Morphological difference between pleural mesothelioma cells in effusion smears with either BAP1 loss or 9p21 homozygous deletion and reactive mesothelial cells without the gene alterations

Our plain-English summary of Morphological difference between pleural mesothelioma cells in effusion smears with either BAP1 loss or 9p21 homozygous deletion and reactive mesothelial cells without the gene alterations, by S. Matsumoto, M. Hamasaki, Y. Kinoshita, et al (Pathology International, 2019).

The study

• Authors: S. Matsumoto, M. Hamasaki, Y. Kinoshita, T. Kamei, K. Kawahara, K. Nabeshima
• Journal: Pathology International
• Published: 2019;69(11):637-645
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

We previously characterized the morphological characteristics of malignant pleural mesothelioma (MPM) cells with 9p21 homozygous deletion (HD) using a combination of the virtual microscopy and fluorescence in situ hybridization (FISH). In this study, we investigated whether MPM cells with BRCA1-associated protein 1 (BAP1) loss show the same morphological characteristics identified in MPM cells with 9p21 HD. MPM cells with either BAP1 loss detected by immunocytochemistry (ICC) or 9p21 HD detected by FISH were identified via virtual microscopy prior to ICC or FISH, followed by analysis and quantification of their morphological characteristics. MPM cells with BAP1 loss or 9p21 HD exhibited significantly more frequent cell-in-cell engulfment, multinucleation, and larger multicellular clusters composed of more than 10 cells than reactive mesothelial cells. In conclusion, MPM cells with BAP1 loss or 9p21 HD share similar cytological features, indicating that the same morphological criteria can be used to detect MPM cells harboring such genetic aberrations.

© 2019 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

In plain English

This laboratory study from Fukuoka University Hospital, Japan, examined smears of fluid from around the lungs (pleural effusions). The smears came from 43 patients with malignant pleural mesothelioma and 45 patients with reactive, non-cancerous mesothelial cells linked to conditions such as tuberculosis and pneumonia. Cases dated from 2005 to 2016. The study asked whether mesothelioma cells lacking BAP1 in the cell nucleus look the same under the microscope as those with homozygous deletion (loss of both copies) of the 9p21 gene region. Each change appeared in 21 of 43 mesothelioma samples (48.8%), but in none of 17 reactive samples tested for BAP1 and none of 28 tested for 9p21. Both tests together detected 81.4% of mesothelioma cases. Mesothelioma cells with either change showed significantly more cell-in-cell engulfment, more cells with several nuclei, and more large three-dimensional clusters than reactive cells. For example, engulfment averaged 13.0% of mesothelioma cells with BAP1 loss versus 3.3% of reactive cells. The authors concluded that the same appearance-based criteria can detect mesothelioma cells with either change. They noted that they examined only selected features. Asbestos exposure was not studied.

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: Laboratory cytology study of archived pleural effusion smears. It compared the microscopic appearance of mesothelioma cells that had BAP1 loss or 9p21 homozygous deletion with the appearance of reactive mesothelial cells.
• Who was studied: Pleural effusion smears from 43 patients with malignant pleural mesothelioma (32 males, 11 females; mean age 72.1 years; 40 epithelioid, 3 biphasic). Also smears from 45 patients with reactive mesothelial cells associated with tuberculosis, pneumonia, cardiovascular disease, lung cancer and bullae. All cases came from Fukuoka University Hospital, Japan, including consultation cases from 2005 to 2016.
• Exposure: Asbestos exposure was not assessed. The groups were compared by two cell changes: loss of nuclear BAP1 expression (tested by immunocytochemistry) and homozygous deletion of the 9p21 region (tested by FISH).
• Main results:
  • Loss of nuclear BAP1 was found in 21 of 43 mesothelioma samples (48.8%). All 17 reactive samples tested retained BAP1.
  • 9p21 homozygous deletion was found in 21 of 43 mesothelioma samples (48.8%). It was found in none of the 28 reactive samples tested.
  • Each test alone had 100% specificity and 48.8% sensitivity for telling mesothelioma from reactive cells. The two tests combined had a sensitivity of 81.4%.
  • Cell-in-cell engulfment was seen in 13.0 ± 7.1% of mesothelioma cells with BAP1 loss. The figure was 3.3 ± 1.4% for reactive cells that retained BAP1.
  • Cell-in-cell engulfment was seen in 17.4 ± 10.6% of mesothelioma cells with 9p21 deletion. The figure was 3.5 ± 2.5% for reactive cells that retained the 9p21 locus.
  • Multinucleation (more than 2 nuclei) was seen in 7.3 ± 2.9% of mesothelioma cells with BAP1 loss, versus 1.3 ± 1.1% of reactive cells. It was seen in 11.0 ± 7.0% of mesothelioma cells with 9p21 deletion, versus 1.0 ± 0.9% of reactive cells.
  • Three-dimensional clusters of 10 to 99 cells were found in 11.2 ± 10.1% of mesothelioma cells with BAP1 loss and in 16.1 ± 12.4% of mesothelioma cells with 9p21 deletion. The comparison figures for reactive cells were 0.7 ± 1.1% (BAP1 retained) and 1.2 ± 1.5% (9p21 retained). The 9p21 cluster analysis was limited to 12 cases in which more than 90% of cells had the deletion.
  • Clusters of more than 100 cells were found in 11 of 14 mesothelioma cases with BAP1 loss (78.6%) and in 10 of 12 mesothelioma cases with 9p21 deletion (83%). They were found in none of the reactive cases with retained BAP1, and in 2 of 28 reactive cases with retained 9p21 (7.1%).
  • Cutoffs were set at the reactive-cell mean plus 3 standard deviations. The share of mesothelioma cases above the cutoff was 71.4% for engulfment, 78 to 86% for multinucleation, and 71 to 83% for clusters. No reactive case exceeded any cutoff (100% specificity).
• The authors' conclusion: The authors concluded that mesothelioma cells with BAP1 loss or with 9p21 homozygous deletion share similar microscopic features. They concluded that the same morphological criteria can therefore be used to detect mesothelioma cells with either change.
• Limitations the authors state:
  • Only the features previously found in 9p21-deleted mesothelioma cells were studied. Other criteria in the International Mesothelioma Interest Group guidelines were not examined.
  • Mesothelioma cells that retained BAP1 or lacked 9p21 deletion could not be compared. They could not be reliably told apart from reactive cells in the same smears.
  • FISH could assess 9p21 deletion only at the edges of cell clusters. The 9p21 cluster analysis was therefore restricted to 12 cases in which the deletion predominated.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, BAP1, Homozygous Deletion, Reactive Mesothelial Cells, Fluorescence In Situ Hybridization (FISH).

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• A combination of MTAP and BAP1 immunohistochemistry in pleural effusion cytology for the diagnosis of mesothelioma — Y. Kinoshita, T. Hida, et al. (2018)
• Loss of expression of BAP1 is a useful adjunct, which strongly supports the diagnosis of mesothelioma in effusion cytology — J. Andrici, A. Sheen, et al. (2015)
• Loss of BAP1 Expression in Atypical Mesothelial Proliferations Helps to Predict Malignant Mesothelioma — R. Pillappa, J.J. Maleszewski, et al. (2018)
• Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma — S. Brich, F. Bozzi, et al. (2020)

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