MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma

Our plain-English summary of MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma, by D.B. Chapel, J.J. Schulte, K. Berg, et al (Modern Pathology, 2020).

The study

• Authors: D.B. Chapel, J.J. Schulte, K. Berg, A. Churg, S. Dacic, C. Fitzpatrick, F. Galateau-Salle, K. Hiroshima, T. Krausz, N. Le Stang, S. McGregor, K. Nabeshima, A.N. Husain
• Journal: Modern Pathology
• Published: 2020;33(2):245-254
• Cited by: 141 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Ancillary studies facilitate accurate diagnosis of morphologically challenging mesothelial proliferations. The current diagnostic algorithm proceeds from BAP1 immunohistochemistry to CDKN2A fluorescence in situ hybridization. While MTAP immunohistochemistry has recently shown promise as a surrogate for CDKN2A fluorescence in situ hybridization, it has been examined in only a few single-institution studies. Furthermore, there are no published reports on interobserver agreement or interlaboratory reproducibility for MTAP immunohistochemistry. We performed MTAP immunohistochemistry on 20 benign mesothelial lesions and 99 malignant mesotheliomas from five mesothelioma centers in four countries, and each MTAP stain was independently interpreted by four pathologists. CDKN2A fluorescence in situ hybridization data were available for a subset of cases, and a subset of cases was subjected in MTAP immunohistochemistry in multiple laboratories to assess interlaboratory reproducibility. Interobserver agreement in MTAP immunostain interpretation was excellent for all mesothelial lesions (kappa: 0.85) and for malignant mesothelioma cases only (kappa: 0.82). Interlaboratory reproducibility was also excellent (kappa values for paired protocols: 0.77-0.89). MTAP loss by immunohistochemistry was 78% sensitive and 96% specific for CDKN2A homozygous deletion. MTAP immunohistochemistry is a reliable surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant mesothelioma. Interobserver agreement is excellent for interpretation of MTAP staining, and protocols performed in different laboratories yield concordant MTAP staining results. Rare cases with immunohistochemical MTAP loss may retain normal CDKN2A copy number, and the MTAP staining results should be correlated with clinicopathologic findings and other ancillary studies.

In plain English

This multi-center laboratory study evaluated a diagnostic stain for mesothelioma; it did not examine asbestos exposure. Samples from 20 reactive (benign) mesothelial proliferations and 99 mesotheliomas, from centers in Japan, Canada, France and the United States, were stained for the protein MTAP. Four pathologists independently scored MTAP as lost or retained. All four agreed in 92 of 107 scorable cases (kappa 0.85, 95% CI 0.79 to 0.92) and in 74 of 89 mesotheliomas (kappa 0.82, 95% CI 0.74 to 0.90). Disagreement was more likely with immune-cell infiltrates or faint staining. Of 69 mesotheliomas with genetic (FISH) results, 56 had unanimous MTAP scoring. In these, MTAP was lost in 25 of 32 tumors with homozygous (two-copy) CDKN2A deletion (78% sensitivity), and MTAP was retained in 23 of 24 without it (96% specificity). Laboratories agreed well (kappa 0.77, 95% CI 0.69 to 0.85; kappa 0.89, 95% CI 0.81 to 0.96), except with one extra-strong staining method (kappa 0.39, 95% CI 0.17 to 0.62). The authors concluded the test is robust and accurate, advocating routine use. They noted all scorers were mesothelioma experts.

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: Multi-institutional diagnostic laboratory study of MTAP immunohistochemistry (interobserver agreement, interlaboratory reproducibility, and comparison with CDKN2A FISH)
• Who was studied: 119 tissue cases (20 reactive mesothelial proliferations and 99 mesotheliomas) from five mesothelioma referral centers in Japan, Canada, France and the United States. All four pathologists could score 107 cases (18 reactive, 89 mesotheliomas). The article does not give the dates of the cases.
• Main results:
  • All four pathologists agreed on MTAP status in 92 of 107 cases (86.0%; kappa 0.85, 95% CI 0.79 to 0.92). They agreed in 74 of 89 mesotheliomas (83.1%; kappa 0.82, 95% CI 0.74 to 0.90).
  • Among mesotheliomas, disagreement was significantly more likely with a lymphohistiocytic infiltrate (p = 0.009) and with faint MTAP staining (p less than 0.0001).
  • Of 69 mesotheliomas with CDKN2A FISH results, 56 also had interobserver consensus on MTAP. In these 56, MTAP loss was 78% sensitive (25 of 32) and 96% specific (23 of 24 retained) for CDKN2A homozygous deletion. The 13 cases with disagreement were not included in this calculation.
  • One mesothelioma in the cohort showed MTAP loss despite normal CDKN2A copy number.
  • All 11 cases with faint MTAP staining had CDKN2A homozygous deletion.
  • In biopsies only (17 cases), MTAP loss was 67% sensitive and 100% specific. In cell blocks only (7 cases), it was 75% sensitive and 100% specific.
  • Agreement between laboratories was excellent. Comparing Vancouver General Hospital with the University of Chicago gave kappa 0.77 (95% CI 0.69 to 0.85). Comparing the University of Chicago with the Fukuoka standard and moderately strong protocols gave kappa 0.89 (95% CI 0.81 to 0.96).
  • Agreement between the University of Chicago protocol and the Fukuoka 'strong' protocol was poor (kappa 0.39, 95% CI 0.17 to 0.62).
• The authors' conclusion: The authors concluded that MTAP immunohistochemistry is a robust and accurate diagnostic marker that can stand in for CDKN2A FISH. They advocated adding it to the routine diagnostic workup for malignant mesothelioma.
• Limitations the authors state:
  • The scoring pathologists were mesothelioma experts, so their readings may not reflect those of general surgical pathologists.
  • Staining at Tokyo Women's Medical University (clone DA2, 1:200 dilution) could not be compared with other laboratories.
  • FISH results came from records. For tumors with patchy (subclonal) MTAP loss, it is therefore unclear which cells were tested by FISH.

Topics

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

Medical terms in this study, explained in our Lexicon: MTAP, Immunohistochemistry, CDKN2A, Fluorescence In Situ Hybridization (FISH), Pleural Mesothelioma, BAP1, Malignant Mesothelioma, Mesothelioma.

Related studies

• 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)
• 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)
• 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)
• Usefulness of p16/CDKN2A fluorescence in situ hybridization and BAP1 immunohistochemistry for the diagnosis of biphasic mesothelioma — D. Wu, K. Hiroshima, et al. (2017)
• Hemizygous loss of NF2 detected by fluorescence in situ hybridization is useful for the diagnosis of malignant pleural mesothelioma — Y. Kinoshita, M. Hamasaki, et al. (2020)
• Utility of BAP1 Immunohistochemistry and p16 (CDKN2A) FISH in the Diagnosis of Malignant Mesothelioma in Effusion Cytology Specimens — H.C. Hwang, B.S. Sheffield, et al. (2016)

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