Hepatocellular Carcinoma Workup

  • Author: David A Axelrod, MD, MBA; Chief Editor: John Geibel, MD, DSc, MA   more...
 
Updated: Dec 13, 2011
 

Laboratory Studies

Laboratory evaluation of patients with newly diagnosed hepatocellular carcinoma should include testing to determine the severity of the underlying liver disease and to elucidate the etiology of the underlying disease. Laboratory studies should include a complete blood count, electrolytes, liver function tests, coagulation studies (eg, INR, PTT), and alpha-fetoprotein determination.

Disease severity

  • Anemia: Low hemoglobin may be related to bleeding from varices or other sources.
  • Thrombocytopenia: A platelet count below 100,000/mL is highly suggestive of significant portal hypertension/splenomegaly.
  • Hyponatremia is commonly found in patients with cirrhosis and ascites and may be a marker of advanced liver disease.
  • Increased serum creatinine level may reflect intrinsic renal disease or hepatorenal syndrome.
  • Prolonged PT/INR reflects significant impairment of hepatic function that may preclude resection.
  • Elevated liver enzymes (AST/ALT) reflect active hepatitis due to viral infection, current alcohol use, or other causes.
  • Increased bilirubin level usually indicates advanced liver disease.
  • Hypoglycemia may represent end-stage liver disease (no glycogen stores).

Disease etiology

  • HBsAg/anti-HBc, anti-HCV - Viral hepatitis (current/past)
  • Increased iron saturation (>50%) - Underlying hemochromatosis
  • Low alpha-1-antitrypsin levels - Alpha-1-antitrypsine deficiency
  • Tumor/paraneoplastic phenomena
  • Increased alpha fetoprotein - Levels greater than 400 ng/mL considered diagnostic with appropriate imaging studies
  • Hypercalcemia - Ectopic parathyroid hormone production possible in 5-10% of patients with hepatocellular carcinoma
  • Thrombocytosis (normal/rapid increase in platelet count in patients with a history of thrombocytopenia)
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Imaging Studies

Accurate diagnosis and surgical planning require adequate cross-sectional imaging studies. While ultrasound is commonly used for screening, it does not provide sufficient anatomic detail for planning surgical resection or ablation. Recently, correlation between ultrasonographic findings and explant liver pathology revealed that a significant number of small lesions may not be detected using ultrasound screening. Pooled estimates from a recent meta-analysis suggest that ultrasound is only 60% sensitive.[21]

Ultrasonographic identification of hepatocellular carcinoma can be difficult in the background of regenerative nodules in the cirrhotic liver. In general, hepatocellular carcinoma appears to be a round or oval mass with sharp, smooth boundaries. The lesions have a range of echogenicity, from hypoechoic to hyperechoic, depending on the surrounding parenchyma and the degree of fatty infiltration. The border between the hepatocellular carcinoma and the liver can become indistinct with nodular hepatocellular carcinoma. The use of Doppler analysis to characterize the lesion can be helpful, as hepatocellular carcinoma is more likely to have a significant arterial blood supply and neovascularization as compared to regenerative nodules.

Ultrasonographic image of hepatocellular carcinomaUltrasonographic image of hepatocellular carcinoma.

Triple phase CT scanning including arterial phase, portal venous phase, and late washout phase has been found to be highly accurate in the diagnosis and characterization of hepatocellular carcinomas but, like ultrasound, may miss smaller lesions. Pooled estimates reveal a sensitivity of 68% (95% CI 55–80) and a specificity of 93% (95% CI 89–96).[21] Disadvantages of CT scanning include cost, radiation exposure, and the need for iodinated contrast.

Classic CT findings of hepatocellular carcinoma include a hypervascular pattern with arterial enhancement and rapid washout during the portal venous phase.[27] In contrast, regenerative nodules generally appear isoattenuating or hypoattenuating when compared to the remaining parenchyma. Other characteristics that support the diagnosis of hepatocellular carcinoma include visualization of a tumor capsule, demonstration of an internal mosaic resulting from variable attenuation within the tumor, and portal vein branch invasion. Unfortunately, all of these characteristics are more easily demonstrated in large lesions. Consequently, small lesions are frequently missed on CT examination.

Arterial phase CT scan demonstrating enhancement oArterial phase CT scan demonstrating enhancement of hepatocellular carcinoma. Portal venous phase CT scan demonstrating washout Portal venous phase CT scan demonstrating washout of hepatocellular carcinoma.

MRI provides an excellent method to characterize hepatocellular carcinoma without radiation and the need for iodinated contrast. Recent technological improvements have reduced scanning time and improved the specificity of the study. Pooled analysis demonstrated a sensitivity of 81% (95% CI 70–91) and a specificity of 85% (95% CI 77–93).[21]

Hepatocellular carcinoma demonstrates a variety of features on MRI depending upon the tumor architecture, grade, and amount of intratumoral fat and glycogen.[27] The lesion varies from isointense to hyperintense (bright) on T1-weighted images. Similarly, T2 images may vary from isointense to hyperintense. Well-differentiated tumors are more commonly hyperintense on T1 images and isointense on T2 images, while moderately or poorly differentiated tumors tend to be hyperintense on T2 images and isointense on T1 images. While imaging characteristics may be suggestive, a significant overlap may occur between the tumor and regenerative nodules.

MRI of a liver with hepatocellular carcinoma. MRI of a liver with hepatocellular carcinoma.

The benefits of contrast-enhanced studies must be balanced against the risks if any anatomic or functional renal impairment is possible. Iodinated contrast for CT may worsen renal failure, and gadolinium enhancement on MRI has been linked to a syndrome of severe systemic fibrosis in a patient with renal failure.[28]

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Diagnostic Procedures

The decision to biopsy a lesion suspected of being hepatocellular carcinoma is the subject of ongoing controversy. In patients with large tumors who are not candidates for resection or transplantation, biopsy is frequently not indicated to confirm the diagnosis prior to initiating palliative procedures, because clinical and imaging evidence is convincing and biopsy is potentially risky.

In patients with lesions less than 1 cm, less than half will be malignant, and the false-negative result rate is high. Thus, conservative management with close follow-up and no biopsy is recommended.[13]

In patients with 1- to 2-cm lesions, a biopsy should be performed, as these patients have a significant risk of malignancy. If the result is positive, they are candidates for resection, transplantation, or ablative therapy. As in the smaller lesions, there is a significant false-negative result rate, and close follow-up is indicated in patients with a negative biopsy result.

Patients with lesions greater than 2 cm, cirrhosis, characteristic imaging studies, and elevated AFP values can be managed without biopsy. In these patients, the risk of tumor seeding must be taken into account. While some groups require biopsy prior to transplantation,[13] others are willing to proceed on clinical characteristics alone.[29] In patients with more atypical findings on imaging studies, the value of AFP should not be overemphasized, because an excessive number of patients submitted to transplantation did not have hepatocellular carcinoma.[15]

In patients with cirrhosis who are being considered for resection, survival following resection has been previously correlated with the degree of portal hypertension. In some centers, determination of the wedged hepatic vein pressure is advocated to then determine the safety of resection. Resection can, in general, be safely undertaken in patients with a wedged hepatic venous pressure gradient of less than 10.[13] Patients should also have a platelet count greater than 100,000/mL and a normal bilirubin level. In patients with small tumors but significant hepatic dysfunction, transplantation is the preferred option.

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Staging

The prognosis of hepatocellular carcinoma is a reflection of both tumor characteristics (ie, size, location, tumor biology) and the degree of underlying liver disease. The traditional pathological TNM (tumor, node, metastasis) staging system, while helpful in determining a prognosis in patients undergoing resection, is not as useful in planning treatment, as it fails to include measures of the severity of the liver disease. However, the tumor size is predictive of outcome, as it predicts the likelihood of major venous involvement.[30]

Likewise, the Child-Pugh-Turcotte score predicts perioperative survival following resection, but it does not incorporate tumor size, number, and location, which have important implications for respectability and treatment. Among the scales that integrate the tumor and liver disease characteristics, the Barcelona Clinic Liver Cancer (BCLC),[13] the Japan Integrated Staging System, and the Cancer of the Liver Italian Program (CLIP) are the most widely used staging systems. The BCLC system is very useful in deciding among potential treatment options and correlates best with patient outcome among the major staging systems.[31]

The Barcelona-Clinic Liver Cancer (BCLC) approach The Barcelona-Clinic Liver Cancer (BCLC) approach to hepatocellular carcinoma management. Adapted from Llovet JM, Fuster J, Bruix J, Barcelona-Clinic Liver Cancer Group. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl. Feb 2004;10(2 Suppl 1):S115-20.

In the BCLC system, stage 0 patients have lesions less than 2 cm, normal bilirubin levels, and normal portal pressure measurements. These patients can often undergo resection safely with excellent long-term survival.

Patients with larger tumors (ie, single tumors < 5 cm or multiple tumors [≤3] < 3 cm) are considered for resection if they have preserved liver function or for transplantation if they have decompensated cirrhosis.

In patients whose tumor exceeds these measurements, palliative therapy can be offered depending upon hepatic reserve, but long-term survival (>3 y) occurs in less than 10% of patients.

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Contributor Information and Disclosures
Author

David A Axelrod, MD, MBA  Assistant Professor of Surgery, Section Chief, Solid Organ Transplantation, Dartmouth-Hitchcock Medical Center

David A Axelrod, MD, MBA is a member of the following medical societies: American College of Surgeons, American Society of Transplant Surgeons, and New Hampshire Medical Society

Disclosure: Nothing to disclose.

Coauthor(s)

Dirk J van Leeuwen, MD, PhD  Professor of Medicine, Dartmouth Medical School; Consulting Staff, Director of Hepatology, Associate Director, Hepatopancreatico-biliary Center, Dartmouth-Hitchcock Medical Center; Consulting Gastroenterologist, White River Junction Veterans Administration Medical Center

Dirk J van Leeuwen, MD, PhD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, Dutch Society of Gastroenterology/Enterology, Dutch Society of Hepatology, European Association for the Study of the Liver, and New Hampshire Medical Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Burt Cagir, MD, FACS  Assistant Professor of Surgery, State University of New York Upstate Medical University; Consulting Staff, Director of Surgical Research, Robert Packer Hospital; Associate Program Director, Department of Surgery, Guthrie Clinic

Burt Cagir, MD, FACS is a member of the following medical societies: American College of Surgeons, American Medical Association, and Society for Surgery of the Alimentary Tract

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Paolo Zamboni, MD  Professor of Surgery, Chief of Day Surgery Unit, Chair of Vascular Diseases Center, University of Ferrara, Italy

Paolo Zamboni, MD is a member of the following medical societies: American Venous Forum and New York Academy of Sciences

Disclosure: Nothing to disclose.

Chief Editor

John Geibel, MD, DSc, MA  Vice Chair and Professor, Department of Surgery, Section of Gastrointestinal Medicine, and Department of Cellular and Molecular Physiology, Yale University School of Medicine; Director, Surgical Research, Department of Surgery, Yale-New Haven Hospital

John Geibel, MD, DSc, MA is a member of the following medical societies: American Gastroenterological Association, American Physiological Society, American Society of Nephrology, Association for Academic Surgery, International Society of Nephrology, New York Academy of Sciences, and Society for Surgery of the Alimentary Tract

Disclosure: AMGEN Royalty Consulting; ARdelyx Ownership interest Board membership

Additional Contributors

The authors would like to acknowledge Arief Suriawinata, MD, of the Department of Pathology at Dartmouth Medical School for the gross images and the photomicrographs contained in this article.

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Large hepatocellular carcinoma.
Photomicrograph of a liver demonstrating hepatocellular carcinoma.
MRI of a liver with hepatocellular carcinoma.
Ultrasonographic image of hepatocellular carcinoma.
Arterial phase CT scan demonstrating enhancement of hepatocellular carcinoma.
Portal venous phase CT scan demonstrating washout of hepatocellular carcinoma.
The Barcelona-Clinic Liver Cancer (BCLC) approach to hepatocellular carcinoma management. Adapted from Llovet JM, Fuster J, Bruix J, Barcelona-Clinic Liver Cancer Group. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl. Feb 2004;10(2 Suppl 1):S115-20.
Hepatocellular carcinoma: pathobiology.
Table 1. Risk Factors for Primary Liver Cancer and Estimate of Attributable Fractions[3]
Europe and United StatesJapanAfrica and Asia
EstimateRangeEstimateRangeEstimateRange
HBV224-582018-446040-90
HCV6012-726348-94209-56
Alcohol458-572015-33-11-41
Tobacco120-14409-5122-
OCPs-10-50--8-
AflatoxinLimited exposureLimited exposureLimited exposure
Other< 5---< 5-
Table 2. Serum Alpha-Fetoprotein (AFP) Determination in Liver Disease[17]
Alpha-fetoprotein (ng/mL)Interpretation
>400-500- HCC likely if accom­panied by space-occupying solid lesion(s) in cirrhotic liver or levels are rapidly increasing.



- Diffusely growing HCC, may be difficult to detect on imaging.



- Occasionally in patients with active liver disease (particularly HBV or HCV infection) reflecting inflammation, regeneration, or seroconversion



Normal value to < 400- Frequent: Regeneration/inflammation (usually in patients with elevated transaminases and HCV) - Regeneration after partial hepatectomy



- If a space-occupying lesion and transaminases are normal, suspicious for HCC



Normal valueDoes not exclude HCC (cirrhotic and noncirrhotic liver)
Table 3. Patient Survival Rates Following Liver Transplantation for Hepatocellular Carcinoma
Author (Year)NSurvival Rate
1 year5 years
Mazzefero (1996)4884%74%
Bismuth (1999)4582%74%
Llovet (1999)7986%75%
Jonas (2001)12090%71%
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