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      Drugs & Diseases > General Surgery

      Hepatocellular Carcinoma (HCC) Guidelines

      Updated: Dec 07, 2022
      • Author: Luca Cicalese, MD, FACS; Chief Editor: John Geibel, MD, MSc, DSc, AGAF  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, diagnosis, and treatment 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 for Medical Oncology (ESMO)
      • American Society of Clinical Oncology (ASCO)
      • American Gastroenterological Association (AGA)

      Surveillance and diagnosis

      In its 2018 guidelines for the management of HCC, the AASLD recommends surveillance for HCC in adults with cirrhosis, because it improves overall survival. Surveillance should be conducted with ultrasonography (US), with or without alpha-fetoprotein (AFP) testing, every 6 months. Computed tomography (CT) and magnetic resonance imaging (MRI) are not recommended as the primary modality for surveillance but may be used in select patients with a high likelihood of having an inadequate US or if US is attempted but inadequate.

      Although the risk of HCC is reduced in patients with hepatitis C virus (HCV) infection who have a sustained virologic response after direct-acting antiviral therapy, the risk is not eliminated, and continuing surveillance is recommended. However, the AASLD advises that risk for HCC is too low to justify surveillance in patients with HCV infection or nonalcoholic fatty liver disease (NAFLD) who do not have cirrhosis. The AASLD recommends not performing surveillance of patients with Child-Pugh class C cirrhosis unless they are on the transplant waiting list, given their low anticipated survival. [4]

      Similarly, the NCCN guidelines recommend screening with US, with or without AFP testing, every 6 months in patients with cirrhosis due to any of the following [49] :

      • Hepatitis B or C
      • Alcohol
      • Genetic hemochromatosis
      • NAFLD
      • Stage 4 primary biliary cholangitis
      • Alpha-1-antitrypsin deficiency 
      • Other causes

      Unlike the AASLD, the NCCN also recommends surveillance in hepatis B virus (HBV) carriers without cirrhosis. The following patients are at additional risk:

      • Carriers with family history of HCC
      • Asian males ≥40 y
      • Asian females ≥50 y
      • African/North American blacks

      ESMO guidelines include the following recommendations on screening for HCC [105] :

      • Cost-effectiveness studies suggest that surveillance of HCC is warranted in all cirrhotic patients, irrespective of its etiology, as long as their liver function and comorbidities allow curative or palliative treatments.

      • Surveillance of hepatitis-infected patients without cirrhosis is also advocated, especially in HBV carriers with serum viral load > 10 000 copies/mL or HCV-infected patients with bridging fibrosis.

      The AASLD recommendations for follow-up of abnormal screening results include the following [4] :

      • For nodules identified on US that are < 1 cm, repeat US at intervals of 3-6 months; if no growth is observed over a period of up to 2 years, revert to routine surveillance.
      • A lesion of ≥10 mm on ultrasound or an AFP level > 20 ng/mL should trigger recall procedures for the diagnosis of HCC. 

      Noninvasive diagnosis of HCC requires multiphase imaging evaluated using stringent criteria.  The American College of Radiology has published guidelines on the performance interpretation, and reporting of multiphase CT and MR exams through its CT/MRI Liver Imaging Reporting And Data System (CT/MRI LI-RADS). [106]

      For multiphase CT and MRI, key imaging features include the following:

      • Size ≥1 cm
      • Arterial phase hyperenhancement
      • Depending on exact size, a combination of washout, threshold growth, and capsule appearance

      If these criteria are not present but HCC or other malignancy is considered probable, then a liver biopsy should be considered for diagnosis. In patients without cirrhosis, the diagnosis of HCC cannot be made by imaging, even if the scan shows hypervascularity in the arterial phase with washout in the portal venous or delayed phase; biopsy is required in these cases. [4]

      The NCCN notes that biopsy may be considered in the following circumstances [49] :

      • When a lesion is suspicious for malignancy, but multiphasic CT or MRI results do not meet imaging criteria for HCC
      • In patients who are not considered to be at high risk for HCC (ie, patients who do not have cirrhosis, chronic HBV, or a previous history of HCC)
      • In patients with conditions associated with formation of nonmalignant nodules that may be confused with HCC on imaging (eg, cardiac cirrhosis; congenital hepatic fibrosis; cirrhosis due to a vascular disorder such as Budd-Chiari syndrome, hereditary hemorrhagic telangiectasia, or nodular regenerative hyperplasia)
      • In patients with elevated CA 19-9 or carcinoembryonic antigen (CEA), in order to rule out intrahepatic cholangiocarcinoma

      The AASLD guidelines include the following recommendations regarding biopsy [4] :

      • If the diagnosis of HCC cannot be established from routine histology, staining for several biomarkers, including the diagnostic panel of glypican-3 (GPC3), heat shock protein 70 (HSP70), and glutamine synthetase, can be used to help distinguish HCC from high-grade dysplastic nodules. 
      • 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 ACG guidelines for the diagnosis and management of focal liver lesions (FLLs) include the following recommendations [107] :

      • 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.

      The 2018 ESMO guidelines contain the following recommendations regarding diagnosis of HCC [105] :

      • The diagnosis of HCC is based on histological analysis and/or contrast-enhanced imaging findings.

      • The diagnosis can be established if the typical vascular hallmarks of HCC (hypervascularity in the arterial phase with washout in the portal venous or delayed phase) are identified in a nodule of > 1 cm diameter using one of those two modalities in a cirrhotic patient. 

      • Based on techniques such as diffusion-weighted imaging and the use of hepatobiliary contrast agents, MRI may allow identification and stratification of nodules as high-risk nodules (either HCC not displaying the typical imaging hallmarks features or high-grade dysplastic nodules).

      • For contrast-enhanced ultrasound (CEUS), an overlap between the vascular profile of HCC and cholangiocarcinoma has been described. However, recent data suggest CEUS as a suitable technique to diagnose HCC noninvasively in the setting of liver cirrhosis.

      • When tumor biopsy fails to demonstrate a correlate for a focal lesion, a second tumor biopsy, a different contrast-enhanced imaging modality or (if amenable) direct resection of the lesion may be considered, according to tumor size.

      • Histopathological diagnosis of tumor biopsies relies on standard (hematoxylin and eosin [H&E]) and special stains (eg, reticulin), and—if required—immunohistochemistry (IHC).

      • It is important to distinguish combined HCC/cholangiocarcinoma from HCC, because treatments for the two differ; however, the mixed differentiation features might not be visible in the biopsy. In addition, although HCC is commonly negative for cytokeratin 19 (CK19), significant expression of CK19 may be present in HCC and is considered as a sign of poor prognosis in HCC.

      • In highly differentiated HCC, definitive signs of malignancy (interstitial or vascular invasion) are frequently absent from biopsy. Further consented histological criteria (trabecular alterations—more than two cell broad trabeculae, pseudoglands, reticulin loss, capsule formation) and cytological criteria (increased nuclear/cytoplasmic ratio; ie, ‘nuclear crowding’, increased cytoplasmic basophilia) support the diagnosis of HCC.

      • IHC should be carried out in unclear cases: capillarization of sinusoids could be assessed using CD34 IHC.

      • Further immunohistochemical markers have been shown to improve the diagnosis of highly differentiated HCC, including glutamine synthetase, GPC3, circulating tumor cells (CTC) , EZH2, and HSP70.

      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. [49]

      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 and ESMO guidelines recommend the Barcelona Clinic Liver Cancer (BCLC) system for prognostic prediction and treatment stratification. [4, 107]

      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:

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

      See Table 4, below.

      Table 4. Barcelona Clinic Liver Cancer staging (Open Table in a new window)

      Stage

      Criteria

      0 – Very Early

      Child-Pugh class A

      Single < 2 cm nodule

      ECOG PS 0-1

      A – Early

      Child-Pugh class A-B

      Single or 2-3 nodules < 3 cm

      ECOG PS 0-1

      B – Intermediate

      Child-Pugh class A-B

      Multinodular

      ECOG PS 0-1

      C - Advanced

      Child-Pugh class A-B

      Portal vein invasion, N1, M1

      ECOG PS 0-2

      D - Terminal

      Child-Pugh class C

      Any T, N, or M

      ECOG PS > 2

      ECOG PS  = Eastern Cooperative Oncology Group Performance Status

      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

      AASLD guidelines divide therapeutic options into curative and noncurative interventions. [4] Curative therapies, which offer the chance of long-term response and improved survival, include the following:

      • Surgical resection
      • Orthotopic liver transplantation
      • Ablative techniques (eg, thermal ablation)

      Noncurative therapies, which attempt to prolong survival by slowing tumor progression, include the following:

      • Transarterial chemoembolization (TACE)
      • Transarterial radioembolization (TARE)
      • Stereotactic body radiation therapy (SBRT)
      • Systemic chemotherapy

      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. NCCN and AASLD guidelines also recommend ablation as a possible bridge therapy for patients awaiting transplantation. [4, 49]

      The AASLD recommends TACE as first-line noncurative therapy for BCLC stage B HCC. For stage BCLC disease, sorafenib or lenvatinib is recommended as first-line therapy. [4]

      For patients with unresectable HCC who are not candidates for transplantation, NCCN recommendations for first-line systemic therapy are as follows [49] :

      • Sorafenib is the preferred therapy for Child-Pugh Class A (category 1) or B7 HCC
      • Lenvatinib is a preferred therapy for Child-Pugh Class A only
      • Systemic chemotherapy (category 2B)

      Recommended agents for subsequent-line therapy if disease progression occurs are as follows [49] :

      • Regorafenib (Child-Pugh Class A only) (category 1)
      • Cabozantinib (Child-Pugh Class A only) (category 1)
      • Ramucirumab (alpha fetoprotein ≥400 ng/mL only) (category 1)
      • Nivolumab (Child-Pugh Class A or B7)
      • Sorafenib (Child-Pugh Class A or B7) (after first-line lenvatinib)
      • Pembrolizumab (Child-Pugh Class A only) (category 2B)
      • Larotrectinib and entrectinib (for NTRK gene fusion–positive HCC)

      ASCO recommendations for first-line systemic therapy of advanced HCC are as follows [108] :

      • Atezolizumab/bevacizumab may be offered to most patients with Child-Pugh class A, Eastern Cooperative Oncology Group performance score (ECOG PS) 0-1, and following management of esophageal varices, when present, according to institutional guidelines.
      • Patients who have contraindications to atezolizumab and/or bevacizumab may be offerered tyrosine kinase inhibitor (TKI) therapy with sorafenib or lenvatinib

      ASCO recommendations for second-line therapy are as follows [108] :

      • TKI therapy (ie, sorafenib, lenvatinib, cabozantinib, or regorafenib) may be recommended for patients who received first-line therapy with atezolizumab/bevacizumab.
      • In patients who received first-line therapy with sorafenib or lenvatinib, second-line therapy with another TKI (cabozantinib or regorafenib), ramucirumab (if alpha fetoprotein level is ≥ 400 ng/mL), or atezolizumab/bevacizumab may be recommended for appropriate candidates. 
      • Pembrolizumab or nivolumab may reasonably be considered in appropriate patients who received first-line therapy with sorafenib or lenvatinib; those agents may be especially beneficial for patients who have contraindications to or cannot tolerate TKIs.

      AGA recommendations for systemic therapy of HCC are as follows (note that these are conditional recommendations, with low or very low certainty of evidence, and in most cases advising that choice of therapy be guided by patient preference with regard to risks and benefits) [109] :

      • For first-line treatment, in patients with preserved liver function who are not eligible for locoregional therapy or resection or who have metastatic disease, consider atezolizumab plus bevacizumab over sorafenib; if they are not candidates for atezolizumab/bevacizumab, consider either lenvatinib or sorafenib.
      • For second-line treatment, in patients with preserved liver function who are not eligible for locoregional therapy or resection or who have metastatic disease and who had progression of disease on sorafenib, consider cabozantinib, pembrolizumab, or regorafenib.
      • For second-line treatment, in patients with preserved liver function and alpha fetoprotein (AFP) > 400 ng/mL who are not eligible for locoregional therapy or resection or who have metastatic disease, who had progression of disease on sorafenib, consider using ramucirumab.
      • In patients with poor liver function who are not eligible for locoregional therapy or resection or who have metastatic disease, the AGA suggests against routine use of sorafenib.
      • In patients undergoing curative surgical resection or curative local ablation for HCC, the AGA suggests against adjuvant therapy with sorafenib.
      • In patients undergoing TACE, the AGA suggests against adjuvant therapy with sorafenib or bevacizumab.
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