ANATOMICAL PATHOLOGY| Volume 52, ISSUE 6, P635-642, October 2020

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Malignant mesothelioma in situ: diagnostic and clinical considerations

  • Emily Pulford
    Department of Anatomical Pathology, Flinders University, Bedford Park, SA, Australia
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  • Author Footnotes
    ∗ now deceased but contributed to this publication
    Douglas W. Henderson
    ∗ now deceased but contributed to this publication
    Department of Anatomical Pathology, Flinders University, Bedford Park, SA, Australia

    SA Pathology at Flinders Medical Centre, Bedford Park, SA, Australia
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  • Sonja Klebe
    Address for correspondence: A/Prof Sonja Klebe, Department of Anatomical Pathology, Flinders University, Flinders Medical Centre, Bedford Park, SA 5042, Australia.
    Department of Anatomical Pathology, Flinders University, Bedford Park, SA, Australia

    SA Pathology at Flinders Medical Centre, Bedford Park, SA, Australia
    Search for articles by this author
  • Author Footnotes
    ∗ now deceased but contributed to this publication


      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.

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