Failure to detect HCC

1. To overcome the above mentioned US limitations, CT- or MRI-based surveillance has been proposed.84,85 MRI proved the best method of surveillance for early HCC (sensitivity of 83.7%)85 but high costs, long scan times and low availability prevent the widespread use of MRI as an imaging technique for screening. An abbreviated MRI protocol (AMRI) which comprises two sequences performed approximately 20 mins after the intravenous injection of gadoxetate disodium86,87 can be performed at a lower cost in a shorter time than a complete examination, thus making it more suitable for routine HCC surveillance. In retrospective studies,86,88 AMRI has proven superior to US in diagnostic per-patient and per-lesion performance. Another AMRI protocol utilizing only T1-weighted pre contrast and dynamic post contrast images using an extracellular gadolinium contrast agent has recently been proposed.89 In this retrospective study conducted on 164 consecutive screenings, this AMRI protocol afforded examination time (7–10 mins) even shorter than an accurate US examination and showed a strong agreement with conventional MRI in categorizing newly detected lesions according to liver imaging reporting data system (LI-RADS). In addition, it is likely that AMRI would prove especially useful in the NAFLD populations where the diagnostic accuracy of US is greatly reduced.

In a recent mathematical model, bi annual contrast-enhanced AMRI showed a higher sensitivity than US and proved affordable when applied to high-risk patients, resulting in improvement of early tumor detection in a cost-effective manner.90 If these data are confirmed in controlled trials, AMRI could become a cost-effective alternative to conventional MRI for screening in cirrhosis even though scarce availability and costs of MRI remain problems to be solved.

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2. AFP performance can be improved by monitoring longitudinal patterns of AFP over time: if the rate of increase of AFP and the degree of fluctuation of all AFP-values recorded within each patient are used rather than the last value of AFP, the accuracy of the test in detecting HCC among patients with hepatitis C and either advanced fibrosis or cirrhosis may increase.91,92 Several other tumor markers have been reported as good complements to AFP and have been used in clinical diagnosis, including lens culinaris agglutinin reactive AFP (AFP-L3%), des-γ-carboxy prothrombin (DCP), fucosylated biomarkers (such as Golgi protein 73 and AFP), osteopontin, glypican-3, and micro-RNAs.93–101 Albeit these biomarkers have been evaluated as potential tools for HCC screening in some studies,94,100,101so far they have not met the clinical requirements for HCC surveillance. Prospective studies are needed to externally validate their accuracy for early detection of HCC.102


In the era of precision medicine and limited resources, screening programs have to accomplish the difficult task of personalized surveillance according to the risk of disease since HCC risk is not uniform across all patients with the same clinical conditions such as cirrhosis owing to different etiologies.

Risk scores providing a numerical cut off for the 5- and 10-year risk of developing HCC have been proposed. These scores have been developed for hepatitis B and for hepatitis C separately, as well as for cirrhosis (of any etiology). Several risk scores have been developed for hepatitis B.40,103–105Among them the Risk Estimation for Hepatocellular Carcinoma in chronic hepatitis B (REACH-B)40 and the Platelets, Age, Gender in chronic hepatitis B (PAGE-B)105 and their recent modifications106,107 are the most popular. The first has been developed and validated in Asian patients without cirrhosis using clinical parameters such as sex, age, serum alanine aminotransferase (ALT) concentration, HBeAg status plus HBV-DNA status.40 Accordingly, atminimum score values (0–6), the 10-year risk of having HCC is negligible (<1%), while at the value of 16 the 3-, 5-, 10-yeas risk is 15%, 32%, 64%, respectively. Recently, HBV-DNA status has been replaced by liver stiffness (as a measure of liver fibrosis) based on the assumption that HBV clearance can easily be achieved in the era of effective antiviral therapy, therefore leading to overestimation of the incidence of HCC.106

PAGE-B score was first developed in Caucasian patients with chronic hepatitis without HCC and treated with first-line oral antivirals for ≥12 months. Based on simple clinical variables (age, gender, and platelets), this score proved useful in the assessment of the 5-year risk of HCC: a high PAGE-B score (≥18) should prompt continuous and careful surveillance in that the 5-year cumulative risk of HCC is 17% in this subgroup of patients. Recently, a modified PAGE-B score by adding serum albumin levels has been validated in Asian populations.107

A risk score for HCV patients has been developed using the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) cohort.41This model includes age, alkaline phosphatase (ALP), black race, albumin, gastroesophageal varices and platelets. The calculation is complex, and the score has not been validated so far. For these reasons, its use is not recommended.

To further refine HCC prediction, the combination of serum concentrations of three biomarkers (AFP, AFP-L3% and DCP), with patient sex and age has been proposed as a diagnostic model (GALAD),108and preliminary clinical results seem to support a widespread use in clinical practice.109 Improvement of the GALAD score has recently been reported by adding US results (presence of a solid lesion on surveillance).110 Another risk score, the Doylestown algorithm, incorporates biomarkers (AFP and fucosylated biomarkers) and relevant clinical variables (age, gender and ALT) with ALP.111 Although promising, these clinical scores have not yet been widely approved for HCC screening.

To supplement these imperfect clinical scores, new molecular biomarkers have been explored.112,113Several germline single-nucleotide polymorphisms in epidermal growth factor and myeloperoxidase genes have been associated with elevated HCC risk.114,115 Similarly, a prognostic 186-gene signature has been identified and validated as an HCC risk predictor in patients with chronic liver disease with different etiologies.116,117

Once again, all these molecular biomarkers are far from being in widespread use in clinical practice.

In summary, although there is evidence of the benefits of HCC surveillance in terms of improved specific cancer mortality, improving modality of, and tools for, screening is necessary in order to cope with future scenarios where the etiology of cirrhosis is changing and the population at risk is becoming larger.


The authors certify that they have no affiliations with, or involvement in, any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Giampiero Francica,1 Mauro Borzio2

1Unità Operativa Ecografia ed Ecointerventistica, Pineta Grande Hospital, Castel Volturno, Italy; 2Unità Operativa Complessa Gastroenterologia ed Endoscopia Digestiva, Azienda Socio Sanitaria TerritorialeMelegnano e della Martesana, Milano, Italy


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Source: Journal of Hepatocellular Carcinoma.
Originally published July 24, 2019.

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