Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is strongly associated with cirrhosis, from both alcohol and viral etiologies. HCC constitutes approximately 5% of all cancers partly due to the high endemic rates of hepatitis B infection 1.
HCC is the fifth most common cancer in the world and is the third most common cause of cancer-related death (after lung and stomach cancer). The incidence of HCC is rising, largely attributed to a rise in hepatitis C infection 11.
The demographics are strongly influenced by the regions in which chronic hepatitis B infection is common, which account for over 80% of cases worldwide. The highest prevalence is in Asia.
In western countries the rate is lower and alcohol accounts for a greater proportion of cases.
Risk factors include 1:
- hepatitis B (HBV) infection: 10% 5 year cumulative risk 5
- hepatitis C (HCV) infection: 30% 5 year cumulative risk
- alcoholism: 8% 5 year cumulative risk
- biliary cirrhosis: 5% 5 year cumulative risk
- food toxins, e.g. aflatoxins
- congenital biliary atresia
- inborn errors of metabolism
HCC are typically diagnosed in adults in late middle age or elderly. The tumor is however also identified in the pediatric population where it is the second most common primary liver tumor after hepatoblastoma.
Presentation is variable, and in affluent nations is often found in the setting of screening programs for patients with known risk factors. Otherwise presentation may include:
- constitutional symptoms
- portal hypertension from invasion of the portal vein
The origin of HCCs is believed to be related to repeated cycles of necrosis and regeneration, irrespective of cause. In addition the HBV and HCV genome contains genetic material that may predispose cells to accumulate mutations, or disrupts growth control, thus allowing for a second mechanism by which infection with these agents predisposes to HCC 1.
On gross pathology, HCCs typically appear as pale masses within the liver, and may be unifocal, multifocal or diffusely infiltrative at the time of presentation. Microscopically they range from well differentiated to undifferentiated .
Metastasis occurs in the final stages of disease (IVA) and carry a poor prognosis 13-14.The most frequently involved sites are the lung, adrenal glands, lymph nodes, and bone.
Fibrolamellar hepatocellular carcinoma is distinct variant with different demographics and risk factors.
- alpha-fetoprotein (AFP) levels are elevated in 50-75% of cases.
Hepatocellular carcinomas can have a variety of appearances:
- focal (massive)
- multifocal (nodular)
Hepatocellular carcinoma receives most of its blood supply from the hepatic artery, accounting for its characteristic enhancement pattern: early arterial enhancement with early "washout." Hence, a small foci of HCC may be seen within a regenerative liver nodule, as a foci of arterial enhancement (nodule-in-nodule appearance) 15.
Additionally these tumors have a propensity to invade vascular structures, most commonly the portal vein, but also the hepatic veins, IVC and right atrium. One should remember that a large number of patients will have concomitant cirrhosis, and thus be at risk for bland portal vein thrombosis also.
Several pattern may be seen:
- focal HCC
- large usually hypoattenuating mass
- may have necrosis/fat/calcification
- multifocal HCC
- multiple masses of variable attenuation lesions
- may also have central hypoattenuating necrotic portions
- diffuse HCC
- may be difficult to distinguish from associated cirrhosis
Enhancement pattern is the key to correct assessment of HCCs. Usually the mass enhances vividly during late arterial (~35 seconds) and then washes out, becoming indistinct or hypoattenuating in the portal venous phase, compared to the rest of the liver.
Additionally, they may be associated with a wedge shaped perfusion abnormality due to arterioportal shunts (APS), and this in turn can result in focal fatty change in the normal liver or focal fatty sparing in the diffusely fatty liver 7. A halo of focal fatty sparing may also be seen around an HCC in an otherwise fatty liver 6.
Portal vein tumor thrombus can be distinguished from bland thrombus by demonstrating enhancement.
An imaging classification system (LI-RADS) has been developed to risk stratify lesions in an at-risk liver.
Variable appearance depending on individual lesion, size, and echogenicity of background liver.
Typically a small focal HCC appears hypoechoic compared with normal liver. Larger lesions are heterogeneous due to fibrosis, fatty change, necrosis and calcification 8. Again, a peripheral halo of hypoechogenicity may be seen with focal fatty sparing.
Diffuse HCC may be difficult to identify or distinguish from background cirrhosis. A positive serum AFP level and/or biopsy may be necessary for diagnosis.
- contrast-enhanced ultrasound 17:
- arterial phase:
- arterial enhancement from neovascularity
- portal venous phase:
- decreased echogenicity relative to background liver ("wash out")
- tumor thrombus may be visible
- arterial phase:
Variants have been described with arterial phase hypovascularity with no enhancement or arterial enhancement with no "wash out".
- iso or hyperintense c.f. surrounding liver
- hyperintensity may be due to
- intratumoral fat 5
- decreased intensity in surrounding liver
T1 C+ (Gd)
- enhancement is usually arterial ("hypervascularity")
- rapid "washout," becoming hypointense c.f. remainder of the liver (96% specific) 5
- this is because the supply to HCCs is predominantly from the hepatic artery rather than portal vein
- rim enhancement may persist (referred to as a capsule)
- an imaging classification system (LI-RADS) has been developed to risk stratify lesions
T1 C+ (Eovist)
- similar to assessment with extracellular Gd, but evaluation of the hepatobiliary phase requires care (see: Eovist and LI-RADS)
- T2: variable, typically moderately hyperintense
- C+ post SPIO (Iron oxide): increases sensitivity in diagnosing small HCCs
- hypervascular tumor
- threads and streaks pattern: sign of tumor thrombus in portal vein
There are several staging systems used in hepatocellular carcinoma 16
- Barcelona-Clínic Liver Cancer (BCLC) staging system
- CLIP score
- Okuda staging system
- CUPI (Chinese University Prognostic Index)
- TNM staging
- Japan Integrated Staging (JIS)
- French classification system
Treatment and prognosis
If the lesion is small then resection is possible (partial hepatectomy) and may result in cure. The remarkable ability of the liver to regenerate means that up to 2/3rds of the liver can be resected 10.
Liver transplantation is also a curative option. To be suitable for a liver transplantation it is generally agreed that certain criteria should be met (see Milan criteria).
If neither of these options is possible, then a variety of options exist including chemotherapy, transarterial chemoembolisation (TACE), thermal ablation (RFA, cryoablation, or microwave ablation) and selective internal radiation therapy (SIRT) 12.
If a tumor is resectable, then 5 year survival is at ~37-56% 3.
General imaging differential considerations include: