Hepatocarcinoma or hepatocellular carcinoma (HCC) is a tumor that originates from hepatocytes, the main cells of the liver. About 80% of all primary liver tumors are HCC.
In developing countries, the incidence and lethality of HCC are high and usually appear at an early age (30-40 years). On the other hand, it is relatively infrequent in Europe and its age of onset is later (50-60 years), where it represents 2% of all tumors, although a continuous increase in cases has been recorded in the last 20 years.
Risk factor's
The main risk factor is infection by liver viruses:
- HCV: is the main cause of hepatocellular carcinoma in Western countries. Chronic hepatitis C is a disease of slow evolution and for this reason there is a certain variability for malignant transformation and development of cirrhosis. The factors that can accelerate this malignant degeneration are: alcohol abuse, coinfection with HBV, age at the time of infection, male sex. There is still no truly effective vaccine, but some drugs are currently in the experimental phase.
- HBV: is the main cause of liver tumor. Those who carry a chronic HBV infection have a 100 times higher relative risk of developing a liver tumor compared to those who do not carry it; The risk decreases when the infection is contracted in adulthood. Even so, most hepatitis B is the result of an infection acquired at birth or during childhood, and therefore affects patients under 40 years of age. This fact can be prevented thanks to the vaccine, which in Italy is mandatory for all children.
In developed countries, cirrhosis (e.g. the degeneration and regeneration of liver tissue after damage caused by viruses, alcohol, toxic substances or harmful foods) is associated with the development of HCC in 80% of cases. Especially micronodular cirrhosis, often due to alcohol abuse, is associated with the risk of developing cancer. Less frequently, some hereditary metabolic diseases cause early degeneration of the liver that develops HCC around 30-40 years of age. Among these diseases, the most important are:
- Hemochromatosis, which causes iron buildup in the liver
- tyrosinemia
- Alpha-1-antitrypsin deficiency
- hypercitrullinemia
- Glycogenosis
- Wilson's disease, which causes hepatic accumulation of copper
Among the risk factors for the development of HCC, we also mention contamination by a natural carcinogen called Aflatoxin B1, which however is more common in developing countries. Even so, all of these latter conditions play a minor role in the development of liver cancer.
Some factors that can favor the appearance of HCC are cigarette smoke (immune system alteration), insulin resistance syndrome, obesity, diabetes, and to a lesser extent, the use of contraceptives and anabolic androgens.
Signs and symptoms
The signs are objective evidence of a disease and can be identified by the doctor during a clinical evaluation; the symptoms, on the other hand, are disturbances or annoyances that the patients perceive and are thus communicated to the doctor.
Liver cancer does not have specific symptoms during its initial phase. In fact, it is a silent disease, and when it produces signs and symptoms it is already an advanced disease that leads to liver failure. Also, because the liver lacks pain receptors, it rarely presents with this symptom. Only when there is compromise or distension of the covering capsule, the patient may (sometimes) complain of localized pain in the lower right portion of the flank of the abdomen.
The most frequent signs that suggest a serious liver disease are:
Jaundice: yellowing of the skin and the white part of the eyes; it is due to the accumulation of bile in the blood that does not pass to the intestine; the accumulation of bilirubin in the skin in turn causes pruritus.
Decreased muscle mass; general weakness (asthenia)
dark colored urine
Poorly colored, clay-colored stools
Mental confusion, drowsiness, coma: these symptoms are also due to hepatic encephalopathy
Ascites, which is the presence of fluid in the abdomen, due to increased pressure within the hepatic portal vein
Hepatorenal syndrome: compromised renal function due to a secondary effect of liver failure. This causes alteration of electrolytes (sodium, potassium,...) in the blood and formation of edema, which is swelling due to the accumulation of fluid in various tissues (mainly due to decreased albumin levels in the blood, a protein present in the blood plasma produced by the liver)
Tendency to vomit blood (hematemesis), due to the presence of gastroesophageal varices, that is, dilations of the veins of the stomach and esophagus
Tendency to bleeding, due to the lack of coagulation factors, produced by the liver
Diagnosis
The tests to make the diagnosis and to determine the degree of extension of the disease are:
Determination of alpha-fetoprotein (AFP) concentration in blood: levels above the normal limit (>10-15 ng/ml) may lead to suspicion of a liver tumor in an apparently healthy individual, but do not represent sufficient evidence for diagnosis. A high AFP value is normal in patients who smoke, with chronic viral hepatitis and/or cirrhosis, and depends on the degree of liver inflammation . In these patients, the level of suspicion for hepatocellular carcinoma is generally higher than 500 ng/ml;
Liver ultrasound: it is the test that is performed in the first instance and the most effective. It also allows the selective taking of liver tissue samples (biopsy) and does not present risks;
Computed Tomography (CT)
Magnetic resonance imaging (MRI): allows better visualization of the tissue compared to CT;
Angiography: uses the injection of a contrast medium into the hepatic artery with subsequent visualization of the vessels that supply the liver and possible tumors. It currently has a more therapeutic than diagnostic function: it is essential to perform chemoembolization, that is, a localized drug administration technique;
The main test to arrive at a certain diagnosis is a biopsy: a tissue sample is taken with a fine needle introduced by ultrasound or CT guidance and then analyzed under a microscope. This histological examination is very important, not only for diagnosis, but also because in this way the biological characteristics of the tumor can be determined, which can condition the choice of treatment.
Treatment
There are several types of therapies for the treatment of HCC. The choice of the most appropriate therapy (or combination thereof) depends on many factors, according the patient and the disease to be treated. Therefore it is important to evaluate the location of the tumor (according to whether it is in accessible or difficult-to-reach regions), stage (that is, its extension in the liver or its possible spread to other organs), residual liver function, rate of growth of the tumor, the general state of the patient, previous treatment received.
The only potentially curative treatment is liver resection, which consists of the surgical removal of the portion of diseased liver. In operable cases, it is the only treatment that offers the possibility of a complete cure. It is only feasible when the cancer is localized and liver function is not severely compromised. Depending on the situation, only the part of the liver containing the tumor mass may be removed (segmental resection), or a larger portion of the liver may be removed (hemihepatectomy) or an entire lobe (lobectomy), provided that the remaining liver parenchyma is sufficient to maintain normal functions.
On the other hand, even in patients who have undergone surgical resection, the risk of disease recurrence (recurrence) 5 years after surgery is quite high, so close follow-up after surgery is important. For all patients with unresectable or recurrent disease, treatment is palliative only.
Depending on availability, liver transplantation can be performed, with satisfactory results, in patients with HCC smaller than 5 cm and with fewer than three nodules, even in cirrhotic patients with liver failure. Patients are placed on waiting lists based on a score that depends on tumor characteristics: favored candidates are those with small solitary HCC (<2 cm) and those with HCC of 2-5 cm or three nodules each no larger than of 3 cm. If the waiting time for transplantation is longer than 6 months, preoperative therapies or living donor transplantation may be useful to avoid the risk of progression. The latter may be a valid way to overcome the limited number of donors. It is clearly a risky and complex procedure that can only be implemented in a few centers.
If the tumor cannot be removed surgically or there is no possibility of a transplant, the treatments of choice are the so-called "locoregional" therapies, which act by means of needles, probes or catheters introduced through the abdominal wall or through blood vessels directly into the liver, in or near the tumor, under ultrasound guidance. They are chemoembolization (TACE), which acts through the intra-arterial infusion of chemotherapeutic drugs that attack tumor cells, percutaneous alcoholization, which uses the toxic action of alcohol, or thermoablation, through the administration of heat.
Another treatment option is radiation therapy, which uses radiation from X-rays or another radiant source to destroy tumor cells. This can be delivered from the outside of the body or from the inside, by infusion of particles labeled with radioisotopes (for example yttrium 90). An alternative form of radiotherapy is called immunoradiotherapy: it consists of the injection of antibodies labeled with radioisotopes, which are concentrated in the liver (e.g. iodine-131 labeled antibodies against ferritin). However, radiotherapy is rarely used for the treatment of HCC.
Unfortunately, the results of chemotherapy are quite disappointing, given the natural chemoresistance of HCC. Chemotherapy can be administered locally, intra-arterially (which makes it possible to limit side effects and use higher doses), when the tumor is inoperable but trusting the liver, or systemically, that is, in the blood circulation of the whole body. A single drug (monochemotherapy) or a combination thereof (polychemotherapy) can be administered. A better effect of polychemotherapy compared to monochemotherapy has not been proven. Systemic chemotherapy may be a treatment option in patients with advanced disease.
Prognosis
Unfortunately, most HCC patients have a poor prognosis: despite improvements in diagnostic techniques and advances in new drug research, the survival of HCC patients has not improved significantly in the past 30 years. In fact, less than a third of patients survive one year after diagnosis and less than 10 percent survive 5 years. This depends both on the high percentage of people with advanced disease at diagnosis and on the limited availability (and sometimes effectiveness) of therapies. The prognosis depends on several factors, and is influenced by the intrinsic characteristics of the tumor (such as stage, aggressiveness, histological classification, speed of growth), residual liver function, general conditions of the patient, and specific therapy, the latter in turn depending on the previous factors.
Follow-up
After completing all treatments, the patient cannot be considered exempt from new recurrences, and must undergo periodic controls throughout his life, to evaluate the effects of the therapy and ensure that the tumor does not recur. The frequency and type of controls depend on the risk factors for tumor recurrence, and are used to identify recurrence when the disease is still localized, such as single and/or small lesions, making it possible to attack it with local therapies, such as resection, surgery or chemoembolization.
The recommended follow-up for patients undergoing surgery or subjected to other local therapies consists of CT every 3-4 months during the first 2 years after the intervention. Subsequently, the frequency of controls can be decreased every 6-12 months. In patients with elevated AFP values, CT should be associated with the measurement of this marker.