Primary Hepatic Carcinoma Workup

  • Author: Keith E Stuart, MD; Chief Editor: Jules E Harris, MD   more...
 
Updated: May 14, 2012
 

Laboratory Studies

Expect total bilirubin, aspartate aminotransferase (AST), alkaline phosphatase, albumin, and prothrombin time to show results consistent with cirrhosis.

Alpha-fetoprotein (AFP) is elevated in 75% of cases. The level of elevation correlates inversely with prognosis. An elevation of greater than 400 ng/mL predicts for hepatocellular carcinoma with specificity greater than 95%. In the setting of a growing mass, cirrhosis, and the absence of acute hepatitis, many centers use a level greater than 1000 ng/mL as presumptive evidence of hepatocellular carcinoma (without biopsy). AFP is inadequate for screening purposes because of the high rate of false positives in active hepatitis; it only begins to rise when vascular invasion occurs.[16]

Des-gamma-carboxy prothrombin (DCP) has been studied as a biomarker for early diagnosis of hepatocellular carcinoma. Lok et al found that the sensitivity and specificity of DCP at the time of diagnosis of hepatocellular carcinoma was 74% and 86%, respectively, at a cutoff of 40 mAU/mL and 43% and 100%, respectively, at a cutoff of 150 mAU/mL. Twelve months before diagnosis, the sensitivity and specificity at the 40 mAU/mL cutoff was 43% and 94%.[17] Combining DCP with AFP increased the sensitivity to 91% but lowered the specificity to 74%. Lok et al concluded that DCP is not optimal for detection of early HCC.

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Imaging Studies

Obtain liver imaging using ultrasonography, CT scanning, or MRI (see image below). When performed for suspected hepatocellular carcinoma due to a rising AFP, each test has a 70-85% chance of finding a solitary lesion; sensitivity is higher with multiple tumors.

Hepatic carcinoma, primary. Noncontrast CT scans aHepatic carcinoma, primary. Noncontrast CT scans at 1 day and 3 months following chemoembolization with doxorubicin/Ethiodol Gelfoam.

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 hepatocellular carcinoma 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 hepatocellular carcinoma 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 hepatocellular carcinoma.

Chest radiography may demonstrate pulmonary metastases (see image below).

Hepatic carcinoma, primary. Plain radiograph immedHepatic carcinoma, primary. Plain radiograph immediately following chemoembolization, demonstrating catheter placement and Ethiodol enhancement of tumors.

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 hepatocellular carcinoma is not recommended.

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Procedures

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 hepatocellular carcinoma. 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 (< 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 hepatocellular carcinoma. 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.

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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 hepatocellular carcinoma 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 hepatocellular carcinoma that can be detected by fluorescent in situ hybridization (FISH) technique. The role of FISH in the diagnosis of hepatocellular carcinoma is still under investigation.

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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.[18] Below is a summary of the TNM staging criteria and the CLIP scoring system.

  • TNM staging criteria for hepatocellular carcinoma
    • 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.
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Contributor Information and Disclosures
Author

Keith E Stuart, MD  Chairman, Department of Hematology and Oncology, Lahey Clinic

Disclosure: Nothing to disclose.

Coauthor(s)

Zsofia K Stadler, MD  Clinical Fellow, Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School

Disclosure: Nothing to disclose.

Specialty Editor Board

Antoni Ribas, MD  Assistant Professor of Medicine, Division of Hematology-Oncology, University of California at Los Angeles Medical Center

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

Rajalaxmi McKenna, MD, FACP  Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD  Clinical Professor of Medicine, Section of Hematology/Oncology, University of Arizona College of Medicine, Arizona Cancer Center

Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research

Disclosure: GlobeImmune Salary Consulting

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Hepatic carcinoma, primary. Dilated collateral superficial abdominal veins in a 67-year-old man with cirrhosis, hepatocellular carcinoma (HCC), and portal vein occlusion.
Hepatic carcinoma, primary. Large multifocal hepatocellular carcinoma (HCC) in an 80-year-old man without cirrhosis.
Hepatic carcinoma, primary. Noncontrast CT scans at 1 day and 3 months following chemoembolization with doxorubicin/Ethiodol Gelfoam.
Hepatic carcinoma, primary. Unusual location of a bone metastasis from hepatocellular carcinoma (HCC).
Hepatic carcinoma, primary. Plain radiograph immediately following chemoembolization, demonstrating catheter placement and Ethiodol enhancement of tumors.
 
 
 
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