January 17, 2007

Hepatic Carcinoma, Primary

Synonyms and related keywords: hepatocellular carcinoma, HCC, hepatoma, liver cancer, primary liver cancer, liver carcinoma, primary liver carcinoma, cirrhosis, liver failure, liver dysfunction, hepatic dysfunction, liver tumor, hepatic tumor, liver disease, jaundice, hepatitis B, hepatitis C, hepatitis virus, alcoholism, alcoholic liver disease, hemochromatosis, aflatoxin, liver function test, liver function testing, LFTs, OLT, orthotopic liver transplantation, liver transplantation, liver transplant


Background: Hepatocellular carcinoma (HCC) is a primary malignancy of the hepatocyte, generally leading to death within 6-20 months. HCC frequently arises in the setting of cirrhosis, appearing 20-30 years following the initial insult to the liver. However, 25% of patients have no history or risk factors for the development of cirrhosis. The extent of hepatic dysfunction limits treatment options, and as many patients die of liver failure as from tumor progression.

Although it is currently one of the most common worldwide causes of cancer death, a major impact on the incidence of HCC should be achieved through current vaccination strategies for hepatitis B virus (HBV) infection, screening and treatment for hepatitis C virus (HCV) infections, and from the reduction of alcoholic liver disease. However, because the latency period from hepatic damage to HCC development is very long, it may be many years until the incidence of HCC decreases as a result of these interventions.

Pathophysiology: Tumors are multifocal within the liver 75% of the time. Late in the disease, metastases may develop in the lung, portal vein, periportal nodes, bone, or brain.


  • In the US: Although HCC is uncommon, comprising only 2% of all malignancies, since the mid-1980s the incidence of HCC has been rising at an alarming rate. The age-adjusted incidence rates increased 2-fold between 1980 and 1998. Much of this increase is likely due to hepatitis C infection, a known risk factor for HCC. The current incidence is 4 cases per 100,000, with about 8,500-11,000 new cases diagnosed each year.
  • Internationally: HCC is the fifth most common cancer in men and the eighth most common cancer in women worldwide. An estimated 560,000 new cases are diagnosed annually. The incidence of HCC worldwide varies according to the prevalence of hepatitis B and C infections. Areas such as Asia and sub-Saharan Africa with high rates of infectious hepatitis have incidences as high as 120 cases per 100,000.


  • Cure, usually through surgery, is possible in less than 5% of all patients.
  • Median survival from time of diagnosis is generally 6 months. Length of survival depends largely on the extent of cirrhosis in the liver; cirrhotic patients have shorter survival times and more limited therapeutic options; portal vein occlusion, which occurs commonly, portends an even shorter survival.
  • Complications from HCC are those of hepatic failure; death occurs from cachexia, variceal bleeding, or (rarely) tumor rupture and bleeding into the peritoneum.

Race: HCC is most commonly found among Asians, due to childhood infections with hepatitis B. However, due to the implementation of childhood hepatitis B vaccination programs in many Asian countries, a decrease in the incidence of HCC among Asians is expected.


  • HCC occurs more commonly in men than in women.
  • In the United States, 74% of HCC occurs in men.
  • In high-risk areas (China, sub-Saharan Africa, Japan), the difference between genders is more pronounced, with male-to-female ratios as high as 8:1.


  • Age at diagnosis varies widely according to geographic distribution.
  • In the United States and Europe, the median age at diagnosis is 65 years. HCC is rarely diagnosed before age 40 years. However, between 1975 and 1998, the 45- to 49-year age group had the highest rate, a 3-fold increase in the incidence of HCC.
  • In Africa and Asia, age at diagnosis is substantially younger, occurring in the fourth and fifth decades of life, respectively. Diagnosis at a younger age is thought to reflect the natural history of hepatitis B and C related HCC.


History: Patients generally present with symptoms of advancing cirrhosis.




Hepatocellular Adenoma

Other Problems to be Considered:

Dysplastic nodules in cirrhosis
Fibrous nodular hyperplasia
Metastatic disease
Primary hepatic lymphoma


Lab Studies:

Imaging Studies:

  • Ultrasonography is the least expensive choice for screening, but it is highly operator-dependent. A suspicious lesion on a sonogram generally requires additional imaging studies to confirm the diagnosis and the stage of the tumor. Sensitivity of ultrasonography for detection of small nodules is low. An advantage is that Doppler imaging can be performed at the same time to determine the patency of the portal vein.
  • Use the triphasic technique when performing CT scanning (ie, without contrast, then with early [arterial] and late [portal] imaging). The addition of arterial phase imaging to conventional CT scanning increases the number of tumor nodules detected. Unfortunately, in nodular cirrhotic livers, the sensitivity of CT scanning for detecting HCC is low. CT scanning has the added benefit of detecting extrahepatic disease, especially lymphadenopathy.
  • MRI may detect smaller lesions and can also be used to determine flow in the portal vein. The overall sensitivity of MRI is thought to be similar to that of triphasic CT scanning. However, in patients with nodular cirrhotic livers, MRI has been shown to have better sensitivity and specificity. High cost and restricted access to MRIs makes its widespread use limited.
  • Angiography shows characteristic tumor blush in HCC lesions. Less invasive imaging with CT scan and MRI has decreased the necessity for this mode of imaging. Angiography is still used for chemoembolization, one of the treatment options for HCC.
  • Chest radiography may demonstrate pulmonary metastases.
  • Bone scanning and head CT scanning are of low yield in the absence of specific symptoms.
  • PET scan has been evaluated in the experimental setting, but, to date, its role is uncertain. Routine use of PET scan for diagnosis or staging of HCC is not recommended.


  • Biopsy is frequently necessary in order to make the diagnosis. In general, core biopsy is favored over fine needle biopsy since larger amounts of tissue, often with normal surrounding parenchyma, can be obtained.
  • Controversy exists regarding the potential risk of tumor seeding along the needle tract. Some studies report a small increase in risk (approximately 1/1000), while others show no difference. Regardless, potential risks and complications should be considered before performing a biopsy.
  • Biopsy may be omitted in a clinical setting of a growing mass in a cirrhotic liver (>2 cm) noted on 2 coincident imaging techniques with at least one imaging showing contrast enhancement. Likewise, a growing mass in a cirrhotic liver on one imaging modality with an associated AFP level greater than 500-1000 ng/mL is clinically diagnostic of HCC. The need for biopsy should be carefully evaluated, especially if the risk for complications is high.
  • Biopsy is generally obtained percutaneously under ultrasonographic or CT guidance. Prior to obtaining biopsy, large-volume paracentesis may be useful in patients with massive ascites; similarly, platelet transfusion may be necessary in patients with cirrhosis with severe thrombocytopenia (less than 50,000). Bleeding risk does not correlate with elevations in prothrombin time.
  • Lesions that are 2-3 cm or smaller may be dysplastic nodules in a cirrhotic background. These are probably premalignant, and obtaining a biopsy is especially important to distinguish them from HCC. False-negative rates as high as 30-40% have been reported for biopsied tumors smaller than 2 cm in size.
  • Using laparoscopic guidance may make obtaining a percutaneous biopsy easier. Laparoscopy allows visualization of the liver to evaluate the extent of cirrhosis if surgery is being contemplated.
  • Obtaining a biopsy may be unnecessary in patients who will undergo resection regardless of diagnosis.
Histologic Findings: Histology is quite variable, ranging from well-differentiated tumors to anaplastic tumors. The fibrolamellar subtype is associated with a better prognosis, possibly because it is not associated with cirrhosis and is more likely to be resectable. The presence of intracellular bile or staining for AFP may be helpful in distinguishing HCC from other hepatic malignancies (eg, cholangiocarcinoma). Immunohistochemistry using the marker Hep-Par 1 may aid in the diagnosis. Aberrations of chromosome 1 and 8 are common features of HCC that can be detected by fluorescent in situ hybridization (FISH) technique. The role of FISH in the diagnosis of HCC is still under investigation.

Staging: The tumor, node, and metastases (TNM) staging system, while widely accepted, is really only useful in patients who undergo surgical resection. This is a small minority of patients.

Since most patients are unresectable, and prognosis actually depends more upon the state of the liver rather than the size of the tumor, several staging systems have been evaluated that incorporate clinical features of the liver and the patient, such as ascites, portal vein involvement, and performance status. One such system is the CLIP (Cancer of the Liver Italian Program) scoring system, which assigns a cumulative prognostic score ranging from 0-6 based upon Child-Pugh stage, tumor morphology, alpha-fetoprotein level, and portal vein thrombosis, which can predict median survival time. Below is a summary of the TNM staging criteria and the CLIP scoring system.

  • TNM staging criteria for HCC
    • T1 - Solitary tumor without vascular invasion
    • T2 - Solitary tumor with vascular invasion or multiple tumors none more than 5 cm
    • T3 - Multiple tumors more than 5 cm or tumor involving a major branch of the portal or hepatic vein(s)
    • T4 - Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum
    • N0 - Indicates no nodal involvement
    • N1 - Indicates regional nodal involvement
    • M0 - Indicates no distant metastasis
    • M1 - Indicates metastasis presence beyond the liver
  • Stage grouping
    • Stage I = T1 + N0 + M0
    • Stage II = T2 + N0 + M0
    • Stage IIIA = T3 + N0 + M0
    • Stage IIIB = T4 + N0 + M0
    • Stage IIIC = TX + N1 + M0
    • Stage IVB = TX + NX + M1
  • CLIP scoring system: Score of 0-2 is assigned for each of the 4 features listed below; cumulative score ranging from 0-6 is the CLIP score.
    • Child-Pugh stage
      • Stage A = 0
      • Stage B = 1
      • Stage C = 2
    • Tumor morphology
      • Uninodular and extension less than 50% = 0
      • Multinodular and extension less than 50% = 1
      • Massive and extension greater than 50% = 2
    • Alpha-fetoprotein
      • Less than 400 = 0
      • Greater than 400 = 1
    • Portal vein thrombosis
      • Absent = 0
      • Present = 1
    • Estimated survival based on CLIP score: Patients with a total CLIP score of 0 have an estimated survival of 31 months; those with score of 1, about 27 months; score of 2, 13 months; score of 3, 8 months; and scores 4-6, approximately 2 months.


Medical Care: Available treatment options depend on the size, number, and location of tumors; presence or absence of cirrhosis; operative risk based on extent of cirrhosis and comorbid diseases; overall performance status; patency of portal vein; and presence of metastatic disease.

Before instituting definitive therapy, it is best to treat the complications of cirrhosis with diuretics, paracentesis for ascites, lactulose for encephalopathy, ursodiol for pruritus, sclerosis or banding for variceal bleeding, and antibiotics for spontaneous bacterial peritonitis.

Surgical resection and liver transplantation are the only chances of cure but have limited applicability. The main prognostic factors for resectability are tumor size and liver function. Other local therapies are chemoembolization, ethanol ablation, radiofrequency ablation, cryoablation, and radiotherapy. Systemic treatment with chemotherapy may be used.

Surgical Care:



Further Outpatient Care:




Patient Education:


Medical/Legal Pitfalls:

Special Concerns:

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