Hepatocellular carcinoma

Hepatocarcinoma is the most common primary malignant tumor of the liver. This tumor is known also as:

• Hepatocellular carcinoma (HCC)
• Hepatoma
• Hepatic cancer

Hepatocarcinoma usually appears in people who already have some kind of liver disease such as chronic hepatitis due to the hepatitis B or hepatitis C virus, or cirrhosis.

Clinical signs

Hepatocarcinoma often does not produce any symptoms. It is not rare for it to show up as decompensation of liver function in a patient with stable liver cirrhosis. When there are signs, the most usual are of non specific symptoms such as weight loss, abdominal pain, early satiety or palpable mass.

Other symptoms may be secondary to the effect of the tumor mass, like obstructive jaundice or intraperitoneal hemorrhage. Less frequently, paraneoplastic symptoms are observed, such as diarrhea, erythrocytosis, hypercalcemia, hypoglycemia or cutaneous signs.

Imaging

Diagnosis of hepatocarcinoma has been made possible in recent times thanks to the advances in dynamic imaging techniques:

• Computed axial tomography (CT scan) of abdomen
• Nuclear magnetic resonance imaging (MRI scan) of abdomen

In patients with indicative symptoms, it is recommended to proceed directly to some of the techniques mentioned.

The challenge of the diagnosis of hepatocarcinoma lies in detecting lesions at earlier stages, which are more receptive to radical treatments with curative aims. The detection of hepatocarcinoma requires the defining of those people who are at increased risk of developing such tumors. There exists clear evidence that cirrhosis in itself, independent of the cause, is a risk factor in developing hepatocarcinoma. However, cirrhosis secondary to chronic viral hepatitis B and C, hemochromatosis and alcoholic cirrhosis presents the greatest risk. Patients with chronic hepatitis B are at risk of presenting with this tumor, even before developing cirrhosis.

It is currently accepted that people at risk of developing hepatocarcinoma (all those with cirrhosis regardless of the cause) must be screened for detecting the tumor early. The most accepted strategy is to carry out abdominal ultrasound every 6 months. In addition to this, levels of blood alpha fetoprotein (AFP) should be checked.

The following gives an account of aspects of the most frequent investigations carried out in the diagnosis of hepatocarcinoma:

Abdominal ultrasound

This is a non-invasive investigation which allows images of the liver to be obtained using waves of ultrasound. It is the most used examination for detecting hepatocarcinoma. It has an advantage of being relatively inexpensive and does not need intravenous contrast medium. Hepatocarcinoma presents usually as an hypoechogenic lesion, although as it grows it can be iso or hyperechogenic. However, the sensitivity of the ultrasound in detecting hepatocarcinoma is relatively low, in the order of 40 to 80%, according to different studies. A suspicious image on the ultrasound always requires a scan for confirmation (CT scan or resonance). The use of contrast medium for ultrasound increases the sensitivity, but currently its use is restricted to a few centers.

Abdominal CT scan

Computed axial tomography (CAT), also called CT scanning, is a powerful technique in obtaining images of the liver. The current technique of choice is a dynamic multi-slice helicoidal CT scan. This requires intravenous contrast medium to be injected very rapidly with the aim of obtaining early images rapidly in the arterial, portal and late phases (triphasic). Hepatocarcinoma, being a very vascularised tumor, presents a typical behaviour in the CT scan, consistent in reinforcement of the signal in the arterial phase (hypervascular nodule). The sensitivity of the dynamic multi-slice helicoidal CT scan in detecting hepatocarcinoma can be more than 90%.

Nuclear magnetic resonance

This is known as MRI scanning. It is a relatively new technique compared to CT scanning. It is important to have an expert radiologist interpret the scan. It has the advantage of using contrast mediums which are not nephrotoxic. Its sensitivity is equal or greater than that of the CT scan in detecting hepatic tumor-type lesions, in particular in cirrhotic livers. It has the advantage over CT scanning of differentiating dysplastic nodules from hepatocarcinoma and of better characterization of other hypervascular lesions such as hemangioma.

Other techniques

Occasionally more invasive imaging techniques are used to confirm the diagnosis, for example hepatic angiography. At the moment this is reserved for when a treatment is planned to take place during the same session (chemoembolization). The positron emission tomography (PET) scan is not routinely used for the diagnosis of hepatocarcinoma.

Tumor markers

Alpha fetoprotein is the most used tumor marker for the diagnosis and monitoring of hepatocarcinoma. This glycoprotein is produced normally by the fetal liver and can also be synthesized by hepatocarcinoma. In addition it can be raised during pregnancy and in testicular tumours. Slight elevations can also be found in people with chronic hepatitis when there is a flare, in particular with viral hepatitis B and C. It is important to emphasize that the sensitivity of the alpha fetoprotein is low, particularly in tumors smaller than 3 cm. Its performance as an investigation depends on the cut off point employed, for example if levels > 20 µg/L are used the sensitivity is 62% and specifity is 89%. If a cut off point of > 400 µg/L is used the sensitivity is only 22% and specificity rises to 99%. Other tumor markers exist which have been used with a view to improving the performance of alpha fetoprotein. However, up to now it has not been possible to better this.

Biopsy

In order to confirm the diagnosis of the majority of malignant lesions, histology by means of biopsy or cytology is required. This concept has gradually been discarded in the diagnostic algorithms for hepatocarcinoma, due to the fact that in the majority of cases imaging enables a very high degree of certainty in diagnosis. Biopsy of lesions is used in cases where a doubt persists over the diagnosis. Biopsy carries risks: hemorrhage and dissemination of the tumor in the tract of the puncture needle. The characteristic of the tumour histology (well or poorly differentiated) is important for prognosis.

Treatment

Due to the fact that hepatocarcinoma is a tumour which normally appears in a cirrhotic liver, therapeutic management requires special attention to the degree of the patient’s liver dysfunction, as well as the tumour’s own characteristics (staging).

There are currently multiple treatment options, therefore deciding on the best handling calls for an assessment by a medical team experienced in the evaluation and management of patients with this pathology. This multidisciplinary group will usually include liver disease specialists, liver surgeons and radiologists.

The following are the available treatment options:

Liver resection

Surgery to resect the liver segment compromised by the tumor is considered the treatment of choice in those resectable cases with good liver function. Unfortunately only a minority of patients with hepatocarcinoma are candidates for resection. By resectable it is understood that the tumor is confined to the liver and a sufficient portion of liver will be left to maintain an acceptable liver function post-operatively. Good hepatic function is referred to in the Child Pugh classification.

Liver transplant

Liver transplant is an excellent option for those patients with non-metastatic hepatocarcinoma who fulfil the conditions for a transplant and who also meet certain conditions regarding tumor size. The size criteria most used in considering liver transplant are known as theMilancriteria:

1. A lesion of less than 5 cm in diameter
2. Not more than 3 lesions, each one smaller than 3 cm in diameter.

When these criteria are fulfilled, the survival following hepatic transplant is comparable to that of patients transplanted who do not have hepatocarcinoma. One of the problems of transplant is that the waiting time can be more than one year, a period in which the tumor can continue to grow and exceed the criteria described. For this reason, ‘bridging’ therapies are often used in patients awaiting a transplant. The most used is chemoembolization.

Radiofrequency

Radiofrequency ablation is one way of producing tumor necrosis by means of local application of heat with a needle which produces a high frequency alternating electricity current. Radiofrequency is applied generally to patients with Child-Pugh A or B, not transplant candidates or those who have lesions which exceed theMilancriteria. It is also used as bridge therapy before liver transplant. The application of radiofrequency can be made percutaneously or intraoperatively (either laparoscopic or by laparotomy).

Alcoholization

The injection of ethanol (ethyl alcohol) directly into the tumor produces necrosis and is an inexpensive alternative which is relatively simple to carry out. Radiofrequency has replaced it for the most part due to its greater effectiveness. Instead of alcohol, acetic acid has also been used with good results.

Chemoembolization

Chemoembolization comprises the injection of a chemotherapy substance (doxorubicin, mitomycin or cisplatin) and an embolizing agent through an hepatic intra-arterial route. The procedure requires catheterization of the hepatic artery. Patients frequently present the so-called post-embolization syndrome, which is characterized by fever, abdominal pain, nausea and elevation of transaminases. In some cases it leads to acute liver insufficiency. It is very important to make an appropriate selection of patients to avoid this feared complication.

Systemic therapies

Both systemic chemotherapy and radiotherapy are of very limited use in hepatocarcinoma and their application is only recommended within investigation protocols.

It has recently been demonstrated that in the treatment of advanced hepatocellular carcinoma sorafenib (Nexavar®) is useful in prolonging life.

In spite of all these alternative therapies, there exists an important group of patients to whom few treatment alternatives can be offered, either because their hepatic function is poor (patients with Child-Pugh classification C) or because the liver carcinoma is very advanced.