Integrated Histogenetic Analysis Reveals BAP1-Mutated Epithelioid Mesothelioma in a Patient With Cancer of Unknown Primary

Our plain-English summary of Integrated Histogenetic Analysis Reveals BAP1-Mutated Epithelioid Mesothelioma in a Patient With Cancer of Unknown Primary, by T. Bochtler, V. Endris, A. Reiling, et al (Journal of the National Comprehensive Cancer Network, 2018).

The study

• Authors: T. Bochtler, V. Endris, A. Reiling, J. Leichsenring, M.R. Schweiger, S. Klein, F. Stögbauer, B. Goeppert, P. Schirmacher, A. Krämer, A. Stenzinger
• Journal: Journal of the National Comprehensive Cancer Network
• Published: 2018;16(6):677-682
• Type of article: Case report
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

This case report presents a male patient with epithelioid mesothelioma that was initially misdiagnosed as cancer of unknown primary (CUP) and correctly identified using molecular panel sequencing. The patient had a prior history of colon and breast cancer. To assess the enlarged mediastinal lymph nodes, retrosternal lymphadenectomy was performed in 2016. The lymph nodes were histologically deemed unrelated to the known breast cancer by the reference pathologist, thus leading to the diagnosis of a CUP syndrome. When the patient presented to our center, targeted deep sequencing of both breast cancer and presumed CUP was performed to address the clonal relationship between both malignancies. A missense mutation in BAP1 was revealed in both samples, with coverage data indicating a germline event. The patient was subsequently counseled by a human geneticist and underwent genetic testing, which confirmed the germline nature of this mutation. Collectively, these data led to the diagnosis of BAP1 (BRCA1-associated protein-1) tumor predisposition syndrome (TPDS). With the knowledge of an underlying BAP1 mutation and its known frequent association with epithelioid mesothelioma, the histology was reassessed and the diagnosis was revised to epithelioid mesothelioma. At this point, peritoneal involvement of mesothelioma could be diagnosed and histologically confirmed. This case illustrates the potential of integrated histopathologic and molecular diagnostics in helping to decipher CUP syndromes and establish the correct diagnosis. Additionally, this case highlights typical features of BAP1 TPDS with its general susceptibility to cancers, with pleural and peritoneal mesotheliomas as most prevalent clinical entities and the typically more benign course of these epithelioid mesotheliomas compared with BAP1-unrelated cases of mesotheliomas.

Copyright © 2018 by the National Comprehensive Cancer Network.

In plain English

This case report described one male patient who had colon cancer in 1984 at age 36 and breast cancer 28 years later. In July 2016, cancer found in enlarged chest lymph nodes did not match the breast cancer, so it was diagnosed as cancer of unknown primary. Gene sequencing found the same BAP1 mutation in the breast cancer, the lymph node and later surgical tissue. Testing of blood DNA confirmed that the patient was born with this mutation (a germline mutation). After surgery in January 2017, the tumor was diagnosed as epithelioid pleural mesothelioma. The article states that there was no history of asbestos exposure. Mesothelioma involving the peritoneum (the lining of the abdomen) was also confirmed. The tumor cells had lost the BAP1 protein. The enlarged lymph nodes could already be seen on 2012 scans and had progressed slowly. Instead of further treatment, the authors and patient chose to watch and wait; as of December 2017 the patient had not required therapy. Several relatives on the father's side had cancers. The authors concluded that the case showed the value of combining tissue and genetic analysis in some cancers of unknown primary.

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 report
• Who was studied: One male patient with a prior colon cancer (1984, at age 36) and a breast cancer diagnosed 28 years later (2012)
• Exposure: No asbestos exposure was reported. The patient carried an inherited (germline) BAP1 mutation, and the diagnosis was attributed to BAP1 tumor predisposition syndrome.
• Main results:
  • Tumor in the chest lymph nodes, removed in July 2016, was first diagnosed as cancer of unknown primary because it did not match the breast cancer.
  • All 3 tumor specimens carried the same BAP1 mutation: the breast cancer (2012), the lymph node (July 2016) and the mesothelioma (January 2017). Allele frequencies ranged from 51.9% to 73.6%.
  • Testing of the patient's blood DNA confirmed that the BAP1 mutation was germline (inherited).
  • BAP1 protein was lost in all tumor cells of the mesothelioma.
  • Peritoneal involvement of the mesothelioma was also diagnosed and confirmed by tissue examination.
  • Other genes often involved in mesothelioma (TP53, NF2, CDKN2A) were tested and no mutations were found in any of the 3 samples.
  • The lymph nodes removed in 2016 were already visible in 2012 and had progressed only slowly.
  • After the surgery, the authors and the patient chose not to start further treatment and followed a watch-and-wait strategy. As of December 2017 the patient had not required therapy.
  • Malignancies occurred on the father's side of the family: in the father, 1 aunt, 1 brother, 3 first cousins and 1 niece.
• The authors' conclusion: The authors concluded that the case showed the value of combining histologic (tissue) and molecular (genetic) analysis to work out some cases of cancer of unknown primary.
• Limitations the authors state:
  • This specific BAP1 mutation had not yet been listed in databases as either disease-causing or harmless. Its harmful effect was predicted by computer analyses.
  • Some other possible causes of BAP1 loss in the tumor (methylation, or mutations in promoter or UTR regions) were not covered by the gene panel used.
  • The role of additional mutations found in the ERCC5 and RECQL4 genes is unknown.

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: BAP1, Epithelioid, Mesothelioma, Mediastinal Lymph Nodes, Histology, Peritoneal Mesothelioma.

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• Histomorphologic spectrum of BAP1 negative melanocytic neoplasms in a family with BAP1-associated cancer susceptibility syndrome — Z. Marušić, M. Buljan, et al. (2015)
• Connecting molecular pathways to hereditary cancer risk syndromes — J.R. Testa, D. Malkin, et al. (2013)
• Post-thoracotomy neuralgic amyotrophy in a patient with BAP1 tumor predisposition syndrome: Multimodality longitudinal follow-up — N. Jazebi, N. Dargah-Zada, et al. (2021)
• Poorly differentiated neoplasms of unknown primary site: diagnostic usefulness of a molecular cancer classifier assay — F.A. Greco, W.J. Lennington, et al. (2015)

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