Hepatocellular carcinoma of the liver is the most common primary malignant tumor liver. It is closely associated with the liver’s cirrhosis, both due to its alcoholic and viral etiology. Globally, hepatocellular carcinoma accounts for approximately 5% of all cancers due to the high rate of hepatitis B infection. It is also the third most common cause of death associated with cancer (after lung and stomach cancer).
Infected hepatitis B and C have a very high risk of developing hepatocellular carcinoma. In areas with endemic hepatitis B, 90% of patients with this cancer are positive for the hepatitis B virus. The development of hepatocellular carcinoma is associated with viral integration DNA hepatitis B in the hepatocyte host genome and the degree of viral replication (more than 10,000 copies / mL).
Unlike hepatitis B infection, cirrhosis is always present. Hepatocellular carcinoma is also associated with other cirrhosis forms, such as alcoholic cirrhosis (in the West, most cases are due to alcoholic cirrhosis) and hemochromatosis. Men are affected more than women. Other etiological factors are aflatoxin and androgenic steroids.
Risk factors for hepatocellular carcinoma:
- hepatitis B: 10% five-year cumulative risk
- hepatitis C: 30% five-year cumulative risk
- alcoholism: 8% five-year cumulative risk
- biliary cirrhosis: 5% five-year cumulative risk
- toxins from food, e.g., aflatoxin
- congenital biliary atresia
- congenital metabolic errors: hemochromatosis (21% five-year cumulative risk), alpha-1 antitrypsin deficiency, type 1 glycogen storage disease, Wilson’s disease.
It is typically diagnosed in adulthood – in late middle age or adults, often as part of a program to monitor high-risk patients. You can also find it in children, but it is still more common with hepatoblastoma.
Forms of hepatocellular carcinoma
Macroscopically, hepatocellular carcinoma occurs as a massive form (one large tumor), a multinodular form (multiple nodes in the liver), or most rarely as a diffuse infiltrative form permeate the entire liver. Tumor tissue is usually yellowish-white or greenish due to bile presence, and often larger tumors contain areas of bleeding and necrosis.
Microscopic is hepatocellular carcinoma built of atypical epithelial cells that retain a certain resemblance to hepatocytes and have large bright nuclei with large nucleoli and abundant eosinophilic cytoplasm. The degrees of differentiation vary, but we will not mention them further as they do not affect the prognosis.
Fibrolamellar hepatocellular carcinoma is a special version of hepatocellular carcinoma, with different demographics and risk factors. It occurs in younger adults (20-40 years), is not associated with cirrhosis, alcoholism, or hepatitis. It is less aggressive than “ordinary” HCC but is later detected and does not secrete alpha-fetoprotein.
Symptoms and signs
Previously stable patients with cirrhosis come with abdominal pain, weight loss, anorexia, and mass in the upper right quadrant. Fever may occur. In a small number of patients, the first manifestation may be bloody ascites, shock, or peritonitis caused by bleeding tumors. Jaundice and portal hypertension due to portal vein invasion may be present. Occasionally, systemic metabolic complications such as hypoglycemia, erythrocytosis, hypercalcemia, and hyperlipidemia may occur.
Diagnosis is made based on α-fetoprotein measurements and imaging (CT, ultrasound, MRI). Hepatocellular carcinoma should be suspected if the patient comes with liver enlargement, unexplained decompensation of chronic liver disease, or if a mass in the upper right quadrant is imaged. However, monitoring programs for high-risk patients allow detection of hepatocellular carcinoma before symptoms develop. Monitoring of high-risk patients usually consists of an ultrasound examination every 6 or 12 months.
α-fetoprotein is produced by yolk sac and liver cells during fetal development. It is one of the more significant plasma proteins during fetal development and is considered the fetal form of serum albumin. In adults, α-fetoprotein means hepatocyte dedifferentiation (although it can also occur in some other tumors), and its level correlates well with tumor size. However, only 40-65% of patients with hepatocellular carcinoma have high levels of α-fetoprotein (> 400 μg / L). Lower levels are less specific and may occur with hepatocyte regeneration (e.g., in hepatitis).
The ultrasound is typically small focal hepatocellular carcinoma hyperechoic relative to the surrounding normal liver. Larger lesions are heterogeneous due to fibrosis, fatty changes, necrosis, and calcifications.
On CT, hepatocellular carcinoma is often hypoathenuous in the late arterial phase (35 seconds) and then flushes out (“wash out”) and becomes either hypoathenuous or indistinguishable from the surrounding tissue in the venous phase.
A radiological classification system has been developed ( LI-RADS ) to stratify these lesions.
If imaging studies show characteristic findings and AFP is elevated, the diagnosis is clear. Ultrasound-guided biopsy is sometimes indicated for a definitive diagnosis.
You can use various systems to stage hepatocellular carcinomas, but none is used universally. One of the systems is the TNM system, although it is not as prognostically as useful as other epithelial tumors. The TNM system can predict prognosis better than other systems for patients undergoing resection (and potentially transplantation). In contrast, e.g., The Barcelona system can predict the prognosis better for patients who do not go for surgery.
In general, the TNM system says the following:
Numbers 0 to 4 are added after T, N, and M to indicate an increase in disease severity.
For one lesion less than 5 cm or three lesions less than 3 cm that is confined to the liver (Milan criteria), liver transplantation gives an equally good prognosis as any other liver transplant for non-cancer-related conditions. Alternatively, resection may be performed, but cancer usually recurs. Chemotherapy and radiotherapy do not help. Palliation and tumor growth retardation are provided by ablative therapies (e.g., arterial chemoembolization) and are used when patients are awaiting transplantation.
If the tumor is larger than 5 cm, multifocal has invaded the portal vein or is metastatic (stage III and higher), the prognosis is much worse, i.e., five-year survival is 5% or less.
Artemisinin is a very effective substance for the alternative treatment of hepatocellular carcinoma. In several studies with artemisinin and more on the treatment of hepatocellular malignancy, many positive properties of this preparation on this malignant form of liver tumor have been proven.
Sources: Merck E., The Merck Manual of Diagnosis and Therapy, Merck Manuals, 2011. Kumar P., Kumar and Clark's Clinical Medicine, Saunders ltd., 2012. Damjanov I., Pathology, Medicinska naklada, 2010.