Brief Article
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World J Gastroenterol. Jan 28, 2013; 19(4): 523-527
Published online Jan 28, 2013. doi: 10.3748/wjg.v19.i4.523
Role of Ki-67 as a prognostic factor in gastrointestinal stromal tumors
Borislav Belev, Iva Brčić, Juraj Prejac, Zrna Antunac Golubić, Damir Vrbanec, Jadranka Božikov, Ivan Alerić, Marko Boban, Jasminka Jakić Razumović
Borislav Belev, Zrna Antunac Golubić, Damir Vrbanec, Department of Medical Oncology, Clinic of Oncology, Clinical Hospital Center Zagreb, 10000 Zagreb, Croatia
Iva Brčić, Jasminka Jakić Razumović, Department of Pathology, Clinical Hospital Center Zagreb, 10000 Zagreb, Croatia
Juraj Prejac, Department of Gastrointestinal Oncology, Clinic of Oncology, Clinical Hospital Center Zagreb, 10000 Zagreb, Croatia
Jadranka Božikov, Institute for Public Health, Dr. Andrija Štampar, Medical School of Zagreb, 10000 Zagreb, Croatia
Ivan Alerić, Clinical Hospital for Lung Diseases Jordanovac, Clinical Hospital Center Zagreb, 10000 Zagreb, Croatia
Marko Boban, Department of Gastroenterology, Clinical Hospital Center, Sisters of Mercy, 10000 Zagreb, Croatia
Author contributions: Belev B designed the study and wrote the manuscript; Brčić I made the concept of the data, was involved in drafting the manuscript and its editinig as well as their interpretation; Prejac J and Golubić ZA were involved in data collection, especially clinical data; Vrbanec D coordinated the collection of the materials as well as concept of statistical analysis; Razumović JJ provided immunohistochemistry for the tumor specimen as well as pathohistological analysis; Božikov J and Alerić I provided statistical analysis of the data; Boban M was involved in collecting patient data by providing data on clinical basis (patients’ data).
Correspondence to: Borislav Belev, MD PhD, Department of Medical Oncology, Clinic of Oncology, Clinical Hospital Center Zagreb, Medical School of Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia.
Telephone: +385-1-2388725 Fax: +385-1-2376300
Received: July 24, 2012
Revised: October 4, 2012
Accepted: December 25, 2012
Published online: January 28, 2013

AIM: To investigate primarily the prognostic value of Ki-67, as well as other parameters, in gastrointestinal stromal tumors (GISTs).

METHODS: Ki-67, c-KIT, platelet-derived growth factor receptor-alpha (PDGFRα), smooth muscle actin (SMA), CD34, S100 were stained for immunohistochemistry which was performed on formalin-fixed, paraffin-embeded sections on representative block from each case. Proliferation index counted by Ki-67 antibody was calculated as a number of positive nuclear reaction over 100 cells. Immunoreactivity for c-KIT and PDGFRα was evaluated semiquantitatively (weak, intermediate, strong) and for c-KIT type of reactivity was analyzed (cytoplasmic, membrane and "dot-like" staining). Immunoreactivity for SMA, CD34 and S100 were was evaluated as positive or negative antigen expression. Pathologic parameters investigated in this study included tumor size, cell type (pure spindle, pured epitheloid mixed spindle and epitheloid), mitotic count, hemorrhage, necrosis, mucosal ulceration. Clinical data included age, gender, primary tumor location and spread of disease. χ2 test and Student's t-test were used for comparisons of baseline characteristics. The Cox’s proportional hazard model was used for univariable and multivariable analyses. Survival rates were calculated by Kaplan-Meier method and statistical significance was determined by the log-rank test.

RESULTS: According to the stage of disease, there were 36 patients with localized disease, 29 patients with initially localized disease but with its recurrence in the period of follow up, and finally, 35 patients had metastatic disease from the very beginning of disease. Tumor originated most commonly in the stomach (41%), small intestine was the second most common location (36%). The mean size of primary tumors was 6.5 cm. The mean duration of follow-up was 60 mo. Multiple parameters were analyzed for their effect on overall survival, but no one reached statistical significance (P = 0.06). Analysis of time to progression/relapse in initially localized disease (univariate analysis), tumor size, mitotic count, Ki-67 and type of d-KIT distribution (cytoplasmic vs membrane/”dot-like”) showed statistically significant correlation. In multivariate analysis in the group of patients with localized disease, there were only 2 parameters that have impact on relapse, Ki-67 and SMA (P < 0.0001 and P < 0.034, respectively). Furthermore, Ki-67 was analyzed in localized disease vs localized with recurrence and metastatic disease. It was shown that there is a strict difference between these 2 groups of patients (median value was 2.5 for localized disease vs 10.0 for recurrent/metastatic disease, P < 0.0001). It was also shown that the cut-off value which is still statistically significant in terms of relapse on the level of 6%. The curves for survival on that cut-off level are significantly different (P < 0.04, Cox F).

CONCLUSION: Ki-67 presents a significant prognostic factor for GIST recurrence which could be of great importance in evaluating malignant potential of disease.

Keywords: Gastrointestinal stromal tumors, Prognostic factor, Ki-67, Recurrence