الفهرس 
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Abstract
Hepatocellular carcinoma is a major health problem and defining its aggressiveness in relation to clinicopathologic or specific marker may change treatment strategies and predict survival.
This was a retrospective study conducted on liver biopsies from 114 patients who had partial or total hepatectomy for hepatocellular carcinoma (HCC). The aim of this study was to investigate the role of p53, beta-catenin, CD133 and ki-67 in subclassification of hepatocellular carcinoma into different aggressive subtypes and to study the correlation between those markers and the clinicopathologic characteristics of patients with hepatocellular carcinoma.
Paraffin embedded blocks of liver specimens were retrieved from Pathology Department, National Liver Institute, Menoufia University in the period between 2010 and 2017.
The median age of HCC cases was 57 years with the predominance of male gender. Also, 99 cases (86.8%) were positive for HCV. Eighty three cases (72.8%) displayed solitary lesions and the median size for studied HCC cases was 4 cm. Classic type of HCC was found in 104 studied cases of total 114 cases (91.1%) while 106 cases were moderately differentiated (93%) and 93 cases (81.6) developed on a background of cirrhotic liver.
Regarding previous treatment of HCV by direct acting antiviral drugs (DAA), it was significantly associated with age >60 years (p< 0.001), recurrence of tumor (p< 0.001), low AFP level (p= 0.043) and solitary focal lesions (p< 0.001) in comparison to those previously treated by interferon. Forty five out of 114 studied cases showed nuclear p53 expression (36.5%). This expression was significantly associated with old age (p=0.028), HBV positivity (p=0.032), HCV negativity (p=0.046), large sized tumors (p< 0.001) and poor tumor differentiation (p=0.012 and 0.009) as regards positivity and percentage of expression.
The present study demonstrated expression of beta catenin in 97 out of 114 of studied cases (85.1%). Nuclear predominant expression was seen in 22 cases (22.7%), while cytoplasmic predominant expression was seen in 75 cases (77.3%). Beta catenin expression showed a significant association with HBV negativity (p=0.014), small sized tumors (p=0.005 and 0.019) and stage II tumors (p=0.029). Furthermore, predominantly cytoplasmic pattern of expression was significantly associated with large sized tumors (p=0.046).
Cytoplasmic expression of CD133 was detected in 82 out of 114 cases of hepatocellular carcinoma (79.1%). The percentage of its expression was significantly related to old age (p=0.035) and HBV positivity (p=0.045) while CD133 positivity did not show significant association with any studied clinicopathological parameters.
Nuclear expression of Ki-67 was identified in 91 out of 114 studied HCC cases (79.8%). It was significantly associated with old age (p=0.035), previous treatment of HCV by direct acting antiviral agents (DAA) (p=0.005), large tumor size (p=0.049 and 0.015), advanced tumor stage (p=0.056) and presence of vascular invasion (p=0.05) as regards positivity and percentage of expression.
The correlation among all markers revealed that p53 expression correlated with both CD133 (p=0.048, p=0.015) and Ki-67 expression (p=0.00.004, p=0.010) and also, Ki-67 correlated with CD133 expression HCC score, high score was associated with old age (p=0.002), previous treatment of HCV by DAA (p=0.001), large tumor size (p < 0.001) and poorly differentiated tumors (p=0.009).
As regards overall survival, among clinicopathological parameters, old age (> 60 years) (p=0.022), previous treatment of HCV by DAA (p=0.014) and clear cell type HCC (p=0.033) were of poor prognostic impact and by multivariate analysis, old age was found to be the first independent prognostic factor (p=0.007). While, regarding IHC markers in relation to survival, a near statistically significant association was found between HCC cases with high immunohistochemical expression level (≥ 50%) of p53 (p=0.073), CD133 (p=0.077) and Ki-67 (p=0.062) and decreased survival time. Consequently, high HCC score was a possible poor prognostic factor (p= 0.075).
Recurrence free survival analysis revealed that beta catenin expression was associated with longer recurrence free survival of HCC patients (p=0.045), while decreased recurrence free survival time was associated with involved surgical margins (p=0.012) and presence of vascular invasion (p=0.015). The presence of vascular invasion was found to be the only independent prognostic factor for recurrence free survival.