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

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Abstract

Background

Inactivation of p16INK4A 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 p16INK4A 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 p16INK4A 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. P16INK4A 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.

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Acknowledgments

This work was supported in part by grants from National Science Council, Taiwan (NSC93-2320-B-182A-011) and Chang Gung Memorial Hospital (CMRPG83019).

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Authors and Affiliations

  1. Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Hsuan-Ying Huang MD, Hock-Liew Eng MD & Shih-Chen Yu BS

  2. Department of Family Medicine, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan

    Wen-Wei Huang MD

  3. Department of Pathology, Chi-Mei Foundation Medical Center, Tainan, Taiwan

    Ching-Nan Lin MD & Chien-Feng Li MD

  4. Division of Oncology, Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Shau-Hsuan Li MD

  5. Department of Pathology, Chi-Mei Foundation Hospital, Liouying Campus, Tainan, Taiwan

    David Lu MD

  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

    Ching-Yeh Hsiung MD

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Huang, HY., Huang, WW., Lin, CN. et al. Immunohistochemical Expression of p16INK4A, Ki-67, and Mcm2 Proteins in Gastrointestinal Stromal Tumors: Prognostic Implications and Correlations with Risk Stratification of NIH Consensus Criteria. Ann Surg Oncol 13, 1633–1644 (2006). https://doi.org/10.1245/s10434-006-9188-4

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