Recurrent Tumor Suppressor Alterations in Primary Pericardial Mesothelioma

Our plain-English summary of Recurrent Tumor Suppressor Alterations in Primary Pericardial Mesothelioma, by I.M. Schaefer, A. Mariño-Enríquez, M.M. Hammer, et al (Modern Pathology, 2023).

The study

• Authors: I.M. Schaefer, A. Mariño-Enríquez, M.M. Hammer, R.F. Padera, L.M. Sholl
• Journal: Modern Pathology
• Published: 2023;36(9):100237
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Primary pericardial mesotheliomas are extremely rare, accounting for <1% of all mesotheliomas, and their molecular genetic features and predisposing factors remain to be determined. Here, we report the clinicopathologic, immunohistochemical, and molecular genetic findings of 3 pericardial mesotheliomas without pleural involvement. Three cases diagnosed between 2004 and 2022 were included in the study and analyzed by immunohistochemistry and targeted next-generation sequencing (NGS); corresponding nonneoplastic tissue was sequenced in all cases. Two patients were female and 1 was male, aged between 66 and 75 years. Two patients each had prior asbestos exposure and were smokers. Histologic subtypes were epithelioid in 2 cases and biphasic in 1 case. Immunohistochemical staining identified expression of cytokeratin AE1/AE3 and calretinin in all cases, D2-40 in 2 cases, and WT1 in 1 case. Staining for tumor suppressors revealed loss of p16, MTAP, and Merlin (NF2) expression in 2 cases and loss of BAP1 and p53 in 1 case. Abnormal cytoplasmic BAP1 expression was observed in an additional case. Protein expression abnormalities correlated with NGS results, which showed concurrent complete genomic inactivation of CDKN2A/p16, CDKN2B, MTAP, and NF2 in 2 mesotheliomas and of BAP1 and TP53 in 1 mesothelioma each, respectively. In addition, 1 patient harbored a pathogenic BRCA1 germline mutation, which resulted in biallelic inactivation in the mesothelioma. All mesotheliomas were mismatch repair proficient and showed several chromosomal gains and losses. All patients died from disease. Our study demonstrates that pericardial mesotheliomas share common morphologic, immunohistochemical, and molecular genetic features with pleural mesothelioma, including recurrent genomic inactivation of canonical tumor suppressors. Our study adds new insights into the genetic landscape of primary pericardial mesothelioma and highlights BRCA1 loss as a potential contributing factor in a subset of cases, thereby contributing to refined precision diagnostics for this rare cancer.

Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.

In plain English

The authors described three patients with primary pericardial mesothelioma, a cancer of the lining around the heart, with no pleural involvement. All were diagnosed between 2004 and 2022 at Brigham and Women’s Hospital in Boston. The patients were a man aged 75 and women aged 66 and 68. Patients 1 and 2 had a history of asbestos exposure, and patient 3 had no known exposure. No fiber type, job or dose was reported. Patients 2 and 3 smoked. Two tumors were epithelioid and one was biphasic. The authors stained the tumors for proteins and genetically sequenced both tumor and normal tissue. The tumors showed inactivation of tumor-suppressor genes also seen in pleural mesothelioma, including CDKN2A, MTAP, NF2, BAP1 and TP53. Patient 1 carried an inherited harmful BRCA1 mutation, and both copies of BRCA1 were inactivated in that tumor. All three patients died of the disease, between 0 and 15 months after diagnosis. The authors concluded that BRCA1 loss may contribute in some cases. They stated that, with so few cases, their observations do not allow conclusions about causation.

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 (three cases retrieved from hospital pathology files) with tissue staining (immunohistochemistry) and targeted next-generation sequencing of tumor and matched normal tissue
• Who was studied: Three patients with primary pericardial mesothelioma without pleural involvement, diagnosed between 2004 and 2022 at Brigham and Women’s Hospital, Boston. Cases #1 and #3 were examined at autopsy and case #2 on surgical resection. The patients were one man aged 75 and two women aged 66 and 68.
• Exposure: Reported history of asbestos exposure in patients #1 and #2. Patient #3 had no known asbestos exposure. Smoking history was also recorded. No fiber types, products, jobs or doses were given.
• Main results:
  • The three patients were a 75-year-old man (case #1) and women aged 66 (case #2) and 68 (case #3).
  • Patient #2 had a history of asbestos exposure and 40 pack-years of smoking.
  • Patient #3 was a smoker with no known asbestos exposure.
  • Cases #1 and #2 were epithelioid mesothelioma. Case #3 was biphasic, with sarcomatoid components making up 60% of the tumor.
  • All three tumors expressed the mesothelioma markers cytokeratin AE1/AE3 and calretinin. According to the results text and Table 2, D2-40 was positive only in case #1, and WT1 was positive only in case #2.
  • Tumor-suppressor staining showed:
• loss of p16 and MTAP in cases #1 and #2
• loss of BAP1 in case #2
• loss of Merlin (NF2) in cases #2 and #3
• loss of p53 in case #3
• abnormal cytoplasmic BAP1 staining in case #3
  • The tumor of patient #1 had a harmful BRCA1 frameshift mutation (allele fraction 0.8). The same mutation was found in one copy in the patient's normal tissue (allele fraction 0.5), showing it was inherited (germline).
  • Sequencing found no BAP1 genetic abnormality in case #3, despite its abnormal BAP1 staining. No germline mutations were found in patients #2 and #3.
  • All three tumors were mismatch repair proficient. The mean tumor mutational burden was 4.31 mutations per megabase (range 3 to 6). The authors described this as comparable to the average of 4.56 for mesotheliomas in the GENIE database.
  • All three patients died of disease. Patient #2 died 15 months after treatment, and patients #1 and #3 died within a week (Table 2).
• The authors' conclusion: The authors concluded that the three pericardial mesotheliomas showed features typical of pleural mesothelioma, including recurrent inactivation of tumor-suppressor genes. They also concluded that BRCA1 loss is a potential contributing factor in a subset of cases.
• Limitations the authors state:
  • The authors stated that the study is limited by small case numbers. They said their observations on smoking and asbestos exposure do not allow conclusions about causation.
  • Sequencing coverage of the case #3 tumor was low (27), which the authors attributed to DNA breakdown after death.
  • The authors said the failure to find a BAP1 abnormality in case #3 might be due to technical limits of their sequencing test or to the low coverage.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pericardial Mesothelioma, Mesothelioma, Immunohistochemistry, Next-Generation Sequencing (NGS), Asbestos Exposure, Histological Subtype, Epithelioid, Biphasic Mesothelioma.

Related studies

• Primary pericardial mesothelioma: a case report of a patient treated with an immune checkpoint inhibitor as the second-line treatment — O. Arponen, V. Salo, et al. (2021)
• Surgical pathology of primary cardiac and pericardial tumors — C. Basso, M. Valente, et al. (1997)
• Primary pericardial tumors — C.S. Restrepo, D. Vargas, et al. (2013)
• Three-year survival after surgery for primary malignant pericardial mesothelioma: report of a case — K. Fujita, M. Hata, et al. (2014)
• Primary malignant pericardial sarcomatoid mesothelioma: An autopsy report — H. Muta, Y. Sugita, et al. (2017)
• Primary pericardial mesothelioma: report of two cases and review of the literature — A.L. Sytman, R.N. MacAlpin (1971)

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