-type tumors (p = 0.37)
• The authors' conclusion: The authors concluded that localized pleural mesotheliomas are genetically heterogeneous, with BAP1-mutated, TRAF7-mutated and near-haploid subgroups. In their view, the BAP1-mutated subgroup resembles diffuse malignant pleural mesothelioma, while the TRAF7-mutated subgroup overlaps genetically with adenomatoid tumors and well-differentiated papillary mesotheliomas.
• Limitations the authors state:
  • The small number of cases prevented the authors from relating genetic features to outcome

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Histopathology, Next-Generation Sequencing (NGS), Neoadjuvant Chemotherapy, Mesothelioma, Histology, Biphasic Mesothelioma, Epithelioid.

Related studies

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• Highlights of the 14th international mesothelioma interest group meeting: Pathologic separation of benign from malignant mesothelial proliferations and histologic/molecular analysis of malignant mesothelioma subtypes — A. Churg, K. Nabeshima, et al. (2018)
• Molecular characterization of diffuse malignant peritoneal mesothelioma — Y.P. Hung, F. Dong, et al. (2020)
• Integrative Molecular Characterization of Malignant Pleural Mesothelioma — J. Hmeljak, F. Sanchez-Vega, et al. (2018)
• Hemizygous loss of NF2 detected by fluorescence in situ hybridization is useful for the diagnosis of malignant pleural mesothelioma — Y. Kinoshita, M. Hamasaki, et al. (2020)
• BAP1 loss is unusual in well-differentiated papillary mesothelioma and may predict development of malignant mesothelioma — H.E. Lee, J.R. Molina, et al. (2018)

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