Primary liver cancer refers to malignant tumors originating from hepatocytes and intrahepatic bile duct epithelial cells. It includes three pathological types: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Among these, HCC accounts for 75%–85%, ICC for 10%–15%, and "liver cancer" in clinical practice typically refers to HCC.
Etiology and Pathogenesis
More than 80% of HCC cases arise from liver cirrhosis. Therefore, any factor causing chronic liver damage and eventually leading to cirrhosis is considered a risk factor for HCC.
Viral Hepatitis
HBV infection is the primary cause of liver cancer in Asian, while HCV infection is more common in Western countries. HBV-related carcinogenesis involves disruption or integration of HBV DNA sequences with host cell genes, leading to oncogene activation and tumor suppressor gene inactivation, which promotes cellular transformation. HCV-related carcinogenesis is associated with HCV sequence mutations that evade immune recognition, resulting in persistent infection. Chronic inflammation, hepatocyte necrosis, and repeated regeneration lead to accumulated genetic mutations, disrupting the dynamic balance of cell proliferation and ultimately causing malignant transformation.
Aflatoxins
Epidemiological studies have shown that regions with significant aflatoxin contamination in food have higher liver cancer incidence. Aflatoxin B1, a metabolic product of aflatoxins, contributes to liver cancer by affecting the expression of genes such as RAS and TP53.
Other High-Risk Factors for Liver Cancer
Alcohol and Smoking
Daily alcohol consumption of more than 40–60 g is associated with a linear increase in HCC risk. Smoking also increases HCC risk and has a synergistic effect with alcohol.
Obesity, Diabetes, and Metabolic Syndrome
These are risk factors for non-alcoholic fatty liver disease, which can lead to steatohepatitis, cirrhosis, and HCC.
Parasitic Infections
Infections caused by Schistosoma or Clonorchis sinensis are also risk factors.
These factors promote changes in the biological characteristics of hepatocytes during the process of regeneration and repair after damage, leading to genetic mutations, oncogene expression, and tumor suppressor gene inhibition. Imbalances between cell proliferation and apoptosis, along with active angiogenesis during chronic inflammation and fibrosis, create essential conditions for the development and progression of liver cancer.
Pathology
Gross Pathological Types
Solitary Nodular Type
The lesion is relatively well-defined, often spherical, with a homogeneous cut surface. A capsule may or may not be present. Liver cancer with a single nodule ≤5 cm in diameter or multiple nodules (≤3 lesions with the largest ≤3 cm) is referred to as small liver cancer.
Nodular Type
This is the most common type, characterized by multiple cancerous nodules, often accompanied by liver cirrhosis.
Diffuse Type
This rare type features cancer tissues diffusely distributed throughout the liver, making it difficult to distinguish from cirrhotic areas. Patients often die from liver failure.
Massive Type
The tumor is large, typically exceeding 10 cm in diameter, and more commonly found in the right lobe of the liver. A capsule may be present. The cut surface often shows necrosis and hemorrhage at the center. Tumors near the liver capsule are prone to rupture, causing intraperitoneal bleeding and direct dissemination.
Histopathological Types
HCC
The most common type, derived from hepatocytes, shows significant cellular atypia. The cells are polygonal with abundant cytoplasm and are arranged in nests or cords with rich sinusoidal capillaries. In normal liver tissue, arterial blood accounts for about 30% of the blood supply, but in HCC, arterial blood accounts for more than 90%. This serves as the basis for imaging diagnosis and interventional treatment of liver cancer.
ICC
Less common, ICC originates from epithelial cells lining intrahepatic bile duct branches. Adenocarcinoma is the most prevalent subtype.
cHCC-CCA
This is the rarest type, characterized by the coexistence of HCC and ICC components within the same tumor nodule.
Metastatic Pathways
Intrahepatic Metastasis
Cancer cells frequently invade the portal vein and its branches, forming tumor thrombi that detach and cause multiple metastatic lesions within the liver.
Extrahepatic Metastasis
Extrahepatic metastasis includes:
- Hematogenous Metastasis: The lungs are the most common site of metastasis, followed by the brain, adrenal glands, kidneys, and bones. Tumor thrombi in the hepatic veins may extend into the inferior vena cava and the right atrium.
- Lymphatic Metastasis: Commonly involves the lymph nodes of the hepatic hilum, pancreas, spleen, para-aortic region, and supraclavicular nodes.
- Seeding Metastasis: Rarely, cancer cells shed from the liver surface may seed the peritoneum, diaphragm, pelvis, and other areas, causing hemorrhagic ascites or pleural effusion. Ovarian metastasis may occur in females.
Clinical Manifestations
This disease is more common in middle-aged males, with a male-to-female ratio of approximately 3:1. The onset is insidious, and early stages lack typical symptoms. By the time clinical symptoms become apparent, the disease has often progressed to the middle or late stages. It frequently develops on the basis of liver cirrhosis or may initially present with symptoms of metastatic lesions, which can lead to misdiagnosis or missed diagnosis. The clinical manifestations in the middle and late stages are as follows:
Pain in the Liver Region
This is the most common symptom of liver cancer, typically presenting as persistent distending pain or dull pain in the right upper abdomen. The pain is related to tumor growth and stretching of the liver capsule. If the lesion invades the diaphragm, the pain may radiate to the right shoulder or back. When cancerous nodules on the liver surface rupture, sudden severe abdominal pain may occur, starting in the liver region and rapidly spreading throughout the abdomen. Massive bleeding can lead to shock.
Hepatomegaly
The liver progressively enlarges, becoming hard with an inhomogeneous surface. It often presents with nodules of varying sizes, blunt and irregular edges, and varying degrees of tenderness. When the tumor protrudes below the right costal margin or xiphoid process, localized bulging or fullness may be observed in the upper abdomen. If the tumor is located on the diaphragmatic surface, it may mainly manifest as elevation of the diaphragm without downward displacement of the liver margin.
Jaundice
Jaundice generally occurs in the late stages of liver cancer and is mostly obstructive in nature, with a minority being hepatocellular. Obstructive jaundice is often caused by tumor compression or invasion of the bile ducts, or by enlarged metastatic lymph nodes in the hepatic hilum compressing the bile ducts. Hepatocellular jaundice may result from extensive infiltration of cancer tissue within the liver or from coexisting liver cirrhosis and chronic hepatitis.
Signs of Cirrhosis
In cases where liver cancer develops on the basis of decompensated cirrhosis, rapid and refractory ascites may occur. The ascitic fluid is often transudative, while bloody ascites may result from liver cancer invading the liver capsule or rupturing into the abdominal cavity. Portal hypertension can lead to esophageal and gastric varices.
Systemic Symptoms
Progressive emaciation, fever, loss of appetite, fatigue, malnutrition, and cachexia are common. In some patients, the initial presentation may be symptoms related to metastatic lesions.
Paraneoplastic Syndromes
These syndromes result from abnormal metabolism of the tumor itself or endocrine/metabolic dysfunction in liver cancer patients. They may include spontaneous hypoglycemia and erythrocytosis. Other rare manifestations include hypercalcemia, hyperlipidemia, and carcinoid syndrome.
Complications
Hepatic Encephalopathy
This is the most severe complication in the terminal stage of liver cancer. The prognosis is poor once hepatic encephalopathy occurs.
Upper Gastrointestinal Bleeding
Upper gastrointestinal bleeding accounts for approximately 15% of liver cancer-related deaths. The bleeding is associated with the following factors:
- Esophageal and gastric varices.
- Portal hypertensive gastropathy combined with coagulation dysfunction, leading to widespread bleeding. Massive bleeding often precipitates hepatic encephalopathy.
Rupture and Hemorrhage of Liver Cancer Nodules
Approximately 10% of liver cancer patients experience rupture and hemorrhage of cancer nodules. Rupture may be confined to the subcapsular region of the liver, causing localized pain. If subcapsular bleeding increases rapidly, a tender hematoma may form. Rupture into the abdominal cavity can lead to acute abdominal pain, peritoneal irritation signs, and bloody ascites. Massive bleeding may result in shock or death.
Secondary Infections
Due to prolonged systemic depletion or treatments such as chemotherapy and radiotherapy, patients often experience weakened immunity, making them susceptible to secondary infections such as pneumonia, spontaneous peritonitis, intestinal infections, and fungal infections.
Laboratory and Other Auxiliary Examinations
Liver Cancer Biomarkers
Alpha-Fetoprotein (AFP)
AFP is a commonly used indicator for the diagnosis, therapeutic monitoring, and recurrence prediction of liver cancer. In the absence of chronic or active hepatitis, pregnancy, and gonadal germ cell tumors, an AFP level >400 ng/ml strongly suggests liver cancer. Mildly elevated AFP levels require comprehensive analysis or dynamic observation in conjunction with imaging findings and liver function changes. The detection of AFP isoforms can improve diagnostic accuracy.
Other Liver Cancer Biomarkers
Abnormal prothrombin (PIVKA-II or DCP), γ-glutamyl transferase isoenzyme II (γ-GT2), and plasma free microRNA (miRNA) are helpful for the diagnosis and differentiation of AFP-negative liver cancer.
Imaging Studies
Ultrasound (US)
Ultrasound offers advantages such as convenience, real-time imaging, non-invasiveness, and low cost, and it can detect liver lesions larger than 1 cm in diameter. Contrast-enhanced ultrasound allows dynamic observation of tumor blood flow perfusion changes, aiding in the differentiation of liver tumors of various natures. Intraoperative ultrasound can significantly improve the detection rate of small, hidden lesions.
Contrast-Enhanced CT/MRI
Dynamic contrast-enhanced CT and multiparametric MRI are the preferred diagnostic methods for individuals with abnormal findings on liver ultrasound and/or serum AFP screening. MRI, being a non-radiative examination, allows for repeated short-term evaluations. In the arterial phase, liver tumors typically show homogeneous or heterogeneous intense enhancement, while in the portal venous phase and/or delayed phase, enhancement is lower than that of liver parenchyma, demonstrating a "rapid wash-in and wash-out" pattern. Hepatocyte-specific contrast agents such as gadoxetic acid disodium (Gd-EOB-DTPA) used in enhanced MRI can improve the sensitivity of detecting liver cancers smaller than 1.0 cm in diameter.
Digital Subtraction Angiography (DSA)
Selective or superselective hepatic artery DSA can visualize the vascular structure of liver tumors, clarify the number, size, and blood supply of tumors, and is also applicable for local treatment of liver cancer or management of spontaneous rupture and bleeding of liver tumors.
Nuclear Medicine Imaging
Techniques such as positron emission tomography-CT (PET-CT), single-photon emission computed tomography-CT (SPECT-CT), and positron emission tomography-MRI (PET-MRI) are useful for staging liver cancer and evaluating treatment efficacy.
Liver Biopsy
Liver tumor biopsy can confirm the nature of the lesion. Fine-needle aspiration guided by US or CT for histological examination is a reliable method for diagnosing liver cancer. However, potential risks include bleeding and tumor seeding along the needle tract.
Diagnosis
The clinical diagnosis of liver cancer should be based on a combination of high-risk factors, imaging characteristics, and serum molecular markers. For individuals with HBV or HCV infection, or liver cirrhosis caused by any etiology, liver cancer can be clinically diagnosed if either of the following criteria is met:
- The lesion is ≤2 cm in diameter and exhibits two typical imaging characteristics of liver cancer (dynamic contrast-enhanced CT, multiparametric MRI, contrast-enhanced ultrasound, or Gd-EOB-DTPA-enhanced MRI).
- The lesion is >2 cm in diameter and exhibits one typical imaging characteristic of liver cancer, accompanied by elevated serum AFP levels, particularly if the elevation is persistent.
In the following situations, liver lesion biopsy or close monitoring of serum AFP changes and imaging alterations is required to confirm the diagnosis:
- Lesions ≤2 cm in diameter with none or only one typical imaging characteristic of liver cancer.
- Lesions >2 cm in diameter without typical imaging characteristics of liver cancer.
The Barcelona Clinic Liver Cancer (BCLC) staging system is currently one of the most widely used staging systems internationally.
Differential Diagnosis
Liver cancer often needs to be differentiated from secondary liver cancer, liver cirrhosis, liver abscess, and other conditions.
Secondary Liver Cancer
Primary cancers originating from the respiratory tract, gastrointestinal tract, genitourinary system, or breast frequently metastasize to the liver, with colorectal cancer being the most common. These typically present as multiple nodules, with clinical manifestations primarily reflecting the primary cancer. Serum AFP levels are generally negative.
Liver Cirrhosis Nodules
On contrast-enhanced CT/MRI, lesions with arterial phase enhancement and a "rapid wash-in and wash-out" pattern suggest liver cancer. Lesions without enhancement are more likely to be cirrhotic nodules. An AFP level >400 ng/ml supports the diagnosis of liver cancer.
Active Viral Hepatitis
During active viral hepatitis, serum AFP levels often show a transient, mild elevation. Regular follow-up with repeated measurements of serum AFP and ALT is necessary, along with the combined detection of other liver cancer biomarkers and analysis.
Liver Abscess
Liver abscesses present clinically with fever, liver pain, and significant tenderness, accompanied by elevated white blood cell and neutrophil counts. Ultrasound can reveal hypoechoic fluid-filled areas characteristic of abscesses. Diagnostic aspiration under ultrasound guidance or trial therapy with antibiotics may confirm the diagnosis if necessary.
Echinococcosis of the Liver
Patients often have a history of living in pastoral areas or exposure to infected dogs.
Other Liver Tumors or Lesions
When differentiation from benign liver tumors such as hemangiomas, hepatic adenomas, or focal nodular hyperplasia is challenging based on imaging, tumor biomarkers like AFP can be assessed. Follow-up with ultrasound or contrast-enhanced CT/MRI may be required, and liver biopsy under ultrasound or CT guidance can be performed when necessary.
Treatment
The treatment of liver cancer involves multidisciplinary collaboration and a combination of therapeutic approaches. Common treatments include surgical resection, ablation therapy, transcatheter arterial chemoembolization (TACE), liver transplantation, radiotherapy, and systemic anti-tumor therapies. Selecting the appropriate treatment based on the stage of liver cancer can achieve optimal outcomes.
Surgical Treatment
Surgical resection is a key approach for achieving long-term survival in liver cancer patients. The principle of resection is to completely remove the tumor while preserving sufficient functional liver tissue. This requires comprehensive preoperative evaluation of liver function reserves and tumor characteristics. Preoperative assessments often include the Child-Pugh score and the indocyanine green retention rate at 15 minutes (ICGR15) to evaluate liver function. Surgical resection is generally considered feasible under one of the following conditions:
- Liver function classified as Child-Pugh A and ICGR15 < 30%.
- The remaining liver volume should account for more than 30% of the standard liver volume (in patients without fibrosis or cirrhosis) or more than 40% (in patients with chronic liver disease, liver parenchymal damage, or cirrhosis).
Ablation Therapy
Ablation therapy targets tumor lesions directly using physical or chemical methods under the guidance of ultrasound, CT, or MRI. This approach is minimally invasive and effective. Common ablation methods include radiofrequency ablation (RFA), microwave ablation (MWA), percutaneous ethanol injection (PEI), and high-intensity focused ultrasound ablation (HIFU).
Ablation therapy can achieve curative outcomes for patients with single tumors ≤5 cm in diameter or 2–3 tumors with the largest ≤3 cm. For single tumors measuring 3–7 cm or multiple tumors that are unresectable, ablation therapy can be combined with TACE.
Transcatheter Arterial Chemoembolization (TACE)
TACE involves injecting embolic agents into the tumor's feeding arteries to block its blood supply, leading to tumor necrosis. Due to its high targeting specificity, minimal invasiveness, and repeatability, TACE is a commonly used non-surgical treatment for liver cancer. Combining TACE with surgery, ablation therapy, radiotherapy, or molecular-targeted drugs can further improve treatment outcomes.
Liver Transplantation
Liver transplantation is a curative treatment for liver cancer, particularly suitable for patients with decompensated liver function, small liver cancers unsuitable for surgical resection or ablation therapy. Liver transplantation is not recommended for patients with major vascular invasion or extrahepatic metastasis. Post-transplantation immunosuppressive therapy, primarily with mammalian target of rapamycin (mTOR) inhibitors, can reduce tumor recurrence rates and improve survival.
Radiotherapy
For patients with unresectable liver cancer, palliative radiotherapy or radiotherapy combined with TACE may extend survival.
Systemic Anti-Tumor Therapy
Systemic therapy includes molecular-targeted therapies, chemotherapy, and immunotherapy for liver cancer, as well as treatment for underlying liver diseases, such as antiviral therapy and supportive care.
Since over 70% of liver cancer patients lose the opportunity for curative treatment at the time of diagnosis due to the disease's insidious onset, systemic anti-tumor therapy plays an important role in the treatment of liver cancer.
Prognosis
The prognosis is better in the following situations:
- Tumor diameter <5 cm, with early surgical intervention.
- Tumor encapsulation is intact, with high differentiation and no evidence of vascular invasion.
- The patient's immune status is favorable.
Poor prognosis is associated with liver cirrhosis, extrahepatic metastasis, tumor rupture, or gastrointestinal bleeding.