الفهرس 
I-IntroductionOnly 14 pages are availabe for public view
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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 fifth leading cause of cancer-related death worldwide. The majority of all HCC cases occur due to chronic liver inflammation and subsequent cirrhosis.
A growing tumour is composed not only of cancer cells but also contains stromal cells and extracellular matrix components that are collectively referred to as tumour 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.
Therefore, this study aimed to study the immunohistochemical expression of CD8, CD4, cytotoxic T lymphocyte associated protein-4 (CTLA-4) and granzyme B in HCC and its correlation with clinicopathological parameters and prognosis.
This study included 112 liver specimens from patients had HCC and survival data (overall survival and recurrence free survival) were available for all 112 HCC cases. Thirty four cases experienced tumor recurrence representing 30.4% of cases.
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The median age of HCC cases was 57 years with predominance of male gender (81.2%). Median level of serum AFP was 33 ng/ml, 90.2% of cases were positive for hepatitis viral infection and 65.9% presented with Child pugh A. DAA for treatment of HCV was received by 43.8% of cases and 18.2% of cases fell in high CLIP prognostic scores. Single mass was presented by 71.4% of cases with median tumor size of 4 cm. Low grade HCC was found in 68.8% of cases, 8% of cases showed clear cell changes, 88.4% of cases presented with early pathological stage and 43.8% showed microscopic vascular invasion. Eighty two percent of cases arouse on top of liver cirrhosis.
The current study showed a statistically significant association between high H score and high percentage of CD8+ lymphocytes and adjacent non-cirrhotic non-tumor liver (P= 0.05, P= 0.035). Also, there was a significant association between high percentage of CD8+ lymphocytes and large tumor size ≥ 5 cm (P= 0.015). The present study showed no impact of CD8 expression on overall survival or recurrence free survival.
The present study showed a statistically significant association between high percentage of CD4+ lymphocytes and low AFP level (P= 0.021), non-viral etiology (P= 0.023) and DAA treatment for HCV (P=0.048). Also, there was a statistically significant association between high H score of CD4+ lymphocytes and low AFP level (P= 0.026), non-viral etiology (P= 0.038) and DAA treatment for HCV (P= 0.048). Furthermore, there was a near significant association between low CD4+ lymphocytes percentage and presence of tumor recurrence (P= 0.064). Also, there was a significant association between low CD4 percentage as well as low H score and better overall survival (P=0.004, P= 0.003).
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The present study showed that there was a significant association between high CD4/CD8 ratio and non-viral etiology (P=0.017), low AFP (>200 ng/ml) (P=0.007) and DAA type of treatment for HCV (P=0.020). Also, there was a significant association between low CD4/CD8 ratio and better overall survival (P= 0.047).
Regarding CTLA-4, the current study showed that high H score of CTLA-4+ tumor infiltrating lymphocytes tended to be associated with bad prognostic factors such as presence of lymphovascular invasion (P= 0.07) and its high percentage tended to be associated with high tumor grade of differentiation (G III/IV) (P= 0.08).
The present study also showed that there was a significant association between high H score of CTLA-4 expression in tumor cells and old age ≥ 60 (P= 0.041) and a near significant association with unilobar presentation (P= 0.077). Furthermore, there was a significant association between CTLA-4 low percentage of expression in tumor cells and single lesions (P=0.05) as well as tumor high grades (G III-IV) (P= 0.047). On the other hand, the current study showed no impact of CTLA-4 expression on overall survival and recurrence free survival.
The current study showed that there was a significant association between high H score and high percentage of granzyme B expression in lymphocytes and good prognostic factors such as low grade (I/II) (P=0.043, P=0.039), early stage (T1/T2) tumors (P=0.05, P=0.038) and absence of tumor recurrence (P=0.040, P=0.043). Furthermore, granzyme B+ tumor infiltrating lymphocytes was associated with absence of recurrence (P= 0.029) and tended to be associated with female gender (P=0.066). This study showed no
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impact of granzyme B+ infiltrating lymphocytes on overall or recurrence free survival.
The current study found that tumor cells also expressed granzyme B. There was a significant association between granzyme B low percentage of expression by tumor cells and younger aged patients > ) 60 years( (P=0.018) and tended to be associated with early pathologic stage (T1/T2) (P=0.066). However, there was no impact of granzyme B expression in tumor cells on overall survival and recurrence free survival.
Moreover, the present study revealed that there was a highly significant positive correlation between CD8 and CD4 expression. Also, there was a significant positive correlation between CTLA-4 expression and both CD8 and CD4. Furthermore, a significant positive correlation between CD8 and granzyme B expression was also documented. On the other hand, no correlation between CTLA-4 and granzyme B expression was identified.
Univariate analysis of overall survival showed the bad prognostic impact of old age (≥60) (P=0.042), absence of clear cell changes (P=0.042), high CD4 percentage (P=0.004), high CD4 H score (P=0.003) and high CD4/CD8 ratio (P= 0.047) on patients‘ outcome. However, only advanced pathologic stage (T3/T4) affected tumor recurrence using recurrence free survival analysis (P= 0.010).