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Hepatocellular Carcinoma

(Hepatoma)

By

Danielle Tholey

, MD, Sidney Kimmel Medical College at Thomas Jefferson University

Last full review/revision Aug 2021| Content last modified Aug 2021
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Hepatocellular carcinoma 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. Diagnosis is based on alpha-fetoprotein (AFP) levels, imaging tests, and sometimes liver biopsy. Screening with periodic AFP measurement and ultrasonography is sometimes recommended for high-risk patients. Prognosis is poor when cancer is advanced or hepatic synthetic function is poor, but for small tumors that are confined to the liver, ablative therapies are palliative and surgical resection or liver transplantation is sometimes curative.

Hepatocellular carcinoma is the most common type of primary liver cancer Primary Liver Cancer Primary liver cancer is usually hepatocellular carcinoma. The first manifestations of liver cancer are usually nonspecific, delaying the diagnosis. When diagnosed at advanced stages, prognosis... read more . About 42,230 new cases and about 30,230 deaths due to primary liver cancer, including intrahepatic bile duct cancers, are expected in 2019 in the US. About three-fourths of these liver cancers will be hepatocellular carcinoma. Liver cancer is about 3 times more common in men than in women. However, it is more common outside the US, 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

The presence of HBV increases risk of hepatocellular carcinoma 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.

Environmental carcinogens may play a role; eg, ingestion of food contaminated with fungal aflatoxins is believed to contribute to the high incidence of hepatocellular carcinoma in subtropical regions.

Symptoms and Signs of Hepatocellular Carcinoma

Most commonly, previously stable patients with cirrhosis present with abdominal pain, weight loss, right upper quadrant mass, and unexplained deterioration. Fever may occur. In a few patients, the first manifestation of hepatocellular carcinoma 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 if

However, screening programs enable clinicians to detect many hepatocellular carcinomas 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 Imaging Tests of the Liver and Gallbladder . In adults, AFP signifies dedifferentiation of hepatocytes, which most often indicates hepatocellular carcinoma; 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 hepatocellular carcinoma (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 More Information Hepatocellular carcinoma 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 hepatocellular carcinoma is diagnosed, evaluation usually includes chest CT without contrast, imaging of the portal vein (if not already done) by MRI or CT with contrast to exclude thrombosis, and sometimes bone scanning, if the AFP is particularly elevated.

  • 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.

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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 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 alfa-fetoprotein < 500 mcg/L).

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 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 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 ).

Ablative treatments (eg, hepatic arterial chemoembolization, 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), prognosis is poor (eg, 5-year survival rates of about 5% or less). 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 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 prolong survival longer or cause fewer adverse effects than sorafenib; these include levatinib, regorafenib, and immunotherapy such as nivolumab. Progression-free survival was higher with levatinib 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 now 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 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 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 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 these drugs, 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 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 ).

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

Prevention of Hepatocellular Carcinoma

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 is an English-language resource that may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

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