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Immunohistochemical Expression of p16^INK4A, Ki-67, and Mcm2 Proteins in Gastrointestinal Stromal Tumors: Prognostic Implications and Correlations with Risk Stratification of NIH Consensus Criteria

¹ Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
² Department of Family Medicine, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan
³ Department of Pathology, Chi-Mei Foundation Medical Center, Tainan, Taiwan
⁴ Division of Oncology, Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
⁵ Department of Pathology, Chi-Mei Foundation Hospital, Liouying Campus, Tainan, Taiwan
⁶ Department of Radiation Oncology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, College of Medicine, Chang Gung University, 123 Ta-Pei Road, Niao-Sung, Kaohsiung County, Taiwan

Correspondence: Address correspondence and reprint requests to: Ching-Yeh Hsiung, MD; E-mail: a120600310{at}yahoo.com

Background: Inactivation of p16^INK4A promotes G1/S progression of cell cycle. Mini-chromosome 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.

Key Words: p16^INK4A • Ki-67 • Mcm2 • GIST • NIH consensus criteria