Primary Hepatic Carcinoma Guidelines

Updated: Feb 21, 2018
  • Author: Keith E Stuart, MD; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Guidelines

Guidelines Summary

Guidelines Contributor:   Elwyn C Cabebe, MD Physician Partner, Valley Medical Oncology Consultants; Medical Director of Oncology, Clinical Liason Physician, Cancer Care Committee, Good Samaritan Hospital

Guidelines for the screening, surveillance, and diagnosis of hepatocellular carcinoma (HCC) have been issued by the following organizations:

  • American Association for the Study of Liver Diseases (AASLD)
  • National Comprehensive Cancer Network (NCCN)
  • American College of Gastroenterology (ACG)
  • European Association for the Study of the Liver (EASL)–European Organisation for Research and Treatment of Cancer (EORTC)
  • European Society of Medical Oncology (ESMO)–European Society of Disease Oncology (ESDO)

Screening and Surveillance

In their 2010 guidelines for the management of HCC, the American Association for the Study of Liver Diseases (AASLD) recommends HCC screening and surveillance for the following high-risk groups [59] :

  • Asian male hepatitis B carriers over age 40
  • Asian female hepatitis B carriers over age 50
  • Hepatitis B carriers with a family history of HCC
  • Africans and African Americans with hepatitis B
  • Cirrhotic hepatitis B carriers
  • Individuals with hepatitis C cirrhosis
  • Individuals with stage 4 primary biliary cirrhosis
  • Individuals with genetic hemochromatosis and cirrhosis
  • Individuals with alpha 1-antitypsin deficiency and cirrhosis
  • Individuals with cirrhosis from other etiologies

In addition, individuals awaiting liver transplantation should be screened because HCC may progress beyond the listing criteria for liver transplantation and those with HCC are given increased priority on the transplant waiting list. [59]

In accordance with the AASLD guidelines, HCC screening should be performed in a setting in which screening tests and recall procedures have been standardized and quality control procedures are in place. Surveillance should be performed at 6-month intervals, using ultrasonography.{ref70

The NCCN guidelines identify similar high-risk groups but recommend screening with alfa-fetoprotein (AFP) testing and ultrasonography every 6 to 12 months. [22]

The AASLD recommendations for follow-up of abnormal screening results include the following [59] :

  • For nodules identified on ultrasound that are < 1 cm, ultrasound should be repeated at intervals of 3-6 months; if no growth is observed over a period of up to 2 years, revert to routine surveillance
  • For nodules >1 cm on a cirrhotic liver, follow-up with either four-phase multidetector CT scan or dynamic contrast enhanced MRI. If the appearances are typical of HCC (ie, hypervascular in the arterial phase with washout in the portal venous or delayed phase), the lesion should be treated as HCC; if the findings are not characteristic or the vascular profile is not typical, a second contrast enhanced study with the other imaging modality should be performed, or the lesion should be biopsied
  • Biopsies of small lesions should be evaluated by expert pathologists; tissue that is not clearly HCC should be stained with all the available markers (including CD34, CK7, glypican 3, HSP-70, and glutamine synthetase) to improve diagnostic accuracy
  • If the biopsy is negative, the lesion should be followed by imaging at 3- to 6-month intervals until the nodule disappears, enlarges, or develops features characteristics of HCC
  • If the lesion enlarges but remains atypical for HCC, the biopsy should be repeated

The 2014 American College of Gastroenterology (ACG) guidelines for the diagnosis and management of focal liver lesions (FLLs) include the following recommendations [60] :

  • Patients with cirrhosis in whom an ultrasound shows a lesion of >1 cm should undergo an MRI or triple-phase CT scan
  • Patients with chronic liver disease who are at a very high risk for HCC and who present with a solid FLL must be considered to have HCC until proved otherwise
  • HCC can be diagnosed with CT or MRI if the typical characteristics are present
  • If an FLL in a patient with cirrhosis does not have typical characteristics of HCC, then a biopsy should be performed

NCCN guidelines recommend that diagnosis be made with one or more of the following imaging modalities if clinical suspicion is high [22] :

  • Four-phase helical CT
  • Four-phase dynamic contrast-enhanced MRI
  • Contrast-enhanced ultrasound

The NCCN does not consider PET/CT appropriate for diagnosis.

NCCN surveillance recommendations are as follows [22] :

  • Lesions ≤1 cm should be reevaluated every 3 to 6 months; if the lesion remains stable, after 2 years the surveillance schedule can return to every 6 to 12 months
  • Liver nodules >1 cm in size should first be evaluated with at least three-phase contrast-enhanced CT or MRI (including late arterial and portal venous phases)
  • Additional imaging depends on the pattern of classic enhancement observed on CT/MRI: a finding of two classic enhancements (arterial hyperenhancement with washout in the venous phase) is diagnostic of HCC, whereas if fewer than two enhancement patterns are seen, a second imaging (the other of CT or MRI) is recommended; if two enhancements are seen with additional imaging, the diagnosis of HCC is confirmed
  • For nodules that do not demonstrate both hyperenhancement and washout, core biopsy (preferred) or fine-needle aspiration (FNA) is recommended; alternatively, patients with nodules 1-2 cm in size can be followed with repeat imaging in 3 mo

The AASLD considers a single imaging study sufficient to diagnosis HCC in patients with cirrhosis and liver nodules between 1 and 2 cm. [59]

Joint guidelines published in 2012 by the European Association for the Study of the Liver (EASL) and the European Organisation for Research and Treatment of Cancer (EORTC) are generally in agreement with NCCN and AASLD guidelines on noninvasive diagnosis using one imaging technique (four-phase CT or dynamic contrast-enhanced MRI). [61]

The European Society of Medical Oncology (ESMO)–European Society of Disease Oncology (ESDO) 2012 joint guidelines for diagnosis and treatment of HCC require biopsy for diagnosis except in the following patients with cirrhosis [61] :

  • Individual is not a candidate for any therapy due to serious comorbidity
  • Individual is on the waiting list for a liver transplantation
  • Individual is candidate for resection

Staging

The tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control/ (AJCC/UICC) is useful only in patients who undergo surgical resection, which is a small minority of patients. Only the NCCN guidelines follow TNM for staging. [22]

Since most patients have unresectable disease and prognosis depends more on the state of the liver than on the size of the tumor, the AASLD, EASL-EORTC, and ESMO-ESDO guidelines recommend the Barcelona Clinic Liver Cancer (BCLC) system for prognostic prediction and treatment stratification. [59, 60, 61, 62]

The BCLC staging system attempts to overcome the limitations of previous staging systems by identifying prognostic stages (0 and A through D) based on five variables [63] :

  • Tumor stage
  • Functional status of the liver
  • Physical status
  • Cancer-related symptoms

The BCLC staging system also links each HCC stage to appropriate treatment modalities as follows:

  • Patients with early-stage HCC (stage 0 and A) may benefit from curative therapies (ie, liver transplantation, surgical resection, radiofrequency ablation).
  • Patients with intermediate-stage(stage B) or advanced-stage (stage C) disease may benefit from palliative treatments (ie, transcatheter arterial chemoembolization and sorafenib)
  • Patients with end-stage disease (stage D) are offered supportive care and palliation

Treatment

The guidelines agree that resection is the treatment of choice for solitary tumors in non-cirrhotic patients or cirrhotic patients with well-preserved liver function. Pre- or post-resection adjuvant therapy is not recommended.

The guidelines further concur that liver transplantation is the best available curative option for patients with early-stage non-resectable HCC who meet the Milan criteria (single tumors ≤5 cm in diameter or no more than three nodules ≤3 cm in diameter in patients with multiple tumors). Ablation should be considered as definitive treatment for patients with stage 0-A tumors who are not candidates for resection or transplantation. [59, 22, 61, 62]  NCCN and AASLD guidelines also recommend ablation as a possible bridge therapy for patients awaiting transplantation. [59, 22]

The AASLD recommends transarterial chemoembolization as first-line noncurative therapy for advanced disease. Sorafenib is recommended for patients who have preserved liver function and cannot benefit from surgery, transplantation, ablation, or transarterial chemoembolization. Yttrium-90 radioembolization is not recommended outside of clinical trials. Systemic or selective intra-arterial chemotherapy is not recommended. [59]