Hepatocellular Carcinoma

Hepatocellular carcinoma, the most common primary liver malignancy, is typically found in adults with cirrhosis or chronic hepatitis, characterised by elevated AFP, malignant hepatocytes, and appears as an arterially enhancing lesion with rapid washout.

General

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and the most common type of liver cancer. It often develops in the setting of chronic liver disease, including viral hepatitis and alcoholic liver disease. It’s known for its high mortality rate due to its aggressive nature and late presentation.

Epidemiology

HCC is the fourth most common cause of cancer death worldwide, with over 700,000 deaths annually. The prevalence is highest in East Asia and sub-Saharan Africa (85% of cases), largely due to the high prevalence of hepatitis B.

Major risk factors include:

Chronic Hepatitis B infection (50-80% of cases): Increases HCC risk by a hundredfold. Particularly seen in East Asia and sub-Saharan Africa.
Chronic Hepatitis C infection (10-20%): Increases HCC risk by 15-20 times. Particularly seen in Western countries.
Cirrhosis: Regardless of the cause, cirrhosis increases risk of HCC by 1-7% annually.
Alcoholic Liver Disease: Increasing risk with the amount and duration of alcohol consumption.
Non-alcoholic Steatohepatitis (NASH) (~10-20% of cases in developed countries): Becoming an increasingly common cause of HCC with the rising prevalence of obesity and metabolic syndrome.
Aflatoxin exposure: A potent carcinogen produced by a fungus that contaminates peanuts, corn, and other nuts and grains, is associated with a high risk of HCC, particularly in areas with poor food storage facilities. The risk is further increased in individuals with chronic HBV infection.

Pathogenesis

The development of HCC is a multistep process that involves the progression from chronic hepatitis to cirrhosis and finally to carcinoma. This process is associated with a variety of genetic and epigenetic changes. Chronic inflammation in the liver, often due to hepatitis B or C infection or alcohol-induced liver damage, leads to cirrhosis, which is the primary risk factor for HCC. Once cirrhosis is present, continuous liver cell damage and regeneration increase the chance of mutations and the development of HCC.

Subtypes

Nodular: Multiple nodules with nearly the same size. Most common.
Massive: Large, single tumour or a dominant tumour with smaller satellites.
Diffuse/Infiltrative: Numerous small tumours scattered throughout the liver, often seen in cirrhotic livers. Most aggressive.
Fibrolamellar: A rare subtype of HCC that typically occurs in adolescents and young adults no association with hepatitis, cirrhosis, or other common risk factors for liver cancer. Histologically, it is characterised by large, polygonal, eosinophilic cells separated by fibrous stroma, leading to a lamellar pattern. It carries a better prognosis.

Clinical Features

In the early stages, HCC may be asymptomatic. As the disease progresses, clinical features may include:

Abdominal pain (most common)
Weight loss
Anorexia
Jaundice
Ascites
Hepatomegaly

Pathological Features

Histopathology

HCC can range from well-differentiated tumours, which closely resemble normal hepatocytes, to poorly differentiated tumours, which may be difficult to distinguish from cholangiocarcinoma or metastatic carcinomas.

Serology

Serum alpha-fetoprotein (AFP) is elevated in about 70% of HCC patients, but it can also be raised in other liver diseases, such as hepatitis and cirrhosis.

Biochemistry

Liver function tests may show elevated liver enzymes and bilirubin levels.
Ascites fluid cytology specimens in patients with cirrhosis, even those known or suspected to have HCC, are almost always negative¹.

Genetics

Mutations in the TERT promoter region and the TP53 gene have been identified in HCC. The CTNNB1, AXIN1, and ARID1A genes may also be involved.

Radiological Features

General Features

Highly vascular tumour with the hepatic artery as the major source (v.s. portal vein as with normal liver parenchyma). Thus HCC demonstrates non-rim hyperenhancement in the arterial phase and non-peripheral washout in the portal venous or delayed phases
- Hyperenhancement means greater than the enhancement of the surrounding liver
- Rim arterial enhancement is not a feature of HCC.
May appear as a solitary focal mass (50%), multifocal mass (40%) or diffusely infiltrative tumour (10%).
Capsular enhancement (in delayed phase) is due to lack of portal supply to tumour
Central scar may be seen
Nodule-within-a-nodule: Small foci of HCC may be seen within a regenerative liver nodule as foci of arterial enhancement
Background features of cirrhosis, including ascites
Both bland thrombus (from synthetic dysfunction of clotting factors) and tumour thrombus (from vascular invasion) may be present, differentiated on contrast-enhanced phase. This may be seen in the portal vein, hepatic veins, IVC or right atrium.
Associated wedge-shaped perfusion abnormality due to arterioportal shunt.

Post-Treatment Features

Lipiodol (iodised oil) is hyperdense on pre-contrast CT.
Necrotic tissue should not enhance.
Zone of Ablation– refers to post-ablation region

CT

Non-contrast: Hyperattenuating material may be seen as sequalae of locoregional therapy
Early arterial: Not usually preferred as has a reduced sensitivity for detecting HCC
Late arterial (35 sec post-contrast): Vivid non-rim hyperenhancement. Peripheral halo of fatty sparing may be seen around a HCC in an otherwise fatty liver. Portal vein tumour thrombus may demonstrate enhancement.
Portal venous (60 – 90 sec): Rapid washout, becoming isodense or hypodense to liver (which is at peak parenchymal enhancement)
Delayed (3 – 5 min): Smooth capsular enhancement may be seen (relatively specific sign). Presence of a central scar can be differentiated from focal nodular hyperplasia by the absence of delayed contrast enhancement

US

Background cirrhotic changes (nodular surface contour, heterogenous echotexture)
HCC does not have a characteristic appearance on US:
- Small focal HCC tend to be hypoechoic compared to normal liver
- Large HCC tend to be heterogenous due to fibrosis, fatty change, necrosis, calcification
Peripheral halo of hypoechogenicity suggests focal fatty sparing
Arterial phase: Arterial enhancement from neovascularity
Portal venous phase: Contrast wash-out: Decreased echogenicity relative to background liver

MRI

T1: Iso- or hypointense compared to surrounding liver. Hyperintensity may be due to intratumoral fat or decreased intensity in the surrounding liver.
T2: Moderately hypertintense.
Gd+: Enhances in arterial phase, rapid washout and delayed rim enhancement.

Grading and Staging

Grading of HCC is typically based on the histological assessment of tumour differentiation, which reflects how much the cancer cells resemble normal liver cells. The World Health Organisation (WHO) grading system is commonly used:

Grade I (Well-differentiated): Tumour cells closely resemble normal hepatocytes, with minimal nuclear atypia and mitotic activity.
Grade II (Moderately differentiated): Tumour cells show more variation in size and shape, with increased nuclear atypia and mitotic activity.
Grade III (Poorly differentiated): Tumour cells are markedly atypical, with high mitotic activity and abnormal structures.
Grade IV (Undifferentiated): Tumour cells are highly abnormal and do not resemble normal hepatocytes at all.

Several staging systems are used for HCC, each incorporating various aspects of tumour burden, liver function, and overall health status. The most commonly used systems include:

Barcelona Clinic Liver Cancer (BCLC) Staging System

Stage 0 (Very early stage): Single tumour < 2 cm, preserved liver function, no vascular invasion, or extrahepatic spread.
Stage A (Early stage): Single or up to three tumours ≤ 3 cm, preserved liver function, no vascular invasion, or extrahepatic spread.
Stage B (Intermediate stage): Multiple tumours > 3 cm, preserved liver function, no vascular invasion, or extrahepatic spread.
Stage C (Advanced stage): Tumours with vascular invasion or extrahepatic spread, preserved liver function.
Stage D (Terminal stage): Tumours with poor liver function or very poor performance status.

TNM Staging (American Joint Committee on Cancer, AJCC)

T1: Single tumour without vascular invasion.
T2: Single tumour with vascular invasion or multiple tumours, none > 5 cm.
T3: Multiple tumours > 5 cm or a tumour involving a major branch of the portal or hepatic vein.
T4: Tumours with direct invasion of adjacent organs (other than the gallbladder) or with perforation of the visceral peritoneum.
N0: No regional lymph node metastasis.
N1: Regional lymph node metastasis.
M0: No distant metastasis.
M1: Distant metastasis.

Child-Pugh Score

Although not a staging system for HCC per se, the Child-Pugh score is used to assess liver function and helps inform treatment decisions:

Class A: Well-compensated liver disease.
Class B: Significant functional compromise.
Class C: Decompensated liver disease.

These grading and staging systems provide a comprehensive framework for assessing HCC severity, guiding treatment, and predicting prognosis.

Diagnosis

HCC can be diagnosed on the basis of imaging features alone, without histologic confirmation.

Differential Diagnosis

Hepatic adenoma: Typically seen in young women and associated with oral contraceptive use. Adenomas are often well circumscribed and lack the vascular invasion seen in HCC.
Focal nodular hyperplasia: A benign condition typically found in healthy livers. Unlike HCC, it does not have a propensity to bleed or become malignant.
Metastases: The liver is a common site for metastasis. In patients with a known primary tumour elsewhere, the discovery of liver lesions may suggest metastasis.

Management

HCC is primarily managed by a multidisciplinary team including hepatologists, oncologists, interventional radiologists and surgeons.
Treatment options depend on the stage of the disease and the patient’s overall health, and may include surgical resection, liver transplantation, locoregional therapies (such as transarterial chemoembolisation and radiofrequency ablation), and systemic therapy with multikinase inhibitors like sorafenib.
- TACE – High concentration chemotherapy within lipiodol (iodised oil transport agent) directly delivered to tumour via hepatic arterial system, followed by drug-eluting embolic agents to occlude blood supply and minimise systemic exposure. Tumour necrosis therefore occurs via cytotoxicity and selective ischaemia.²
- Radiofrequency ablation – Uses high-frequency electrical currents to generate thermal energy causing coagulative necrosis of tumour cells.
Regular surveillance for early detection of HCC is recommended in high-risk patients, such as those with chronic hepatitis B or C and those with cirrhosis.

References

Updated on 14 October 2024

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