Hepatocellular carcinoma

Last updated: April 11, 2022

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Hepatocellular carcinoma (HCC) is the most common primary liver malignancy in adults and one of the leading causes of cancer-related mortality worldwide. It primarily affects patients with preexisting liver disease (e.g., liver cirrhosis, chronic hepatitis) and often manifests as a solitary tumor. HCC is commonly asymptomatic in the early stage. Patients typically present with features of the underlying liver disease (e.g., ascites, jaundice). Advanced HCC can manifest with nonspecific features of abdominal pain, weight loss, and anorexia. Regular (6-monthly) surveillance with abdominal ultrasound, with or without serum AFP levels, is recommended for individuals at risk of developing HCC. If screening is suggestive of HCC (i..e, liver lesion ≥10 mm or AFP ≥ 20 ng/mL), the diagnosis should be confirmed with multiphase imaging and, if needed, a liver biopsy. Management is based on tumor burden, the patient's performance status, and the severity of liver dysfunction. Potentially curative treatment options include tumor resection, liver transplantation, and ablative therapy, most commonly radiofrequency ablation (RFA). Patients with advanced tumors may be treated with noncurative locoregional therapy (LRT) such as transarterial chemoembolization (TACE), or systemic chemotherapy. As HCC mostly occurs in patients with advanced underlying liver disease, the prognosis is generally poor.

Epidemiological data refers to the US, unless otherwise specified.

Aflatoxins are considered one of the most potent carcinogens.

HCC may be detected via screening for HCC in at-risk groups (e.g., patients with known cirrhosis) or after symptoms develop.

Approach [5][6][7]

  • Initial diagnostics
    • Ultrasound abdomen (preferred initial imaging modality in most cases)
    • Consider serum AFP levels to increase detection rate.
  • Perform further imaging (typically multiphase imaging e.g., CT or MRI abdomen) if the following are detected:
    • Lesion ≥10 mm
    • Lesion of any size and AFP (if performed) ≥ 20 ng/mL
  • Perform a liver biopsy in the following cases:
  • Laboratory studies: to evaluate liver function and assess for underlying etiologies
  • Confirmed HCC diagnosis: Perform further studies for staging of HCC.

A liver biopsy is not routinely required to confirm the diagnosis in patients with underlying liver disease and characteristic imaging findings of HCC. [5]

Imaging [5][8][9]

Ultrasound is typically the primary screening modality, but diagnostic confirmation requires imaging multiphase imaging using intravenous contrast.

Ultrasound abdomen

  • Indications
    • Initial evaluation for suspected HCC
    • Screening in high-risk patients
    • May be used to investigate focal lesions found on noncontrast CT or MRI
  • Supportive findings

Any hepatic lesion in a patient with cirrhosis should be considered suspicious for a primary liver tumor.

Multiphase imaging [9][10]

  • Indications
    • Ultrasound features of HCC
    • Serum AFP ≥ 20 ng/mL
    • Alternative initial screening modality in select patients (e.g., if the liver cannot be assessed appropriately by ultrasound because of habitus)
  • Modalities
  • Findings: a lesion(s) with irregular borders and possible signs of local invasion ; [9][11]

A hypodense or isodense lesion with arterial phase hyperenhancement followed by portal venous phase washout is characteristic of HCC. [10]

All multiphase image findings for suspected HCC are graded using the Liver Imaging Reporting and Data System to help standardize diagnostic criteria and improve data collection on treatment outcomes by imaging stage.

Laboratory studies [5][12]

Liver biopsy [5][15]

  • Indications
  • Risks
  • Findings
    • See “Pathology” section.
    • Immunostaining can be considered for inconclusive or uncharacteristic findings.

False negatives with biopsy are possible as a result of the similarities between the early changes of HCC and dysplastic nodules or from insufficient tissue being obtained; if clinical suspicion remains high, repeat the biopsy or ensure regular surveillance of the lesion. [15]

Barcelona Clinic Liver Cancer (BCLC) Staging System [18]
BCLC Stage Criteria
Very early hepatocellular carcinoma (Stage 0)
  • Single tumor ≤ 2 cm
  • AND Child–Pugh A
  • AND ECOG PS 0–1
Early-stage hepatocellular carcinoma (Stage A)
  • Single tumor > 2 cm or 2 to 3 tumors ≤ 3 cm
  • AND Child–Pugh A or B
  • AND ECOG PS 0–1
Intermediate stage hepatocellular carcinoma (Stage B)
  • > 3 tumors OR 2–3 tumors, any > 3 cm in size
  • AND Child–Pugh A or B
  • AND ECOG PS 0–1
Advanced stage hepatocellular carcinoma (Stage C)
End-stage hepatocellular carcinoma (Stage D)

Patients with advanced liver disease (Child-Pugh class C) or a poor ECOG performance status are always classified as having end-stage HCC, regardless of tumor burden.

Gross pathology

Histopathology

Approach

  • Refer the patient to specialist multidisciplinary team.
  • Initiate treatment based on stage of hepatocellular carcinoma.
  • Prevent further deterioration of any associated liver disease:

Overview [5][6]

Overview of treatment by HCC stage [5]
Stage of cancer Treatment aim Treatment
Very early-stage HCC or early-stage HCC
  • Curative
Intermediate-stage HCC
Advanced HCC
  • Noncurative
End-stage HCC
  • Typically supportive care only

Despite high recurrence rates following surgical, ablative, and locoregional therapies, adjuvant treatment is not routinely recommended as it has not been shown to be effective. [5]

Patients should additionally undergo treatment of underlying etiologies e.g., antiviral therapy for hepatitis C infection.

Surgery [5][20]

Resection

  • Indication: resectable, early-stage HCC in patients with minimal concomitant liver disease
  • Technique: open or laparoscopic tumor resection
  • Recurrence risk

Resection is the first-line treatment option for patients with very early and early-stage HCC and good liver function.

Liver transplantation

  • Indications
    • Early stage HCC with significant concomitant liver disease
    • AND tumor(s) meet Milan criteria (a set of criteria used to assess HCC patients for transplant) [5][22]
      • 1 tumor measuring ≥ 2 cm and ≤ 5 cm
      • OR 2–3 tumors measuring ≥ 1 cm and ≤ 3 cm
  • Bridge to transplant: Consider using ablative therapy or locoregional therapy to prevent tumor progression beyond the Milan criteria.
  • Recurrence risk [5]
    • 11–18%; most commonly extrahepatic
    • Monitor with abdominal and chest CT (surveillance frequency and benefit is uncertain).

Ablation [5][23]

Locoregional therapy [5][25]

  • Indications
  • Techniques
    • Transarterial chemoembolization (TACE): catheter-directed localized application of a chemotherapeutic and an embolic agent
    • Transarterial radioembolization (TARE): catheter-directed selective irradiation via the injection of radioactive spheres into the tumor-feeding artery

Chemotherapy [5][26][27]

Malignant liver tumors [7]

Metastatic liver disease [28]

Intrahepatic cholangiocarcinoma

Hepatic angiosarcoma [33][34][35]

  • Epidemiology: rare (2% of primary hepatic malignancies) [36]
  • Etiology: associated with exposure to vinyl chloride, arsenic, or thorium dioxide
  • Clinical features
  • Diagnostics
    • CT abdomen (with IV contrast)
      • Variable appearance; single or multiple lesions, typically hypervascular
      • Rapid growth on serial imaging
    • Histology: endothelial cells positive for PECAM-1 (CD31)
  • Treatment
    • Surgical resection; adjuvant therapy may be considered
    • TACE may be beneficial in patients manifesting with acute hemorrhage.
  • Complications: rupture with intraabdominal hemorrhage
  • Prognosis
    • Poor (∼ 6 months)
    • Often metastatic at time of diagnosis, high recurrence rate

Primary hepatic lymphoma [37]

  • Epidemiology
    • Very rare [38]
    • Typically occurs in the 5th decade with slight male preponderance [37]
  • Etiology: Risk factors include HIV, hepatitis B, hepatitis C, and chemical exposure.
  • Clinical features: nonspecific; abdominal pain, fatigue, anorexia, weight loss, jaundice, night sweats
  • Diagnostics
    • Ultrasound abdomen
      • Usually performed as the initial imaging modality
      • Appearance typically shows a hypoechoic lesion(s)
    • MRI or CT abdomen (with IV contrast) may show single or multiple lesions, or diffuse infiltration.
    • Diagnostic confirmation: liver biopsy
  • Treatment: surgery when possible, followed by chemotherapy

Benign liver tumors [8]

See “Benign liver tumors and hepatic cysts” for details.

Liver lesions are most often benign, even in patients with preexisting malignancies. [8]

The differential diagnoses listed here are not exhaustive.

We list the most important complications. The selection is not exhaustive.

  • 5-year survival rate of early-stage HCC: > 70% [39]
  • 5-year survival rate for advanced HCC: ∼20% (median survival ∼1–1.5 years) [40][41][42]

High-risk conditions

  • Cirrhosis from any cause
  • Chronic hepatitis B
    • With active infection
    • With a family history of HCC
    • In Asian men > 40 years of age or Asian women > 50 years of age
    • African individuals ≥ 20 years (not applicable for US-born African-Americans)

Patients at high-risk for HCC are advised to attend regular screenings every 6 months.

Patients with Child-Pugh class C cirrhosis should only undergo screening if they are on the transplant waiting list as life expectancy in decompensated liver cirrhosis is limited.

Screening modalities and intervals

  • Imaging
    • Abdominal ultrasound is the preferred screening modality.
    • Screening intervals depend on imaging findings.
      • No lesion: Repeat US in 6 months.
      • Lesion < 10 mm: Repeat US in 3–6 months. [5]
      • Lesion ≥ 10 mm: Perform further imaging (typically multiphase imaging).
  • Consider measuring serum AFP level: perform multiphase imaging if AFP ≥ 20 ng/mL in a patient with a liver lesion of any size [5]

Concerning features for malignancy (i.e., liver lesion ≥ 10 mm or AFP ≥ 20 ng/mL) should be evaluated further by multiphase imaging (see “Diagnostics of HCC” for details).

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