| disease | Primary Liver Cancer |
| alias | Primary Carcinoma of the Liver |
Primary liver cancer (primary carcinoma of the liver) is one of the common malignant tumors in China, with a high mortality rate. It ranks third in the sequence of malignant tumor deaths, following stomach and esophageal cancers, and in some rural areas, it ranks second, only after stomach cancer. Approximately 110,000 people die from liver cancer each year in China, accounting for 45% of the global liver cancer deaths. Due to the monitoring of high-risk groups through serum alpha-fetoprotein (AFP) testing combined with ultrasound imaging, liver cancer can be diagnosed at the subclinical stage, and the long-term effects of early resection are particularly significant. In addition, active comprehensive treatment has significantly improved the five-year survival rate of liver cancer.
bubble_chart Epidemiology
The incidence of primary liver cancer is high in Southeast Asia and sub-Saharan Africa, while it is relatively low in Europe, America, the Soviet Union, and Oceania. In China, the incidence is higher in coastal areas than in inland regions, and higher in the southeast and northeast compared to the northwest, north, and southwest. Specifically, in coastal areas such as Jiangsu Province, the incidence is higher in regions with rivers, lakes, or islands compared to other coastal areas. In high-incidence regions like Guangxi, Qidong in Jiangsu, and Fujian, the annual mortality rate from liver cancer can exceed 40 per 100,000. The male-to-female ratio in high-incidence areas is approximately 3-4:1, while in low-incidence areas, it is 1-2:1. In high-incidence regions, the disease is most common in the 40-49 age group, whereas in low-incidence areas, it is more frequently seen in the elderly.
bubble_chart EtiologyTo date, it remains unclear, based on epidemiological surveys in high-incidence areas, that the following factors may be related to the prevalence of liver cancer.
(1) Viral hepatitis and cirrhosis: Studies on the relationship between hepatitis B virus and liver cancer have found: ① Over 90% of liver cancer patients have hepatitis markers in their serum (compared to only about 15% in the control group); ② The chance of developing liver cancer in HBsAg-positive individuals in high-incidence areas is 6 to 50 times higher than in negative individuals; ③ Molecular biology studies show that 51.5% of liver cancer cases in China have integrated HBV-DNA; ④ The X gene of HBV can alter the gene expression of HBV-infected liver cells and may be related to carcinogenesis. The above indicates a close relationship between hepatitis B virus and liver cancer, making it a significant risk factor for liver cancer. In recent years, attention has been drawn to the relationship between hepatitis C and liver cancer. Data from China show that 5-8% of hepatocellular carcinoma patients are anti-HCV positive, compared to 0-2% in the control group. Many liver cancer cases have co-infection of anti-HCV and HBV. The relationship between HCV and liver cancer is extremely important in Japan, but remains to be confirmed in China. The relationship between cirrhosis and liver cancer is also noteworthy. In 500 autopsy cases of liver cancer, the co-occurrence rate of liver cancer and cirrhosis was 83.6%, and the co-occurrence rate of cirrhosis and liver cancer was 49.9%, with macronodular cirrhosis accounting for 73.3%, indicating a close relationship between liver cancer and cirrhosis. Among those with cirrhosis, 56.5% had varying degrees of chronic active hepatitis lesions, indicating that cirrhosis is still ongoing. The results suggest that persistent infection with hepatitis virus is closely related to hepatocellular carcinoma. It is speculated that the process may involve hepatitis B virus causing liver cell damage, followed by hyperplasia or atypical hyperplasia, making the cells sensitive to carcinogens. In the multi-disease cause and staged pathogenesis, multiple genes may undergo changes, i.e., a group of proto-oncogenes are activated into oncogenes, and one or more anti-oncogenes are inactivated, resulting in uncontrolled cell growth, persistent proliferation of liver cells, and ultimately leading to cancer.
(2) Aflatoxin: Surveys in high-incidence areas of liver cancer, especially in southern regions where corn is the staple food, suggest that the prevalence of liver cancer may be related to the contamination of food by aflatoxin. The content of aflatoxin M1, a metabolite of aflatoxin B1, is very high in the urine of the population. Aflatoxin B1 is the strongest carcinogen for animal liver cancer, but there is no direct evidence of its relationship with human liver cancer to date.(3) Water pollution: In Qidong, Jiangsu, the incidence of liver cancer among those who drink ditch-pond water is 60-101/100,000, while among those who drink well water, it is only 0-19/100,000. The relative risk for those who drink ditch water is 3.00. Investigations found that a type of blue-green algae in ditch-pond water produces algal toxins, which may be a clue to the relationship between water pollution and liver cancer.
(4) Genetic factors: In high-incidence areas, liver cancer sometimes shows familial clustering, especially among those who live together and have blood relationships. This may be related to the vertical transmission of hepatitis virus, but it remains to be confirmed.
(5) Others: Other suspected carcinogens or carcinogenic factors that cause liver cancer include: ① Alcoholism; ② Nitrosamines; ③ Pesticides such as organochlorines; ④ Trace elements, with higher levels of copper and zinc and lower levels of molybdenum in water, soil, food, human hair, and blood in liver cancer epidemic areas; ⑤ Clonorchis sinensis, which stimulates bile duct epithelial hyperplasia and leads to cholangiocarcinoma. ⑥ Trace elements, sex hormones, radioactive substances, Chinese Taxillus Herb, alcohol abuse, smoking, genetic factors, etc.
The disease progresses rapidly with a high mortality rate, posing a serious threat to life and health. As it is currently difficult to satisfactorily explain the causes and distribution of liver cancer in China and around the world with a single factor, the occurrence of liver cancer may be caused by multiple factors through various pathways; the carcinogenic and promoting factors may not be entirely the same in different regions. What the main factors are and how the various factors are interrelated still need to be studied.bubble_chart Pathological Changes
Primary liver cancer is approximately 4/5 hepatocellular carcinoma (HCC), 1/5 cholangiocarcinoma, and mixed liver cancer is rare.
(1) Gross Classification Based on the analysis of 500 cases of hepatocellular carcinoma autopsy materials in China:
1. Massive type (Figure 1) 370 cases (74%), with cancer masses larger than 5cm in diameter, and those exceeding 10cm are considered giant masses. This type can be further divided into single mass, multiple masses, and fused masses. The edges of the masses may have small or scattered satellite nodules.
Figure 1 Primary liver cancer (massive type)
2. Nodular type (Figure 2) 111 cases (22.2%), with the largest diameter of cancer nodules not exceeding 5cm. This type can be further divided into single nodule, multiple nodules, and fused nodules. Sometimes there are small cancer nodules beside the nodules.
Figure 2 Primary liver cancer (nodular type)
3. Diffuse type (Figure 3) 13 cases (2.6%), with smaller cancer nodules diffusely distributed throughout the liver, making it difficult to distinguish from cirrhosis.
Figure 3 Primary liver cancer (small cancer type)
4. Small cancer type (Figure 3) 6 cases (1.2%). Single nodule tumor diameter <3cm, or the sum of the diameters of two adjacent cancer nodules <3cm. Patients have no clinical symptoms, but serum AFP is positive, and it returns to normal after tumor resection.
Cholangiocarcinoma mostly presents as a single mass, with more connective tissue stroma, gray-white color, firm texture, and tends to irregularly infiltrate around.
(2) Histological Classification
1. Hepatocellular type Mostly associated with cirrhosis. Cancer cells are polygonal, with large nuclei, prominent nucleoli, and abundant cytoplasm. Cancer cells are arranged in nests or cords, with abundant sinusoids between cancer nests. Cancer cells tend to grow into sinusoids. The degree of tumor differentiation is classified into four grades according to Edmonson's criteria, with grades II and III being the most common, but different degrees of differentiation can be present in the same case. Fibrolamellar carcinoma of the liver is a recently noted type of hepatocellular carcinoma, with lamellar fibers surrounding the cancer nests, high surgical resection rate, more common in young people, and better prognosis than the common type.
2. Cholangiocellular type Cells are cuboidal or columnar, arranged in glands. Cancer cells mostly originate from bile duct epithelium, and some from large bile ducts.
3. Mixed type Some tissue morphology resembles hepatocellular, some resembles cholangiocellular, and some cancer cells show transitional morphology.
Pathological characteristics of early liver cancer: The degree of tumor differentiation and tumor size are mostly positively correlated. Small liver cancer is mostly well differentiated, with Edmonson grade I accounting for 75%. As the tumor grows, the DNA ploidy level of cancer cells develops from diploid to aneuploid.
Under the electron microscope, the structure of well-differentiated liver cancer cells resembles that of hepatocytes, with abundant mitochondria in the cytoplasm, increased rough endoplasmic reticulum and ribosome particles, and visible glycogen granules and capillaries. The nuclear volume increases, the nuclear-to-cytoplasmic ratio increases, the nuclear membrane loses smoothness, folds increase leading to the formation of lacunae, the nuclear material becomes uneven, and the nucleolus enlarges irregularly. In poorly differentiated cells, the microvilli and bile canaliculi on the membrane decrease or disappear, the number of mitochondria decreases, parallel long cristae may appear, the endoplasmic reticulum is also reduced, glycogen granules disappear, and the nucleus becomes significantly irregular, reflecting the undifferentiated state of the cells.
(3) Metastasis Among 207 autopsy cases, 137 cases showed metastasis, accounting for 66.2%.
1. Intrahepatic Metastasis Intrahepatic hematogenous metastasis occurs earliest and is most common, potentially invading the portal vein and forming tumor thrombi. The detachment of tumor thrombi within the liver can lead to multiple metastatic lesions, and the blockage of the main portal vein by tumor thrombi can cause portal hypertension and refractory ascites.
2. Extrahepatic Metastasis Found in 50% of autopsy cases.
(1) Hematogenous Metastasis: The lung has the highest metastasis rate, accounting for 43.5% in 207 cases. After tumor thrombi form in the hepatic vein, they can extend upward to the inferior vena cava, even reaching the right atrium, or smaller thrombi can enter the pulmonary circulation, causing small pulmonary embolisms and forming metastatic foci. Hematogenous metastasis can also affect organs such as the adrenal glands, bones, kidneys, and brain.
(2) Lymphatic Metastasis: Local metastasis to the hepatic hilar lymph nodes is most common (12.6%), but metastasis can also occur to lymph nodes near the aorta, supraclavicular, pancreas, spleen, and other areas.
(3) Implantation Metastasis: Occasionally occurs, such as implantation on the peritoneal membrane, which can lead to spontaneous ascites. In females, ovarian metastatic cancer can also occur.
bubble_chart Clinical Manifestations
The onset of the disease is often insidious, and liver cancer is usually discovered incidentally during follow-up for liver disease or during physical examinations and screenings using AFP and B-type ultrasound. This seasonal disease presents no symptoms, and physical examinations also lack signs of the tumor itself. This stage is referred to as subclinical liver cancer. Once symptoms appear and patients seek medical attention, the disease course has mostly entered the middle to advanced stage. The clinical manifestations of liver cancer vary significantly at different stages.
(1) Symptoms of liver cancer: Liver pain, lack of strength, poor appetite, and weight loss are the most characteristic clinical symptoms.
1. Liver pain: The most common symptom, intermittent and persistent, dull or distending pain, caused by the rapid growth of the cancer stretching the liver membrane. If the tumor invades the diaphragm, the pain may radiate to the right shoulder or back. Tumors growing towards the right rear can cause pain in the right waist. Sudden severe abdominal pain and signs of peritoneal irritation suggest bleeding under the membrane of the cancerous nodule or rupture into the abdominal cavity.
2. Digestive symptoms: Decreased appetite, indigestion, nausea, vomiting, and diarrhea, which are easily overlooked due to their lack of specificity.
3. Lack of strength, weight loss, and general weakness. In the advanced stage, a few patients may present with cachexia.
4. Fever: Generally low-grade, occasionally reaching above 39℃, persistent or afternoon low-grade fever or remittent high fever. Fever is related to the absorption of necrotic tumor tissue. Compression or invasion of the bile ducts by the tumor can lead to biliary tract infection.
5. Symptoms of metastatic sites: Symptoms corresponding to the site of tumor metastasis, sometimes becoming the initial symptoms of liver cancer. For example, metastasis to the lungs can cause cough and hemoptysis, pleural metastasis can cause chest pain and bloody pleural effusion. Pulmonary embolism caused by tumor thrombi can lead to sudden severe dyspnea and chest pain. Blockage of the inferior vena cava by tumor thrombi can cause severe lower limb edema, even a drop in blood pressure; blockage of the hepatic vein can cause Budd-Chiari syndrome, and can also lead to lower limb edema. Metastasis to the bones can cause local pain or pathological fractures. Metastasis to the spine or compression of the spinal nerves can cause local pain and paralysis. Intracranial metastasis can present with corresponding localized symptoms and signs, and intracranial hypertension can lead to brain herniation and sudden death.
6. Other systemic symptoms: Syndromes caused by abnormal metabolism of the tumor itself or various effects of the tumor tissue on the body, known as paraneoplastic syndromes, sometimes may precede the symptoms of liver cancer itself. Common ones include:
(1) Spontaneous hypoglycemia: 10-30% of patients may experience this, due to ectopic secretion of insulin or insulin-like substances by liver cells; or tumor suppression of insulinase or secretion of a pancreatic β-cell stimulating factor or excessive glycogen storage; it can also be caused by excessive glucose consumption by liver cancer tissue. Severe cases can lead to unconsciousness and shock, leading to death. Correct judgment and timely symptomatic treatment can save the patient from death.
(2) Polycythemia: 2-10% of patients may experience this, possibly due to increased erythropoietin in the circulation.
(3) Other rare conditions include hyperlipidemia, hypercalcemia, carcinoid syndrome, early sexual and gonadotropin secretion syndrome, cutaneous porphyria, and abnormal fibrinogenemia, which may be related to abnormal protein synthesis, ectopic endocrine function, and porphyrin metabolism disorders in liver cancer tissue.
(2) Signs of liver cancer
1. Hepatomegaly: Progressive hepatomegaly is one of the most common characteristic signs. The liver is hard in texture, with an irregular surface and edges, often nodular. In a few cases where the tumor is deeply embedded in the liver parenchyma, the liver surface may be smooth, with or without obvious tenderness. Tumors on the diaphragmatic surface of the right lobe of the liver can cause significant elevation of the right diaphragm.
2. Splenomegaly: Commonly seen in cases with cirrhosis and portal hypertension. Tumor thrombi in the portal vein or splenic vein, or compression of the portal vein or splenic vein by liver cancer, can also cause congestive splenomegaly.
3. Ascites is straw-colored or bloody, mostly caused by combined cirrhosis, portal hypertension, portal vein or hepatic vein tumor thrombus. Local ulceration and erosion of the cancer infiltrating the liver surface or coagulation dysfunction of the liver can lead to bloody ascites.
4. Jaundice When the cancer extensively infiltrates, it can cause hepatocellular jaundice; when it invades the intrahepatic bile ducts or the enlarged lymph nodes at the hepatic hilum compress the bile ducts, obstructive jaundice may occur. Sometimes, necrotic tumor tissue and blood clots falling into the bile ducts can cause biliary obstruction, leading to obstructive jaundice.
5. Hepatic Vascular Bruit Due to the tumor compressing the large intrahepatic blood vessels or the tumor itself being highly vascularized.
6. Hepatic Friction Rub Occasionally heard over the liver area, indicating that the liver membrane is invaded by the tumor.
7. Signs of Metastasis May include enlarged supraclavicular lymph nodes, pleural effusion or hemothorax from pleural metastasis. Bone metastasis may present as outward protrusion of the bone surface, sometimes leading to pathological fractures. Spinal metastasis compressing the spinal nerves may manifest as paraplegia, and intracranial metastasis may present with hemiplegia and other neuropathological signs.
(3) Liver cancer progresses rapidly. Once clear clinical symptoms appear and without effective treatment, the average survival time is six months. From the perspective of surgical clinical needs, the clinical manifestations can be categorized into the following types.
1. Early Liver Cancer Early or subclinical liver cancer, where the tumor is small and often in a hidden location, patients usually have no symptoms and are only incidentally discovered during physical examination. Patients may have some non-specific symptoms such as upper abdominal discomfort and bloating.
2. Typical Clinical Liver Cancer Patients have a history of hepatitis, HBsAg(+), and before seeking medical attention, they experience worsening distending pain in the upper abdomen and liver area, especially after meals, accompanied by loss of appetite, weight loss, and lethargy; examination reveals asymmetrical liver enlargement, hard and irregular texture, and rapid growth. Advanced stage patients often have obvious cirrhosis, portal hypertension, ascites, jaundice, and cachexia.
3. Acute Abdomen Type Liver Cancer Internal bleeding or rupture of the surface of the cancerous nodule can cause acute abdominal pain or intra-abdominal bleeding. Common in liver cancer at the top of the right lobe, rupture can cause pain in the lower right chest and right shoulder and back, worsening with body movement and breathing; if it penetrates into the abdominal cavity, hemorrhagic shock may occur.
4. Fever Type Liver Cancer Central necrosis can cause fever, and advanced stage patients may have irregular grade II fever.
5. Jaundice Type Besides the terminal manifestations of jaundice, ascites, and liver failure in advanced liver cancer patients, some patients are in relatively good general condition, the liver cancer is not large, and sometimes CT cannot find a definite space-occupying lesion, but intermittent upper abdominal pain and obstructive jaundice may occur, sometimes it may also be painless persistent obstructive jaundice, the cause of jaundice is due to liver cancer tissue adjacent to the bile duct penetrating into the bile duct forming a tumor thrombus growing downward and blocking the opening of the contralateral hepatic duct or the common bile duct. The tumor thrombus is often accompanied by bleeding, causing biliary colicky pain.
6. Gastrointestinal Bleeding Type Gastrointestinal bleeding is often a fatal cause in advanced liver cancer. Most liver cancers occur on the basis of cirrhosis; cirrhosis, portal hypertension, and esophageal varices rupture can lead to upper gastrointestinal bleeding. However, gastrointestinal bleeding caused by liver cancer itself can occur through the following aspects: ① Acute portal vein pressure rise and gastrointestinal bleeding caused by portal vein tumor thrombus obstruction. ② Direct tumor ulceration into the stomach causing bleeding, occasionally seen in massive liver cancer of the left lobe. ③ Bleeding through the bile ducts, intra-tumor bleeding and ulceration into the intrahepatic bile ducts or liver cancer penetrating into the bile ducts growing to form tumor thrombus and bleeding.
Natural Course of Liver Cancer
According to a domestic group of pathologically confirmed but not surgically removed subclinical liver cancer observations, from the appearance of low-concentration AFP to the establishment of subclinical liver cancer (early stage) diagnosis; from the subclinical stage to the appearance of clinical symptoms (intermediate stage [second stage]); from the appearance of clinical symptoms to jaundice, ascites, or distant metastasis or cachexia (advanced stage); from the advanced stage to death, the intervals are 10, 8, 4, and 2 months respectively, with a total of at least 24 months. It was previously thought that the course of liver cancer was short, only 3-6 months, but in fact, this only reflects the course of advanced stage liver cancer.
Clinical Classification
(1) According to the staging criteria formulated by the National Liver Cancer Research Collaboration Conference:
Stage I: No obvious symptoms or signs, also known as the subclinical stage.
Stage II: Clinical symptoms or signs appear but without the features of Stage III.
Stage III: Presence of obvious cachexia, jaundice, ascites, or distant metastasis.
Stage I liver cancer is the subclinical stage, where apoplexy involving meridians is confirmed by surgery, and the tumor is a single nodule with a diameter less than 5cm, referred to as small liver cancer; therefore, most small liver cancers are subclinical liver cancers or Stage I liver cancers. However, exceptions include cases where the liver cancer is small but near the liver edge or pedunculated and easily palpable; early distant metastasis; or small cancerous nodules on the liver surface that are prone to rupture, bleeding, and acute abdomen. Conversely, tumors located in non-critical areas may not show symptoms or signs even if the tumor nodule diameter is greater than 5cm, so subclinical cancer also includes some tumors larger than 5cm in diameter.
(2) TNM Staging Criteria for Liver Tumors In recent years, China has adopted the TNM staging criteria set by the International Union Against Cancer for liver tumor staging, as described below.
The Japanese Liver Cancer Study Group has developed a staging method from I to IVB based on TNM staging, as follows:
Stage I T1 No Mo
Stage II T2 No Mo
Stage III T1 No Mo
T2 N1 Mo
T3 N1 or N1 Mo
Stage IV T4 No or N1 Mo
Stage IV T1～T4 No or N1 M1
T-Primary Tumor N-Lymph Nodes M-Metastasis
T1 Solitary tumor, maximum diameter 2cm or less, without vascular invasion.
T2 One of the three conditions in T1 is not met.
T3 Two of the three conditions in T1 are not met.
T2, T3 Includes multiple tumors but confined to one lobe. (For staging purposes, the plane dividing the liver into two lobes is set between the gallbladder bed and the vena cava).
T4 Multiple tumors distributed over more than one lobe, or tumor involving the main branches of the portal or hepatic veins.
N-Regional Lymph Nodes No No regional lymph node metastasis.
N1 Regional lymph node metastasis
M-Distant Metastasis Mo No distant metastasis.
M1 Distant metastasis.
bubble_chart Auxiliary Examination
1. Serology
⑴AFP: AFP is currently the most specific marker for the diagnosis of hepatocellular carcinoma. AFP is an embryonic protein synthesized by the liver during fetal development, and this function can be regained when adult liver cells become malignant. Since AFP can also be present in pregnant women, newborns, and gonadal embryonal carcinomas of the testes or ovaries, AFP has only relative diagnostic value for liver cancer. Due to the increased sensitivity of detection methods, low concentrations of AFP can also be detected in some cases of hepatitis, cirrhosis, and a few gastrointestinal cancers such as stomach cancer, intestinal cancer, pancreatic cancer, and metastatic liver cancer. Therefore, the results of AFP testing must be correlated with clinical findings to have diagnostic significance.
Currently, radioimmunoassay (RIA) or AFP monoclonal antibody enzyme immunoassay (EIA) rapid testing methods are commonly used to measure serum AFP levels. Normal individuals may have trace amounts of AFP in their serum, typically less than 20 μg/L. Elevated AFP levels are found in 70-90% of hepatocellular carcinoma cases. Generally, AFP concentration correlates with tumor size, but there is considerable individual variation. It is generally believed that AFP levels are often low or undetectable in cases where the pathological differentiation is close to normal liver cells or extremely low. International standards are often set higher, which can lead to misdiagnosis of fistula disease. In China, there is a focus on the dynamic observation of moderate and low concentrations of AFP elevation. In clinical practice, patients with low AFP concentrations often require follow-up with imaging diagnostic techniques to help establish an early diagnosis. Liver cancer often occurs on the basis of chronic active liver disease, so differentiation is necessary. In chronic hepatitis and post-hepatitis cirrhosis, 19.9% to 44.6% of patients have elevated AFP levels, usually between 25-200 μg/L. In benign liver disease activity, there is often a significant increase in alanine aminotransferase (ALT) first, followed by a corresponding or synchronous increase in AFP, which peaks and then decreases, usually within 1-2 months as the condition improves and ALT levels drop, leading to a transient decrease in AFP. Sometimes, benign liver disease activity can also show fluctuating or persistently low AFP levels, but it is important to be vigilant for the possibility of early cancer coexisting with liver disease activity.
⑵ Detection of other liver cancer markers: In recent years, there has been an increasing trend of primary liver cancer cases with negative serum AFP. Therefore, the development of newer, more specific, and sensitive markers has become an urgent task. The search for isoenzymes and isoforms with carcinogenic characteristics, as well as specific subcomponents, is the current direction of liver cancer serum marker research. In recent years, both domestic and international reports have highlighted the following markers as having high diagnostic value for liver cancer:
① r-GT isoenzyme (GGTⅡ): Using polyacrylamide gradient electrophoresis, 12 isoenzyme bands can be separated. Bands I´, II, and II´ are specific to primary liver cancer, with a positive rate of 79.7%. For AFP-negative cases, the positive rate of this enzyme is 72.7%.
② Alpha-fetoprotein isoform (Fuc AFP): Currently, the diagnostic value of AFP isoforms measured by Hyacinth Bean lectin (LCA) affinity cross-immunoautoradiography is high. There are two isoforms: LCA non-binding (AFP-N-L) and binding (AFP-R-L). Liver cancer contains an average of 49.13±27.20% AFP-N-L (0-100%), with <75% being the diagnostic standard for liver cancer, and a positive rate of 86.0%, which decreases as the condition worsens. Non-cancerous liver disease has an AFP-N-L level of 93.30±7.66%, with a false positive rate of 1.6%.
③Abnormal prothrombin: The liver synthesizes the inactive precursor of prothrombin, which is carboxylated to its active form by vitamin K. In liver cancer, the function of the vitamin K-dependent carboxylation system in the microsomes of liver cancer cells is impaired, and the activity of hydroxylase is reduced, leading to incomplete carboxylation of glutamic acid, thus forming abnormal prothrombin. Recently, it has been discovered that liver cancer cells have the ability to synthesize and release abnormal prothrombin independently. In China, the determination of abnormal prothrombin ≥250μg/L by radioimmunoautography is used as a standard, with a positive rate of 69.4% for liver cancer. The positive rates for low-concentration AFP and AFP-negative liver cancer are 68.3% and 65.5% respectively, and the concordance rate for small liver cancer is 62.2%. Most data indicate that abnormal prothrombin has high specificity for primary liver cancer, with very low false positives in various non-cancerous liver diseases, secondary liver cancer, and benign liver tumors, potentially making it a valuable marker for liver cancer.
④ Serum fucosidase (AFu): AFu belongs to the lysosomal acid hydrolase class, and its main physiological function is to participate in the catabolism of biologically active macromolecules such as glycoproteins and glycolipids containing fucose. An AFu level exceeding 110 Kat/L should raise suspicion for primary liver cancer. Domestic reports indicate that the positive rate of AFu in diagnosing primary liver cancer is 81.2%, with positive rates of 76.1% and 70.8% for AFP-negative liver cancer and small liver cancer, respectively. Secondary liver cancer and benign liver space-occupying lesions are negative, but there is a high rate of false positives in cirrhosis and chronic hepatitis.
⑤ M2-type pyruvate kinase (M2-PyK): Pyruvate kinase (PyK) is a key enzyme in glycolysis, with four isoenzymes: L, R, M1, and M2 (K). The M2 (K) type is predominant in fetal liver and liver cancer tissues and can be considered a type of oncofetal protein. The ELISA sandwich method can detect trace amounts of this cancer marker with high sensitivity at the picogram level. The normal value is 575.8 ± 259.5 ng/L, and levels in liver cancer patients are five times higher than normal. Levels are significantly elevated even in the small liver cancer stage, and the poorer the differentiation, the more pronounced the increase in M2-PyK. The positive rate is 5.2%, and levels can also be elevated in gastrointestinal tumors, but not in hepatitis or benign liver tumors.
⑥ Isoferritin (AIF): In liver cancer, the synthesis of isoferritin by liver cancer cells increases, and its release accelerates, making it diagnostically significant. The normal range is 16–210 μg/L, with a diagnostic threshold of 300 μg/L. In liver cancer patients, 72.1% exceed this value, with a false positive rate of 10.3%. The positive rate for AFP-negative or low-concentration AFP liver cancer is 66.6%, and for small liver cancer (<5 cm), it is 62.5%.
⑦ α-Antitrypsin (AAT): Human liver cancer cells have the ability to synthesize and secrete AAT, which increases when tumors are accompanied by cell necrosis and inflammation. Immunoperoxidase techniques show that 74.9% of liver cancer cases have levels above 4000 ng/L, compared to 3–10.9% in benign liver diseases. The positive rate for AFP-negative liver cancer is 22.7%.
⑧ Aldolase isoenzyme A (ALD-A): In liver cancer, ALD-A appears and increases, and levels >800 ng/ml aid in diagnosis. The positive rate for AFP-negative liver cancer is 73.6%.
In summary, the above liver cancer markers have auxiliary significance in diagnosing primary liver cancer, especially in AFP-negative cases, but they cannot replace the role of AFP in liver cancer diagnosis. Based on practical experience, combined testing is superior to single testing, and combining serum AFP testing with 1–2 liver cancer markers can significantly improve the positive detection rate of primary liver cancer. Clinical analysis should also integrate medical history, imaging diagnostics, or histological data to reach an accurate conclusion.
2. Liver cancer imaging diagnostics:
⑴Real-time ultrasound imaging (US): Ultrasound imaging is widely used in clinical practice due to its high sensitivity in displaying lesions in parenchymal soft tissue organs, minimal impact on human tissues, and low cost. As liver cancer gradually increases in size, ultrasound imaging shows changes in internal echoes from hypoechoic to hyperechoic and mixed echoes. Tumors with a diameter of less than 2cm are commonly seen as hypoechoic nodular types; those between 2-3cm show hypoechoic areas with the same echo frequency as the surrounding tissue; those between 3-5cm are mostly surrounded by hypoechoic areas; and those larger than 5cm are mostly hyperechoic or mixed echoes. In addition to the above-mentioned polymorphism and variability characteristics, hepatocellular carcinoma also has the following features as the tumor grows: ① Acoustic halo (Halo): A clear tumor membrane, with the center of the nodule showing relatively uniform hyperechoic areas and the area adjacent to the membrane showing a hypoechoic dark ring, known as the "acoustic halo," which is a fibrous membrane or interpreted as blood vessels around the tumor. ② Nodule within a nodule: Within the hyperechoic tumor area, there are nodules with different echoes, indicating new tumor foci growing within the hepatocellular carcinoma. In addition to locating liver cancer, ultrasound imaging can also show whether there is cancer thrombus formation in the main portal vein and its branches, understand the anatomical relationship between the mass and large blood vessels, whether there is cancer spread and intraperitoneal lymph node metastasis, which is of great value for determining the treatment plan before surgery, estimating the possibility of resection, selecting indications for hepatic artery embolization, and monitoring recurrence after surgery.
In recent years, color Doppler flow imaging has been widely used in clinical practice. In addition to displaying space-occupying lesions, it can also measure the blood flow into and out of tumors to differentiate the blood supply of the lesions and infer the nature of the tumors. Ultrasound-guided biopsy and intratumoral local injection have been widely used for the diagnosis and treatment of small liver cancer. The use of high-resolution intraoperative ultrasound imaging can precisely locate lesions to improve the surgical resection rate.
⑵Computed Tomography (CT) Among various imaging examinations, CT best reflects the pathological morphology of the liver, such as lesion size, shape, location, number, and the presence of intralesional hemorrhage or necrosis. The infiltration of lesions can be understood from their edge conditions, and the invasiveness can be assessed from the presence of tumor thrombi in the portal vein and the extent of vascular invasion. CT is considered the preferred non-invasive diagnostic method to supplement ultrasound imaging in estimating the extent of lesions. The CT manifestations of liver cancer on plain scans generally show lesions as low-density areas, lower than the surrounding liver parenchyma, with some lesions surrounded by a lower-density ring (halo sign). Nodular types have clearer edges, while massive and mixed types often have blurred or partially clear edges. Enhancement: After intravenous injection of iodine contrast, the density of the lesion and liver tissue increases to varying degrees, known as enhancement. This includes: ① Dynamic enhancement scanning: Using bolus injection dynamic scanning or spiral CT rapid scanning, lesions show high-density enhancement in the early stage (hepatic arterial phase), higher than the surrounding normal liver tissue for 10-30 seconds, then the density rapidly decreases, becoming isodense with normal liver tissue, during which fistula disease is easily missed; the density continues to decrease, and the liver tissue appears as a low-density lesion, which can last for several minutes. Early dynamic enhancement scanning is useful for detecting satellite lesions smaller than 1cm or 1-2cm in diameter and also aids in the discovery of small lesions. ② Non-dynamic scanning: Ordinary scanning takes at least 15 seconds each time, so the liver layer where the lesion is located may fall into any initial stage of the dynamic scanning, showing different densities. Most lesions fall into the low-density phase, making the lesions significantly lower in density compared to plain scans. Manifestations of portal system and other system invasions: Primary liver cancer has a high rate of portal vein tumor thrombus formation. Enhanced scans show a significant difference between non-enhanced tumor thrombi and significantly enhanced blood, presenting as strip-like filling defects leading to irregular or non-visualization of the main portal vein or branch vessels. A few patients have inferior vena cava tumor thrombi. Hepatic hilum invasion can cause intrahepatic bile duct dilation, occasionally with retroperitoneal lymph node enlargement, ascites, etc. Lung metastases appear abnormal on chest CT, more sensitive than chest X-rays.
In recent years, new CT machines have been continuously updated, and CT examination techniques have been constantly improved, especially the combination of angiography and CT techniques such as CTA (CT-Angiography) with direct injection of contrast agent into the hepatic artery for CT enhancement, CTAP (CT during arterial portography) with injection of contrast agent into the superior mesenteric artery or splenic artery during the portal venous phase for CT scanning, and Lipiodol-CT (Lp-CT) with intrahepatic injection of Lipiodol followed by plain CT scanning after 2-3 weeks. These methods have a better detection rate for small liver cancer, especially micro liver cancer smaller than 1cm, compared to dynamic CT scanning. However, among the various methods mentioned, plain CT plus enhancement is still the routine, and CTA and CTAP are the most effective methods for confirming suspected lesions or micro liver cancer.
⑶Magnetic Resonance Imaging (MRI): In liver cancer, the T1 and T2 relaxation times are prolonged. In more than half of the cases, the tumor appears as a lower signal intensity or isointense compared to the surrounding liver tissue on T1 weighted images, while it shows high signal intensity on T1 weighted images. The characteristic MRI features of primary liver cancer include: ① Fatty degeneration of the tumor, with short T1 relaxation time, producing isointense or high signal on T1 weighted images, and heterogeneous high signal intensity on T2 weighted images, with unclear lesion margins. In liver cancer with fibrosis, long T1 relaxation time results in low signal intensity. ② Presence of tumor capsule, which appears as a low signal intensity ring around the tumor on T1 weighted images, and the capsule is not well visualized on T2 weighted images. ③ Tumor invasion of blood vessels, an advantage of MRI is that it can show the branches of the portal vein and hepatic vein, as well as the compression and displacement of blood vessels without the need for contrast injection. In cases of tumor thrombus, T1 weighted images show medium signal intensity, while T2 weighted images show high signal intensity. ④ Daughter nodules show higher signal intensity than normal liver parenchyma on T2 weighted images.
(4) Primary liver cancer angiography: Non-invasive methods such as ultrasound, CT, and MRI have been able to detect many small liver cancers. However, angiography still holds a certain position in the diagnosis of liver cancer, often providing more precise and rapid diagnosis for small liver cancers below 2 cm. Currently, the Seldinger percutaneous femoral artery catheterization method is still used for liver angiography, with the highest success rate achieved using a twisted catheter for superselective angiography. To diagnose liver cancer and understand the hepatic artery's course and anatomical relationships, catheter insertion into the common hepatic artery or proper hepatic artery is sufficient. If vascular anomalies are suspected, selective superior mesenteric artery angiography can be added. For the purpose of embolization therapy, the catheter should be advanced as deeply as possible to reach the tumor's feeding artery, minimizing the impact on non-tumor areas. The angiographic manifestations of liver cancer include: ① Tumor vessels and tumor staining, which are characteristic features of small liver cancers. The arterial phase shows disordered tumor vessel proliferation, and the capillary phase shows tumor staining. Small liver cancers may sometimes only show tumor staining without vessel proliferation. The reduction or disappearance of tumor vessels and changes in tumor staining are important indicators for assessing treatment response. ② Larger tumors may display malignant features such as straightened, twisted, or displaced arteries; tumor lakes, where contrast agent pooling in the tumor is delayed during the arterial phase; the tumor encasement sign, where the tumor's growth and infiltration cause the encased artery to be compressed irregularly or become rigid; arteriovenous fistula, where the portal vein is visualized during the arterial phase; and portal vein tumor thrombus, where a cord-like "velvet sign" parallel to the portal vein is seen during the venous phase, indicating tumor invasion of the portal vein. This sign can also be seen during the arterial phase if an arteriovenous fistula is present. The detection capability of angiography for liver cancer depends on the amount of neovascularization in the lesion. Hypervascular liver cancers, even those below 2 cm or smaller, are easily visualized. In recent years, digital subtraction angiography (DSA) has been developed, which uses a computer to convert the video signal of the image into a digital signal, then amplifies and transfers the subtracted data signal back into a video signal, reconstructing a simulated image output that displays a clear background and enhanced contrast. Liver angiography is not only significant for diagnosis and differential diagnosis but also for estimating the extent of the disease before surgery or treatment, especially for understanding intrahepatic disseminated nodules; it provides accurate and objective information on vascular anatomical variations and the anatomical relationships of important vessels, as well as portal vein infiltration. It is of great value for assessing the feasibility and thoroughness of surgical resection and for deciding on a reasonable treatment plan. Angiography is not included in routine examinations and is only considered when the above non-invasive examinations are unsatisfactory. Additionally, angiography not only serves a diagnostic purpose but can also be used for immediate chemoembolization or the introduction of anticancer drugs or other biological immunotherapeutic agents in patients who are not suitable for surgery.
⑸ Radionuclide Imaging Hepatobiliary radionuclide imaging uses gamma cameras or single-photon emission computed tomography (SPECT). In recent years, efforts have been made to improve imaging effectiveness by seeking highly specific and strongly affinity radioactive drugs, such as radionuclide-labeled specific monoclonal antibodies against liver cancer or related tumor markers. Radiommunoimaging diagnosis has begun to be used clinically, effectively increasing the cancer-to-liver ratio of radioactivity; 99mTc-PMT (99mTc-pyridoxyl-5-methyltryptophan) is an ideal hepatobiliary imaging agent. The hepatobiliary transit time is short, and since liver cancer and hepatic adenomas lack a biliary system for gall excretion and have a certain affinity for PMT, they can accumulate and remain in liver cancer and hepatic adenomas for a longer time. In delayed imaging (2-5 hours), 99mTc-PMT remains in liver cancer and hepatic adenoma tissues, while it has been cleared from surrounding liver parenchymal cells, resulting in a much higher radioactivity in the cancer or adenoma than in normal liver tissue, creating a "hot spot." Therefore, it is clinically used for the qualitative and localization diagnosis of liver cancer; for the qualitative diagnosis of AFP-negative liver cancer; to differentiate between primary and secondary liver cancer; and for the diagnosis of extrahepatic metastases and hepatic adenomas. Since the positive rate for hepatocellular carcinoma is only about 60% and is affected by the resolution of the instrument, lesions within 2 cm are still difficult to display, making its clinical application less than ideal.
3. Liver tissue biopsy or cytological examination In recent years, histological or cytological examination through biopsy or fine-needle aspiration under real-time ultrasound or CT conduction exercise has become an effective method for diagnosing small liver cancers with a diameter of less than 2cm. However, liver cancers near the edge are prone to rupture, and there is also a risk of needle tract metastasis.
In summary, if AFP is significantly elevated, combined with typical ultrasound images, a preliminary diagnosis of primary liver cancer can be made; for those with negative or low AFP levels, appropriate liver cancer markers other than AFP should be selected. Imaging diagnosis also has qualitative and localization diagnostic value. CT examination with contrast enhancement or dynamic enhancement scanning is helpful for liver cancer diagnosis. The characteristic manifestations of magnetic resonance can aid in the diagnosis and differential diagnosis of liver cancer. Radioimmunoimaging diagnosis has high specificity. The diagnosis of small liver cancers and the differentiation from certain small benign sexually transmitted disease changes still require further in-depth research.
(I) Pathological Diagnosis
1. Histological examination of liver tissue confirms primary liver cancer.
2. Histological examination of extrahepatic tissue confirms hepatocellular carcinoma.
(II) Clinical Diagnosis
1. In the absence of other evidence of liver cancer, positive AFP by countercurrent electrophoresis or radioimmunoassay AFP >400ng/ml, lasting for more than four weeks, and excluding pregnancy, active liver disease, gonadal embryonic tumors, and metastatic liver cancer.
2. Imaging studies show definite intrahepatic solid space-occupying lesions, excluding liver hemangioma and metastatic liver cancer, and meeting one of the following conditions:
① AFP >20ng/ml. ② Typical imaging features of primary liver cancer. ② No jaundice but significant increase in AKP or r-GT. ④ Distant metastatic lesions or bloody ascites, or finding cancer cells in ascites. ⑤ Positive hepatitis B markers with cirrhosis.
(III) Qualitative Diagnosis The qualitative diagnosis of primary liver cancer requires comprehensive analysis of the patient's symptoms, signs, and various auxiliary examination data.
1. Symptoms and signs as before.
2. Auxiliary examinations.
① Alpha-fetoprotein (AFP) test: positive by countercurrent electrophoresis or radioimmunoassay >400mg/ml; lasting for four weeks, excluding pregnancy, active liver disease, and gonadal embryonic tumors.
② Other marker tests: Alkaline phosphatase (ALP) is elevated in about 20% of liver cancer patients. r-Glutamyl transpeptidase (r-GT) is elevated in 70% of liver cancer patients. 5'-Nucleotidase isoenzyme V (5'-NPDase-V) is present in about 80% of patients, with higher positive rates in metastatic liver cancer patients. α-Antitrypsin (α-AT) is elevated in about 90% of liver cancer patients. Ferritin is elevated in 90% of liver cancer patients. Carcinoembryonic antigen (CEA) is elevated in 70% of liver cancer patients. Abnormal prothrombin >300mg/ml.
③ Liver function and hepatitis B antigen-antibody system tests, abnormal liver function and positive hepatitis B markers suggest a liver disease basis for primary liver cancer.
④ Various imaging studies suggest intrahepatic space-occupying lesions. ⑤ Laparoscopy and liver biopsy: Laparoscopy can directly display the liver surface; liver biopsy.
⑧ Other tests: Lymph node biopsy, finding cancer cells in ascites, etc.
(IV) Localization Diagnosis
1. B-ultrasound examination, obtaining cross-sectional images of the liver and adjacent organs, can detect small liver cancers below 2-3cm.
2. Radionuclide liver imaging, lesions larger than 2cm can show positive results.
3. CT and MRI: Beneficial for the diagnosis of liver cancer. When the liver cancer diameter is less than 2cm or the density is similar to normal liver parenchyma, CT is difficult to display. Diffuse liver cancer is not easily detected by CT; distinguishing between primary and secondary liver cancer is difficult. After contrast enhancement, lesions with a diameter of 1-2cm can be displayed. MRI has the advantages of CT and can more clearly display metastatic lesions of liver cancer, allowing for scans in different orientations.
4. Selective hepatic angiography and digital subtraction angiography, selective hepatic angiography (DSA), is a sensitive examination method that can display liver cancers within 1cm in diameter.
bubble_chart Treatment Measures
Early treatment is the most important factor in improving the prognosis of liver cancer. Early-stage liver cancer should be treated with surgical resection whenever possible. For large liver cancers that cannot be resected, multimodal comprehensive treatment can also be used.
(1) Surgical treatment: Surgical resection remains the preferred treatment for liver cancer. Early resection is key to improving survival rates, and the smaller the tumor, the higher the five-year survival rate. The indications for surgery are: ① Clear diagnosis, with the lesion estimated to be confined to one lobe or half of the liver; ② No significant jaundice, ascites, or distant metastasis; ③ Liver function compensation is still good, with prothrombin time not less than 50%; ④ Heart, liver, and kidney function can tolerate the surgery. In patients with normal liver function, the liver resection volume should not exceed 70%; in patients with grade II cirrhosis, it should not exceed 50%, or only left hemihepatectomy can be performed; in patients with severe cirrhosis, liver lobe resection cannot be performed. Surgery and pathology have confirmed that more than 80% of liver cancers are associated with cirrhosis. It is widely accepted that local resection can replace regular liver lobe resection with the same long-term effects, while postoperative liver function disorders are reduced, and surgical mortality is also decreased. Since radical resection still has a relatively high recurrence rate, regular follow-up with AFP and ultrasound imaging is recommended to monitor for recurrence.
Due to close follow-up after radical resection, "subclinical" recurrences of small liver cancers are often detected, and reoperation is the preferred treatment. The five-year survival rate after the second surgery can still reach 38.7%. Although liver transplantation is a method for treating liver cancer, with many reports from abroad, its role in the treatment of liver cancer has not been confirmed for a long time. The long-term use of immunosuppressants after surgery often leads to patient death from recurrence. For developing countries, due to donor sources and cost issues, it remains difficult to promote in recent years.
(2) Palliative surgical treatment: Suitable for larger tumors or those scattered or located near major blood vessels, or those that cannot be resected due to cirrhosis. Methods include hepatic artery ligation and/or hepatic artery catheterization chemotherapy, cryotherapy, laser therapy, microwave therapy, intraoperative hepatic artery embolization, or anhydrous alcohol intratumoral injection, etc. These methods can sometimes reduce tumor size and lower serum AFP levels, providing an opportunity for secondary resection.
(3) Multimodal comprehensive treatment: This is an active and effective treatment method for intermediate-stage [second stage] large liver cancers in recent years, sometimes transforming unresectable large liver cancers into resectable smaller liver cancers. There are various methods, generally based on the combination of hepatic artery ligation and hepatic artery catheterization chemotherapy, adding external radiotherapy as a triple therapy, and combining with immunotherapy as a quadruple therapy. The best results are achieved with triple or more therapies. The tumor shrinkage rate in patients undergoing multimodal comprehensive treatment reaches 31%, and due to significant tumor shrinkage, secondary resection is possible, with a secondary resection rate of 38.1%. The Liver Cancer Research Institute of Shanghai Medical University has also studied hyperfractionated radiotherapy and targeted therapy. The method of combining hyperfractionated external radiotherapy and hepatic artery catheterization chemotherapy is as follows: in the first week, intra-arterial chemotherapy with cisplatin (CDDP) 20mg daily for 3 consecutive days. In the second week, local external radiotherapy to the liver tumor area, 2.5Gy (250rads) twice a day (morning and afternoon) for 3 consecutive days; two weeks constitute one course, and this alternation can be repeated for 3 to 4 courses. Targeted therapy involves 131I-anti-liver cancer ferritin antibody or anti-liver cancer monoclonal antibody or 131I-lipiodol intra-arterial injection, once every 1 to 2 months, with intra-arterial CDDP 20mg daily for 3 to 5 days during the treatment interval. If the above treatments are combined with immunotherapy such as interferon, lentinan, interleukin-2, etc., the results are even better.
(4) Hepatic artery embolization chemotherapy (TAE) This is a non-surgical tumor treatment method developed in the 1980s, which has good efficacy for liver cancer and is even recommended as the first choice among non-surgical therapies. It often uses lipiodol mixed with chemotherapy drugs or 131I or 125I-lipiodol, or 90Y microspheres to embolize the distal blood supply of the tumor, and then uses gelatin sponge to embolize the proximal hepatic artery, making it difficult to establish collateral circulation, leading to ischemic necrosis of the tumor. Commonly used chemotherapy drugs include CDDP 80~100mg, 5Fu 1000mg, and mitomycin 10mg (or adriamycin (ADM) 40~60mg), which are first infused into the hepatic artery, and then mixed with mitomycin (MMC) 10mg in ultrasonically emulsified Lipiodol for distal hepatic artery embolization. Hepatic artery embolization chemotherapy should be repeated multiple times for better results. According to data from our hospital's radiology department, among 345 cases of large liver cancer that could not be surgically removed, the one-year survival rate with simple hepatic artery infusion chemotherapy was only 11.1%, while the one-year survival rate increased to 65.2% with combined hepatic artery embolization treatment, with the longest follow-up survival being 52 months, and 30 cases of tumor shrinkage gaining the opportunity for surgical resection. This method is contraindicated for patients with severe liver function decompensation and is also unsuitable for those with main portal vein tumor thrombus obstruction.
(V) Intratumoral Injection of Absolute Alcohol Under ultrasound guidance, percutaneous intratumoral injection of absolute alcohol is used to treat liver cancer. This method is preferred for liver cancer patients with tumor diameter ≤3cm, no more than 3 nodules, and cirrhosis who are not suitable for surgery. It has the potential to cure small liver cancers. The effect is poor for tumors ≥5cm.
(VI) Radiotherapy Due to advancements in radiation sources, equipment, and technology, and the accurate localization provided by various imaging techniques, the role of radiotherapy in the treatment of liver cancer has been enhanced, and its efficacy has improved. Radiotherapy is suitable for non-resectable liver cancers that are still localized. Generally, if a higher dose can be tolerated, the efficacy is better. External radiotherapy has evolved from whole liver radiation, local radiation, whole liver moving strip radiation, local hyperfractionated radiation, to stereotactic radiation. Recently, proton therapy has been used for liver cancer radiotherapy. It has been reported that a total radiation dose exceeding 40Gy (4000rads) combined with regulating qi and invigorating spleen Chinese medicinals can achieve a one-year survival rate of 72.7% and a five-year survival rate of 10%. Combined with surgery and chemotherapy, it can help eliminate residual cancer cells, and chemotherapy can also enhance the sensitivity of radiotherapy. Intraparenchymal injection of Y-90 microspheres, 131I-iodized oil, or isotope-labeled monoclonal antibodies can provide internal radiotherapy.
(VII) Targeted Therapy The use of specific antibodies and monoclonal antibodies or tumor-affinitive chemical drugs as carriers, labeled with radionuclides or conjugated with chemotherapeutic drugs or immune toxins for specific targeted therapy, is one of the promising treatments. Clinically used antibodies include anti-human liver cancer protein antibodies, anti-human liver cancer monoclonal antibodies, and anti-alpha-fetoprotein monoclonal antibodies. Besides 131I and 125I, 90Y has also been tested. Additionally, the conjugation of toxic proteins and chemotherapeutic drugs with antibodies, humanized monoclonal antibodies, or genetically engineered antibodies is under research.
(VIII) Chemotherapy The more effective drugs for liver cancer include CDDP as the first choice, commonly used are 5Fu, doxorubicin (ADM) and its derivatives, mitomycin, VP16, and methotrexate. Generally, single-drug intravenous administration is less effective. Intrahepatic arterial administration and/or embolization, combined with internal and external radiotherapy, are more commonly used and show more significant effects. For some intermediate and advanced stage liver cancers without surgical indications, and those with portal vein main trunk tumor thrombus obstruction not suitable for intrahepatic arterial intervention, or some patients after palliative surgery, combined or sequential chemotherapy can be used. Common combination regimens include cisplatin 20mg + 5Fu 750mg～100mg intravenous infusion for 5 days, once a month, 3～4 times as a course. Doxorubicin 40～60mg on the first day, followed by 5Fu 500mg～750mg intravenous infusion for 5 consecutive days, once a month for 3～4 times as a course. The efficacy of the above regimens varies.
(IX) Biological Therapy Biological therapy not only complements surgery, chemotherapy, and radiotherapy to reduce immune suppression and eliminate residual tumor cells. In recent years, due to the development of genetic recombination technology, it has become possible to obtain a large number of immunologically active factors or cytokines. The application of recombinant lymphokines and cytokines as biological response modifiers (BRM) for tumor biological therapy has attracted widespread attention in the medical community and is considered the fourth anti-tumor treatment. Currently, α and γ interferons (IFN) are widely used in clinical treatment. Natural and recombinant IL-2, TNF have been developed. Additionally, lymphokine-activated killer cells-LAK cells, tumor-infiltrating lymphocytes (TIL), etc., have begun to be tested. The efficacy of various biological therapeutic agents still requires more practice and summary. Gene therapy provides new prospects for the biological treatment of liver cancer.
(10) Chinese Herbal Medicine Chinese herbal medicine is suitable for patients with advanced stage liver cancer and those with severe liver function decompensation who cannot tolerate other treatments. It can improve the overall condition of the body and prolong life. It can also be used in conjunction with surgery, radiotherapy, and chemotherapy to reduce adverse reactions and enhance efficacy.
In summary, early-stage liver cancer should be surgically removed as soon as possible. For those that cannot be removed, hepatic artery embolization chemotherapy is the preferred option. Intratumoral injection of anhydrous alcohol is suitable for small liver cancers in patients with poor liver function who are not suitable for surgery, and it may achieve a curative effect. Intermediate-stage (second-stage) large liver cancers should be treated with multimodal therapy primarily involving hepatic artery catheterization and ligation or hepatic artery embolization chemotherapy to kill tumor cells and reduce tumor burden. Once the tumor shrinks, a second-step or sequential surgical resection should be pursued. Advanced-stage liver cancer can be managed with a comprehensive Chinese and Western medicine approach, primarily using Chinese herbal medicine, which may improve symptoms and prolong survival. Targeted therapy has achieved initial success, and gene therapy holds promising prospects.
The evaluation criteria for the efficacy of primary liver cancer are as follows:
1. The change in tumor volume is used as a standard for measuring efficacy, with the following stipulations:
(1) Complete remission: Visible tumors disappear and persist for more than one month.
(2) Partial remission: The product of the two largest perpendicular diameters of the tumor shrinks by more than 50% and persists for more than one month.
(3) Stable: The product of the two largest perpendicular diameters of the tumor shrinks by less than 50%, and the increase does not exceed 25%, persisting for more than one month.
(4) Deterioration: The product of the two largest perpendicular diameters of the tumor increases by no more than 25%.
2. The change in alpha-fetoprotein (AFP) levels is used as a standard for measuring efficacy. A postoperative reduction of AFP to normal levels is considered evidence of a curative surgery.
3. The survival period after treatment is used as a standard for measuring efficacy. The length of the patient's survival after treatment reflects the ultimate effectiveness of the treatment, making it the most valuable efficacy criterion.
Tumor size, treatment methods, and the biological characteristics of the tumor are important factors influencing prognosis. According to our data, the five-year survival rate for those who underwent radical resection reached 53.0%, most of whom had small liver cancer or large liver cancer that was resected after reduction. The survival rate for palliative resection was only 12.5%, and it is rare for patients undergoing drug treatment to survive more than five years. Early-stage liver cancer is characterized by small tumor size, intact membrane, rare or absent tumor thrombi, good tumor differentiation, few distant metastases, and a better immune status of the body, all of which are favorable conditions for radical surgery. For intermediate and advanced-stage liver cancer, despite various comprehensive treatment measures, the chance of radical cure is low, and distant metastases are common, leading to a poorer prognosis.
Active prevention and treatment of toxic hepatitis are of significant importance in reducing the incidence of liver cancer. Inactivated hepatitis B virus vaccine injections not only prevent and treat hepatitis but also play a certain role in preventing liver cancer. Preventing grain mold and improving water quality are also important measures for preventing liver cancer.
In the absence of perfect prevention for liver cancer, early detection, early diagnosis, and early treatment of liver cancer are referred to as "secondary prevention" in oncology. Since the 1970s, with the application of alpha-fetoprotein (AFP) for liver cancer screening in China, the diagnosis of primary liver cancer has reached a subclinical level, the proportion of early liver cancer has continuously increased, and the five-year survival rate has also significantly improved. Since the 1980s, the detection rate in high-risk populations (history of hepatitis, HBsAg positive, over 40 years old) has been about 501 per 100,000, which is 34.4 times the detection rate in the general population, with one-third being early liver cancer. The basic method for detecting early liver cancer is the highly sensitive AFP test once or twice a year, supplemented by ultrasound imaging. The combined detection rate of these two methods can reach 97.9%, which not only compensates for the shortcomings of AFP-negative patients in fistula disease detection but also has significant value in the timely diagnosis of low-concentration AFP liver cancer. There is a contradiction between "cost and benefit" in liver cancer screening, and some believe that the early detection through screening is essentially a "leading time" in diagnosis and treatment. However, before effective prevention of liver cancer disease causes is achieved, the "leading time" gained from screening is of significant value for the increasing number of long-term survival cases among detected patients. It must be emphasized that for small liver cancers detected early, surgical resection should be actively pursued to achieve a cure. The five-year survival rate after radical resection of small liver cancer is about 70%, while non-surgical treatments mostly result in death within two years. Data from Zhongshan Hospital of Shanghai Medical University shows that 212 cases have survived more than five years after radical resection, most of which were early liver cancers detected through screening. Therefore, screening not only improves the level of early diagnosis and treatment but also promotes basic medical research on the occurrence and development of early liver cancer. There has been significant progress in the treatment of liver cancer in recent years. The Liver Cancer Research Institute of Shanghai Medical University reported that the five-year survival rate after radical resection of subclinical liver cancer is as high as 72.9%, and for liver cancers with a diameter of less than 2 cm, the five-year survival rate after surgical resection is as high as 86.4%. The key to effective treatment of this disease lies in early diagnosis, with "improving water quality, preventing mold, and preventing hepatitis" as the main preventive measures.
Complications can be caused by liver cancer itself or coexisting cirrhosis, commonly seen in the advanced stage of the disease, and are often the cause of death.
(1) Hepatic encephalopathy: Often a terminal complication, accounting for 34.9% of the causes of death.
(2) Gastrointestinal bleeding: Accounts for 15.1% of the causes of death. Patients with coexisting cirrhosis or portal vein or hepatic vein tumor thrombus may experience bleeding due to rupture of esophageal or gastric varices caused by portal hypertension. Bleeding can also occur due to gastrointestinal mucosal erosion, coagulation disorders, etc.
(3) Liver cancer nodule rupture and bleeding: The incidence is about 9-14%. Necrosis and liquefaction of liver cancer tissue can lead to spontaneous rupture or rupture due to external force. If limited to the subcapsular area, there may be sudden pain and rapid liver enlargement; if it ruptures into the abdominal cavity, it can cause acute abdominal pain, peritoneal irritation, and in severe cases, hemorrhagic shock or death. In mild cases, bleeding stops after a few days, and the pain gradually decreases.
(4) Hemorrhagic pleural effusion: Liver cancer on the diaphragmatic surface can directly infiltrate or spread through blood or lymphatic flow, causing hemorrhagic pleural effusion, commonly seen on the right side.
(5) Secondary infections: Due to the long-term consumption by the tumor and weakened resistance, especially after radiation and chemotherapy when white blood cell counts drop, patients are prone to various infections such as pneumonia, intestinal infections, fungal infections, etc.
Primary liver cancer sometimes needs to be differentiated from the following diseases.
(1) Secondary liver cancer (secondary liver cancer) The liver is rich in blood supply, and other cancers can metastasize to the liver. According to our school's pathological anatomy data, secondary liver cancer is 1.2 times more common than primary liver cancer, with the majority originating from stomach cancer, followed by cancers of the lung, colon, pancreas, etc. Secondary liver cancer is mostly multiple nodules, and clinically, the primary cancer is the main manifestation. A few cases may only show signs of secondary liver cancer such as hepatomegaly, liver nodules, liver pain, jaundice, etc. Except for individual cases of secondary liver cancer originating from the stomach, colon, or pancreas, serum AFP is mostly negative.
(2) Liver cirrhosis, hepatitis Primary liver cancer often occurs on the basis of liver cirrhosis, making differentiation between the two often difficult. Differentia
