الفهرس 
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Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer globally followed by cholangiocarcinoma (CC). Liver cancer was the fourth leading cause of cancer death after lung, colorectal, and stomach cancer.
Owing to its extremely aggressive nature and poor survival rate, it is an important health issue worldwide. In Egypt, liver cancer ranked the first among cancers in males and second among females after only breast cancer.
As the liver is also a common metastatic site for a large variety of primary tumors either with known and unknown primary origin, it is important to differentiate between HCC and non-HCC including CC and metastatic carcinoma which is usually difficult with small biopsy.
Therefore, this study aimed to study immunohistochemical expression of BSEP, arginase1 and HepPar1 in HCC and non-HCC trying to identify their possible diagnostic roles, sensitivity, specificity, positive predictive value, negative predictive value and overall accuracy.
This study included 85 liver specimens from patients had HCC, 43 liver specimens from patients had non-HCC including (18 cases of CC, 17 cases of metastatic carcinoma and 8 cases with unsettled diagnosis either CC or metastatic carcinoma) and10 liver specimens obtained from donors for liver transplantation. Tissue microarray (TMA) was done for 45 cases of HCC.
In our study, comparison between HCC, CC and metastatic carcinoma revealed a statistical significant difference regarding viral etiology (P=0.001), serum AFP (P=0.000), size of tumor (P=0.008), background liver (P=0.000) and peri-neural invasion (P= 0.008).
Also, there was a statistical significant difference between HCC and CC, HCC and metastatic carcinoma and between CC and metastatic carcinoma regarding viral etiology (P1=0.008, P2=0.000 and P3=0.037), respectively. Furthermore, there was a statistical significant difference between HCC and CC as well as HCC and metastatic carcinoma regarding AFP level (P1=0.000 & P2=0.001), respectively. There was a statistical significant difference between HCC and CC as well as HCC and metastatic carcinoma regarding tumor size (P1=0.056 & P2=0.008), respectively. Furthermore, there was a statistical significant difference between HCC and CC as well as HCC and metastatic carcinoma regarding adjacent non-neoplastic liver tissue (P1=0.000 & P2=0.000), respectively. Finally, a highly significant difference was found between HCC cases and non-HCC cases regarding peri-neural invasion (P=0.008).
In the present study, HepPar1, arginase1 and BSEP showed diffuse positive expression in all control group cases.
Regarding HepPar1 in HCC group, 96.5% of HCC cases showed positive expression to HepPar1. 90.2% of them showed diffuse positivity. In low grade HCC, HepPar1 showed positive expression in 98.4% with diffuse expression in 93.7% while in high grade HCC, HepPar1 showed positive expression in 90.5% with diffuse expression in 78.9%. This made a significant difference between low and high grade HCC regarding pattern of HepPar1 expression as diffuse expression was more in low grade HCC (P=0.05). Regarding expression of HepPar1 in non-HCC, it showed positive expression in 11.6% with negative expression in 88.4%. The positive cases were two cases of CC, one case of metastatic pulmonary adenocarcinoma and two cases of unsettled diagnosis either CC or metastatic carcinoma.
Regarding expression of arginase1 in HCC group, 97.6% of HCC cases showed positive expression to arginase1. Most of them (97.6%) showed diffuse positivity. In low grade HCC, arginase1 showed positive expression in all cases (100%). Most of them showed diffuse expression (96.9%) while in high grade HCC, arginase1 showed positive expression in 90.5% with diffuse expression in 100% of positive cases. Regarding expression of arginase1 in non-HCC, it showed positive expression in 9.3% cases with negative expression in 90.7%. Arginase1 positive non- HCC cases were one case of CC, one case of metastatic pulmonary adenocarcinoma and two cases of unsettled diagnosis either CC or metastatic carcinoma.
Regarding expression of BSEP in HCC group, 84.7% of HCC cases showed positive expression with diffuse expression in 76.4% of positive cases. In low grade HCC, BSEP showed positive expression in 93.8%. Most of them showed diffuse expression (81.7%). While in high grade, BSEP showed positive expression in 57.1% with diffuse expression in 50% of positive cases. Regarding expression of BSEP in non-HCC, it showed negative expression in all cases.
There was a significant association between BSEP expression in HCC and patient’s gender, pattern of HCC, adjacent non-neoplastic liver & vascular invasion (P=0.05), (P=0.000), (P=0.018) & (P=0.015), respectively.
In our study, the sensitivity, specificity, positive, negative predictive values and overall accuracy of HepPar1 in distinguishing HCC from non-HCC are 96.5%, 88.4%, 93.2%, 92.5% and 92.9% compared with 97.6%, 90.7%, 95.4%, 95.1 and 95.3% for arginase1 and 84.7%, 100%, 100%, 76.8% and 89.8% for BSEP, respectively. The sensitivity of arginase1 for diagnosis of HCC (97.6%) was higher than that of HepPar1 (96.5%). The combination of both immune-markers for the diagnosis of HCC leads to increased sensitivity (98.8%) and decreased specificity (83.7%).
The sensitivity of arginase1 for diagnosis of HCC (97.6%) was higher than that of BSEP (84.7%). The combination of both immune-markers for the diagnosis of HCC leads to the same specificity (90.7%) and the same sensitivity of arginase1 alone (97.6%).
The sensitivity of HepPar1 for diagnosis of HCC (96.5%) was higher than that of BSEP (84.7%). The combination of both immune-markers for the diagnosis of HCC leads to the same specificity of HepPar1 (88.4%) and increased sensitivity to 98.8%.
The combination of the three markers together leads to increase in sensitivity (98.8%) as that of combining only HepPar1 & arginase1 and combining only HepPar1& BSEP.
Finally, we concluded that arginase1 has the highest sensitivity (97.6%) with the highest overall accuracy (95.3%) while BSEP has the highest specificity (100%) but with the lowest sensitivity (84.7%). Arginase1 is the first choice for diagnosis of HCC. The favorable combination to achieve the highest sensitivity (especially when poorly differentiated HCC is suspected) is using Arginase1 & HepPar1 with sensitivity of 98.8%. Usage of combination is preferred when arginase1 is negative and diagnosis of HCC is highly suggested. This is attributed to the high sensitivity of arginase1 and HepPar1 in diagnosis of poorly differentiated HCC and the more diffuse pattern of them make arginase1 & HepPar1 is the best combination.