الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 226 |  |  |
| | | from | 226 | | |
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver in adults accounting for 85% - 90% of liver tumors. It represents the sixth most common malignancy and the second cause of cancer mortality, after lung cancer, contributing to 11% of cancer-related deaths. In Egypt, it represents the fourth common cancer. Most of HCC cases occur due to chronic liver inflammation and subsequent cirrhosis.
A growing tumor is not only consisted of cancer cells but also contains stromal cells and extracellular matrix components together creating tumor microenvironment (TME), which is formed by the interplay of cells and signaling molecules comprising it. TME are known to be active contributors to cancer development by supporting carcinogenesis, progression, and metastasis and thus becomes a very promising target for anticancer treatment.
Tumor infiltrating lymphocytes (TILs) are a crucial component of the TME and thus can affect carcinogenesis. TILs are found in the context of pro-tumorigenic inflammation and anti-cancer immune surveillance. Hence, their detailed composition, density and function must be more finely analyzed to understand their prognostic impact.
This study aimed to study immunohistochemical expression of ICOS and FOXP3 in hepatocellular carcinoma and its correlation with different clinicopathological and prognostic factors.
It included 114 liver specimens from patients had HCC and 54 control cases (non-neoplastic).
The median age of HCC cases was 58 years with male predominance. Most of cases showed positive HCV virology. 78.1% of HCC cases presented with single liver tumor mass and common occurrence
Summary
148
at the right lobe of the liver. Median tumor size was 4.5cm. 75.4% of the cases displayed trabecular pattern as the predominant pattern while 17 cases (14.9%) displayed acinar pattern and 7 cases (6.1%) showed solid pattern. Macro trabecular pattern was seen only in 4 cases (3.5%) as the predominant type while other subtypes were scarce and only seen as a minor component in few cases beside the predominant pattern. Low histopathological grade was seen in 64.9% of the cases with 78.7% showing early pathological stage. 55.3% of the cases exhibited microvascular invasion and about 73.7% arose on a background of liver cirrhosis while 26.3% arose on a background of non-cirrhotic liver but chronic hepatitis instead.
The current study showed a statistical difference between HCC cases and non-tumor cases as regarding ICOS IRS. Malignant hepatocytes showed higher ICOS IRS in HCC cases than non-neoplastic hepatocytes of non-tumor cases (P value < 0.001).
Tumor infiltrating lymphocytes showed higher ICOS expression in HCC cases than infiltrating lymphocytes in non-neoplastic cases with statistically significant difference (P value= 0.032).
The present study showed a significant association between high IRS of ICOS in tumor infiltrating lymphocytes and chronic hepatitis in the adjacent tissue. While low ICOS expression in TILS was significantly associated with cirrhosis in adjacent liver tissue (P value = 0.009).
Also, there was a significant association between high ICOS H score in TILS and chronic hepatitis in the adjacent tissue, also between low ICOS H score in TILS and cirrhosis in adjacent liver tissue (P value =0.018).
In this study, there was a statistically difference between HCC and non-tumor cases as regarding FOXP3 expression with HCC cases showing higher H score (P value <0.001) and tumor infiltrating lymphocytes
Summary
149
showed higher FOXP3 expression in HCC cases than infiltrating lymphocytes in non-neoplastic cases (P value= 0.018).
In the current study, a significant association was found between high percentage of FOXP3 in malignant hepatocytes and the presence of microscopic vascular invasion (P value =0.031).
In the present study also, it was found that immuno-reactivity score (IRS) and H score of FOXP3 in tumor infiltrating lymphocytes were positively correlated with ICOS expression and H score (P value= 0.037, P value= 0.002) and H score of FOXP3 in non-tumor hepatocytes was positively correlated with H score of ICOS (P value= 0.007). While there was no significant correlation between H score and expression of FOXP3 and ICOS in malignant tumor hepatocytes.
Regarding survival analysis also, male gender was significantly associated with short survival (P value=0.045).
Interestingly, the current study showed significant higher H-score of FOXP3 in male cases (P value= 0.043) which, in part, could explain the short survival of these male patients.
In this study, univariate recurrence free survival analysis showed rapid recurrence in HCC cases with acinar/pseudo glandular pattern (P value=0.001) however, trabecular pattern was associated with delayed recurrence.
Conclusions and Recommendations
150
Conclusions 1. Both ICOS and FOXP3 operate as oncogenic drivers in hepatocellular carcinoma, being expressed more in malignant cells rather than in non- tumorous hepatocytes. 2. ICOS and FOXP3 positive TILs have curial roles in hepatocellular carcinogenesis evidenced by higher expression of ICOS and FOXP3 in TILs of hepatocellular carcinoma cases compared to non-tumorous ones. 3. ICOS and FOXP3 mediate crosstalk between tumor cells and the neighboring tumor infiltrating lymphocytes as their expression in the hepatocytes and lymphocytes were positively correlated. 4. FOXP3 in hepatocellular carcinoma has a poor prognostic impact on patient outcome being associated with shorter survival and early recurrence. 5. In hepatocellular carcinoma, ICOS has an oncogenic role only in contrary to FOXP3 that has a pro-metastatic one side by side to its pro-tumoral role as its expression was increased in correlation with vascular invasion. This could stratify responders from ICOS /FOXP3 target therapy according to tumor stage. 6. ICOS and FOXP3 behave synergistically through TILs in hepatocellular carcinoma, this is supported by their positively correlated expression in lymphocytes. 7. Prior administration of direct acting antiviral drug (DAAD) should be taken in consideration when assessing behavior of HCC cases as it was positively correlated with low lymphocytic ICOS expression.
Conclusions and Recommendations
151
8. Histopathologic pattern stands as one of the pathological prognostic indicators of HCC cases, with the acinar pattern carry a poor prognostic impact, while trabecular one carry more favorable outcome. 9. Androgen may enhance expression of FOXP3 in hepatocellular carcinoma cases, evidenced by higher expression of FOXP3 in males compared to females.