Screening

There is a very narrow therapeutic time frame for patients with hepatocellular carcinoma (HCC), as the prognosis is poor by the time patients have developed symptoms. Therefore, screening and surveillance are intended to identify HCC at the earliest possible stage, when treatment has the highest possible likelihood of cure.

One systematic review found that HCC surveillance is associated with improved tumour detection, receipt of curative therapy, and overall survival in patients with cirrhosis.[83] The addition of alpha-fetoprotein (AFP) testing to ultrasound screening significantly increases the sensitivity of early HCC detection in clinical practice.[84]

Guidelines on surveillance for HCC differ slightly in their recommendations. They all advise that patients with cirrhosis of any aetiology should undergo screening, and most recommend that patients with hepatitis B without cirrhosis should also undergo screening if they have certain characteristics that put them at higher risk of HCC.

The American Association for the Study of Liver Diseases (AASLD) specifies that all patients listed for liver transplantation should undergo HCC screening twice a year because the priority for transplantation may change if a patient is detected with an early-stage HCC.[7]​ Surveillance is not recommended in patients with life-limiting comorbid conditions that cannot be cured by transplantation.[7]

All guidelines recommend that abdominal ultrasound is the screening modality of choice and should be performed every 6 months. AFP can be combined with ultrasound to enhance sensitivity, but it should not be used alone for surveillance because of its poor sensitivity and specificity.[2][7][59]​​​​​​​​​​​​​[62]​​​​​​ The National Institute for Health and Care Excellence specifies that AFP testing should be included for adults with cirrhosis and concomitant hepatitis B.[85] The National Comprehensive Cancer Network (NCCN) suggests dynamic contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) as an alternative to ultrasound for screening and surveillance if ultrasound is unable to detect nodules or if visualisation is poor.[2]

Proteomic technology has led to the development of new molecular biomarkers, including des-gamma carboxyprothrombin (DCP), AFP-L3, and human growth factors. While promising, particularly when combined in biomarker panels or models that incorporate clinical factors, they require further validation before they can be recommended for routine use in HCC screening.[7][62]

Populations to screen

Patients with cirrhosis

Patients with cirrhosis of any aetiology (including hepatitis B virus ([HBV], hepatitis C virus [HCV], alcohol, genetic haemochromatosis, metabolic dysfunction-associated steatotic liver disease, stage 4 primary biliary cirrhosis, and alpha-1-antitrypsin deficiency) should be enrolled for screening or surveillance, unless they have a high risk of mortality from other causes or would be ineligible for curative-intent treatment.[2][7][59]​​​​​​​​​​​​[62][85][86]​​​​​​​​ AASLD specifies that among patients with cirrhosis, only those with Child-Turcotte-Pugh class A or B disease should be screened. An exception is made for patients with Child-Turcotte-Pugh class C disease if they are awaiting liver transplant.[7] [ Child Pugh classification for severity of liver disease (SI units) Opens in new window ]

Patients with chronic HBV without cirrhosis

The US and European guidelines differ in their recommendations for the screening of patients with chronic HBV without cirrhosis:

  • NCCN and AASLD guidelines recommend that all hepatitis B carriers without cirrhosis should be enrolled in an HCC screening programme. They cite additional risk factors in this patient group as: platelet, age, and gender-HBV score ≥10; family history of HCC; man from endemic country aged >40 years; woman from endemic country aged >50 years; and person from Africa at earlier age.[2]​​[7]​​​​

  • The European Association for the Study of the Liver (EASL) and European Society for Medical Oncology (ESMO) guidelines advise that cost-benefit modelling is needed in this scenario. Experts recommend that surveillance is warranted if the HCC incidence is at least 0.2% per year. To help determine if patients meet this threshold, the PAGE-B (Platelet, Age, GEnder-hepatitis B) classification is used to stratify them into the following categories:[59][87][88]​​

    • Low risk of HCC (PAGE-B score ≤9, almost 0% incidence of HCC at 5 years)

    • Intermediate risk of HCC (PAGE-B score 10-17, 3% incidence of HCC at 5 years)

    • High risk of HCC (PAGE-B score ≥18, 17% incidence of HCC at 5 years)

    Screening is recommended for patients who fall into the intermediate and high-risk categories. The PAGE-B score is based on the decade of age (16-29 years = 0 points, 30-39 years = 2 points, 40-49 years = 4 points, 50-59 years = 6 points, 60-69 years = 8 points, ≥70 years = 10 points), sex (male = 6 points, female = 0 points), and platelet count (≥200 x 10⁹/L = 0 points, 100-199 x 10⁹/L = 1 point, <100 x 10⁹/L = 2 points). The PAGE-B score has yet to be validated in Asia. Individual risk assessment is recommended for patients in the low HCC risk class (PAGE-B score ≤9) who do not reach the 0.2%/year threshold for starting screening.[87]

Patients with advanced fibrosis without cirrhosis

Patients with chronic liver disease (e.g., HCV, metabolic dysfunction-associated steatotic liver disease) and advanced fibrosis without cirrhosis have an increased risk of developing HCC. Surveillance recommendations for this group vary. While the AASLD and EASL recommend there is insufficient evidence to recommend routine surveillance for these patients, the ESMO suggests that patients with HCV and advanced fibrosis should have surveillance even after achieving sustained virological response on antiviral treatment.[7][59]​​[62]​​

Patients with other risk factors

Guidelines do not recommend routine HCC surveillance for patients without cirrhosis or viral hepatitis.[7][59][62]​​​ However, one large retrospective cohort study (using data from the US Department of Veterans Affairs electronic health records) developed a clinically useful risk score for HCC among adults without viral hepatitis or cirrhosis, outperforming the Fibrosis-4 Index and highlighting modifiable factors like body mass index, diabetes, alcohol, and smoking for broadening surveillance strategies.[89]

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