Summary
Hepatocellular carcinoma (HCC) is a malignant, most often solitary tumor of the liver, which occurs primarily in patients with preexisting liver cirrhosis or chronic hepatitis. Typically, it is an incidental diagnosis in these high-risk patients that is made either via ultrasound or an increase in the hepatic tumor marker alpha-fetoprotein. Most patients typically present with symptoms caused by underlying disease (e.g., ascites, jaundice) rather than the tumor itself. Potentially curative treatment options include tumor resection, liver transplantation, and ablative therapies. Unfortunately, it is usually not possible to remove all tumor tissue, which explains the poor prognosis of HCC. In western countries, the five-year survival is less than 50%.
Epidemiology
- Fifth most common malignancy worldwide
- Most common primary liver malignancy in adults
- Highest incidence in Southeast Asia and Africa [1]
- 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.
Etiology
- Liver cirrhosis: 80% of cases (see “Etiology” in cirrhosis) [2]
-
Risk factors independent of cirrhosis
- Chronic hepatitis B or C virus infection
- Alcoholic liver disease
- Nonalcoholic steatohepatitis (NASH)
- Hemochromatosis
- Wilson's disease
- Alpha-1 antitrypsin deficiency
- Hepatic autoimmune diseases (e.g., autoimmune hepatitis)
- Schistosomiasis
- Glycogen storage disease
-
Chronic ingestion of food contaminated with aflatoxin (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!
Clinical features
- 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
Diagnostics
Laboratory tests
- ↑ Serum alpha-fetoprotein (AFP)
- Laboratory studies consistent with hepatitis and cirrhosis (e.g., ↑ transaminases, positive hepatitis serologies, ↓ coagulation factors)
- Paraneoplastic syndromes: erythrocytosis , hypoglycemia, hypercalcemia
Imaging
-
Ultrasound: best initial test
- Irregular mass borders
- Echogenicity ranging from homogeneous to inhomogeneous and from hypoechoic to hyperechoic
- Vascular invasion of the tumor may be visible (e.g., portal vein thrombosis)
- Underlying cirrhosis may be seen
-
Abdominal CT or MRI (with contrast): confirmatory test
- Hypodense lesions (single or multifocal)
- Irregular mass borders
- Possible local invasion
- Quick and vivid contrast enhancement during late arterial phase, followed by rapid washout [3]
- Chest CT: detection of pulmonary metastases (rare)
- Bone scintigraphy: detection of bone metastases (rare)
Liver biopsy
- Can provide a definitive diagnosis but carries the risk of bleeding and tumor spread
- Recommended when both lab and imaging studies are inconclusive
Differential diagnoses
Malignant liver tumors
-
Metastatic liver disease
- Epidemiology
- Diagnostics
- Abnormal liver function tests
- Ultrasound
-
CT scan: typically multiple hypodense lesions (solitary metastases are very rare)
- Alternative: MRI
- Intrahepatic cholangiocellular carcinoma (CCC): second most common primary hepatic malignancy after HCC [4]
-
Hepatic angiosarcoma [5]
- Epidemiology: third most common primary hepatic malignancy
- Etiology: associated with exposure to vinyl chloride, arsenic, and thorium dioxide
- Histology (biopsy): endothelial cells positive for PECAM-1 (CD31)
- Treatment: surgical resection +/- adjuvant therapy [6]
- Prognosis: high rate of recurrence, poor overall prognosis
- Primary hepatic lymphoma
Benign liver tumors
- Hepatic cyst
- Liver hemangioma
- Focal nodular hyperplasia (FNH)
- Hepatocellular adenoma with/without dysplasia
- Arteriovenous malformation
- Hepatic lipoma
- Regenerative liver nodules in cases of cirrhosis
The differential diagnoses listed here are not exhaustive.
Treatment
Curative approach [7]
Surgery
-
Surgical resection
- Provides the best outcome
- Can only be performed in patients with sufficient liver function and without nodular invasion of the liver vasculature or distant metastases
- Liver transplantation
Ablative therapies
Ablative options are mostly palliative, but can also be curative. They usually result in shrinking and scarring of the tumor and involve the following methods:
-
Radiofrequency ablation (RFA)
- An image-guided technique that involves the placement of a needle electrode within the tumor to destroy cancer cells using heat generated by high-frequency electrical currents
- Indicated as primary treatment with curative intention under the following conditions :
- Multiple (≤ 3), small liver lesions (largest lesion ≤ 3 cm) in patients that require bridging/downsizing while on a waiting list for liver transplant
- Solitary, small lesion (≤ 3 cm)
- Transcatheter arterial chemoembolization (TACE): local application of chemotherapy and embolic agent
- Percutaneous ethanol injection (PEI)
- Selective internal radiation therapy (SIRT)
Follow-up
- Vaccination against HBV in high-risk individuals
- Surveillance with ultrasound in patients with cirrhosis or chronic hepatitis B
Palliative care [8][9]
Palliative care is indicated mainly for individuals with decompensated, unresectable, multinodular, or metastatic disease and has the following options:
-
Targeted therapy
- First-line agents include sorafenib, sunitinib, and linifanib
- Second-line agents include brivanib, everolimus, and ramucirumab
- Systemic chemotherapy: rarely used
- Hepatic arterial infusion chemotherapy (HAIC): placement of a catheter into the hepatic artery and subsequent infusion of cytotoxic chemotherapeutics (e.g., cisplatin, 5-FU)
-
Immunotherapy
- Involves anti-CTLA-4 antibodies and anti-PD-1/PD-L1 antibodies
- The usefulness of immunotherapy as monotherapy or in combination with targeted molecular drugs is currently the subject of clinical trials.
Complications
- 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.
Prognosis
-
5-year survival rate
- Western countries: 27–49%
- Asia and Africa: < 10%
Screening
-
Recommended in high-risk patients with one or more of the following: [10]
- Cirrhosis
-
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
- Individuals of African descent
- Chronic hepatitis C with cirrhosis
- Hemochromatosis with cirrhosis
- Alpha-1 antitrypsin deficiency with cirrhosis
-
Screening modalities and screening intervals [10]
- Abdominal ultrasound should be performed every 6 months
- Periodic monitoring of alpha-fetoprotein (AFP)