Expression Of Bcl-2and C-Flip_L And Their Significance In Pre-Malignant And Malignant Lesions Of Uterine Cervix

Objective:(1) Study the expression of anti-apoptotic markers Bcl-2and c-FLIPL in non-neoplastic, pre-neoplastic and neoplastic cases of uterine cervix to assess their possible involvement in the pathogenesis of cervical cancer.(2) Evaluate their expression with various clinicopathological parameters to assess the significance of these markers in predicting the clinical outcome of cervical cancer.Materials and methods:163tissue samples with similar inclusion criteria were collected from pathology department archives at Tianjin Central Hospital of Gynaecology and Obstetrics, P.R.China. It included65cases of cervical cancer,36cases of CIN II-III and32cases of CIN I.30cervices obtained from benign leiomyomata cases were used as controls. Immunohistochemical study was done to study the expression of c-FLIP1and Bcl-2on these tissues. Expressions of these markers were evaluated using microscope and were analysed together with other clinical information collected from patients’case history. Their expression in different study groups were assessed using Fischer’s exact test (two-sided) and/or Pearson’s chi square test and their correlation with various clinicopathological parameters was assessed using Spearman correlation test. In each of these analytical studies, values of P less than0.05were regarded statistically significant.Results:1. The expression of Bcl-2was mainly in the cytosol. No statistically significant difference was seen in its expression in CIN1and control cases(P>0.05) whereas a significantly high expression was observed in CIN2-3cases as compared to CIN1cases(P<0.05). In cancer cases its expression was significantly down-regulated compared to CIN2-3(P<0.05).2. C-FLIP1was exclusively expressed in the cytoplasm of cells. There was a progressive increase in its expression with increasing severity of lesions, difference of expression being significant among different groups (P<0.05). 3. Expression of c-FLIPL in CIN1is significantly higher than its expression in normal cervices (P<0.05). Similarly, a higher expression was noted in CIN2-3when compared to CIN1cases (P<0.01). Cancer cases showed an extremely significant expression of c-FLIPL as compared to CIN2-3cases (P<0.01).4. No significant difference was seen in the expression of Bcl-2in HR-HPV positive and negative groups (P>0.05) whereas a statistically significant difference was noticed in the expression of c-FLIPL in those groups (P<0.05). A positive linear relation was observed between HR-HPV status and c-FLIPL expression (P<0.05).5. Expression of c-FLIPL was found to be positively correlated with FIGO staging(P<0.05)6. A positive correlation was seen between the expression of c-FLIPL and lymph node metastasis whereas no association was found between Bcl-2expression and lymph node metastasis.7. Expressions of both Bcl-2and c-FLIPL were not correlated with tumor gradings (P>0.05for both).8. Expressions of both Bcl-2and c-FLIPL were not found to be correlated with vascular invasion.Conclusion:1. The expression of Bcl-2was highest in CIN2-3cases amongst all other groups including control groups and study groups, and its expression was downregulated in cancer cases. On the other hand, there was a progressive increase in the expression of c-FLIPL with increasing severity of the cervical lesions, being highly expressed in cancer cases.2. Both of these markers were mostly negative in control groups, but expression of Bcl-2showed no difference among normal cervices and CIN1cases whereas a significant difference was observed in the expression of c-FLIPL among these two groups. These results show the possibility that c-FLIPL can prove to be a good marker in early stage diagnosis. 3. C-FLIPL was significantly over-expressed in HR-HPV positive cases and a positive correlation was observed between HR-HPV infection and c-FLIPL expression which refers to the possibility that extrinsic pathway might be the major pathway being deregulated by the persistent HR-HPV as a gradual change was seen in the expression of c-FLIPL with increasing severity of dysplasticity.4. The expression of c-FLIPL was found to be positively correlated with FIGO staging and lymph nodes whereas Bcl-2had no correlation only with either of them. Thus c-FLIPL might prove to be an important biomarker in predicting the clinical outcome of the cervical cancer.5. This study somewhere reveals the fact that extrinsic pathway of apoptosis seems to be more exploited than intrinsic pathway in the progression of the cervical cancer.