Hepatocellular carcinoma

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.

• Fifth most common malignancy worldwide
• Most common primary liver malignancy in adults
• Highest incidence in Southeast Asia and Africa
• Peak incidence in the US: 70–75 years
• Peak incidence in Africa and Asia: 30–40 years
• ♂ > ♀

Epidemiological data refers to the US, unless otherwise specified.

• Liver cirrhosis: 80% of cases (see “Cirrhosis etiology”) ^[4]
• Additional risk factors
  • Chronic hepatitis B or C virus infection
  • Alcoholic liver disease
  • Nonalcoholic steatohepatitis (NASH)
  • Hemochromatosis
  • Wilson disease
  • Alpha-1 antitrypsin deficiency
  • Hepatic autoimmune diseases (e.g., autoimmune hepatitis)
  • Schistosomiasis
  • Glycogen storage disease
  • Chronic ingestion of food contaminated with aflatoxin
    • Aflatoxin is a carcinogen produced by Aspergillus flavus
    • Results in G:C → T:A transversion in codon 249 of TP53 gene leading to an inactivating mutation

Aflatoxins are considered one of the most potent carcinogens.

• Usually asymptomatic apart from symptoms of the underlying disease (mostly cirrhosis or hepatitis)
• Possible symptoms of advanced disease
  • Weight loss, anorexia
  • Hepatomegaly and right upper quadrant tenderness
  • Jaundice
  • Ascites

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:
  • Inconclusive multiphase imaging
  • Liver lesions suspicious for HCC in patients without cirrhosis
• 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 multiphase imaging with 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
  • Solid nodule(s), typically ≥ 10 mm, of varying homogeneity and echogenicity with irregular borders
  • May show infiltration into the portal vein causing portal vein thrombosis
  • Signs of cirrhosis may be present (see “Diagnosis of liver cirrhosis” for details).

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
  • Typically CT or MRI abdomen
  • Contrast-enhanced ultrasound abdomen may serve as an alternative.
• Findings: a lesion(s) with irregular borders and possible signs of local invasion ; ^[9][11]
  • Without contrast
    • CT: hypodense or isodense lesion(s)
    • MRI: hyperintense or isointense lesion(s) on T2
  • With IV contrast
    • Arterial phase hyperenhancement
    • Nonperipheral washout
    • Enhancing capsule

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]

• All patients
  • CBC: may show thrombocytopenia or paraneoplastic erythrocytosis
  • Liver chemistries: may be abnormal in preexisting liver disease or advanced malignancy
  • Coagulation screen: may be abnormal in severe preexisting liver disease or advanced malignancy
  • Serum AFP: typically elevated ^[13]
• Suspected paraneoplastic syndromes: depending on clinical presentation ^[14]
  • Blood glucose: hypoglycemia
  • Serum calcium: hypercalcemia
  • Lipid panel: hypercholesterolemia
• Assessment of underlying etiology (if unknown): e.g., hepatitis panel, iron studies

Liver biopsy ^[5][15]

• Indications
  • Patients with cirrhosis: if malignancy is suspected but imaging is inconclusive
  • Patients without cirrhosis: any lesion suspicious for HCC
• Risks
  • Bleeding
  • Tumor seeding
• 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]

• TMN scoring system is not widely used in HCC.
• The American Association for the Study of Liver Diseases (AASLD) recommends the Barcelona Clinic Liver Cancer staging system, which requires an assessment of the following factors:
  • Tumor burden ^[5][17]
    • Assessment of local extension: Multiphase CT or MRI abdomen
    • Assessment for metastatic disease: FDG-PET OR CT chest, abdomen, and pelvis with bone scintigraphy
  • Liver function, determined by the Child-Pugh score
  • Eastern Cooperative Oncology Group (ECOG) performance status

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:
  • Treat underlying etiologies e.g., antivirals for hepatitis, chelation therapy for hemochromatosis.
  • Advise alcohol abstinence. ^[19]
  • Avoid hepatoxic drugs.

Overview ^[5][6]

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
  • Up to 70% after 5 years
  • Monitor with multiphase imaging and serum AFP every 3–6 months ^[5][21]

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]

• Indications
  • Early-stage HCC in patients who are not candidates for surgery
  • Downstaging and/or as a bridge to transplant
• Techniques ^[20][24]
  • First line: radiofrequency ablation (RFA)
  • Alternative techniques: include microwave ablation and chemical ablation e.g., percutaneous ethanol injection
• Recurrence risk
  • Up to 70% after 5 years
  • Assess with multiphase imaging every 3 months for ≥ 1 year, then at least every 6 months ^[5]

Locoregional therapy ^[5][25]

• Indications
  • Intermediate-stage HCC and early-stage HCC in patients who are not candidates for curative treatments
  • Downstaging and/or as a bridge to transplant
• 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]

• Indications
  • Advanced-stage HCC
  • Patients who progress after LRT
• First line: targeted therapy ^[27]
  • Preferred: atezolizumab/bevacizumab
  • Alternative: sorafenib or lenvatinib ^[26]

Malignant liver tumors ^[7]

Metastatic liver disease ^[28]

• Epidemiology
  • Most common malignant liver lesion
  • Typical primary tumor sites: gastrointestinal tract (colon, stomach, pancreas), lung, and breast
• Clinical features
  • Often asymptomatic
  • Can manifest with nonspecific symptoms, such as malaise, anorexia, weight loss, jaundice, ascites
  • Features of the underlying primary may be present.
• Diagnostics ^[8][29]
  • Liver chemistries: may be abnormal depending on the degree of liver involvement
  • Ultrasound abdomen
    • Often used for initial assessment, but typically less sensitive than other imaging modalities
    • Typical appearance: “bulls-eye” with a hyperechoic center and hypoechoic periphery (target sign)
  • CT abdomen with IV contrast
    • Recommended imaging modality for suspected liver metastases
    • Can simultaneously evaluate the site of the primary tumor
    • Findings: multiple hypodense lesions (very rarely, solitary metastases) ^[30]
• Treatment
  • Management depends on extent of disease, the underlying malignancy, and patient performance status.
  • Options include:
    • Surgery, if resectable ^[28]
    • Ablative therapy
    • Systemic chemotherapy
    • Palliative care

Intrahepatic cholangiocarcinoma

• Epidemiology: second most common primary hepatic malignancy after HCC ^[31]
• Clinical features: See “Clinical features of intrahepatic cholangiocarcinoma.”
• Diagnostics: CT abdomen (with IV contrast) or MRI abdomen (without and with IV contrast and with MRCP) ^[32]
  • Lobulated irregular masses with rim enhancement and peripheral washout
  • Intrahepatic metastasis and daughter nodules may be seen.
• Treatment: See “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
  • Nonspecific (abdominal pain, weight loss, jaundice, ascites, anemia)
  • Can manifest acutely with hypotension and abdominal pain (indicating hemorrhage)
• 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 5^th 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.

• Hepatic cyst
• Liver hemangioma
• Focal nodular hyperplasia
• Hepatocellular adenoma with or without dysplasia
• Arteriovenous malformation
• Hepatic lipoma
• Regenerative liver nodules in cases of cirrhosis

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

The differential diagnoses listed here are not exhaustive.

• May cause Budd-Chiari syndrome
• Metastasis (hematogenous): rare, usually only occurs in advanced stages

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]

• Reduce the risk of bloodborne viruses.
  • Hepatitis B immunization
  • Patient education on risk factors for bloodborne viruses
  • Counseling on safer sex practices and provision of harm reduction strategies
  • Early detection and treatment of chronic hepatitis B infection and treatment of hepatitis C.
• Maintain alcohol intake within normal limits.
  • Patient education on low-risk drinking
  • Counseling for alcohol use disorder
• Manage obesity to reduce the risk of NASH.
  • Counseling on weight and diet changes and counseling on regular exercise
  • Weight loss drugs and weight loss surgery

High-risk conditions ^[5][44]

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

• 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 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 ^[5][44]

• 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).