Hepatocellular carcinoma-the role of the underlying liver disease in clinical practice

Hepatocellular carcinoma(HCC)is one of the most common causes of cancerrelated mortality.This particular type of cancer has the distinctive characteristic of mostly happening in individuals with an underlying liver disease.This makes the management of patients more challenging,since physicians must take into consideration two different conditions,the chronic liver disease and the tumor.The underlying liver disease has several implications in clinical practice,because different kinds of chronic liver disease can lead to varying degrees of risk of developing HCC,obstacles in surveillance,and differences in the efficacy of the treatment against HCC.A shift in the prevalence of liver diseases has been evident over the last few years,with viral hepatitis gradually losing the leading position as cause of HCC and metabolic dysfunction-associated steatotic liver disease gaining importance.Therefore,in an era of personalized medicine,it is imperative that physicians are aware of the underlying liver disease of individuals with HCC and its impact in the management of their tumors.

Current impact of viral hepatitis on liver cancer development: The challenge remains

Chronic infections due to hepatitis B and hepatitis C viruses are responsible for most cases of hepatocellular carcinoma(HCC)worldwide,and this association is likely to remain during the next decade.Moreover,viral hepatitis-related HCC imposes an important burden on public health in terms of disability-adjusted life years.In order to reduce such a burden,some major challenges must be faced.Universal vaccination against hepatitis B virus,especially in the neonatal period,is probably the most relevant primary preventive measure against the development of HCC.Moreover,considering the large adult population already infected with hepatitis B and C viruses,it is also imperative to identify these individuals to ensure their access to treatment.Both hepatitis B and C currently have highly effective therapies,which are able to diminish the risk of development of liver cancer.Finally,it is essential for individuals at high-risk of HCC to be included in surveillance programs,so that tumors are detected at an early stage.Patients with hepatitis B or C and advanced liver fibrosis or cirrhosis benefit from being followed in a surveillance program.As hepatitis B virus is oncogenic and capable of leading to liver cancer even in individuals with early stages of liver fibrosis,other high-risk groups of patients with hepatitis B are also candidates for surveillance.Considerable effort is required concerning these strategies in order to decrease the incidence and the mortality of viral hepatitis-related HCC.

Immune aspects of hepatocellular carcinoma:From immune markers for early detection to immunotherapy

Hepatocellular carcinoma(HCC)is one of the most prevalent cancers and one of the main causes of cancer-related deaths worldwide.Most HCCs develop in an inflammatory microenvironment,and mounting evidence emphasizes the importance of immune aspects in hepatocarcinogenesis.In normal physiology,both innate and adaptive immune responses are responsible for eliminating malignantly transformed cells,thus preventing the development of liver cancer.However,in the setting of impaired natural killer cells and exhaustion of T cells,HCC can develop.The immunogenic features of HCC have relevant clinical implications.There is a large number of immune markers currently being studied for the early detection of liver cancer,which would be critical in order to improve surveillance programs.Moreover,novel immunotherapies have recently been proven to be effective,and the combination of atezolizumab and bevacizumab is currently the most effective treatment for advanced HCC.It is expected that in the near future different subgroups of patients will benefit from specific immunotherapy.The better we understand the immune aspects of HCC,the greater the benefit to patients through surveillance aiming for early detection of liver cancer,which allows for curative treatments,and,in cases of advanced disease,through the selection of the best possible therapy for each individual.

Hepatocellular carcinoma in nonalcoholic fatty liver disease:A growing challenge

Nonalcoholic fatty liver disease(NAFLD)is the most common cause of liver disease worldwide,and its prevalence increases continuously.As it predisposes to hepatocellular carcinoma both in the presence and in the absence of cirrhosis,it is not surprising that the incidence of NAFLD-related hepatocellular carcinoma would also rise.Some of the mechanisms involved in hepatocarcinogenesis are particular to individuals with fatty liver,and they help explain why liver cancer develops even in patients without cirrhosis.Genetic and immune-mediated mechanisms seem to play an important role in the development of hepatocellular carcinoma in this population.Currently,it is consensual that patients with NAFLD-related cirrhosis should be surveilled with ultrasonography every 6 mo(with or without alpha-fetoprotein),but it is known that they are less likely to follow this recommendation than individuals with other kinds of liver disease.Moreover,the performance of the methods of surveillance are lower in NAFLD than they are in other liver diseases.Furthermore,it is not clear which subgroups of patients without cirrhosis should undergo surveillance.Understanding the mechanisms of hepatocarcinogenesis in NAFLD could hopefully lead to the identification of biomarkers to be used in the surveillance for liver cancer in these individuals.By improving surveillance,tumors could be detected in earlier stages,amenable to curative treatments.

Non-alcoholic fatty liver disease-related hepatocellular carcinoma:Is there a role for immunotherapy?

Hepatocellular carcinoma(HCC)is among the most common cancers and it is a major cause of cancer-related deaths.Non-alcoholic fatty liver disease(NAFLD)affects approximately one fourth of individuals worldwide and it is becoming one of the most important causes of HCC.The pathogenic mechanisms leading to NAFLD-related HCC are complex and not completely understood.However,metabolic,fibrogenic,oncogenic,inflammatory and immunological pathways seem to be involved.First-line therapy of advanced HCC has recently undergone major changes,since the combination of atezolizumab and bevacizumab was proven to increase survival when compared to sorafenib.Other immune-oncology drugs are also demonstrating promising results in patients with advanced HCC when compared to traditional systemic therapy.However,initial studies raised concerns that the advantages of immunotherapy might depend on the underlying liver disease,which seems to be particularly important in NAFLD-related HCC,as these tumors might not benefit from it.This article will review the mechanisms of NAFLD-related hepatocarcinogenesis,with an emphasis on its immune aspects,the efficacy of traditional systemic therapy for advanced NAFLD-related HCC,and the most recent data on the role of immunotherapy for this specific group of patients,showing that the management of this condition should be individualized and that a general recommendation cannot be made at this time.