Cyclin D1 immunohistochemical staining to separate benign from malignant mesothelial proliferations

Our plain-English summary of Cyclin D1 immunohistochemical staining to separate benign from malignant mesothelial proliferations, by J. Pors, J. Naso, K. Berg, et al (Modern Pathology, 2020).

The study

• Authors: J. Pors, J. Naso, K. Berg, A. Churg
• Journal: Modern Pathology
• Published: 2020;33(2):312-318
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The separation of benign from malignant mesothelial proliferations is a morphologically difficult problem. Mutations/deletions of components of the Hippo pathway are frequent in malignant mesotheliomas, and one downstream effect of aberrant Hippo signaling is increased production of cyclin D1. We examined expression of cyclin D1 nuclear staining in two tissue microarrays containing 52 reactive epithelial mesothelial proliferations, 51 reactive spindle cell mesothelial proliferations, 54 epithelial mesotheliomas, and 22 sarcomatous/desmoplastic mesotheliomas. When present, cyclin D1 staining was always strong, hence the arrays were scored as 0, 1-25%, 26-50%, 51-75%, and 76-100% staining. Both arrays showed a similar pattern. Reactive epithelial proliferations generally showed no staining (42/52 cases) or 1-25% staining (10/52 cases) with no cases showing >25% staining. Overall for reactive epithelial proliferations the maximum staining was 14.8% and mean 1.1 ± 2.9%. For epithelial mesotheliomas 39/54 (72%) cases demonstrated >25% staining, with 8/54 in the 26-50% staining range, 9/54 in the 51-75% range, and 22/54 in the >75% range. Combinations of staining using cyclin D1 >50% plus BAP1 or MTAP loss in epithelial mesotheliomas produced about a 10% increase in sensitivity. Reactive spindle cell proliferations showed a broader range of staining with 27/51 in the 1-25% range, 5/51 in the 26-50% range, and 1/51 >50%. Eleven of 22 sarcomatous/desmoplastic mesotheliomas scored 50% or greater. We conclude that for epithelial mesothelial proliferations, the finding of >50% of tumor cells staining supports a diagnosis of epithelial mesothelioma with 100% specificity but only modest (57%) sensitivity.

In plain English

This laboratory study of archived Vancouver cases tested whether staining for a protein called cyclin D1 helps pathologists tell mesothelioma from benign (reactive) mesothelial growths. Two tissue microarrays held 52 reactive epithelial proliferations, 51 reactive spindle cell proliferations, 54 epithelial mesotheliomas and 22 sarcomatous/desmoplastic mesotheliomas. None of the 52 reactive epithelial cases stained in more than 25% of cells. Among epithelial mesotheliomas, 9 of 54 stained in 51 to 75% of cells and 22 of 54 in more than 75%. With more than 50% staining as the cut-off, the test had 100% specificity and 57% sensitivity for epithelial mesothelioma. Reactive spindle cell cases stained more often. In epithelial mesotheliomas with evaluable BAP1 (37 cases) or MTAP (38 cases) staining, adding loss of either marker to cyclin D1 above 50% raised sensitivity by about 10%. The authors concluded that an epithelial mesothelial growth with more than 50% staining should be viewed as malignant. They said negative or lower results are not informative, and that the stain should not be used to separate desmoplastic mesothelioma from organizing pleuritis. 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: Retrospective diagnostic study of archived tissue: cyclin D1 immunohistochemical staining on two tissue microarrays, compared between reactive mesothelial proliferations and mesotheliomas
• Who was studied: Archived cases from the anatomical pathology archives at Vancouver General Hospital, Canada, on two tissue microarrays. In total: 52 reactive epithelial mesothelial proliferations, 51 reactive spindle cell mesothelial proliferations, 54 epithelial mesotheliomas and 22 sarcomatous/desmoplastic mesotheliomas. Mesotheliomas were confirmed by immunohistochemistry and reactive cases by clinical follow-up. Dates are not given.
• Exposure: Not an asbestos exposure study. The study evaluated a laboratory test: nuclear staining for cyclin D1, scored by the proportion of cells stained (0, 1 to 25%, 26 to 50%, 51 to 75%, 76 to 100%). BAP1 and MTAP staining were also assessed.
• Main results:
  • Reactive epithelial proliferations: 42 of 52 showed no staining at all, and none showed staining in more than 25% of cells.
  • Epithelial mesotheliomas: 39 of 54 (72%) showed more than 25% staining. Of these, 8 of 54 were in the 26 to 50% range, 9 of 54 in the 51 to 75% range and 22 of 54 above 75%.
  • Epithelial mesotheliomas versus reactive epithelial proliferations, at a 50% cut-off: sensitivity 57%, specificity 100%, positive predictive value 100%, negative predictive value 69%.
  • Reactive spindle cell proliferations stained more often: 27 of 51 (53%) in the 1 to 25% range, 5 of 51 (10%) in the 26 to 50% range, and 1 of 51 in the 51 to 75% range.
  • Sarcomatous/desmoplastic mesotheliomas (combined arrays): 1 of 22 showed 51 to 75% staining and 10 of 22 (45%) showed more than 75% staining.
  • Sarcomatous/desmoplastic mesotheliomas versus reactive spindle cell proliferations, at a 50% cut-off: sensitivity 50%, specificity 98%, positive predictive value 92%, negative predictive value 82%. At a 75% cut-off, sensitivity was 45% and specificity 100%.
  • The differences in staining distribution between mesotheliomas and reactive proliferations were statistically significant. For sarcomatous/desmoplastic mesotheliomas versus reactive spindle cell proliferations, chi-square was 23.1 (p = 0.0001).
  • The BAP1 and MTAP comparisons were done only in epithelial mesotheliomas, with BAP1 evaluable in 37 cases and MTAP in 38.
  • In epithelial mesotheliomas, combining cyclin D1 staining above 50% with loss of BAP1 or MTAP increased sensitivity by about 10%.
• The authors' conclusion: The authors proposed that an epithelial mesothelial proliferation with more than 50% cyclin D1 staining should be viewed as malignant. They noted 100% specificity but moderate (57%) sensitivity at that cut-off.
• Limitations the authors state:
  • For epithelial cases, the stain is useful only when a high fraction of cells stains. Negative cases and cases with 1 to 50% staining are not informative.
  • Cyclin D1 overexpression can occur in many other tumors and is not specific to mesothelioma, so the process must first be confirmed as mesothelial.
  • Staining in blood vessels can be hard to tell apart from staining in mesothelial cells.
  • Microarrays could not show whether desmoplastic mesotheliomas stain unevenly, which could cause false negatives. The authors advised against using the stain to separate desmoplastic mesothelioma from organizing pleuritis.
  • There is no information on how MTAP or cyclin D1 perform in peritoneal mesotheliomas.

Topics

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

Medical terms in this study, explained in our Lexicon: Immunohistochemistry, Malignant Mesothelioma, Spindle Cell, Mesothelioma, Desmoplastic Mesothelioma, BAP1, MTAP.

Related studies

• CD146 immunohistochemical staining for the separation of benign from malignant mesothelial proliferations — T. Salisbury, A. Churg (2021)
• Utility of Methylthioadenosine Phosphorylase Compared With BAP1 Immunohistochemistry, and CDKN2A and NF2 Fluorescence In Situ Hybridization in Separating Reactive Mesothelial Proliferations From Epithelioid Malignant Mesotheliomas — K.B. Berg, S. Dacic, et al. (2018)
• BAP1 immunohistochemistry and p16 FISH to separate benign from malignant mesothelial proliferations — B.S. Sheffield, H.C. Hwang, et al. (2015)
• Immunohistochemistry for NF2, LATS1/2, and YAP/TAZ Fails to Separate Benign From Malignant Mesothelial Proliferations — B.S. Sheffield, J. Lorette, et al. (2016)
• BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations — M. Cigognetti, S. Lonardi, et al. (2015)
• New Markers for Separating Benign From Malignant Mesothelial Proliferations: Are We There Yet? — A. Churg, B.S. Sheffield, et al. (2016)

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