{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T04:46:49Z","timestamp":1793249209562,"version":"4.5.0"},"reference-count":42,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/diagnostics16132069","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T16:50:33Z","timestamp":1782924633000},"page":"2069","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Immunohistochemical Loss of MTAP as a Diagnostic and Prognostic Surrogate of CDKN2A\/B Homozygous Deletion: A Narrative Review"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3669-8759","authenticated-orcid":false,"given":"Serena","family":"Salzano","sequence":"first","affiliation":[{"name":"Department of Medical and Surgical Sciences and Advanced Technologies \u201cG.F. Ingrassia\u201d Anatomic Pathology, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8591-8010","authenticated-orcid":false,"given":"Rosario","family":"Caltabiano","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences and Advanced Technologies \u201cG.F. Ingrassia\u201d Anatomic Pathology, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2299-5160","authenticated-orcid":false,"given":"Andrea","family":"Palicelli","sequence":"additional","affiliation":[{"name":"Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9841-7856","authenticated-orcid":false,"given":"Maurizio","family":"Zizzo","sequence":"additional","affiliation":[{"name":"Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5102-0210","authenticated-orcid":false,"given":"Massimiliano","family":"Fabozzi","sequence":"additional","affiliation":[{"name":"Surgical Oncology Unit, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9502-7916","authenticated-orcid":false,"given":"Nektarios","family":"Koufopoulos","sequence":"additional","affiliation":[{"name":"Second Department of Pathology, Medical School, National and Kapodistrian University of Athens, Attikon University Hospital, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Boutas","sequence":"additional","affiliation":[{"name":"Second Department of Pathology, Medical School, National and Kapodistrian University of Athens, Attikon University Hospital, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0325-4316","authenticated-orcid":false,"given":"Gerardo","family":"Cazzato","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), Section of Molecular Pathology, University of Bari \u201cAldo Moro\u201d, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8733-9933","authenticated-orcid":false,"given":"Magda","family":"Zanelli","sequence":"additional","affiliation":[{"name":"Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2576-6523","authenticated-orcid":false,"given":"Giuseppe","family":"Broggi","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences and Advanced Technologies \u201cG.F. Ingrassia\u201d Anatomic Pathology, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Fan, N., Zhang, Y., and Zou, S. (2023). Methylthioadenosine phosphorylase deficiency in tumors: A compelling therapeutic target. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1173356"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1016\/j.biocel.2003.11.016","article-title":"Methylthioadenosine","volume":"36","author":"Avila","year":"2004","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1073\/pnas.78.2.1219","article-title":"Selective killing of human malignant cell lines deficient in methylthioadenosine phosphorylase, a purine metabolic enzyme","volume":"78","author":"Kamatani","year":"1981","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.pathol.2023.01.005","article-title":"Evaluation of MTAP and p16 immunohistochemical deficiency as surrogate marker for CDKN2A\/B homozygous deletion in gliomas","volume":"55","author":"Maragkou","year":"2023","journal-title":"Pathology"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Tirr\u00f2, E., Massimino, M., Broggi, G., Romano, C., Minasi, S., Gianno, F., Antonelli, M., Motta, G., Certo, F., and Altieri, R. (2022). A Custom DNA-Based NGS Panel for the Molecular Characterization of Patients With Diffuse Gliomas: Diagnostic and Therapeutic Applications. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.861078"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"152524","DOI":"10.1016\/j.anndiagpath.2025.152524","article-title":"MTAP and p16 as immunohistochemical surrogates of CDKN2A\/B homozygous deletion in central nervous system tumors: A multicentre Italian experience","volume":"79","author":"Salzano","year":"2025","journal-title":"Ann. Diagn. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1093\/jnen\/nlad109","article-title":"Reliability assessment of methylthioadenosine phosphorylase immunohistochemistry as a surrogate biomarker for CDKN2A homozygous deletion in adult-type IDH-mutant diffuse gliomas","volume":"83","author":"Gundogdu","year":"2024","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/neup.13005","article-title":"Integrated assessment of malignancy in IDH-mutant astrocytoma with p16 and methylthioadenosine phosphorylase immunohistochemistry","volume":"45","author":"Masui","year":"2025","journal-title":"Neuropathology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s11060-024-04661-y","article-title":"Loss of methylthioadenosine phosphorylase immunoreactivity correlates with poor prognosis and elevated uptake of 11C-methionine in IDH-mutant astrocytoma","volume":"168","author":"Yamamura","year":"2024","journal-title":"J. Neuro-Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1093\/jnen\/nlaf033","article-title":"MTAP immunohistochemistry as a surrogate marker of CDKN2A loss in brain tumors: A meta-analysis and literature review","volume":"84","author":"Dono","year":"2025","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ozkizilkaya, H.I., Vinocha, A., Dono, A., Ogunbona, O.B., Toruner, G.A., Aung, P.P., Kamiya Matsuoka, C., Esquenazi, Y., DeMonte, F., and Ballester, L.Y. (2024). MTAP and p16 IHC as Markers for CDKN2A\/B Loss in Meningiomas. Cancers, 16.","DOI":"10.3390\/cancers16193299"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1007\/s11060-025-05029-6","article-title":"Pitfalls in the evaluation of CDKN2A copy number status in meningioma","volume":"173","author":"Zschernack","year":"2025","journal-title":"J. Neuro-Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1093\/jnen\/nlab127","article-title":"Correlation of MTAP Immunohistochemistry With CDKN2A Status Assessed by Fluorescence In Situ Hybridization and Clinicopathological Features in CNS WHO Grade 2 and 3 Meningiomas: A Single Center Cohort Study","volume":"81","author":"Sasaki","year":"2022","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"vdae002","DOI":"10.1093\/noajnl\/vdae002","article-title":"Molecular prognostication in grade 3 meningiomas and p16\/MTAP immunohistochemistry for predicting CDKN2A\/B status","volume":"6","author":"Tosefsky","year":"2024","journal-title":"Neuro-Oncol. Adv."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1093\/jnen\/nlae076","article-title":"Comparing loss of p16 and MTAP expression in detecting CDKN2A homozygous deletion in pleomorphic xanthoastrocytoma","volume":"83","author":"Vizcaino","year":"2024","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1111\/his.14324","article-title":"Correlation of methylthioadenosine phosphorylase (MTAP) protein expression with MTAP and CDKN2A copy number in malignant pleural mesothelioma","volume":"78","author":"Chapel","year":"2021","journal-title":"Histopathology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.jasc.2022.07.003","article-title":"Diagnostic capacity of BAP1 and MTAP in cytology from effusions and biopsy in mesothelioma","volume":"11","author":"Panou","year":"2022","journal-title":"J. Am. Soc. Cytopathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"152004","DOI":"10.1016\/j.anndiagpath.2022.152004","article-title":"Challenges and limitation of MTAP immunohistochemistry in diagnosing desmoplastic mesothelioma\/sarcomatoid pleural mesothelioma with desmoplastic features","volume":"60","author":"Hamasaki","year":"2022","journal-title":"Ann. Diagn. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100420","DOI":"10.1016\/j.modpat.2023.100420","article-title":"Comparison of Immunohistochemistry, Next-generation Sequencing and Fluorescence In Situ Hybridization for Detection of MTAP Loss in Pleural Mesothelioma","volume":"37","author":"Chang","year":"2024","journal-title":"Mod. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1111\/his.15502","article-title":"Loss of MTAP expression is not an accurate surrogate for CDKN2A homozygous deletions in peritoneal mesothelioma","volume":"87","author":"Quaranta","year":"2025","journal-title":"Histopathology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"107963","DOI":"10.1016\/j.lungcan.2024.107963","article-title":"MTAP as an emerging biomarker in thoracic malignancies","volume":"197","author":"Brune","year":"2024","journal-title":"Lung Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Bajbouj, K., Ramakrishnan, R.K., Saber-Ayad, M., Omar, H.A., Saheb Sharif-Askari, N., Shafarin, J., Elmoselhi, A.B., Ihmaid, A., AlHaj Ali, S., and Alalool, A. (2021). L\u2019inibitore selettivo di PRMT5 migliora l\u2019efficacia terapeutica del cisplatino nelle cellule del cancro al polmone. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22116131"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"627","DOI":"10.4161\/cbt.11.7.14948","article-title":"Targeting dei tumori privi di attivit\u00e0 della metiltioadenosina fosforilasi (MTAP): Strategie attuali","volume":"11","author":"Bertino","year":"2011","journal-title":"Cancer Biol. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.ccell.2019.05.014","article-title":"L\u2019attivit\u00e0 antitumorale dell\u2019inibitore PRMT di tipo I, GSK3368715, agisce in sinergia con l\u2019inibizione di PRMT5 attraverso la perdita di MTAP","volume":"36","author":"Fedoriw","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3540","DOI":"10.1158\/0008-5472.CAN-25-1507","article-title":"Combination of the MTA-Cooperative PRMT5 Inhibitor BMS-986504 and KRAS Inhibitors Is an Effective Treatment Strategy for MTAP-Deleted KRAS-Mutant Pancreatic Cancer","volume":"85","author":"Engstrom","year":"2025","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/s41591-024-03362-3","article-title":"Clinicogenomic landscape of pancreatic adenocarcinoma identifies KRAS mutant dosage as prognostic of overall survival","volume":"31","author":"Varghese","year":"2025","journal-title":"Nat. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"a031435","DOI":"10.1101\/cshperspect.a031435","article-title":"KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer","volume":"8","author":"Waters","year":"2018","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.ajpath.2010.11.059","article-title":"Down-regulation of methylthioadenosine phosphorylase (MTAP) induces progression of hepatocellular carcinoma via accumulation of 5\u2019-deoxy-5\u2019-methylthioadenosine (MTA)","volume":"178","author":"Kirovski","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6963","DOI":"10.1158\/1078-0432.CCR-09-1511","article-title":"Homozygous deletion of MTAP gene as a poor prognosticator in gastrointestinal stromal tumors","volume":"15","author":"Huang","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3754","DOI":"10.1158\/1078-0432.CCR-05-2780","article-title":"Lack of methylthioadenosine phosphorylase expression in mantle cell lymphoma is associated with shorter survival: Implications for a potential targeted therapy","volume":"12","author":"Colomo","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"83","DOI":"10.4161\/cbt.4.1.1380","article-title":"Homozygous deletion of the MTAP gene in invasive adenocarcinoma of the pancreas and in periampullary cancer: A potential new target for therapy","volume":"4","author":"Hustinx","year":"2005","journal-title":"Cancer Biol. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1097\/DAD.0000000000003139","article-title":"Methylthioadenosine Phosphorylase (MTAP) and p16 Expression in Melanocytic Nevi and Melanoma with Molecular Correlation","volume":"47","author":"He","year":"2025","journal-title":"Am. J. Dermatopathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0046-8177(98)90221-0","article-title":"Allelic Deletion at Chromosome 9p21(P16) and 17p13(P53) in Microdissected Sporadic Dysplastic Nevus","volume":"29","author":"Park","year":"1998","journal-title":"Hum. Pathol."},{"key":"ref_34","first-page":"675","article-title":"Alteration of Chromosome 9p21 and\/or P16 in Benign and Dysplastic Nevi Suggests a Role in Early Melanoma Progression (United States)","volume":"13","author":"Tran","year":"2002","journal-title":"Cancer Causes Control"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1016\/j.annonc.2024.08.2339","article-title":"First-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP-deleted solid tumors: Results from phase I dose exploration","volume":"35","author":"Rodon","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1111\/his.15324","article-title":"MTAP protein status is highly concordant with CDKN2A fluorescent in situ hybridization and allows stratification of the luminal subtype in muscle-invasive bladder cancer","volume":"86","author":"Oberc","year":"2025","journal-title":"Histopathology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/s41392-019-0035-z","article-title":"Targeting the insulin-like growth factor-1 receptor in MTAP-deficient renal cell carcinoma","volume":"4","author":"Xu","year":"2019","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"100495","DOI":"10.1016\/j.modpat.2024.100495","article-title":"Loss of MTAP Expression by Immunohistochemistry Is a Surrogate Marker for Homozygous 9p21.3 Deletion in Urothelial Carcinoma","volume":"37","author":"Vlajnic","year":"2024","journal-title":"Mod. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"25581","DOI":"10.1038\/s41598-025-10157-0","article-title":"MTAP deficiency is highly homogeneous in advanced, muscle-invasive urothelial carcinoma of the urinary bladder","volume":"15","author":"Gorbokon","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"151582","DOI":"10.1016\/j.anndiagpath.2020.151582","article-title":"Evaluation of MTAP immunohistochemistry loss of expression in ovarian serous borderline tumors as a potential marker for prognosis and progression","volume":"48","author":"Nilforoushan","year":"2020","journal-title":"Ann. Diagn. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s10014-022-00447-0","article-title":"Correlation of MTAP immunohistochemical deficiency with CDKN2A homozygous deletion and clinicopathological features in pleomorphic xanthoastrocytoma","volume":"40","author":"Lou","year":"2023","journal-title":"Brain Tumor Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1097\/01.pas.0000170349.47680.e8","article-title":"Concordant loss of MTAP and p16\/CDKN2A expression in gastroesophageal carcinogenesis: Evidence of homozygous deletion in esophageal noninvasive precursor lesions and therapeutic implications","volume":"29","author":"Powell","year":"2005","journal-title":"Am. J. Surg. Pathol."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/13\/2069\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T04:44:51Z","timestamp":1783053891000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/13\/2069"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,1]]},"references-count":42,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["diagnostics16132069"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics16132069","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,1]]}}}