Malignant mesothelioma in situ: diagnostic and clinical considerations

Our plain-English summary of Malignant mesothelioma in situ: diagnostic and clinical considerations, by E. Pulford, D.W. Henderson, S. Klebe (Pathology, 2020).

The study

• Authors: E. Pulford, D.W. Henderson, S. Klebe
• Journal: Pathology
• Published: 2020;52(6):635-642
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

In situ stages of malignancy have been characterised in various neoplasms. Mesothelioma in situ (MIS) has been a controversial diagnosis, lacking clear diagnostic criteria and understanding as to whether it is truly a premalignant lesion in the progression of malignant mesothelioma (MM). Originally understood as a concept and defined as atypical mesothelial proliferation in the presence of invasion, it has now been suggested that loss of nuclear labelling for BRCA1-associated protein-1 (BAP1) in flat, non-invasive mesothelial lesions can define MIS. This study aimed to characterise BAP1 expression in a cohort of 19 patients diagnosed with MIS (either pure MIS, n=3, or MIS-predominant invasive MM, n=16) and to compare survival between MIS, MIS-predominant MM and MM (n=114) in order to gain insight into the characteristics of MIS. We defined pure MIS as any architectural pattern of surface mesothelial cells with loss of BAP1 in the absence of invasion, but in specimens with superficial stromal invasion we also accepted the original definition of cytologically and architecturally atypical mesothelial proliferation, in the absence of inflammatory features, with or without loss of BAP1. We observed that MIS associated with minimal invasion was associated with significantly improved survival compared to MM (8 months vs 22 months). This suggests that MIS is indeed a precursor to MM and that these cases represent earlier stage disease. Loss of BAP1 was present in 60% of mesotheliomas with invasion, so not all early cases can be detected by BAP1 loss, but our study provides evidence that BAP1 loss may be an early molecular alteration in MM pathogenesis in patients that have loss of BAP1. We confirm that BAP1 loss can be useful for diagnosis of pure MIS in surgical specimens, permitting earlier diagnosis. However, identification of a predominant MIS component with minimal invasion has prognostic and conceptual implications. Whilst no approved therapy is available for MIS, close follow up of patients with BAP1 mutation in mesothelial cells and/or diagnosis of MIS is required to monitor for disease progression and potentially investigate earlier treatment interventions.

Copyright © 2020. Published by Elsevier B.V.

In plain English

This Australian study looked at mesothelioma in situ (MIS), a proposed early stage of malignant mesothelioma (MM). The authors reviewed tissue from 133 patients diagnosed at Flinders Medical Centre between 1997 and 2018: 3 with MIS only, 16 with mostly MIS plus minimal invasion, and 114 with pleural MM without an in situ component. They compared BAP1 staining and survival. Median survival was 8 months (95% CI 6.81 to 9.19) for MM and 22 months (95% CI 5.67 to 38.34) for MIS-predominant cases (p<0.001). After allowing for age, gender, subtype and BAP1 status, the in situ component remained significantly linked to longer survival. Complete BAP1 loss occurred in 49% of MM and 56% of MIS-predominant cases; the remaining 44% of the latter had patchy staining, so all 16 had some change. BAP1 loss was part of the definition of the three MIS-only cases; one later developed MM and died, and two showed no progression at 36 and 9 months. The authors concluded MIS-predominant cases likely represent earlier-stage disease and any BAP1 change could trigger close surveillance. They noted BAP1 alone will miss cases.

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: Retrospective single-centre study of pathology cases comparing groups, including descriptions of three patients with MIS only
• Who was studied: 133 patients diagnosed at Flinders Medical Centre, Adelaide, 1997 to 2018. Of these, 3 had MIS only, 16 had MM with a prominent in situ component, and 114 had MM without an in situ component. The MM was of the pleura, and the MM group included consultation cases.
• Exposure: The study examined BAP1 protein staining and the presence of an in situ component, not asbestos exposure. Asbestos exposure was recorded as yes in 58 of 114 MM patients, 6 of 16 (38%) MIS-predominant patients and 2 of 3 (67%) MIS-only patients, with many unknown. No fiber types were reported.
• Main results:
  • Median survival was 8 months (95% CI 6.81 to 9.19) in the MM group and 22 months (95% CI 5.67 to 38.34) in the MIS-predominant MM group, p less than 0.001
  • After controlling for age, gender, subtype and BAP1 status, an in situ component was still significantly associated with longer overall survival (p less than 0.001)
  • Complete BAP1 loss was found in 49% of invasive MM cases and 56% of MIS-predominant cases
  • Heterogeneous (patchy) BAP1 labelling was seen in the other 44% of the MIS-predominant group, so all of these cases had some form of BAP1 alteration
  • The three pure MIS cases were defined by BAP1 loss, so their BAP1 loss was part of the group definition
  • BAP1 loss was an adverse prognostic marker independent of other factors (p less than 0.001). In the whole-cohort analysis, BAP1-negative compared with retained had a ratio of 2.189 (95% CI 1.438 to 3.333). Sarcomatoid subtype was a poor prognostic indicator.
  • Of the three MIS-only patients, one progressed to invasive MM after about one year and died. The other two were alive and free of disease at 36 and 9 months.
• The authors' conclusion: The authors concluded that MIS-predominant MM may indicate earlier-stage disease, which supports the idea that invasive MM develops from a premalignant lesion. They suggested that BAP1 changes, even in a small number of cells, could trigger close clinical surveillance.
• Limitations the authors state:
  • The disease is rare, which limits this and all other published studies on the subject
  • Because of the small sample and the diagnostic criteria used, the study cannot comment on BAP1 as a prognostic marker in MIS or MIS-prominent cases
  • BAP1 as the only marker will likely miss cases; 40% of MM samples kept BAP1
  • Finding mostly MIS in a biopsy could be a sampling artefact. The authors note the biopsies targeted abnormal areas.
  • There is a possibility of over-diagnosis, over-treatment and under-diagnosis, especially given variable BAP1 staining patterns

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Neoplasm, Mesothelioma in Situ, Atypical Mesothelial Proliferation, BAP1, Mesothelial Cells, Mesothelioma, Disease Progression.

Related studies

• Development of mesothelioma in situ and its progression to invasive disease observed in a patient with uncontrolled pleural effusions for 15 years — K. Hidaka, T. Takeda, et al. (2020)
• BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma — S.M. McGregor, J. McElherne, et al. (2017)
• BAP1 gene mutations in Egyptian patients with advanced sporadic malignant pleural mesothelioma (MPM): relation with clinical outcomes and survival — A.A. Bahnasy, R.S. El-Din, et al. (2018)
• Malignant Mesothelioma, BAP1 Immunohistochemistry, and VEGFA: Does BAP1 Have Potential for Early Diagnosis and Assessment of Prognosis? — E. Pulford, K. Huilgol, et al. (2017)
• BAP1 protein is a progression factor in malignant pleural mesothelioma — L. Arzt, F. Quehenberger, et al. (2014)
• Retrospective response analysis of BAP1 expression to predict the clinical activity of systemic cytotoxic chemotherapy in mesothelioma — N. Kumar, D. Alrifai, et al. (2019)

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