Immunohistochemical Expression of p16INK4A, Ki-67, and Mcm2 Proteins in Gastrointestinal Stromal Tumors: Prognostic Implications and Correlations with Risk Stratification of NIH Consensus Criteria

Background Inactivation of p16^INK4A promotes G1/S progression of cell cycle. Minichromosome maintenance protein-2 (Mcm2), a novel cell proliferation marker, is known to better correlate with clinical outcomes than Ki-67 in many carcinomas. Since gastrointestinal stromal tumors (GISTs) sometimes remains challenging in prognostication, we analyzed the utility of these three markers in GISTs.Methods Immunohistochemistry was performed in tissue microarrays of 277 primary GISTs and correlated with NIH consensus criteria and clinical outcomes.Results The increment of NIH risk levels significantly correlated with increasing labeling indices (LI) of both Ki-67 (P <.001) and Mcm2 (P <.001) and loss of p16^INK4A expression (P <.035). However, the latter aberration did occur in 23% of very low/low-risk GISTs. The relationship between Mcm2 and Ki-67 LIs could be modeled as linear (P <.001, r = 0.697), while Mcm2 LI was considerably higher (P <.001) with a stepwise escalation related to risk levels. Ki-67 LI >5% (P <.0001) and Mcm2 LI >10% (P <.0001) were strongly predictive of inferior disease-specific survival (DSS), while aberrant loss of p16^INK4A only reached a trend (P = .0954). In multivariate analyses, independent adverse factors of DSS were high-risk category (RR = 16.93, P <.0001), metastatic disease (RR = 4.12, P = .0015), Ki-67 LI >5% (RR = 3.55, P = .001), and presence of epithelioid histology (RR = 2.17, P = .0308).Conclusions Prognostic efficacy of NIH consensus criteria is substantiated. P16^INK4A deregulation can occur early in GIST tumorigenesis and marginally correlates with patient survival. Despite Ki-67 LI being an independent prognosticator, simultaneous detection of Mcm2 is recommended as a prognostic adjunct of GISTs, given its better sensitivity and stepwise escalation with increasing risk levels.