The diagnostic approach to hepatocellular carcinoma

Risk factors and symptoms of hepatocellular carcinoma (HCC): The main risk factors of HCC include infection with hepatitis B or C virus, as well as alcohol consumption. There are no specific symptoms of HCC, making early diagnosis and detection of the disease difficult. When HCC presents with specific clinical symptoms, the tumour is typically very far advanced. Surveillance in liver cirrhosis: The most common serological marker used in HCC diagnosis is alpha-fetoprotein (AFP), but other tumour markers such as the des-gamma-carboxyprothrombin (DGCP) or fractions of AFP (AFP-L3) exist and there use is discussed in this context. Surveillance should be done by sonography at 6 (to 12) months intervals. The single nodule in the cirrhotic liver: Ultrasound is the most commonly used imaging modality for detecting HCC tumour nodules with a large range of reported sensitivities. HCC may appear as a hypoechoic, isoechoic, or hyperechoic round or oval lesion with intratumoural flow signals on Doppler or power Doppler sonography. The differentiation of smaller malignant lesions in cirrhotic livers can be improved by contrast-enhanced ultrasound (CEUS). Spiral computed tomography (CT) and magnetic resonance imaging (MRI) with and without contrast enhancement play an important role in the diagnosis and staging of HCC. If the vascular pattern on imaging is not typical, biopsy becomes necessary. The patient with known HCC: Different tumour markers are used in the evaluation of tumour progression, prediction of patient outcome and treatment efficacy. Among the various staging systems used in the context of HCC, the Barcelona-Clinic-Liver-Cancer (BCLC) staging system is currently the only staging system that takes into account tumour stage, liver function, physical status and cancer-related symptoms. Beside surgical resection, non-surgical treatments such as percutaneous ethanol injection (PEI), radiofrequency thermoablation (RFTA) and trans-arterial chemoembolisation (TACE) are used. Successful tumour "bridging" with ablative therapy methods can be achieved in carefully selected patients on the waiting list for orthotopic liver transplantation. Contrast-enhanced sonography is able to control the ablation treatment of HCC.     

An evidence-based multidisciplinary approach to the management of hepatocellular carcinoma (HCC): the Alberta HCC algorithm

Hepatocellular carcinoma (HCC) is one of only a few malignancies with an increasing incidence in North America. Because the vast majority of HCCs occur in the setting of a cirrhotic liver, management of this malignancy is best performed in a multidisciplinary group that recognizes the importance of liver function, as well as patient and tumour characteristics. The Barcelona Clinic Liver Cancer (BCLC) staging system is preferred for HCC because it incorporates the tumour characteristics (ie, tumour-node-metastasis stage), the patient's performance status and liver function according to the Child-Turcotte-Pugh classification, and then links the BCLC stage to recommended therapeutic interventions. However, the BCLC algorithm does not recognize the potential role of radiofrequency ablation for very early stage HCC, the expanding role of liver transplantation in the management of HCC, the role of transarterial chemoembolization in single large tumours, the potential role of transarterial radioembolization with 90Yttrium and the limited evidence for using sorafenib in Child- Turcotte-Pugh class B cirrhotic patients. The current review article presents an evidence-based approach to the multidisciplinary management of HCC along with a new algorithm for the management of HCC that incorporates the BCLC staging system and the authors' local selection criteria for resection, ablative techniques, liver transplantation, transarterial chemoembolization, transarterial radioembolization and sorafenib in Alberta.     

WJH 6~(th) Anniversary Special Issues(1): Management of hepatocellular carcinoma Management of “very early” hepatocellular carcinoma on cirrhotic patients

Due to the advances in screening of cirrhotic patients, hepatocellular carcinoma(HCC) is being diagnosed in earlier stages. For this reason the number of patients diagnosed of very early HCC(single tumors ≤ 2 cm) is continuously increasing. Once a patient has been diagnosed with this condition, treatment strategies include liver resection, local therapies or liver transplantation. The decision on which therapy should the patient undergo depends on the general patients performance status and liver disease. Anyway, even in patients with similar conditions, the best treatment offer is debatable. In this review we analyze the state of the art on the management of very early HCC on cirrhotic patients to address the best treatment strategy for this patient population.     

Hepatocellular carcinoma: From clinical practice to evidence-based treatment protocols

Hepatocellular carcinoma (HCC) is one of the major malignant diseases in many healthcare systems. The growing number of new cases diagnosed each year is nearly equal to the number of deaths from this cancer. Worldwide, HCC is a leading cause of cancer-related deaths, as it is the fifth most common cancer and the third most important cause of cancer related death in men. Among various risk factors the two are prevailing: viral hepatitis, namely chronic hepatitis C virus is a well-established risk factor contributing to the rising incidence of HCC. The epidemic of obesity and the metabolic syndrome, not only in the United States but also in Asia, tend to become the leading cause of the long-term rise in the HCC incidence. Today, the diagnosis of HCC is established within the national surveillance programs in developed countries while the diagnosis of symptomatic, advanced stage disease still remains the characteristic of underdeveloped countries. Although many different staging systems have been developed and evaluated the Barcelona-Clinic Liver Cancer staging system has emerged as the most useful to guide HCC treatment. Treatment allocation should be decided by a multidisciplinary board involving hepatologists, pathologists, radiologists, liver surgeons and oncologists guided by personalized -based medicine. This approach is important not only to balance between different oncologic treatments strategies but also due to the complexity of the disease (chronic liver disease and the cancer) and due to the large number of potentially efficient therapies. Careful patient selection and a tailored treatment modality for every patient, either potentially curative (surgical treatment and tumor ablation) or palliative (transarterial therapy, radioembolization and medical treatment, i.e., sorafenib) is mandatory to achieve the best treatment outcome.     

Clinical impact of selective transarterial chemoembolization on hepatocellular carcinoma： A cohort study

AIM： To prospectively long term clinical impact evaluate the short and of selective transarterial chemoembolization （TACE） on fiver function in patients with hepatocellular carcinoma （HCC）. To assess side effects in relation to treatments. To analyze the overall survival and HCC progression free survival probability. METHODS： One hundred and seventeen cirrhotic patients with HCC were enrolled. Baseline liver function included Child-Pugh score and serum levels of alanine- aminotransferase （ALT）, prothrombin time （PT） and bilirubin. According to Cancer Liver Italian Program （CLIP） and Barcelona Clinic Liver Cancer （BCLC） staging systems, 71 patients were eligible for TACE; 32 had previously received treatment for HCC. No significant differences in liver function were observed between previously treated and not treated patients. TACE was performed by selective catheterization of the arteries nourishing the lesions. While hospitalized, patients underwent clinical, hematologic and ultrasonographic assessments. One month after TACE a CT scan was performed to assess tumor response. A second TACE was performed ＂on demand＂ Liver function tests were checked in all patients every four months. RESULTS： After first TACE, the mean Child-Pugh score increased from a mean baseline 5.62 ±1.12 to 6.11 ±1.57 at discharge time （P 〈 0.0001）, decreasing after four months to 5.81 ± 0.73 （not significant）. ALT, PT and bilirubin significantly （P 〈 0.0001） increased 24 h after TACE and progressively decreased until discharge. After the second TACE, variations in Child-Pugh score, ALT, PT and bilirubin were comparable to that described after the first TACE. No major complications were observed. The mean follow-up was 14.7 ＋ 6.3 mo （median： 16 mo）. Only one patient died. No other patient experienced important long term worsening of clinical status. The overall survival probability at twenty-four months was 98.18% with a correspondent HCC progression free survival probability of 69%. CONCLUSION： Selective TACE may produce significant, but transitory increases in ALT values, with no major impact on liver function and Child-Pugh score. Preservation of liver function is achievable also in patients previously treated with other therapeutic modalities and in patients undergoing multiple TACE cycles. Liver function can remain stable in the long-term, with optimal medium term survival. This result can be achieved through rigorous patient selection on the basis of tumour characteristics and clinical conditions.     

Role of liver resection in the management of multinodular hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide. Various treatment modalities have been applied to HCC depending on the tumor load, functional capacity of the liver and the general condition of the patient. According to Barcelona Clinic Liver Cancer staging strategy and The American Association for the Study of Liver Disease guidelines, surgical resection is not advocated in the tretment of multinodular HCC. Despite this, many recent clinical studies show that, resection can achieve good results in patients with multinodular HCC and 5-year survival rate around 40% can be reached. If resection or transplantation is not performed, these patients are usually managed with palliative procedures such as transarterial chemoembolization, radioembolization and cytotoxic chemotherapy and 5-year survival of this group of patients will be extremely low. Although survival rates are lower and complications may be increased in this group of patients, liver resection can safely be performed in selected patients in experienced centers for the management of multinodular HCC.     

Guide for diagnosis and treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is ranked as the 5^th common type of cancer worldwide and is considered as the 3^rd common reason for cancer-related deaths. HCC often occurs on top of a cirrhotic liver. The prognosis is determined by several factors; tumour extension, alpha-fetoprotein (AFP) concentration, histologic subtype of the tumour, degree of liver dysfunction, and the patient’s performance status. HCC prognosis is strongly correlated with diagnostic delay. To date, no ideal screening modality has been developed. Analysis of recent studies showed that AFP assessment lacks adequate sensitivity and specificity for effective surveillance and diagnosis. Many tumour markers have been tested in clinical trials without progressing to routine use in clinical practice. Thus, surveillance is still based on ultrasound (US) examination every 6 mo. Imaging studies for diagnosis of HCC can fall into one of two main categories: routine non-invasive studies such as US, computed tomography (CT), and magnetic resonance imaging, and more specialized invasive techniques including CT during hepatic arteriography and CT arterial portography in addition to the conventional hepatic angiography. This article provides an overview and spotlight on the different diagnostic modalities and treatment options of HCC.     

Hepatocellular carcinoma in non-cirrhotic liver: A comprehensive review

Hepatocellular carcinoma(HCC) is the most common type of primary liver cancer, which in turns accounts for the sixth most common cancer worldwide.Despite being the 6 th most common cancer it is the second leading cause of cancer related deaths. HCC typically arises in the background of cirrhosis, however,about 20% of cases can develop in a non-cirrhotic liver. This particular subgroup of HCC generally presents at an advanced stage as surveillance is not performed in a non-cirrhotic liver. HCC in non-cirrhotic patients is clinically silent in its early stages because of lack of symptoms and surveillance imaging; and higher hepatic reserve in this population. Interestingly, F3 fibrosis in non-alcoholic fatty liver disease, hepatitis B virus and hepatitis C virus infections are associated with high risk of developing HCC. Even though considerable progress has been made in the management of this entity, there is a dire need for implementation of surveillance strategies in the patient population at risk, to decrease the disease burden at presentation and improve the prognosis of these patients. This comprehensive review details the epidemiology, risk factors, clinical features,diagnosis and management of HCC in non-cirrhotic patients and provides future directions for research.     

Hepatocellular carcinoma risk after viral response in hepatitis C virus-advanced fibrosis: Who to screen and for how long?

Hepatitis C virus (HCV) chronic infection is associated with fibrosis progression, end-stage liver complications and HCC. Not surprisingly, HCV infection is a leading cause of liver-related morbidity and mortality worldwide. After sustained virological response (SVR), the risk of developing hepatocellular carcinoma is not completely eliminated in patients with established cirrhosis or with advanced fibrosis. Therefore, lifelong surveillance is currently recommended. This strategy is likely not universally cost-effective and harmless, considering that not all patients with advanced fibrosis have the same risk of developing HCC. Factors related to the severity of liver disease and its potential to improve after SVR, the molecular and epigenetic changes that occur during infection and other associated comorbidities might account for different risk levels and are likely essential for identifying patients who would benefit from screening programs after SVR. Efforts to develop predictive models and risk calculators, biomarkers and genetic panels and even deep learning models to estimate the individual risk of HCC have been made in the direct-acting antiviral agents era, when thousands of patients with advanced fibrosis and cirrhosis have reached SVR. These tools could help to identify patients with very low HCC risk in whom surveillance might not be justified. In this review, factors affecting the probability of HCC development after SVR, the benefits and risks of surveillance, suggested strategies to estimate individualized HCC risk and the current evidence to recommend lifelong surveillance are discussed.     

Hepatitis E virus re-infection accelerates hepatocellular carcinoma development and relapse in a patient with liver cirrhosis: A case report and review of literature

BACKGROUNDHepatitis E virus (HEV) superinfection is a suspected promoting factor for hepatocellular carcinoma (HCC) in patients with chronic hepatitis and cirrhosis. However, to date, very few cases of HEV-related HCC have been reported. Nevertheless, the role of HEV re-infection in cirrhotic liver without other chronic hepatitis infections has rarely been explored.CASE SUMMARYA 53-year-old male farmer was diagnosed with liver cirrhosis and splenomegaly in August 2016, accompanied with negative HEV-IgM and positive HEV-IgG. No evidence of hepatitis B virus or hepatitis C virus infection was found. Since then the patient was evaluated for liver function and viral parameters every 3 mo. In June 2017, the patient presented severe fatigue with whole body itching and was diagnosed with HCC. Afterwards this patient experienced quick HCC development, progression, relapse, and metastasis in the following 8 mo, and presented persistent dual positivity of HEV-IgM and HEV-IgG. This patient had a long history of smoking and alcohol consumption.CONCLUSIONThis unique case invokes the importance of HEV surveillance and treatment among cirrhotic patients, HCC cases, and blood donors.     

Hepatocellular carcinoma in non-cirrhotic liver: A reappraisal

Although not frequently, hepatocellular carcinoma (HCC) can ensue in a non-cirrhotic liver. As compared to cirrhotic HCC, this kind of tumour has some peculiarities, such as: (a) a lower male preponderance and a bimodal age distribution; (b) a lower prevalence of the three main risk factors (hepatitis B and C virus infections and alcohol abuse), with an increased prevalence of other etiologic factors, such as exposure to genotoxic substances and sex hormones, inherited diseases, genetic mutations; (c) a more advanced tumour stage at the time of diagnosis, as it is usually detected due to the occurrence of cancer-related symptoms, outside any scheduled surveillance program; (d) a much higher amenability to hepatic resection, due to the low risk of liver failure even after extended parenchymal mutilation; (e) overall and disease-free survivals after resection of non-advanced tumours (meeting the Milano criteria) comparable to that obtained with liver transplantation in cirrhotic patients carrying an early tumour; (f) overall survival strictly dependent on tumour burden (and its recurrence) and barely influenced by liver function.     

Current management of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the sixth most common cancer worldwide and leading cause of death among patients with cirrhosis.Treatment guidelines are based according to the Barcelona Clinic Liver Cancer staging system.The choice among therapeutic options that include liver resection,liver transplantation,locoregional,and systemic treatments must be individualized for each patient.The aim of this paper is to review the outcomes that can be achieved in the treatment of HCC with the heterogeneous therapeutic options currently available in clinical practice.     

Treatment of hepatocellular carcinoma: Steps forward but still a long way to go

Hepatocellular carcinoma(HCC) is the fifth most common malignancy and the third cause of tumor associated deaths worldwide. HCC incidence rates are increasing in many parts of the world including developing and developed countries. Potentially curative treatments for HCC are resection and liver transplantation, but these are only suitable for patients with small tumors, meeting strict pre-defined criteria, or well-compensated liver disease. Early diagnosis of HCCcan be achieved by surveillance of at-risk populations. For patients with non-resectable disease treatments modalities include loco-ablative and systemic therapies. In this review we focus on treatment options in HCC and their allocation. Although significant research is in progress, to this date, the results are unsatisfactory with limited long-term survival. In the fight against this deadly disease, there is still a long way to go.     

Role of innate immunity in the development of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the most common form of liver cancer worldwide.It is caused by a variety of risk factors,most common ones being infection with hepatitis viruses,alcohol,and obesity.HCC often develops in the background of underlying cirrhosis,and even though a number of interventional treatment methods are currently in use,recurrence is fairly common among patients who have had a resection.Therefore,whole liver transplantation remains the most practical treatment option for HCC.Due to the growing incidence of HCC,intense research efforts are being made to understand cellular and molecular mechanisms of the disease so that novel therapeutic strategies can be developed to combat liver cancer.In recent years,it has become clear that innate immunity plays a critical role in the development of a number of liver diseases,including HCC.In particular,the activation of Toll-like receptor signaling results in the generation of immune responses that often results in the production of proinflammatory cytokines and chemokines,and could cause acute inflammation in the liver.In this review,the current knowledge on the role of innate immune responses in the development and progression of HCC is examined,and emerging therapeutic strategies based on molecular mechanisms of HCC are discussed.     

Natural history of hepatitis-related hepatocellular carcinoma

Hepatocellular carcinoma （HCC） is an important cause of cancer death in the world. It has great regional differences in the pathology and epidemiology. The variation is greatly influenced by the aetiologies of the disease. Hepatitis B and C infection are the most important risk factors. HCC incidence rates are higher but in decreasing trend in developing countries. However, the figures in the developed countries are contrary. Successful hepatitis B virus （HBV） vacdnation programs, better food hygiene, increased global hepatitis C virus {HCV） prevalence and population migration are the possible explanations. A number of clinical and pathogenic differences exist between HBV- and HCV- related HCC. HBV infection leads to the development of HCC through direct and indirect pathways as it has the ability to integrate into the host genome affecting cellular signaling and growth control. HCV causes HCC mainly through indirect pathways： chronic inflammation, cell deaths and proliferation. As a result, HCC is almost exclusively found in cirrhotic HCV patients while HCC is sometimes found in HBV patients without significant liver cirrhosis. Due to the different severities of liver cirrhosis and HCC extent, therapeutic strategies from resection, liver transplantation to symptoms palliation are available. Poorly differentiated histology, lack of fibrous capsule, large tumour size, early vascular invasion and elevated serum levels of alpha fetoprotein （AFP） are the features for more aggressive disease. Combined with markers of liver reserve and performance status, accurate scoring systems and models have been developed to predict patients＇ survival and match best treatment option.     

Clinical usefulness of ^18F-FDG PET/CT in the restaging of esophageal cancer after surgical resection and radiotherapy

AIM： To evaluate the clinical usefulness of lSF-fluorodeoxyglucose positron emission and computed tomography QSF-FDG PET/CT） in restaging of esophageal cancer after surgical resection and radiotherapy. METHODS： Between January 2007 and Aug 2008, twenty histopathologically diagnosed esophageal cancer patients underwent 25 PET/CT scans （three patients had two scans and one patient had three scans） for restaging after surgical resection and radiotherapy. The standard reference for tumor recurrence was histopathologic confirmation or clinical follow-up for at least ten months after ^18F-FDG PET/CT examinations. RESULTS： Tumor recurrence was confirmed histopathologically in seven of the 20 patients （35%） and by clinical and radiological follow-up in 13 （65%）. ^18F-FDG PET/CT was positive in 14 patients （68.4%） and negative in six （31.6%）. ^18F-FDG PET/CT was true positive in 11 patients, false positive in three and true negative in six. Overall, the accuracy of ^18F-FDG PET/CT was 85%, negative predictive value （NPV） was 100%, and positive predictive value （PPV） was 78.6%.The three false positive PET/CT findings comprised chronic inflammation of mediastinal lymph nodes （n = 2） and anastomosis inflammation （n = 1）. PET/ CT demonstrated distant metastasis in 10 patients. ^18F-FDG PET/CT imaging-guided salvage treatment in nine patients was performed. Treatment regimens were changed in 12 （60%） patients after introducing ^18F-FDG PET/CT into their conventional post-treatment follow-up program. CONCLUSION： Whole body ^18F-FDG PET/CT is effective in detecting relapse of esophageal cancer after surgical resection and radiotherapy. It could also have important clinical impact on the management of esophageal cancer, influencing both clinical restaging and salvage treatment of patients.     

Long-term survival of a HCC-patient with severe liver dysfunction treated with sorafenib

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver. Prognosis and treatment options are stage dependent. In general, prognosis of patients with unresectable HCC is poor, especially for those patients with impaired liver function. Whereas treatment with the novel molecular tyrosine kinase inhibitor sorafenib (Nexavar) was shown to result in prolonged survival in patients with preserved liver function, its' possible application in HCC-patients with strongly impaired liver function has not been clearly assessed. Here, we report on a 47-year-old male patient who presented with Child-Pugh class C liver cirrhosis and multifocal, non-resectable HCC. The patient was treated for 27 mo with Sorafenib, which was not associated with major drug-related side effects. During treatment, a reduction in tumour size of 24% was achieved, as assessed by regular CT scan. Moreover, within the 27 mo interval of stable tumour disease, liver function improved from Child-Pugh class C to class A.     

Argentinian clinical practice guideline for surveillance,diagnosis, staging and treatment of hepatocellular carcinoma

The A.A.E.E.H has developed this guideline for the best care of patients with hepatocellular carcinoma (HCC) from Argentina. It was done from May 2018 to March 2020. Specific clinical research questions were systematically searched. The quality of evidence and level of recommendations were organized according to GRADE. HCC surveillance is strongly recommended with abdominal ultrasound (US) every six months in the population at risk for HCC (cirrhosis, hepatitis B or hepatitis C); it is suggested to add alpha-feto protein (AFP) levels in case of inexeperienced sonographers. Imaging diagnosis in patients at risk for HCC has high specificity and tumor biopsy is not mandatory. The Barcelona Clinic Liver Cancer algorithm is strongly recommended for HCC staging and treatment-decision processes. Liver resection is strongly recommended for patients without portal hypertension and preserved liver function. Composite models are suggested for liver transplant selection criteria. Therapies for HCC with robust clinical evidence include transarterial chemoembolization (TACE) and first to second line systemic treatment options (sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab). Immunotherapy with nivolumab and pembrolizumab has failed to show statistical benefit but the novel combination of atezolizumab plus bevacizumab has recently shown survival benefit over sorafenib in frontline.     

Diagnosis and treatment of hepatocellular carcinoma: An update

Hepatocellular carcinoma(HCC) is one of the most common malignancies leading to high mortality rates in the general population; in cirrhotic patients, it is the primary cause of death. The diagnosis is usually delayed in spite of at-risk population screening recommendations, i.e., patients infected with hepatitis B or C virus. Hepatocarcinogenesis hinges on a great number of genetic and molecular abnormalities that lead to tumor angiogenesis and foster their dissemination potential. The diagnosis is mainly based on imaging studies such as computed tomography and magnetic resonance, in which lesions present a characteristic classical pattern of early arterial enhancement followed by contrast medium "washout" in late venous phase. On occasion, when imaging studies are not conclusive, biopsy of the lesion must be performed to establish the diagnosis. The Barcelona Clinic Liver Cancer staging method is the most frequently used worldwide and recommended by the international guidelines of HCC management. Currently available treatments include tumor resection, liver transplant, sorafenib and locoregional therapies(alcoholization, radiofrequency ablation, chemoembolization). The prognosis of hepatocarcinoma is determined according to the lesion’s stage and in cirrhotic patients, on residual liver function. Curative treatments, such as liver transplant, are sought in patients diagnosed in early stages; patients in more advanced stages, were not greatly benefitted by chemotherapy in terms of survival until the advent of target molecules such as sorafenib.