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

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 (<i>CDKN2A/MTAP</i>) locus. We analyzed the molecular underpinnings of the <i>CDKN2A/MTAP</i> 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 <i>CDKN2A</i> inactivation, and <i>MTAP</i>, 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 <i>CDKN2A/MTAP</i> co-deletion, albeit with lower sensitivity. Concordant loss of both markers strongly supports melanoma or high-risk melanocytoma, while <i>MTAP</i> 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.