Immunohistochemical Loss of MTAP as a Diagnostic and Prognostic Surrogate of CDKN2A/B Homozygous Deletion: A Narrative Review

Our plain-English summary of Immunohistochemical Loss of MTAP as a Diagnostic and Prognostic Surrogate of CDKN2A/B Homozygous Deletion: A Narrative Review, by S. Salzano, R. Caltabiano, A. Palicelli, et al (Diagnostics, 2026).

The study

• Authors: S. Salzano, R. Caltabiano, A. Palicelli, M. Zizzo, M. Fabozzi, N. Koufopoulos, I. Boutas, G. Cazzato, M. Zanelli, G. Broggi
• Journal: Diagnostics
• Published: 2026;16(13)
• Type of article: Review
• Read it: PubMed · Publisher · Free full text

Abstract

Methylthioadenosine phosphorylase (MTAP) immunohistochemistry (IHC) has emerged as a valuable diagnostic, prognostic, and therapeutic biomarker in modern oncologic pathology, primarily serving as a surrogate for CDKN2A/B homozygous deletion due to their close genomic proximity at chromosome 9p21. This review aims to systematically evaluate the clinical utility, diagnostic accuracy, and technical limitations of MTAP IHC across a diverse spectrum of human malignancies, while contextualizing its role within current molecular testing algorithms. We first examine the established diagnostic and grading performance of MTAP loss in central nervous system neoplasms and thoracic tumors, particularly malignant pleural mesothelioma, followed by an analysis of its emerging prognostic value in gastrointestinal, cutaneous, and genitourinary malignancies. Furthermore, we discuss the therapeutic implications of MTAP deficiency, focusing on the biological consequences of methylthioadenosine accumulation and the resulting synthetic vulnerabilities in the PRMT5/MAT2A pathway. By synthesizing diagnostic precision, prognostic relevance, and translational therapeutic insights, this review provides a comprehensive framework for integrating MTAP IHC into routine surgical pathology workflows and personalized oncology.

In plain English

This article was a narrative review, not a new study. The authors searched PubMed/MEDLINE and Scopus up to January 2026 for research on MTAP immunohistochemistry, a laboratory stain used as a stand-in for a genetic change (CDKN2A/B homozygous deletion). The review covered tumors of the brain, chest, digestive tract, skin and urinary system. It did not study asbestos exposure. For pleural mesothelioma, one reviewed study reported a strong link between MTAP loss and CDKN2A deletion. Another, of 162 patients with mesothelioma and 20 benign controls, reported that loss of BAP1 and/or MTAP had 100% specificity and about 79–80% sensitivity. That study noted that normal staining does not rule out mesothelioma. A third study reported that MTAP loss was not consistently seen in desmoplastic and sarcomatoid mesothelioma. A study of 39 peritoneal mesothelioma samples found very low, non-significant agreement between MTAP staining and CDKN2A deletion. The authors concluded that the stain works as a screening tool but should not replace molecular testing. They noted a lack of large prospective studies and of standard scoring cut-offs.

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: Narrative review of published literature
• Who was studied: Published research found in PubMed/MEDLINE and Scopus, from database inception through January 2026, on MTAP immunohistochemistry in human tumors (central nervous system, thoracic including pleural and peritoneal mesothelioma, gastrointestinal, skin, genitourinary, ovarian)
• Exposure: No asbestos or other environmental or occupational exposure was studied. The review concerned a diagnostic laboratory test (MTAP immunohistochemistry) as a surrogate for CDKN2A/B homozygous deletion.
• Main results:
  • In a reviewed study of malignant pleural mesothelioma (Chapel et al.), loss of MTAP protein strongly correlated with deletion of the MTAP and CDKN2A genes.
  • In a reviewed study (Lynggård et al.) of 162 patients with mesothelioma (71 cytologic, 91 histologic samples) and 20 benign controls, loss of BAP1 and/or MTAP showed 100% specificity and about 79–80% sensitivity for identifying mesothelioma.
  • In the same reviewed study, normal expression of both markers did not rule out mesothelioma, because sensitivity was lower.
  • In a reviewed study of desmoplastic mesothelioma and sarcomatoid pleural mesothelioma with desmoplastic features, MTAP loss was not consistently observed, which reduced the test's diagnostic sensitivity in these subtypes.
  • In a reviewed study of pleural mesothelioma (Febres-Aldana et al.) comparing two antibodies, antibody 1813 gave stronger and more specific staining, with fewer equivocal results, than EPR6893.
  • In a reviewed study (Quaranta et al.) of 39 peritoneal mesothelioma samples and 14 benign peritoneal lesions, agreement between MTAP staining and CDKN2A deletion (by FISH) in the tumor cases was very low and not statistically significant. The authors of that study concluded that MTAP staining cannot substitute for direct molecular testing in peritoneal mesothelioma.
• The authors' conclusion: The authors concluded that MTAP immunohistochemistry is a cost-effective, rapid surrogate and screening tool for CDKN2A/B homozygous deletion but does not replace molecular testing. They also concluded that its diagnostic performance in mesothelioma is more limited in desmoplastic and sarcomatoid variants and appears unreliable in peritoneal mesothelioma.
• Limitations the authors state:
  • The authors noted a lack of large multi-center prospective studies validating the test in rarer variants such as peritoneal, desmoplastic and sarcomatoid neoplasms.
  • The authors noted that there are no standardized scoring systems or diagnostic cut-offs, and that studies use variable positivity thresholds.
  • The authors noted that technical factors such as antibody clone, tissue fixation and subjective scoring can affect results.
  • The authors noted that MTAP loss can occur without CDKN2A/B deletion, through epigenetic silencing or other events.

Topics

Medical terms in this study, explained in our Lexicon: MTAP, CDKN2A, Homozygous Deletion, Immunohistochemistry, Biomarker, Pathology, Molecular Profiling, Neoplasm.

Related studies

• Malignant mesothelioma in situ diagnosed by methylthioadenosine phosphorylase loss and homozygous deletion of CDKN2A: a case report — K. Minami, N. Jimbo, et al. (2020)
• CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival — A.M. Krasinskas, D.L. Bartlett, et al. (2010)
• Deletions of CDKN2A and MTAP Detected by Copy-Number Variation Array Are Associated with Loss of p16 and MTAP Protein in Pleural Mesothelioma — B. Vrugt, M.B. Kirschner, et al. (2023)
• Homozygous deletion of CDKN2A in malignant mesothelioma: Diagnostic utility, patient characteristics and survival in a UK mesothelioma centre — K. Marshall, S. Jackson, et al. (2020)
• MTAP immunohistochemistry is an accurate and reproducible surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant pleural mesothelioma — D.B. Chapel, J.J. Schulte, et al. (2020)
• Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma — Q. Hu, S. Akatsuka, et al. (2010)

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