Hepatocellular carcinoma is the most common type of primary liver cancer Primary Liver Cancer Primary liver cancer is usually hepatocellular carcinoma (HCC). The first manifestations of liver cancer are usually nonspecific, delaying the diagnosis. When diagnosed at advanced stages, prognosis... read more . About 41,210 new cases and about 29,380 deaths due to primary liver cancer, including intrahepatic bile duct cancers, are expected in 2023 in the United States. About three-fourths of these liver cancers will be HCC. Liver cancer is about 2 times more common in men than in women. However, it is more common outside the United States, particularly in East Asia and sub-Saharan Africa, where the incidence generally parallels geographic prevalence of chronic hepatitis B virus (HBV) infection Hepatitis B, Chronic Hepatitis B is a common cause of chronic hepatitis. Patients may be asymptomatic or have nonspecific manifestations such as fatigue and malaise. Diagnosis is by serologic testing. Without treatment... read more .
Etiology of Hepatocellular Carcinoma
Hepatocellular carcinoma is usually a complication of cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more .
The presence of HBV increases risk of HCC by > 100-fold among HBV carriers. Incorporation of HBV-DNA into the host’s genome may initiate malignant transformation, even in the absence of chronic hepatitis or cirrhosis.
Other disorders that cause hepatocellular carcinoma include cirrhosis due to chronic hepatitis C virus (HCV) infection Hepatitis C, Chronic Hepatitis C is a common cause of chronic hepatitis. It is often asymptomatic until manifestations of chronic liver disease occur. Diagnosis is confirmed by finding positive anti-HCV and positive... read more , hemochromatosis Hereditary Hemochromatosis Hereditary hemochromatosis is a genetic disorder characterized by excessive iron (Fe) accumulation that results in tissue damage. Manifestations can include systemic symptoms, liver disorders... read more 
, and alcoholic cirrhosis Alcohol-Related Liver Disease Alcohol consumption is high in most Western countries. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 8.5% of US adults are estimated to... read more 
. Similar to HBV infection, HCC can develop in patients with noncirrhotic nonalcoholic steatohepatitis Nonalcoholic Fatty Liver Disease (NAFLD) Fatty liver is excessive accumulation of lipid in hepatocytes. Nonalcoholic fatty liver disease (NAFLD) includes simple fatty infiltration (a benign condition called fatty liver), whereas nonalcoholic... read more . Patients with cirrhosis due to other conditions are also at increased risk.
Environmental carcinogens may play a role; eg, ingestion of food contaminated with fungal aflatoxins is believed to contribute to the high incidence of HCC in subtropical regions.
Symptoms and Signs of Hepatocellular Carcinoma
Most commonly, patients are asymptomatic and tumors are diagnosed on routine screening. Patients with advanced HCC may present with abdominal pain, weight loss, right upper quadrant mass, and unexplained deterioration. Fever may occur. In a few patients, the first manifestation of HCC is bloody ascites, shock, or peritonitis, caused by hemorrhage of the tumor. Occasionally, a hepatic friction rub or bruit develops.
Occasionally, systemic metabolic complications, including hypoglycemia, erythrocytosis, hypercalcemia, and hyperlipidemia, occur. These complications may manifest clinically.
Diagnosis of Hepatocellular Carcinoma
Alpha-fetoprotein (AFP) measurement
Imaging (CT, ultrasonography, or MRI)
Clinicians suspect hepatocellular carcinoma (HCC) if
They feel an enlarged liver.
Unexplained decompensation of chronic liver disease develops.
An imaging test detects a mass in the right upper quadrant of the abdomen during an examination done for other reasons, especially if patients have cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more .
However, screening programs enable clinicians to detect many HCCs before symptoms develop.
Diagnosis is based on AFP measurement and an imaging test Imaging Tests of the Liver and Gallbladder Imaging is essential for accurately diagnosing biliary tract disorders and is important for detecting focal liver lesions (eg, abscess, tumor). It is limited in detecting and diagnosing diffuse... read more 
. In adults, AFP signifies dedifferentiation of hepatocytes, which most often indicates HCC; 40 to 65% of patients with the cancer have high AFP levels (> 400 ng/mL [400 mcg/L]). High levels are otherwise rare, except in teratocarcinoma of the testis, a much less common tumor. Lower values are less specific and can occur with hepatocellular regeneration (eg, in hepatitis Overview of Chronic Hepatitis Chronic hepatitis is hepatitis that lasts > 6 months. Common causes include hepatitis B and C viruses, nonalcoholic steatohepatitis (NASH), alcohol-related liver disease, and autoimmune liver... read more ). Other blood tests, such as AFP-L3 (an AFP isoform) and des-gamma–carboxyprothrombin, are being studied as markers to be used for early detection of hepatocellular carcinoma.
Depending on local preferences and capabilities, the first imaging test may be contrast-enhanced CT, ultrasonography, or MRI. Contrast imaging must be ordered as a triple-phase protocol because the third, or delayed-contrast phase is essential for a radiographic diagnosis of hepatocellular carcinoma. Hepatic arteriography is occasionally helpful in equivocal cases and can be used to outline the vascular anatomy when ablation or surgery is planned.
Radiographic criteria known as the LI-RADS (liver imaging reporting and data system) are used to diagnosis HCC with high sensitivity with key radiographic features, including presence of arterial hyperenhancement, pseudocapsule around the lesion, washout of contrast on delayed-phase imaging, and interval growth of the lesion from the prior scan (1 Diagnosis references Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more ).
If imaging shows characteristic findings and AFP is elevated, the diagnosis is clear. However, rarely, liver biopsy Liver Biopsy Liver biopsy provides histologic information about liver structure and evidence of liver injury (type and degree, any fibrosis); this information can be essential not only to diagnosis but also... read more , often guided by ultrasonography or CT, is indicated for definitive diagnosis.
Staging
If a HCC is diagnosed, staging evaluation usually includes chest CT without contrast and imaging of the portal vein (if not already done) by MRI or CT with contrast to exclude thrombosis. In instances of significant alkaline phosphatase or AFP elevation or tumor well outside of Milan, a bone scan is often employed to rule out bone metastases.
Various systems can be used to stage HCC; none is universally used. One system is the TNM system, based on the following (see table ):
T: How many primary tumors, how big they are, and whether the cancer has spread to adjacent organs
N: Whether the cancer has spread to nearby lymph nodes
M: Whether the cancer has metastasized to other organs of the body
Numbers (0 to 4) are added after T, N, and M to indicate increasing severity.
Other scoring systems include the Okuda and the Barcelona–Clinic Liver Cancer staging systems. In addition to tumor size, local extension, and metastases, these systems incorporate information about the severity of liver disease.
Screening
An increasing number of hepatocellular carcinomas are being detected through screening programs. Screening patients with cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more is reasonable, although this measure is controversial and has not been shown to reduce mortality. One common screening method is ultrasonography every 6 or 12 months. However, in obese patients, because sensitivity of ultrasonography is limited in them, alternating ultrasonography with MRI or CT should be considered for screening. Many experts advise screening patients with long-standing hepatitis B even when cirrhosis is absent. Patients with nonalcoholic steatohepatitis Nonalcoholic Fatty Liver Disease (NAFLD) Fatty liver is excessive accumulation of lipid in hepatocytes. Nonalcoholic fatty liver disease (NAFLD) includes simple fatty infiltration (a benign condition called fatty liver), whereas nonalcoholic... read more (NASH) are now recognized to account for 50% of cases of noncirrhotic HCC (2 Diagnosis references Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more ). However, despite this recognition, screening is not yet recommended for such patients.
Diagnosis references
1. Mitchell DG, Bruix J, Sherman M, et al: LI-RADS (liver imaging reporting and data system): Summary, discussion, and consensus of the LI-RADS Management Working Group and future directions. Hepatology 61(3):1056-1065. 2015. doi: 10.1002/hep.27304
2. Galle PR, Forner A, Llovet JM, et al: EASL clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol 69:182-236, 2018.
Treatment of Hepatocellular Carcinoma
Transplantation if tumors are within the Milan criteria (one tumor < 5 cm or three tumors < 3 cm without vascular invasion and alpha-fetoprotein < 500 mcg/L).
Treatment of hepatocellular carcinoma (HCC) depends on its stage (1 Treatment references Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more ) and the underlying severity of liver disease.
For single tumors < 5 cm or ≤ 3 tumors that are all ≤ 3 cm and that are limited to the liver, without microvascular invasion, and if AFP is < 500 mcg/L, liver transplantation Liver Transplantation Liver transplantation is the 2nd most common type of solid organ transplantation. (See also Overview of Transplantation.) Indications for liver transplantation include Cirrhosis (70% of transplantations... read more appears to result in as good a prognosis as liver transplantation done for noncancerous disorders. Liver transplantation can be curative. These Milan criteria are used to identify patients with hepatocellular carcinoma who are good candidates for liver transplantation (2 Treatment references Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more ). The American Association for the Study of Liver Diseases (AASLD) 2018 guidelines also use the Milan criteria for selection of patients for liver transplantation (3 Treatment references Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more ).
In selected patients with singular tumors < 5 cm and no portal hypertension Portal Hypertension Portal hypertension is elevated pressure in the portal vein. It is caused most often by cirrhosis (in North America), schistosomiasis (in endemic areas), or hepatic vascular abnormalities. Consequences... read more , surgical resection is potentially curative, with 5-year survival rates of 60 to 80%.
Ablative treatments (eg, transhepatic arterial chemoembolization [TACE], yttrium-90 microsphere embolization [selective internal radiation therapy, or SIRT], drug-eluting bead transarterial embolization, radiofrequency ablation) provide palliation and slow tumor growth; they are used when patients are awaiting liver transplantation. For small tumors < 2 cm, radiofrequency ablation (RFA) is potentially curative.
If the tumor is large (> 5 cm), is multifocal, has invaded the portal vein, or is metastatic (ie, stage III or higher), transplantation is not an immediate option. However, with a combination of liver-directed therapy (eg, transhepatic arterial chemoembolization [TACE] and systemic chemotherapy), a subset of patients can be downstaged to Milan criteria and may then be eligible for reconsideration for liver transplantation. Management of advanced HCC is best if discussed by a multidisciplinary tumor board. For advanced HCCs, traditional systemic therapy was with sorafenib, which only modestly improves outcomes, with a median survival of 10.7 months as compared to 7.9 months with placebo (4 Treatment references Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more ). Several new chemotherapy agents provide more prolonged survival or cause fewer adverse effects than sorafenib; these include lenvatinib, regorafenib, and immunotherapy such as atezolizumab plus bevacizumab or tremelimumab plus durvalumab. Progression-free survival was higher with lenvatinib than with sorafenib and is an alternate first-line therapy.
Systemic therapies, including immunotherapy, are rapidly evolving and show promise for improved HCC outcomes. Atezolizumab and bevacizumab are available as combination therapy for patients with advanced HCC who have not received prior systemic therapy. Atezolizumab is a humanized monoclonal antibody immune checkpoint inhibitor (PD-L1), whereas bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF). Increasing evidence supports these 2 drugs as first-line therapy for systemic treatment in HCC (5, 6 Treatment references Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more ). A large meta-analysis comparing 6290 patients with first-line systemic chemotherapy revealed better overall survival with bevacizumab/atezolizumab than sorafenib, lenvatinib, or nivolumab (6 Treatment references Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more ). Adverse events were similar between treatment groups. The 2020 American Society of Clinical Oncology guidelines recommends use of atezolizumab and bevacizumab as first line for patients with Child-Pugh class A liver disease and Eastern Cooperative Oncology Group (ECOG) status 0–1 (7 Treatment references Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more ).
Because of an increased risk of bleeding with atezolizumab and bevacizumab, patients should have variceal ligation prior to initiation of therapy. Immunotherapy is not recommended in patients with HCC recurrence post transplant because stimulation of the host immune system may lead to higher rates of rejection (8 Treatment references Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more ). A new regimen combines tremelimumab, an anticytotoxic T-lymphocyte–protein 4 (or "CTLA-4") plus durvalumab (an anti-PD-L1). In the Himalaya trial, tremelimumab plus durvalumab improved survival more than prior first-line sorafenib monotherapy (9 Treatment references Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more ). This combination is now available for patients with unresectable HCC and is often used as an alternative for patients with Child-Pugh class A cirrhosis and excellent performance status who cannot receive bevacizumab.
Treatment references
1. Bruix J, Reig M, Sherman M: Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology 50(4):835-853, 2016. doi: 10.1053/j.gastro.2015.12.041
2. Mazzaferro V, Regalia E, Dorci R, et al: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334 (11): 693-700, 1996. doi: 10.1056/NEJM199603143341104
3. Marrero JA, Kulik LM, Sirlin CB, et al: Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the AASLD. Hepatology 68 (2):723-750, 2018. doi: 10.1002/hep.29913
4. Llovet JM, Ricci S, Mazzaferro V, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390, 2018. doi: 10.1056/NEJMoa0708857
5. Finn RF, Qin S, Ikeda M, et al: Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 382:1894-1905, 2020. doi: 10.1056/NEJMoa1915745
6. Sonbol MB, Riaz IB, Naqvi SAA, et al: Systemic therapy and sequencing options in advanced hepatocellular carcinoma: A systematic review and network meta-analysis. JAMA Oncol 6(12):e204930. doi: 10.1001/jamaoncol.2020.4930
7. Gordan JD, Kennedy EB, Abou-Alfa GK, et al: Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline. J Clin Oncol 38(36):4317-4345, 2020. doi: 10.1200/JCO.20.02672
8. Kumar V, Shinagare AB, Rennke HG, et al: The safety and efficacy of checkpoint inhibitors in transplant recipients: A case series and systematic review of literature. Oncologist 25(6):505-514, 2020. doi: 10.1634/theoncologist.2019-0659
9. Abou-Alfa GK, Lau G, Kudo, et al: Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid 1(8) DOI:https://doi.org/10.1056/EVIDoa2200015. Published June 6, 2022.
Prevention of Hepatocellular Carcinoma
Use of vaccine against HBV Hepatitis B (HepB) Vaccine The hepatitis B vaccine is 80 to 100% effective in preventing infection or clinical hepatitis B in people who complete the vaccine series. For more information, see Hepatitis B Advisory Committee... read more eventually decreases the incidence, especially in endemic areas. Preventing the development of cirrhosis of any cause (eg, via treatment of chronic hepatitis C Treatment Chronic hepatitis is hepatitis that lasts > 6 months. Common causes include hepatitis B and C viruses, nonalcoholic steatohepatitis (NASH), alcohol-related liver disease, and autoimmune liver... read more , early detection of hemochromatosis Diagnosis Hereditary hemochromatosis is a genetic disorder characterized by excessive iron (Fe) accumulation that results in tissue damage. Manifestations can include systemic symptoms, liver disorders... read more , prevention and management of metabolic syndrome, or management of alcoholism Treatment Alcohol consumption is high in most Western countries. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 8.5% of US adults are estimated to... read more ) can also have a significant effect.
Key Points
Hepatocellular carcinoma is usually a complication of cirrhosis and is most common in parts of the world where hepatitis B is prevalent.
Consider the diagnosis if physical examination or an imaging test detects an enlarged liver or if chronic liver disease worsens unexpectedly.
Diagnose hepatocellular carcinoma based on the AFP level and liver imaging results, and stage it using chest CT without contrast, portal vein imaging, and sometimes bone scanning.
Consider liver transplantation if tumors are within the Milan criteria.
Prevention involves use of the hepatitis B vaccine and management of disorders that can cause cirrhosis.
More Information
The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
American Association for the Study of Liver Diseases (AASLD) Guidelines for the Treatment of Hepatocellular Carcinoma: The latest guiding principles and objectives for the treatment of hepatocellular carcinoma.
