Hepatocellular Carcinoma

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)

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

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

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

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