Prognostic significance of MDR-1 gene product P-glycoprotein immunohistochemical expression in hepatocellular carcinoma; its relation to Ki-67 proliferation marker and other clinico-pathological parameters.

Abstract

Author(s): Mona Younis Youssef Abd Allah, and Heba Salah Hany

Background: Hepatocellular Carcinoma (HCC); the second leading cause of cancer-related deaths worldwide; still has a high mortality rate. This is mostly attributable to high recurrence rate, metastasis and chemo-resistance. Recent research works stated that multidrug resistance-1 gene (MDR-1) polymorphism and its P glycoprotein product may be responsible for the resistance to the already used chemotherapeutic regimens in addition to increase the patients’ susceptibility to develop cancer. Ki-67 is a nuclear proliferation marker that was proved to be overexpressed in many aggressive tumors of solid organs. Aim of this study: This study assesses the expression of MDR-1 Pglycoprotein (MDR-1 Pgp) product and the proliferation marker; Ki-67; in hepatocellular carcinoma cells in comparison to the adjacent noncancerous liver cells using immunohistochemistry (IHC) technique to testify their usability as a prognostic markers in HCC and investigates the association between these two markers and the different clinicopathological prognostic parameters in addition to its relation to patients’ survival. Materials and Method: This work is a retrospective study carried out on 100 cases of surgically resected HCC. Tissue microarrays (TMAs) were prepared from the available paraffin blocks of the included cases and IHC for MDR-1 Pgp and Ki-67 were applied to such biopsies then assessed and scored for HCC using cores from the non-cancerous liver tissue for comparison. Finally the data were tabulated for statistical analysis. Results: In this study, MDR-1 showed an increased IHC expression in HCC rather than the non-cancerous liver tissue. Statistically significant relation was observed between MDR-1 expression and patients positive for HCV (P≤0.001), larger tumor size (P≤0.001), multiplicity of tumor mass (P≤0.001), cases associated with cirrhosis (P≤0.001), higher tumor grade (P≤0.001), capsular invasion (P=0.014), higher mitotic count (P=0.036) and cases positive for distant metastasis (P≤0.001). Considering Ki-67 expression in the studied HCC cases, higher Ki-67 expression was in statistically significant relation with larger tumor size (P≤0.001), multiplicity of tumor masses ((P=0.001), cases associated with cirrhosis (P≤0.001), higher tumor grade (P=0.004), cases associated with distant metastasis (P≤0.001) and patients associated with local or distant recurrence (P≤0.001). Interestingly, there was positive statistical significant relation and correlation between tumoral MDR-1 and Ki-67 expression (P≤0.001). Consistently, both MDR-1 overexpression and high Ki-67 index were observed to be associated with lower overall patients survival and disease free survival but with statistical insignificant relation. Conclusion: Our study observed overexpression of MDR-1 and Ki-67 associating aggressive HCC features. Thus, the usage of these markers as prognostic parameters in patients with HCC should be considered in further studies.

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