Assessment of the importance of risk factors, surveillance, and immune profiles in hepatocellular carcinoma progression and treatment outcomes

The incidence of hepatocellular carcinoma (HCC) is rising worldwide. This thesis aimed to contribute to HCC care by first investigating the value of non-invasive fibrosis assessment tools (NIT) in identifying certain patient populations at risk of HCC, secondly by characterising local HCC treatment outcomes, and thirdly by exploring the immune response to HCC tumour and how this may offer us alternative treatment strategies. Fontan associated liver disease (FALD) is a form of congestive hepatopathy occurring in patients who have undergone Fontan cardiac surgery for univentricular congenital cardiac diseases. NIT are felt to be less reliable in FALD. This makes devising a HCC surveillance programme i more complex. We aimed to determine the accuracy of NIT in predicting histologically confirmed advanced fibrosis in patients under investigation for FALD, to contribute important data regarding optimal fibrosis staging. We found that 62% of 71 FALD patients at a median age of 25 had at least advanced fibrosis on biopsy, and that NITs had no meaningful clinical utility for identifying these patients, and reassuring others. For patients with Child Pugh (CP) A cirrhosis, there are no robust tools to predict long term HCC risk, and doubt has persisted around the true benefit of HCC surveillance in a real world setting. In chapter three we assess the performance of NIT in predicting long term risk of decompensation and HCC within a mixed aetiology CP A cohort. We found that increased index liver stiffness measurement was associated with greater decompensation risk but had no association with HCC. Higher index FIB4 scores were found to be associated with increased risk of HCC and decompensation. Following this, a review of HCC diagnoses made in the Mater Misericordiae University Hospital from 2007-2023 was performed to characterise the local HCC population, review outcomes, and identify the effect of a local surveillance programme on survival. We found that our survival outcomes matched international data, and that ultrasound surveillance associates with earlier disease stage at diagnosis and improved long term survival. In our cohort, albumin bilirubin index (ALBI) can risk stratify patients with well-preserved liver function and early Barcelona Clinic Liver Cancer (BCLC) stage disease going for curative treatments. There have been significant advancements in immunotherapeutic options available to patients with advanced disease. Unfortunately, however, effective clinical response is only seen in a modest proportion of cases. We evaluated liver and peripheral blood lymphoid and myeloid populations as prognostic biomarkers in a small cohort of patients with advanced HCC treated with immune checkpoint inhibitors plus transarterial chemoembolization. Lower peripheral blood neutrophil: lymphocyte ratio (NLR) and platelet: lymphocyte ratio correlated with longer overall survival (OS) outcomes. In the uninvolved liver the presence of neutrophils had a similar effect, correlating with poorer one year OS. Patients with higher tumour infiltrating lymphocyte populations had poorer rates of 6-month progression free survival (PFS), and those with higher intratumoural NLR had longer PFS. Our somewhat paradoxical findings support the hypothesis that neutrophils and lymphocytes are susceptible to polarization; and can have pro or anti-tumoural roles depending on their phenotypic state and location. On a series of fresh resection specimens we demonstrate that HCC develops within a dysregulated and immunosuppressive tumour immune microenvironment, characterised by lymphocyte populations expressing co-inhibitory receptors and displaying a pro-tumour regulatory phenotype. We hypothesise that newer therapies focusing on lymphocyte populations such as regulatory CD4+ T cells, natural killer cells and γδ T cell populations may represent effective alternative therapeutic strategies in HCC in order to boost anti-tumour effector function.