The Diagnostic and Prognostic Role of Combined p16 and MTAP Immunohistochemistry in Melanocytic Tumors of Uncertain Malignant Potential: A Comprehensive Review and Clinical Practice Analysis

TL;DR

This paper reviews how combining p16 and MTAP immunohistochemistry improves diagnosis and prognosis of uncertain melanocytic tumors by detecting 9p21 genomic changes.

Contribution

The paper introduces a dual-marker IHC strategy for MELTUMPs that integrates molecular insights with diagnostic practice.

Findings

p16 IHC is sensitive but lacks specificity in borderline melanocytic lesions.

MTAP loss is highly specific for CDKN2A/MTAP co-deletion but less sensitive.

Concordant loss of p16 and MTAP strongly indicates melanoma or high-risk melanocytoma.

Abstract

Melanocytic Tumors of Uncertain Malignant Potential (MELTUMPs) remain among the most challenging entities in dermatopathology due to overlapping morphologic features and marked inter-observer variability. This comprehensive review critically assesses the diagnostic and potential prognostic significance of combining p16 and methylthioadenosine phosphorylase (MTAP) immunohistochemistry (IHC) as a practical surrogate for genomic alterations involving the 9p21 (CDKN2A/MTAP) locus. We analyzed the molecular underpinnings of the CDKN2A/MTAP axis and systematically reviewed existing literature to define an integrated IHC strategy for ambiguous melanocytic lesions. The combined use of p16, a sensitive marker of CDKN2A inactivation, and MTAP, a highly specific marker for homozygous 9p21 deletion, was assessed for its diagnostic complementarity and potential clinical utility. p16 IHC demonstrates high sensitivity but limited specificity due to heterogeneous staining in borderline lesions. In contrast, MTAP loss exhibits near-absolute specificity for CDKN2A/MTAP co-deletion, albeit with lower sensitivity. Concordant loss of both markers strongly supports melanoma or high-risk melanocytoma, while MTAP retention may predict responsiveness to adjuvant interferon therapy. Combined p16/MTAP IHC provides a synergistic, biologically grounded approach that refines diagnostic accuracy in MELTUMPs. This dual-marker algorithm promotes a shift from purely morphology-based evaluation toward a reproducible, molecularly informed classification, improving both diagnostic confidence and patient management.

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