Hepatocellular carcinoma

Overview

The most frequent kind of primary liver cancer is hepatocellular carcinoma (HCC). Hepatocellular carcinoma is more common in persons who have chronic liver disorders, such as cirrhosis caused by hepatitis B or hepatitis C. 

 

Hepatocellular carcinoma (HCC)

Hepatocellular carcinoma (HCC) accounts for more than 90% of all primary liver tumors. Hepatocellular carcinoma affects roughly 85 percent of cirrhotic individuals. HCC is presently the world's fifth most prevalent cause of cancer. HCC is the second greatest cause of cancer mortality among males, after lung cancer. HCC has a five-year survival rate of 18%, ranking second only to pancreatic cancer.

Viral hepatitis (hepatitis B and C), alcoholic liver disease, and non-alcoholic liver steatohepatitis/non-alcoholic fatty liver disease are all significant risk factors for hepatocellular cancer. HCC affects 80-90 percent of people with cirrhosis. The yearly incidence of HCC in cirrhotic patients is 2-4 percent.

 

Epidemiology

Hepatocellular carcinoma (HCC) is now the world's fifth most prevalent cause of cancer. In 2018, over 841,000 new cases of HCC were diagnosed. HCC is the second greatest cause of cancer mortality among males, after lung cancer. HCC was responsible for 780,000 fatalities in 2018. Males are three times as likely as females to get HCC.

More than 80% of new occurrences of HCC occur in developing nations with high hepatitis B viruses infection rates, such as Sub-Saharan Africa, South-East Asia, and China.

NAFLD is becoming a prominent cause of HCC globally, particularly in Western nations. Between 2016 and 2030, the incidence of HCC in the United States is anticipated to grow by 122 percent due to an increase in obesity and diabetes.

In the United States, the median age of HCC is 64 years. Patients born between 1945 and 1965 are more likely to have HCV infection. HCC has a five-year survival rate of 18%, ranking second only to pancreatic cancer.

 

Etiology 

The etiology of hepatocellular carcinoma is hepatitis B, hepatitis C, alcoholic liver disease, and non-alcoholic liver steatohepatitis/non-alcoholic fatty liver disease. 

 

Viral Hepatitis

Chronic hepatitis B and C viruses are linked to more than 70% of instances of hepatocellular cancer.

Hepatitis B virus (HBV) is an enclosed virus with a partly double-stranded DNA genome that belongs to the Hepadnavirus family. Hepatitis B affects over 250 million people globally and is the most prevalent cause of chronic hepatitis. The major pathophysiology for HBV oncogenesis is an integration of the hepatitis B viral genome into the host DNA. The insertion of a viral genome into the human genome's telomerase reverse transcriptase (TERT) promoter regions, resulting in mutation, accounts for 60% of HCC occurrences.

In individuals infected with the hepatitis B virus, HCC can develop in the absence of cirrhosis. Cirrhosis is seen in more than 80% of HBV-related HCC cases. Elevated blood HBV DNA levels (equivalent to or more than 10,000 copies/mL) are a substantial risk factor for hepatocellular carcinoma in HBV patients. This is independent of the patient's hepatitis B e antigen (HBeAg) status.

Furthermore, the presence of the hepatitis B e antigen is linked to an increased risk of HCC. This might be an indication of a lengthy replication process. HBV genotype C has been linked to an increased risk of HCC. Patients with a low hepatitis B viral load but high levels of hepatitis B surface antigen (HBsAg) of more than 1000 IU/mL are substantially more likely to develop HCC. The risk of developing HCC is increased by viral coinfection with the hepatitis C virus and the hepatitis delta virus.

Hepatitis C virus (HCV) is a partly double-stranded, plus-sense RNA virus with 11 primary genotypes and 15 distinct subtypes. HCC is usually related with HCV genotype 1b. HCV does not integrate into the DNA of the host.

Cirrhosis is a critical phase in the viral carcinogenesis of HCC. Chronic inflammation caused by chronic hepatitis C virus infection, followed by fibrosis, necrosis, and regeneration, leads to the development of HCC. Viral structural and non-structural proteins have been identified as molecular indicators in liver carcinogenesis.

HCV-associated HCC is particularly common in patients with cirrhosis or severe fibrosis. There have been fewer instances of HCV-related HCC in individuals who do not have cirrhosis. HCV is responsible for 20% of all HCC cases diagnosed worldwide. Hepatitis B virus coinfection is related to an increased risk of HCC.

 

Non-Alcoholic Liver Steatohepatitis (NASH) and Non-Alcoholic Fatty Liver Disease (NAFLD)

Non-alcoholic fatty liver disease is defined as an excess of fat in the hepatocytes in the absence of a history of alcohol consumption. NAFLD is most commonly found in the context of metabolic syndrome. Metabolic syndrome is characterized by insulin resistance, hypertension, hypertriglyceridemia, and abdominal obesity, all of which raise the risk of cardiovascular disease.

NAFLD is becoming a prominent cause of HCC globally, particularly in Western nations. NAFLD was seen in 13% of individuals with HCC who did not have prior cirrhosis. Between 2016 and 2030, the incidence of HCC in the United States is anticipated to grow by 122 percent due to an increase in obesity and diabetes.

 

Alcohol

In the United States, 30 percent of HCC is associated with a history of heavy alcohol consumption. HCC can be caused by alcohol both directly and indirectly. Cirrhosis, which is caused by alcohol, can lead to HCC. Increased reactive oxidative stress and inflammation are caused by alcohol. Drinking more than 80 g of alcohol each day raises the risk of HCC by a factor of five.

 

Aflatoxins

Aspergillus flavus and Aspergillus parasiticus generate mycotoxin aflatoxin B1. This fungus is mostly found in Sub-Saharan Africa and Southeast Asia, where it contaminates cereals. Carcinogenesis is mostly caused by mutations in tumor suppressor genes (p53). In individuals with chronic hepatitis B virus, aflatoxin B1 is linked to an increased risk of HCC.

Iron overload, Glycogen storage disease, Wilson disease, alpha one antitrypsin illness, hypercitrullinemia, Alagille syndrome, and acute intermittent porphyrias are all risk factors.

 

Pathophysiology

Cirrhosis is a critical phase in the progression of viral carcinogenesis in hepatocellular cancer. The major pathophysiology for HBV oncogenesis is integration of the hepatitis B viral genome into the host DNA. The insertion of a viral genome into the human genome's telomerase reverse transcriptase (TERT) promoter regions, resulting in mutation, accounts for 60% of HCC occurrences.

Chronic inflammation caused by chronic hepatitis C virus infection, followed by fibrosis, necrosis, and regeneration, leads to the development of HCC. Viral structural and non-structural proteins have been identified as molecular indicators in liver carcinogenesis

HCV-associated HCC is particularly common in patients with cirrhosis or severe fibrosis.

 

Symptoms of HCC

The presentation of hepatocellular carcinoma (HCC) is dependent on the stage of the tumor and background cirrhosis.

• In the early stages of the illness, non-cirrhotic HCC may be asymptomatic. The median age of clinical HCC manifestation is 69 years.
• Patients with cirrhotic HCC may exhibit signs of decompensated liver failure, such as increasing jaundice, pruritus, hepatic encephalopathy, ascites, palpable mass in the upper abdomen, fever, malaise, weight loss, early satiety, abdominal distension, and cachexia. The most prevalent symptom of HCC is abdominal discomfort.
• Hypoglycemia, erythrocytosis, hypercalcemia, diarrhea, and skin abnormalities such as pemphigus foliaceous, pityriasis rotunda, dermatomyositis, can all be symptoms of a paraneoplastic syndrome in HCC patients.
• Patients who are symptomatic may experience variceal bleeding, intraperitoneal hemorrhage, obstructive jaundice, pyogenic liver abscess, and hepatic encephalopathy.
• The lung, intra-abdominal lymph node, bone, and adrenal are the most frequent extrahepatic metastatic sites for HCC.

 

Diagnosis

Biochemistry

On the first examination, liver function tests such as bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and albumin may be increased. This might be an indication of the disease's severity. An increased international normalized ratio (INR), prothrombin time (PT), thrombocytopenia, anemia, hyponatremia, or hypoglycemia are some aberrant laboratory results seen in individuals with impaired synthetic liver function or reserve.

These results are more likely to be seen in patients with advanced HCC, chronic hepatitis, or cirrhosis-related HCC. On the initial visit, patients with early non-cirrhotic HCC may have normal LFTs. Patients with HCC paraneoplastic characteristics may exhibit hypoglycemia, hypercalcemia, and erythrocytosis.

Hepatitis B surface antigen, anti-HCV antibody, alpha antitrypsin level, copper levels, and iron saturation are all laboratory tests used to determine the etiology of HCC.

 

Serum Alpha-Fetoprotein (AFP)

During pregnancy, the fetal yolk sac and liver generate alpha-fetoprotein, a blood glycoprotein. Advanced HCC is characterized by elevated serum AFP levels. This has nothing to do with tumor size or vascular invasion. AFP is not secreted by around 40% of small HCC. Serum AFP levels in early non-cirrhotic HCC are normal.

Serum alpha-fetoprotein values of more than 200 ng/ml are highly specific but have a low sensitivity for identifying HCC. Using a cut-off point of 500 ng/mL to detect HCC in individuals with concomitant hepatic disease has a specificity of more than 90%. Patients with chronic hepatitis, cirrhosis, pregnancy, and various germ and non-germ line cancers may have high serum alpha-fetoprotein levels. Alpha-fetoprotein is used in conjunction with ultrasonography to monitor patients.

 

Imaging

HCC may be diagnosed with ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI).

• Ultrasound (US) is a non-invasive, often used screening tool for HCC and monitoring. Sensitivity and specificity vary from 51% to 87 percent and 81% to 100%, respectively. The size, shape, location, and vascular invasion of HCC are all determined by non-contrast US.
• Depending on the degree of fatty infiltration or fibrosis, HCC can be hypoechoic or hyperechoic. HCC is characterized by increased blood flow and neovascularity. USG is only useful for detecting cancers smaller than 2 cm in size.
• Contrast-enhanced ultrasound (CEUS) is used to characterize lesions discovered by non-contrast ultrasonography. CEUS has a specificity of more than 97 percent and sensitivity and sensitivity of 90 percent in detecting lesions previously identified as HCC on non-contrast US.
• In high-risk individuals, ultrasound with or without serum alpha-fetoprotein is indicated every six months for HCC monitoring.

CT: Diagnostic imaging criteria for diagnosing HCC with a triphasic CT scan include hyperenhancement in the arterial phase and fast washout in the portal venous phase relative to the liver background. Contrast CT has a sensitivity and specificity per lesion of 65% and 99%, respectively. Sensitivity drops to 40% for lesions smaller than 2cm in size. For lesions larger than or equivalent to 2cm in size, the positive predictive value rises to more than 92 percent.

T1-weighted MRI scans can range from isointense to hyperintense depending on the degree of fibrosis, fat, and necrosis. Hyperintense tumors on T1 scans are usually well-differentiated tumors that appear isointense on T2 pictures. Tumors that are poorly or moderately differentiated look isointense on T1 scans and hyperintense on T2 pictures. 

The American radiology Association (ARA) created a liver imaging reporting and data system (LI-RADS) for identifying hepatic nodules, which was endorsed by numerous societies in 2018, including the American Association for the Study of Liver Disease (AASLD).

The lesion should have a non-peripheral washout appearance in the portal venous or delayed phase, non-rim arterial phase hyperenhancement in comparison to the background liver parenchyma, a smooth enhancing capsule look, and a size increase of more than 50% in less than 6 months. Patients with chronic hepatitis B virus infection, cirrhosis, a contemporaneous or past diagnosis of HCC, and a lesion found on an HCC surveillance US are considered high-risk.

 

Liver Biopsy

A liver biopsy is not usually performed for HCC since it is linked with the risk of tumor seeding and hemorrhage, as well as a false negative if tissue is not obtained from the relevant place. A liver biopsy has a sensitivity of 66% to 93% depending on the size of the tumor, a positive predictive value of 100%, and a specificity of 100%.

 

Management

Surgical Resection

Patients with very early (0) and early-stage (A) Barcelona-clinic liver cancer (BCLC) are suitable candidates for surgical resection. The very early (0) stage features maintained liver function, an ECOG-PS score of 0, and a single nodule measuring 2 cm. Patients with early-stage (A) cancer who have retained liver function and an ECOG-PS score of 0 and a solitary nodule larger than 2 cm are candidates for surgical excision.

Micro and macrovascular invasion, tumor differentiation, and the development of satellite nodules are all predictors of HCC recurrence following surgical resection. The probability of recurrence after five years is up to 70%. There is no evidence that adjuvant medicines lessen the likelihood of recurrence. 

 

Liver Transplantation

Liver transplantation is related to tumor elimination and the possibility of cure. A single nodule less than or equal to 5 cm in diameter or no more than three nodules, none more than 3 cm in diameter, without macrovascular invasion or extrahepatic dissemination, meets the Milan criteria for liver transplantation.

A patient who fits the Milan criteria for liver transplantation has a 60% - 80% and 50% chance of survival after 5 and 10 years, respectively. In patients with HCC awaiting liver transplantation, adjuvant treatment has been found to be cost-effective. While waiting for a liver transplant, there is a modest increase in life expectancy.

 

Tumor Ablation

Patients with very early (0) and early-stage (A) BCLC who do not fulfill surgical resection criteria are candidates for ablation. Radiofrequency ablation (RFA), cryotherapy, microwave, or laser treatment, or injection of chemical compounds such as ethanol, boiling saline, and acetic acid are all methods of ablation.

Radiofrequency ablation has been demonstrated to be better to percutaneous ethanol and acetic acid injection for ablative treatment in patients with tumors larger than 2 cm. Ablation has been linked with fewer problems than surgical resection.

 

Transarterial Therapies

Transarterial treatments are being evaluated for people with intermediate-stage BCLC (B). The intermediate stage (B) has maintained liver function, an ECOG-PS of zero, and is multinodular with no macrovascular invasion or extrahepatic dissemination. Transarterial chemoembolization (TACE) is the intraarterial infusion of cytotoxic chemicals followed by embolization of the tumor's feeding artery. TACE is not recommended for individuals with decompensated cirrhosis.

 

Systemic Chemotherapy

Sorafenib is the first-line therapy for BCLC advanced stage (C) patients with maintained liver function, an ECOG-PS score of 1-2, and macrovascular invasion or extrahepatic dissemination. Sorafenib functions as a multikinase inhibitor. In the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) study, patients receiving sorafenib had a median survival of 10.7 months compared to 7.9 months in the placebo group.

Furthermore, sorafenib has been demonstrated to be efficacious in patients with advanced HCC in the Asia-Pacific area. Palmar-plantar erythrodysesthesia, diarrhea, weight loss, and hypertension are all common adverse effects of sorafenib. Lenvatinib was shown to be noninferior to sorafenib, but not superior.

The food and drug administration has authorized lenvatinib as the second agent for the first-line treatment of advanced HCC (FDA). When compared to sorafenib, lenvatinib is linked with considerable weight loss but less palmar-plantar erythrodysesthesia. Patients who are intolerant to sorafenib or who have tumor progression are started on the second line of therapy.

The FDA has authorized regorafenib, a multikinase inhibitor, as second-line therapy for advanced HCC. Other second-line treatments include cabozantinib, ramucirumab, and nivolumab, an immune checkpoint inhibitor that inhibits programmed cell death 1 (PD-1).

 

Differential Diagnosis

Differential diagnosis of hepatocellular carcinoma (HCC) includes the following:

• Cholangiocarcinoma
• Fibrous nodular hyperplasia
• Dysplastic/Regenerative nodules in cirrhosis
• Hepatic adenoma
• Primary hepatic lymphoma
• Cirrhosis
• Metastatic cancer

When compared to hemangioma and metastatic illness to the liver, ultrasound with doppler often shows fine branching patterns with enhanced vascularity and flow velocity. On the arterial phase, HCC looks hypervascular with portal venous washout, whereas regenerative nodules appear isoechoic or hypoechoic in comparison to the rest of the parenchyma. Cholangiocarcinoma on multiphasic CT may show vascular and delayed enhancement.

 

Staging

The prognosis of hepatocellular carcinoma is determined by the tumor load as well as liver impairment. The degree of performance status and liver dysfunction is not taken into consideration in tumor-node-metastasis (TNM). The Barcelona clinic liver cancer staging system is the most extensively used (BCLC). The Chinese University Prognostic Index, Japan Integrated Staging, and the Cancer of the Liver Italian Program are among the various staging methods.

The BCLC provides the most predictive information, such as a patient's performance status, liver load, and liver function. The approach categorizes HCC patients into one of five phases. Treatment suggestions are provided by substrata of 0, A, B, C, and D based on the stage.

Tumor burden is determined by the size and number of nodules, the presence or absence of extrahepatic dissemination, and the presence or absence of macrovascular tumor invasion. The Child–Turcotte–Pugh score, Model for End-Stage Liver Disease, and albumin–bilirubin grade are used to evaluate the liver function test.

 

Prognosis

Hepatocellular carcinoma has a five-year survival rate of 18%, ranking second only to pancreatic cancer. The prognosis of individuals with HCC is determined by tumor size, histopathological differentiation or grade of the tumor, severity of the underlying liver disease, presence or absence of metastases, and tumor expansion to surrounding tissues. High levels of alpha-fetoprotein in HCC are associated with poorly differentiated HCC and have a poor prognosis.

Patients with hepatitis B virus-related HCC with positive serum hepatitis B e antigen (HBeAg) have a poor prognosis and a greater risk of HCC recurrence. High levels of serum hepatitis B viral DNA are linked to an increased risk of HCC and recurrence. Diabetes mellitus is a risk factor for the development of HCC, as well as a bad prognosis.

 

Complications

Hepatic encephalopathy, portal vein thrombosis, deteriorating ascites, variceal hemorrhage, obstructive jaundice, and pyogenic liver abscess are among hepatic consequences of hepatocellular carcinoma.

Intraperitoneal hemorrhage is a potentially fatal consequence of HCC. Patients appear with growing abdominal discomfort and girth, as well as hypotension and anemia. Emergency angiography with embolization and surgery for bleeding management. For diagnosis, a CT abdomen scan without contrast is necessary, and a CT abdominal scan with angiography is required for emergency angiography investigations.

The lung, intra-abdominal lymph node, bone, and adrenal are the most frequent extrahepatic metastatic sites for HCC. A uncommon extrahepatic symptom of HCC is a brain tumor.

 

Conclusion 

Hepatocellular carcinoma is the world's second-largest cause of cancer mortality among men. NAFLD is becoming a prominent cause of HCC globally, particularly in Western nations. Between 2016 and 2030, the incidence of HCC in the United States is anticipated to grow by 122 percent due to an increase in obesity and diabetes. The most common cause of HCC globally is chronic hepatitis B virus infection. Globally, universal hepatitis B immunization is predicted to reduce the prevalence of HCC.

HCC has a five-year survival rate of 18%, ranking second only to pancreatic cancer. HCC management is complicated, and there is a range of HCC therapies available from various disciplines. In order to provide a holistic and integrated approach to patients with hepatocellular carcinoma and achieve the best potential results, an interdisciplinary team comprised of medical oncology, surgery, radiation oncology, interventional radiology, and led by a hepatologist is essential.