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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.
- Source :
-
Annals of surgical oncology [Ann Surg Oncol] 2006 Dec; Vol. 13 (12), pp. 1633-44. Date of Electronic Publication: 2006 Sep 30. - Publication Year :
- 2006
-
Abstract
- 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.<br />Methods: Immunohistochemistry was performed in tissue microarrays of 277 primary GISTs and correlated with NIH consensus criteria and clinical outcomes.<br />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).<br />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.
- Subjects :
- Adult
Aged
Aged, 80 and over
Consensus Development Conferences, NIH as Topic
Female
Gastrointestinal Stromal Tumors pathology
Humans
Immunoenzyme Techniques
Liver Neoplasms metabolism
Liver Neoplasms secondary
Male
Middle Aged
Minichromosome Maintenance Complex Component 2
Peritoneal Neoplasms metabolism
Peritoneal Neoplasms secondary
Prognosis
Risk Factors
Survival Rate
Tissue Array Analysis
United States
Biomarkers, Tumor metabolism
Cell Cycle Proteins metabolism
Cyclin-Dependent Kinase Inhibitor p16 metabolism
Gastrointestinal Stromal Tumors metabolism
Ki-67 Antigen metabolism
Nuclear Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1068-9265
- Volume :
- 13
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Annals of surgical oncology
- Publication Type :
- Academic Journal
- Accession number :
- 17013685
- Full Text :
- https://doi.org/10.1245/s10434-006-9188-4