Hepatocellular Carcinoma

Alternative Names: hepatoma; cancer of the liver; liver cancer; primary liver cell carcinoma; tumor –liver

Figure 1: Map of the world showing the incidence of hepatitis B surface antigen and HCC hotspots.

Causes, Incidence and Risk Factors

In Japan, HCC is the third most common cancer in men. In the United States approximately 9,000 cases occur each year, an incidence similar to Hodgkin's lymphoma. It is one of the most common visceral tumors especially in the high-risk populations of South Eastern Asia, sub-Saharan Africa, Japan, Greece and Italy. The incidence of HCC is rising worldwide. HCC is more common in men than women, with a sex ratio ranging from 3:1 to 6:1. In low incidence areas such as the United States and parts of Europe, the average age at diagnosis is between 60-80 years but in areas of high incidence the patient presents earlier between 30-50 years. A low-grade carcinoma is seen in younger patients, 20-40 years of age, in the absence of underlying cirrhosis.

The risk factors for HCC include chronic liver disease, viral hepatitis, hemochromatosis, known liver carcinogens, and aflatoxin B1 found in foods in parts of Africa and Asia. A fungus growing on peanut (groundnut) meal that has been stored in hot and humid conditions produces aflatoxin. Mutations/deletions of tumor suppressor gene, p53, have been linked to the development of HCC. Epidemiologic studies have linked aflatoxin B1 exposure and p53 mutations. Such mutations are common in HCC in patients from mainland China, Africa, and Mexico where aflatoxin B1 contamination of food is high, and rare in Hong Kong, Singapore, Japan, Europe and in Caucasian patients in the United States where food contains little or no aflatoxin B1. HCC may occur in children and has two age peaks: < 4 years and between 12-15 years. Childhood HCC is associated with essentially all types of cirrhosis due to malnutrition, and certain metabolic or structural congenital abnormalities of the liver. Hepatitis B surface antigen (HBsAg) acquired through maternal transmission may result in the development of a HCC by 10 years of age.

Diagnosis

Patients usually present with abdominal pain or tenderness particularly in the right upper abdomen, swelling of the abdomen due to the liver mass or ascites, easy bruising or bleeding and jaundice. We are detecting increasing numbers of HCCs in patients who are being examined for gallstones by sonography. HCC should be suspected in a person with known chronic liver disease who presents with any of the signs or symptoms listed above. The liver function tests are usually abnormal and a specific protein produced by the liver tumor –alpha-fetoprotein–is raised in approximately three-quarter of patients. Before treatment is considered the tumor needs to be imaged with ultrasound, computed tomography (CAT scan), magnetic resonance imaging (MRI), angiography and image guided biopsy. Not all these scans may be required. The purpose of the scans is to detect cancer, assess operability and detect complications.

Photo courtesy of Dr David Butterworth, Consultant Histopathologist, North Manchester General Hospital

Figure 2: A post-mortem specimen of the liver (bisected) showing a large HCC occupying the upper half of the right lobe (pale colored tumor) invading the portal pedicle (the blood supply to the liver). Note a satellite tumor within the cut left lobe. HCCs are often multiple, which makes surgical treatment difficult. The underlying liver appears very nodular, suggestive of cirrhosis.

Since most patients with HCC have underlying cirrhosis, it is important to use clinical criteria to classify the severity of cirrhosis, which has a considerable bearing on therapeutic decisions. The Child-Pugh classification is usually used to stage cirrhosis into Child-Pugh A, B or C, with Child-Pugh A carrying the best prognosis and Child-Pugh C the worst. The parameters measured to stage liver cirrhosis by the Child-Pugh classification include blood biochemical and clinical criteria. Alternatively, hepatic insufficiency can be staged using a Paul Brousse classification and HCC staged by Okuda staging. Diagnostic imaging not only depicts the primary hepatic disease but also shows the presence of complications and the extent of disease.

Natural History

The natural history of HCC in Asia is said to be different from that in Europe and America. Although the etiology is multifactorial, there is a stronger association with hepatitis B and C viruses in Asia and Africa (see Figure 1). Prognosis in HCC without treatment is poor. Okuda et al have reported an overall median survival of only 1.6 months. In the West, a similar study on unselected patients showed a median survival of 14 weeks, with only 13% surviving more than a year. Surgery offers the best chance of cure but resectability is low. HCC is multifocal in 76% patients with underlying cirrhosis in the majority of patients (81% to 87%) [see Figure 2]. The percentage of patients who are candidates for surgical treatment ranges from 3% to 30% depending upon the series. Our own experience suggests 3% is a more accurate figure. Small tumors less than 3 cm have the best outcome; the three-year survival rate without recurrence is 83% when hepatic transplantation is performed. The results of hepatic resection are poor.

Treatment Options

Numerous treatment options are available for patients with HCC. Surgery offers the best chance of survival with HCC in non-cirrhotic liver or Child-Pugh A patients with stable cirrhosis. Vascular invasion is the most important predictor of survival following resection. The prognosis for patients with unresectable HCC is extremely poor. Chemotherapy is ineffective. Even in the case of small nodular lesions detected by ultrasound screening, patients receiving no treatment had a mean survival rate at three years of 12%. Six minimally invasive techniques are available for treatment of HCC, which include chemoembolization (TACE), ethanol ablation (PEI), radio-frequency ablation (RF), microwave ablation, laser ablation and cryoablation. TACE has been used the longest (since the mid-seventies) whilst the other therapies have been comparatively recently introduced. Among non-surgical options, Percutaneous Ethanol Injection (PEI) can be considered the treatment of choice for patients with small tumors (3 cm or less in diameter). Studies in Japan and in Italy have demonstrated that patients treated with PEI showed high long-term survival rates, comparable to those of patients submitted to surgical resection. The greatest drawback of PEI is the difficulty of treating tumors larger than 3 cm. In such cases alcohol diffusion into the tumor is incomplete. As a result, residual viable tumor tissue can be found after treatment, particularly along the periphery of the nodule.

Figure 3: The procedure of TACE. The top left picture shows a catheter within a blood vessel, demonstrating an angry-looking blood supply to the tumor (top left corner). The top right picture, taken following TACE, shows concentration of the poppy seed oil (along with an anti-cancer drug) within the tumor (the black grainy appearance in the top left corner). The bottom two pictures are CAT scans taken ten days following TACE, showing intense concentration of the poppy seed oil (along with the anti-cancer drug), which appears white within the HCC.

In the early 1980s it was discovered that when iodised poppy seed oil is injected into the blood supply of an HCC, it is retained selectively within the tumor. Here then, is a vehicle for delivering anti-cancer agents to tumor sites within the liver. This is the basis of TACE. The blood supply of the liver is approached via the groin by a catheter (a tiny tube) under local anaesthetic. A mixture of poppy seed oil and an anti-cancer drug is delivered into the blood supply of the tumor. Anti-cancer drugs delivered this way are retained within the tumor for several weeks and have no systemic side affects (see figure 3). Radio frequency (RF) ablation is suitable for patients with four or fewer 5cm or smaller HCCs. The tumors should be completely surrounded by normal liver tissue and at least 1cm deep to the liver capsule and at least 2cm or more away from major liver vessels. Patients with sepsis, severe debility and blood coagulation disorders cannot usually be treated with RF. Not all patients can be treated with RF but the results are promising.

Prevention

Control of known hepatic carcinogens may have a preventive effect. Prevention and treatment of viral hepatitis may be beneficial in reducing risk. In Taiwan, the nationwide vaccination against HBV, administered to all newborns since July 1984, showed effective results, and has been found a successful method to the control of HBV infection in an endemic area. The overall prevalence rate of serum HBsAg decreased significantly, from 9.8 % in 1984 to 1.3 % in 1994. Evidence that HBV vaccination reduced the average annual incidence of HCC in children was also obtained. The incidence in children 6 to 14 years of age declined from 0.70 per 100,000 between 1981 and 1986 to 0.57 between 1986 and 1990, and to 0.36 between 1990 and 1994. The corresponding rates of mortality from HCC also decreased. The mortality rates of HCC in children 6 to 9 years of age declined from 0.52 for those born between 1974 and 1984 to 0.13 for those born between 1984 and 1986 - after universal vaccination was initiated in Taiwan. A vaccine for HCV has not yet been developed. However some evidence has emerged that antiviral therapy may be affective in some patients with HCV. In children, tackling malnutrition may reduce the risk of HCC from malnutrition associated cirrhosis. A future development may be gene therapy against inherited metabolic liver disorders. Long-term abstinence from alcohol is the single major factor that may modify the course of liver disease in the alcoholic and thus prevent the development of HCC.

--Ali N Khan FRCP, FRCR
Consultant Radiologist,
North Manchester General Hospital, U.K.

A list of references to this article is available on request to the INCTR.