Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 39-06: Hepatocellular Carcinoma + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Usually a complication of cirrhosis Characteristic CT and MRI features may obviate the need for a confirmatory biopsy +++ General Considerations ++ Hepatocellular carcinoma: malignant neoplasm of the liver that arises from parenchymal cells (accounting for 85% of liver cancers) Contrast cholangiocarcinoma: malignant neoplasm that originates in the ductular cells (≤ 15% of liver cancers) Rare tumors of the liver include angiosarcoma and lymphoma Hepatocellular carcinoma risk factors Cirrhosis in general, including nonalcoholic fatty liver disease, and hepatitis B or C in particular Hepatitis B in Africa and Asia Hepatitis C and alcoholic cirrhosis in the West and Japan High levels of HBV replication, HBV genotype C, hepatitis D coinfection Elevated serum ALT levels in persons with chronic hepatitis B (antiviral therapy to suppress HBV replication appears to reduce the risk) HCV infection with lack of response to antiviral therapy HCV genotype 1b Hemochromatosis, aflatoxin exposure (associated with mutation of the TP53 gene), alpha-1-antiprotease (alpha-1-antitrypsin) deficiency, tyrosinemia, and radiation exposure In patients with cirrhosis, additional risk factors include Male sex Age > 55 years Hispanic or Asian ethnicity Family history in a first-degree relative Tobacco use Diabetes mellitus, hypothyroidism, overweight Alcohol use (especially in combination with obesity) HCV infection HBsAg and anti-HBc positivity Elevated serum transferrin saturation Prolonged prothrombin time Low platelet count Fibrolamellar variant of hepatocellular carcinoma Occurs in young women Characterized by a distinctive histologic picture, absence of risk factors, unique genomic profiles, and indolent course Staging in the TNM classification T0: there is no evidence of primary tumor T1a: solitary tumor ≤ 2 cm T1b: solitary tumor > 2 cm without vascular invasion T2: solitary tumor > 2 cm with vascular invasion or multiple tumors none > 5 cm T3: multiple tumors with at least one > 5 cm T4: single or multiple tumors of any size involving a major branch of the portal or hepatic vein or with direct invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum N1, regional lymph node metastasis M1, distant metastasis F0, no to moderate hepatic fibrosis F1, severe hepatic fibrosis to cirrhosis The BCLC (Barcelona Clinic Liver Cancer) staging system is preferred Includes the Child-Pugh stage, tumor stage, and liver function Has the advantage of linking overall stage with preferred treatment modalities and with an estimation of life expectancy +++ Demographics ++ Worldwide, hepatocellular carcinomas are the fourth most common cause of cancer-related deaths and the sixth most common cancer in incidence In Africa and most of Asia, hepatitis B virus (HBV) infection is a major etiologic factor In the United States and other Western countries, because of the increasing prevalence of cirrhosis caused by chronic hepatitis C virus (HCV) infection and nonalcoholic fatty liver disease, incidence rates have risen rapidly (over twofold since 1978 with some slowing of the rate increase since 2006) + Clinical Findings Download Section PDF Listen +++ +++ Symptoms and Signs ++ May be unsuspected until there is deterioration in a cirrhotic patient who was formerly stable Cachexia, weakness, and weight loss are associated symptoms The sudden appearance of ascites, which may be bloody, suggests portal or hepatic vein thrombosis by tumor or bleeding from the necrotic tumor There may be a tender enlargement of the liver, occasionally with a palpable mass In Africa, young patients typically present with a rapidly expanding abdominal mass. Auscultation may reveal a bruit over the tumor or a friction rub when the tumor has extended to the surface of the liver +++ Differential Diagnosis ++ Metastatic cancer Benign liver tumors Hemangioma Hepatocellular adenoma Focal nodular hyperplasia Pyogenic or amebic liver abscess + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ There may be leukocytosis, as opposed to the leukopenia that is frequently encountered in cirrhotic patients Anemia is common However, hematocrit is normal or elevated in one-third of patients from tumor elaboration of erythropoietin Sudden and sustained elevation of the serum alkaline phosphatase in a formerly stable patient is common Hepatitis B surface antigen in most cases in endemic areas In the United States, anti-hepatitis C virus (HCV) is positive in up to 40% of cases Alpha-fetoprotein levels Elevated in up to 70% of patients in Western countries (though the sensitivity is lower in blacks) Levels are not elevated in patients with fibrolamellar hepatocellular carcinoma However, mild elevations (10–200 ng/mL [10–200 mcg/L]) are also often seen in patients with chronic hepatitis Serum levels of des-gamma-carboxy prothrombin Elevated in up to 90% of patients Also may be elevated in patients with vitamin K deficiency, chronic hepatitis, and metastatic cancer Cytologic study of ascitic fluid rarely reveals malignant cells +++ Imaging Studies ++ Multiphasic helical CT scanning and MRI enhancement are preferred for the location and vascularity of the tumor MRI may be more sensitive than CT, and imaging with gadoxetic acid increases sensitivity Ultrasound is less sensitive but is used to screen for hepatic nodules in high-risk patients Contrast-enhanced ultrasound has a sensitivity and specificity approaching those of arterial phase helical CT +++ Diagnostic Procedures ++ Liver biopsy Diagnostic, though seeding of the needle tract by tumor is a potential risk (1–3%) For lesions < 1 cm, ultrasonography may be repeated every 3 months followed by further investigation of enlarging lesions For lesions ≥ 1 cm, arterial phase enhancement of the lesion followed by delayed hypointensity ("washout") has a 90% specificity for hepatocellular carcinoma based on stringent criteria developed by the American College of Radiology through its Liver Imaging Reporting and Data System, the Organ Procurement and Transplantation Network, and the American Association for the Study of Liver Diseases + Treatment Download Section PDF Listen +++ +++ Medications ++ Sorafenib is standard of care for patients with advanced hepatocellular carcinoma Prolongs median survival Prolongs time to radiologic progression by 3 months Other chemotherapy, hormonal therapy (with tamoxifen), and long-acting octreotide have not been shown to prolong life Adaptive immunotherapy, adjuvant chemotherapy, and treatment of underlying chronic viral hepatitis may lower postsurgical recurrence rates Multikinase inhibitors Lenvatinib is FDA approved for the same indications as sorafenib Regorafenib provides a survival benefit for patients whose disease progresses despite sorafenib therapy Cabozantinib has been approved by the FDA for patients who did not respond to sorafenib Ramucirumab An antibody to the VEGF receptor Approved for patients with an alpha-fetoprotein level ≥ 400 ng/mL (400 mcg/L) and previous treatment with sorafenib Nivolumab and pembrolizumab are immune checkpoint inhibitors that has been approved for advanced hepatocellular carcinoma +++ Surgery ++ Liver transplantation May achieve a better recurrence-free survival than resection with well-compensated cirrhosis and small tumors (Milan criteria: one tumor < 5 cm or three or fewer tumors each < 3 cm in diameter) and in those with expanded [University of California, San Francisco] criteria of one tumor ≤ 6.5 cm or three or fewer tumors ≤ 4.5 cm (or a combined tumor diameter of 8.5 cm) without vascular invasion However, often impractical because of the donor organ shortage; living donor liver transplantation may be considered in these cases May be appropriate for small unresectable tumors in a patient with advanced cirrhosis, with reported 5-year survival rates of up to 75% Laparoscopic liver resection has been performed in selected cases +++ Therapeutic Procedures ++ Chemoembolization via the hepatic artery May be palliative May prolong survival in patients with large or multifocal tumor in the absence of vascular invasion or extrahepatic spread Microwave ablation, radiofrequency ablation, cryotherapy, or injection of absolute ethanol into tumors smaller than 2 cm may prolong survival in patients who are not candidates for resection and have tumors that are accessible; these interventions, as well as stereotactic body radiation therapy, may also provide a "bridge" to liver transplantation Radiofrequency ablation is superior to ethanol injection for tumors > 2 cm (but is not effective for those > 5 cm) Cryoablation may result in slower tumor progression than radiofrequency ablation for tumors that are 3.1–4 cm in diameter Microwave ablation is becoming the preferred approach because it allows shorter treatment times and, like radiofrequency ablation, can be performed after transarterial chemoembolization (TACE) in select cases Stereotactic body radiation therapy is also being used to treat unresectable hepatocellular carcinoma and may be effective in treating lesions larger than those treated with ablation techniques If the disease progresses despite treatment, meticulous efforts at palliative care are essential Severe pain may develop due to expansion of the liver capsule by the tumor and require concerted efforts at pain management, including opioid use + Outcome Download Section PDF Listen +++ +++ Follow-Up ++ Various criteria-based scoring systems (such as the modified Response Evaluation Criteria in Solid Tumors [mRECIST]) are being tested to assess treatment response (eg, based on tumor shrinkage) and prognosis after differing locoregional and antiangiogenic treatments +++ Prognosis ++ In the United States, overall 1- and 5-year survival rates for hepatocellular carcinoma are 23% and 5%, respectively Surgical resection of solitary hepatocellular carcinomas may result in cure if liver function is preserved (Child-Pugh class A or possibly B) 5-year survival rates rise to 56% for patients with localized resectable disease (T1, T2, T3, selected T4; N0; M0) but are almost nil for those with locally unresectable or advanced disease In patients with HCV-related hepatocellular carcinoma, the serum alpha-fetoprotein level at the time of diagnosis of cancer has been reported to be an independent predictor of mortality In patients on a liver transplant waiting list, a serum alpha-fetoprotein level ≥ 200 ng/mL (200 milli-international units/mL) or increases of > 15 ng/mL/month predict worse outcomes Patients with the following have poor posttransplantation survival: Larger tumors (3–5 cm) A serum alpha-fetoprotein level ≥ 1000 ng/mL (1000 mcg/L) A MELD score of ≥ 20 Survival following liver transplantation is improved in patients who undergo downstaging by locoregional therapy to an alpha-fetoprotein level < 500 ng/mL (500 mcg/L) In patients who are not eligible for surgery, an elevated serum C-reactive protein level is associated with poor survival The fibrolamellar variant does not have a better prognosis than conventional hepatocellular carcinoma without cirrhosis +++ Prevention ++ Although the standard approach for patients with chronic hepatitis B or cirrhosis caused by HCV or alcohol is alpha-fetoprotein testing and ultrasonography every 6 months, the value of alpha-fetoprotein screening has been questioned A serum alpha-fetoprotein level of 20 ng/mL (20 mcg/L) is generally the cutoff value that should trigger further evaluation The risk of developing hepatocellular carcinoma in patients with cirrhosis is 3–5% a year +++ When to Refer ++ All patients with hepatocellular carcinoma should be referred to a specialist +++ When to Admit ++ Complications of cirrhosis Severe pain For surgery and other interventions + References Download Section PDF Listen +++ + +European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol. 2018 Jul;69(1):182–236. [PubMed: 29628281] + +Fanwal F et al. Surveillance for hepatocellular carcinoma: current best practice and future direction. Gastroenterology. 2019 Jul;157(1):54–64. [PubMed: 30986389] + +Forner A et al. Hepatocellular carcinoma. Lancet. 2018 Mar 31;391(10127):1301–14. [PubMed: 29307467] + +Fuchs M, Levy MF. Hepatocellular carcinoma. Dig Dis Sci. 2019 Apr;64(4):901–1057. [Full issue] + +Heimbach JK et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018 Jan;67(1):358–80. [PubMed: 28130846] + +Marrero JA et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018 Aug;68(2):723–50. [PubMed: 29624699] + +Sanduzzi-Zamparelli M et al. New systemic treatments in advanced hepatocellular carcinoma. Liver Transpl. 2019 Feb;25(2):311–22. [PubMed: 30317696] + +Singal AG et al. AGA clinical practice update on interaction between oral direct-acting antivirals for chronic hepatitis C infection and hepatocellular carcinoma: expert review. Gastroenterology. 2019 Jun;156(8):2149–57. [PubMed: 30878469] + +Tang A et al. Introduction to the liver imaging reporting and data system for hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2019 Jun;17(7):1228–38. [PubMed: 30326302] + +Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019 Apr 11;380(15):1450–62. [PubMed: 30970190]