Hepatocellular carcinoma - Diagnosis

Biochemical changes

Biochemical changes may not differ from those in liver cirrhosis. Alkaline phosphatase and serum transaminase activity are significantly increased.

Serum protein electrophoresis shows an increase in the level of y and alpha ₂ -globulin fractions. A rare finding is serum macroglobulin of the myeloma type.

Serological markers

Serum A-Fetoprotein

Alpha-fetoprotein is a protein normally found in fetal serum. Ten weeks after birth, its concentration does not exceed 20 ng/ml and remains at this level in adults throughout life. Some patients with hepatocellular carcinoma have a progressive increase in the concentration of alpha-fetoprotein, although in some cases its level remains normal. Detection of an elevated level of alpha-fetoprotein during the first examination of a patient with liver cirrhosis indicates a high probability of developing hepatocellular carcinoma during subsequent observation. A high-risk group for developing hepatocellular carcinoma includes patients with liver cirrhosis caused by HBV or HCV infection, in whom the level of alpha-fetoprotein in the serum exceeds 20 ng/ml or transiently increases to 100 ng/ml or higher. In patients with repeated increases in alpha-fetoprotein levels to 100 ng/ml or more, the incidence of hepatocellular carcinoma over a 5-year observation period is 36%.

A slight increase in the level of alpha-fetoprotein is often found in acute and chronic hepatitis and liver cirrhosis, which can cause difficulties in diagnosis.

The alpha-fetoprotein level usually correlates with the tumor size, but exceptions are possible. Nevertheless, there is a close connection between the time interval during which a twofold increase in the alpha-fetoprotein level is observed and the period of a twofold increase in the tumor size. After resection, as well as after liver transplantation, the alpha-fetoprotein level decreases. Maintaining a slightly elevated alpha-fetoprotein level indicates incomplete removal of the tumor, and its progressive increase indicates its rapid growth. To assess the effectiveness of the therapy, it is advisable to determine the alpha-fetoprotein level in dynamics.

The structure of circulating alpha-fetoprotein in patients with hepatocellular carcinoma differs from that in liver cirrhosis. The study of alpha-fetoprotein fractions plays an important role in the differential diagnosis of hepatocellular carcinoma and liver cirrhosis, as well as in the prognosis of the development of hepatocellular carcinoma.

In fibrolamellar and cholangiocellular carcinoma, the level of alpha-fetoprotein is usually within the normal range. In hepatoblastoma, it can be very high.

Carcinoembryonic antigen levelespeciallyhigh in metastatic liver lesions. Due to its non-specificity, this indicator does not play a significant role in the diagnosis of hepatocellular carcinoma. An increase in the serum concentration of a ₁ -antitrypsin and acidic a-glycoprotein is also a non-specific sign.

Increased serum ferritin concentrationin hepatocellular carcinoma, it is more likely to be due to its production by the tumor than to liver necrosis. Elevated ferritin levels are seen in any active liver cell lesion and do not necessarily indicate hepatocellular carcinoma.

Des-y-carboxyprothrombin (des-y-CPT) is a vitamin K-dependent precursor of prothrombin synthesized by normal hepatocytes as well as hepatocellular carcinoma cells.

An increase in the level of this factor to 100 ng/ml or more indicates possible hepatocellular carcinoma. In chronic hepatitis, cirrhosis and metastatic liver damage, the level of des-y-CPT is normal. The specificity of this indicator is higher than that of a-fetoprotein, but its sensitivity is insufficient for diagnosing small tumors.

Serum aL-fucosidase levelin hepatocellular carcinoma it is elevated, however the mechanism of this elevation is unclear. Determination of the level of this enzyme can be used in the early diagnosis of hepatocellular carcinoma in patients with liver cirrhosis.

Hematological changes

The white blood cell count usually exceeds 10•10 ⁹ /l; 80% are neutrophils. Eosinophilia is sometimes observed. An increase in the platelet count is possible, which is not typical for uncomplicated liver cirrhosis.

The red blood cell count is usually normal, and anemia is mild. Erythrocytosis is observed in 1% of patients, probably due to increased production of erythropoietin by the tumor. Serum erythropoietin concentrations may be elevated even with normal hemoglobin and hematocrit values.

There may be a disruption of the blood coagulation system. Fibrinolytic activity is reduced. This is due to the tumor releasing a fibrinolysis inhibitor into the bloodstream. This may explain the increase in the fibrinogen level in the serum.

Dysfibrinogenemia reflects a reversion to the fetal form of fibrinogen. Ground-glass cells in hepatocellular carcinoma may contain and produce fibrinogen.

Hepatitis virus markers

A study of HBV and HCV markers should be performed. Hepatitis B and C are excluded.

Tumor localization

Plain radiography may reveal calcifications.

Liver scan

Isotope scanning reveals tumors larger than 3 cm in diameter as a filling defect.

During ultrasound, the echogenicity of the liver can be either increased or decreased. The tumor is hypoechoic, with fuzzy contours and heterogeneous echo signals. The diagnosis can be confirmed by targeted biopsy. The sensitivity and specificity of the method are quite high. False-positive results of the study in cirrhosis are due to increased echogenicity of large nodes. Ultrasound is of particular value in screening examinations, it allows detecting lesions with a diameter of less than 2 cm.

On computed tomography (CT), hepatocellular carcinoma appears as a low-density lesion. CT often does not allow determining the size and number of tumors, especially in the presence of cirrhosis. It is also important to conduct a study with contrast. The picture in hepatocellular carcinoma is mosaic, multiple nodes with varying degrees of signal attenuation and clearly defined partitions separating the tumor mass are visible. The tumor may be encapsulated. Fatty liver degeneration is often noted. Infiltration of the portal vein and the presence of arterioportal shunts are possible.

Iodolipol injected into the hepatic artery is excreted from healthy tissue, but remains almost permanently in the tumor, due to which even small tumor foci up to 2-3 mm in diameter can be detected on CT scans obtained 2 weeks after the injection of the contrast agent. In focal modular hyperplasia, iodolipol is also retained, but unlike hepatocellular carcinoma, it is excreted from hyperplastic nodes within 3 weeks.

Magnetic resonance imaging (MRI) provides somewhat clearer images of focal pathology than CT. This method is especially valuable in the presence of concomitant fatty liver disease. On T1-weighted images, the tumor appears as a normal-density formation bordered by a low-intensity belt. T2-weighted images clearly reveal the difference in the density of normal liver tissue and the tumor, as well as tumor invasion of vessels and satellite foci.

Intravenous administration of iodine-containing (gadolinium salt) or magnesium-containing contrast agent (Mnd PDP) increases the efficiency of detection of hepatocellular carcinoma. Administration of supermagnetic iron oxide in T2-mode examination is safe and increases the efficiency of the examination.

Angiography of the liver

Angiography helps to detect liver cancer, establish its location, resectability, and monitor the effectiveness of treatment. The tumor is supplied with blood from the hepatic artery, so it can be detected using selective arteriography with the introduction of a contrast agent into the celiac trunk or superior mesenteric artery. Superselective infusion angiography is especially valuable for detecting small tumors. Selective digital subtraction angiography with intra-arterial administration of a contrast agent allows you to detect tumors with a diameter of 2 cm or less, which over time transform from isovascular to hypervascular.

Computerized arterioportography reveals a decrease in portal blood flow in the tumor node.

Differential diagnostics of hepatocellular carcinoma and regenerated nodes in liver cirrhosis presents certain difficulties. Angiography results may depend on the anatomical structure of the tumor. Its vascular pattern is bizarre, focal accumulations of contrast agent, stretching and displacement of vessels are noted, which may be sclerotic, fragmented, have an uneven lumen. Arteriovenous shunts are often encountered, through which the portal vein can be retrogradely contrasted. When the tumor grows, the portal vein can be deformed.

Doppler ultrasound reveals intravascular tumor spread. Portal vein invasion is confirmed by the presence of an arterial wave in the portal blood flow, spreading in the hepatofugal direction. The maximum blood flow velocity during systole is increased, a significant increase is noted in the presence of an arteriovenous shunt or tumor invasion into the portal vein. Doppler ultrasound allows differential diagnostics with hemangioma.

Liver biopsy

If small focal lesions are detected by ultrasound or CT, the diagnosis must be verified histologically. Liver biopsy should be performed under visual control whenever possible. There is a possibility of tumor spread along the needle, but this complication is rare.

Cytological examination of the material obtained by aspiration biopsy with a fine N22 needle allows the diagnosis of tumors with a low and moderate degree of differentiation. However, it is not easy to detect highly differentiated liver cancer using cytological examination.

Screening examination

Asymptomatic small hepatocellular carcinoma in patients with cirrhosis may be diagnosed during screening of high-risk groups or discovered incidentally during imaging studies of livers removed during transplantation. Early diagnosis of hepatocellular carcinoma is important because it increases the likelihood of favorable outcomes after liver resection or transplantation. The 1-year survival rate of untreated patients with compensated cirrhosis (Child A criteria) and asymptomatic hepatocellular carcinoma is 90%, while the similar figure for patients with clinical manifestations of the disease is only 40%. The success of treatment depends on the rate of tumor growth. Therapy is more effective in the Japanese, in whom the tumor grows more slowly than in residents of South African countries.

Screening is indicated in patients at high risk of developing hepatocellular carcinoma. These include men over 40 years of age with HBsAg or anti-НСV antibodies in the serum, as well as those suffering from chronic liver disease, especially cirrhosis with large regenerative nodes. Ultrasound is a more sensitive examination method than CT. They are usually followed by targeted fine-needle aspiration biopsy of the liver. Samples of non-tumor tissue should also be obtained to detect concomitant cirrhosis and determine its activity.

Every 4-6 months, the serum alpha-fetoprotein level is determined, especially if it was initially elevated, as well as if large regenerative nodes are detected. A normal serum alpha-fetoprotein level does not exclude the presence of hepatocellular carcinoma.

The value of such screening varies depending on the country in which it is performed. Thus, in Japan, where hepatocellular carcinoma is small due to its slow growth and is often encapsulated, the value of screening is great. At the same time, its practical value is minimal in the countries of South Africa, where hepatocellular carcinoma is characterized by rapid growth and high malignancy. European countries occupy an intermediate position in this regard. Preventive examination of the population depends on the level of economic development of the country. In Japan, procedures such as ultrasound and determination of the level of alpha-fetoprotein are widely available and are performed free of charge. However, in most other countries of the world, such opportunities are not available. The prognosis for hepatocellular carcinoma is so poor that in places where the cost of the examination is a significant factor, a reserved attitude towards screening is noted, since there is no firm confidence that it will help reduce mortality from this disease.

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