Hepatocellular carcinoma (HCC), often referred to as liver cancer, is the most common malignant tumor of the liver, accounting for approximately 90% of all cases.
Etiology and Pathology
The development of HCC is believed to be associated with factors such as liver cirrhosis, viral hepatitis, aflatoxin exposure, and certain chemical carcinogens.
Macroscopically, HCC can be categorized into three types: nodular, massive, and diffuse. Tumors are traditionally classified into two groups based on their diameter, with 5 cm as the threshold: small HCC (diameter ≤5 cm) and large HCC (diameter >5 cm). HCC can be further categorized into tiny HCC (diameter ≤1 cm), small HCC (diameter >1 cm and ≤5 cm), large HCC (diameter >5 cm and ≤10 cm), and giant HCC (diameter >10 cm).
HCC cells frequently spread intrahepatically through the portal venous system, often leading to tumor thrombi. Obstruction of the main portal vein by these thrombi can result in clinical manifestations of portal hypertension. Extrahepatic metastasis is most commonly observed in the lungs, followed by bones, the brain, and other organs. Lymphatic spread is relatively uncommon but may involve the hepatic hilar lymph nodes, as well as lymph nodes around the pancreas, retroperitoneum, para-aortic region, and supraclavicular region. Direct invasion of adjacent organs, such as the diaphragm, stomach, or transverse colon, may occur, as well as peritoneal implantation metastasis.
Clinical Manifestations
HCC typically occurs in individuals aged 40–50 years and is more common in men than women. Early-stage HCC often lacks specific clinical features. By the time symptoms or signs appear, the disease is usually in the advanced stage. Common clinical manifestations include liver region pain, hepatomegaly or a palpable mass in the right upper quadrant, fatigue, weight loss, anorexia, jaundice, and abdominal distension.
Patients with metastases to the lungs, bones, brain, or other organs may develop corresponding symptoms. A small number of patients may present with specific manifestations such as hypoglycemia, polycythemia, hypercalcemia, or hypercholesterolemia.
Diagnosis and Differential Diagnosis
The clinical diagnosis of HCC can be established in patients with a history of liver disease, such as hepatitis B or C, an alpha-fetoprotein (AFP) level ≥400 ng/mL, and imaging studies (ultrasound, CT, or MRI) revealing a solid mass in the liver with classic imaging features of HCC.
It is important to note that increased AFP levels may also be observed in conditions such as pregnancy, active liver disease, and germ cell tumors. These should be excluded before making a diagnosis. In cases of mildly elevated AFP, dynamic monitoring, along with analysis of liver function changes and imaging studies, is recommended. Approximately 30% of HCC patients have completely normal AFP levels. In such cases, the detection of AFP isoforms can aid in diagnosis. Liver function-related enzyme levels may be elevated, but they lack specificity.
For cases with diagnostic difficulty, hepatic arteriography can be performed for further evaluation. Therapeutic transarterial chemoembolization (TACE) may also be considered for diagnostic purposes. Ultrasound-guided liver biopsy can provide diagnostic confirmation, although it carries the risk of false-negative results, needle tract bleeding, or tumor seeding along the needle path.
HCC must be differentiated from conditions such as liver cirrhosis, secondary (metastatic) liver cancer, benign liver tumors, liver abscess, hepatic echinococcosis, and tumors of adjacent organs, including the right kidney, hepatic flexure of the colon, stomach, and pancreas.
Treatment
Early diagnosis and comprehensive treatment primarily centered on surgical resection are key to improving the long-term outcomes of hepatocellular carcinoma (HCC).
Liver Resection
Liver resection can be divided anatomically into anatomic and non-anatomic liver resection, and based on surgical radicality into curative and non-curative liver resection. Surgical approaches include open liver resection, laparoscopic liver resection, and robot-assisted liver resection. Overall, the five-year survival rate after liver resection is 30%–40%. For tiny and small HCC, the five-year survival rate may exceed 75%. The main factors influencing surgical outcomes include the number of tumors, vascular invasion, tumor differentiation, and biological characteristics.
Criteria for Curative Liver Resection
Intraoperative assessment:
- No tumor invasion of the main branches or major tributaries of the hepatic vein, portal vein, bile duct, or inferior vena cava.
- No invasion of adjacent organs, hepatic hilar lymph nodes, or distant metastasis.
- Complete tumor resection within the boundaries of liver segments, lobes, hemi-liver, or tri-lobe areas, following liver anatomical landmarks.
- A surgical margin >1.0 cm from the tumor edge, or if the margin is <1.0 cm, histological analysis of the remaining liver tissue on the surgical margin indicates no residual tumor cells (negative surgical margin).
Postoperative assessment:
- Ultrasound, CT, or MRI (at least two of these) performed two months after surgery reveals no residual tumor lesions.
- In cases with preoperative elevated AFP levels, AFP returns to the normal range within two months postoperatively (with rare exceptions where normalization takes longer).
Indications for Surgery
Patient conditions:
- Overall condition is favorable, with a performance status score of 0–1, and no significant organic diseases of critical organs such as the heart, lungs, or kidneys.
- Child-Pugh grade A liver function, or grade B that improves to grade A after short-term liver protective therapy.
- Adequate liver reserve function, confirmed with normal indocyanine green (ICG) retention test results.
Curative liver resection:
- Single tumor with an estimated residual liver volume of at least 50% after resection.
- Multiple tumors confined to a single liver segment or one liver lobe.
- No multiple intrahepatic metastases or extrahepatic metastases.
Non-curative liver resection is performed to provide opportunities for further treatment, prolong survival, or potentially achieve a cure in select cases. For example, patients with HCC invading critical intrahepatic structures, adjacent organs, portal vein tumor thrombus, or inferior vena cava tumor thrombus may undergo liver resection if their overall condition permits. In such cases, since negative surgical margins or complete removal of all tumor tissue cannot be ensured, the resection is considered non-curative.
Patients with moderate to severe hypersplenism and esophageal varices secondary to HCC may undergo limited liver resection combined with splenectomy, and, if necessary, devascularization procedures.
Surgical Treatment for Unresectable HCC
Patients with unresectable HCC may benefit from intraoperative hepatic artery embolization chemotherapy, cryoablation, radiofrequency ablation (RFA), or microwave ablation, depending on the specific situation. These treatments have shown some efficacy.
Liver Transplantation
Indications for liver transplantation include:
- Patients with Child-Pugh grade C liver function or long-standing grade B liver function that does not improve with liver protective therapy.
- Single tumors with a diameter ≤5 cm or no more than three tumors, each with a diameter ≤5 cm.
- No vascular invasion or distant metastases.
Patients selected based on these criteria may achieve favorable long-term outcomes.
Ablation Therapy
Common ablation methods include radiofrequency ablation (RFA), microwave ablation, cryotherapy, and chemical ablation (e.g., ethanol injection). These techniques are typically performed percutaneously under ultrasound guidance, but intraoperative ablation is also possible. Ablation is suitable for patients with small tumors who are ineligible for surgical resection or for those with early postoperative tumor recurrence.
Interventional Therapy
This method involves the insertion of a catheter through the femoral artery into the hepatic artery of the tumor. Once the arterial supply to the tumor is identified, embolic agents (e.g., lipiodol injection or drug-eluting microspheres) and chemotherapeutic drugs are administered. This treatment can partially necrotize the tumor, reduce its size, and prolong survival. In rare cases, complete necrosis of the tumor may occur, leading to a cure.
Immunotherapy and Gene Therapy
Commonly used drugs include thymosin and interferons. In recent years, new drugs such as PD-L1 (programmed death-ligand 1) monoclonal antibodies and CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) monoclonal antibodies have been introduced, often in combination. Combined immunotherapy and targeted therapy regimens include PD-L1 monoclonal antibodies with VEGF monoclonal antibodies, or PD-1 monoclonal antibodies with bevacizumab.
Radiotherapy
Radiotherapy may be utilized for localized tumors without distant metastases when surgical resection is not feasible or for patients with residual cancer on the liver margin or recurrent tumors after surgery.
Management of HCC Complications
The most common complication of HCC is tumor rupture with bleeding. Minor ruptures often resolve spontaneously, while heavy bleeding may require emergency transarterial embolization (TAE) or TACE, or emergency liver resection. In critical cases where surgical conditions are unfavorable, tamponade with gauze may be performed to control bleeding, followed by further interventions once the patient stabilizes.
Patients with portal vein tumor thrombus are prone to gastrointestinal bleeding, which should be managed in accordance with diagnostic and surgical guidelines for gastrointestinal hemorrhage.