Summary
Hepatocellular carcinoma is a cancer that arises from liver cells. It is different to ‘liver cancer’ that has spread to the liver from elsewhere.
It is important that the lay reader does not confuse the term ‘liver cancer’, when referring to secondary cancer spreading to the liver, with primary cancer of the liver. In the Western world, the occurrence of metastatic cancer in the liver far exceeds the incidence of primary liver cancer and such problems in the liver are treated by the methods used to control the primary cancer. That is to say that if a patient has developed secondary breast cancer in the liver then it is treated with chemotherapy to which breast cancer is sensitive and not as a primary liver cancer would be.
Hepatocellular carcinoma is a true carcinoma but usually an aggressive one with a high mitotic rate (i.e. many cells capable of division at any one time). In the most commonly encountered form, the microscopoist can recognise the attempts by the tumour cells to form the trabeculae that are characteristic of normal liver histology, the microtrabecular variant.
Two other forms, the sclerosing variant and the fibrolamellar varant are recognised, the latter tending to occur in younger patients and equally in males and females; it has a relatively better outlook.
Causes
In the Western world, hepatocellular carcinoma is frequently associated with liver cirrhosis, which in turn is usually caused by excess alcohol or by long term infection by the hepatitis virus.
Incidence of hepatocellular carcinoma
In the Far East, Hepatocelluar carcinoma affects up to 1% of the population. In Europe the incidence is only 1 per 100,000 of people. In male Chinese carriers of the hepatitis B virus, there may be a lifetime risk of 50% of developing the disease, and exposure to the hepatitis virus and sometimes other infections (e.g. fungal aflatoxin – found in cereals stored in damp conditions) over a long period of time is unquestionably heavily related to an enhanced incidence of the disease. By contrast for the less common type of liver cancer, Cholangiocarcinoma (which is a cancer arising from the linings of the bile ducts), a chronic infection with the liver fluke (Clonorchis sinensis) predisposes to this cancer.
Symptoms & diagnosis of hepatocellular carcinoma
Most patients who develop Hepatocellular carcinoma (HCC) have chronic liver disease. The tumour itself usually does not cause any further symptoms, and is detected by a scan and/or blood test. If it does cause symptoms, it is usually large and leads to a worsening of the liver.
Sometimes, patients have pain in the upper abdomen, weight loss, jaundice, or bleeding into the tumour or form dilated blood vessels at the top part of the stomach.
If the tumour has spread, there may be symptoms related to effects on the organ affected, for example bone pain.
Diagnosis
The diagnosis is sometimes difficult to make and may be suspected in a patient with chronic liver disease who is found to have a high level of a protein, called Alpafoetoprotein (AFP), on a blood test. A CT scan or MRI scan is usually used to look for a mass in the liver. A tumour is not found, or lots of lumps are seen, one of which is larger than the others. One cannot be certain if the larger lump is a HCC, so then the scan is repeated after a suitable period of time.
If there are suspicions of an HCC in a patient who has not had chronic liver disease, and the image on the scan is not characteristic, a biopsy can be done, but has risks. For example, there is a risk of bleeding and also a risk of spreading the tumour along the line of the biopsy needle. This may impact on the treatment that can be offered.
The Blood test: alpha-foetoprotein (AFP) is a useful serum marker that is raised in approximately two thirds of patients with hepatocellular carcinoma and in much higher levels than in benign liver disease. The fibrolamellar type of HCC does not usually have raised levels of AFP.
The CA19-9 level (see colorectal carcinoma section) is raised in cholangiocarcinoma but the level rises in obstructive jaundice (i.e. when the biliary tree is obstructed) and as this occurs early in cholangiocarcinoma the test is usually of little use.
The definitive proof of the diagnosis is by biopsy (taking a piece of the tumour through a skin needle puncture access) and microscopic examination. Often, the abnormal liver function impacts on the blood’s clotting system and if the coagulation tests in the blood are sufficiently deranged, then the biopsy may be deemed risky and the diagnosis is then based on other criteria.
Stages
The key issue is as to whether the liver cancer has spread outside the liver or not. If it has not, then surgery is an option but only if it is safe and the unaffected liver is healthy enough for the patient to survive after the operation.
Treatment & outcomes of hepatocellular carcinoma
The ideal therapy for a localised hepatocellular carcinoma is an operation to remove the tumour completely. If the patient is fit, has a healthy liver and the tumour is not too large so as to leave behind enough liver to work well, then an operation should work well.
However, many patients with HCC have unhealthy livers (cirrhosis) and are not fit enough to go through major surgery.
Liver transplant has been used to treat some patients, but there are very strict criteria governing which patients are suitable.
If an operation is not possible or safe, then single smaller cancers can be treated by radiofrequency ablation or by embolic methods (by injecting occluding material or drugs up the artery that feeds blood to the area of the cancer. TACE (transarterial chemo-embolization) is a popular method that can be repeated several times over the course of a year or so and can have a significant growth retarding effect of cancer growth.
Where the cancer is widespread in the liver or has metastasised outside the liver then systemic therapy (therapy that circulates all around the body) is required. Smart drug tyrosine kinase/VEGF inhibitor : sorafenib is the first choice and ha been demonstrated to have a significant (albeit modest) growth retarding effect on the cancer. At time of failure, alternative TKI therapy may be trialled, imatinib and other drugs such as regorafenib and lenvatininib have been used but with a lesser durable expectation of success.
Chemotherapy (doxorubicin with cis-platinum) is not highly effective (except hepatoblastoma which is sensitive to this chemotherapy regime) but can prolong life by a modest amount if the patient can tolerate it.
What to do when the foregoing therapies have been trialled and failed?
In this situation then a genomic profile of the tumoor to see if there are any genomic mutations of oncogenes that are susceptible to blockade – a minority chance so far in our knowledge of this cancer. This can be obtained by either a fresh tissue biopsy of the cancer or from cell-free DNA (cfDNA) from a blood draw. If MMR ( mismatch repair deficiency) is present in the analysis, then this predicts for the usefulness of immunotherapy. The alternative Tyrosine Kinase Inhibitors (TKI) to sorafenib have been listed above and are definitely worth a trial.
Immunotherapy may well have a role in the salvage of cases of HCC that have resisted standard therapies. The check-point inhibitors pembrolizumab and nivolumab are currently undergoing trials and the MMR deficient group on the genomic analysis may be the most likely group to respond.
Credit: P N Plowman MD, The Oncology Clinic, 20 Harley Street, London W1G 9PH. (Advanced Genomics).
Screening
Whilst there is no population based screening programme for hepatocellular carcinoma in the UK. However, chronic hepatitis patients and those with established cirrhosis, should be screened with MRI liver scans (looking for new liver masses/tumours) and blood tests for a raised serum AFP at six monthly intervals.