Hepatocellular carcinoma fulfils many of the required prerequisites in a condition that merits screening – it is the second leading cause of cancer deaths in Singaporean males; it has a long lead-in phase; it develops in identifiable at-risk individuals i.e., those with chronic hepatitis viral infection and liver cirrhosis; treatment is effective and acceptable when it is detected early. However, the conditions of another important prerequisite, i.e. that of the availability of a screening tool that possesses ease of use, high sensitivity and specificity, are only partially fulfilled.

At present it is recommended that screening takes the form of 6 to 12 monthly alphafetoprotein (AFP) and abdominal ultrasound (US), targeting individuals with chronic hepatitis B virus infection and liver cirrhosis. (1) Population screening is not recommended given the low risk of HCC in the general population of 5 per 100 000 per year. We should also be aware of the lack of good evidence to indicate that screening improves survival. Retrospective studies comparing with historical controls are given to confounding factors. The largest randomised prospective study to date does support screening; this study of 17 000 Chinese with chronic hepatitis B virus infection, using the strategy of 6monthly AFP and US, resulted in earlier HCC detection and improved 2-year survival in those who underwent screening. (2)

One of the main weaknesses of present screening program is the relatively low sensitivity and specificity of AFP and US. In prospective studies, AFP had a sensitivity ranging from 14-71%, and a specificity of 62%. Up to 40% of HCC are not associated with elevated AFP. In addition, benign liver conditions (chronic viral hepatitis, alcoholic liver disease) and non-liver tumour (non-seminomatous germ cell tumour) are associated with elevated AFP. US carries a sensitivity of 20%-50% and specificity of 92%-96%. For lesions less than 2 cm, only 13% of lesions are detected. Mathematical modelling suggests that combining AFP and US adds 10-20% to the rates of detection.

Improving detection of HCC has been the focus of research and development in this area, and several innovations have emerged. These are in the areas of new tumour markers and also improved imaging technologies. Of the numerous candidate biomarkers identified, des-gamma carboxyprothrombin and Lens culinaris agglutinin-reactive AFP show most promise.

Des-gamma carboxyprothrombin (DCP)
DCP is an abnormal prothrombin molecule produced by malignant cells as a result of a defect in the posttranslational carboxylation of the prothrombin precursor. (3) It can be measured using enzyme immunoassay. It is unclear if DCP performs better than AFP; it has sensitivities of 28%-89% and specificities of 87%-96% but head-to-head studies comparing DCP with AFP show conflicting results as to which is the better tumour marker. (4)

Lens culinaris agglutinin-reactive AFP (AFP L3)
AFP-L3 is the fucosylated variant of AFP produced specifically by HCC. AFP-L3 bears strong affinity to the sugar chain of Lens culinaris, a type of lentil. (5) AFP-L3 had sensitivities and specificities ranging from 36% to 96% and 89% to 94%, respectively. AFP-L3 is less sensitive but more specific than AFP, and therefore cannot replace AFP . The value of AFP-L3 lies mainly in distinguishing HCC from other conditions when AFP is elevated. AFP-L3 is currently available in SGH.

Imaging
As in all diagnostic tools, imaging modalities have problems in ensuring low false negative and false positive rates. These are exemplified by the difficulty in detecting small lesions and the high prevalence of small benign nodules in the liver which, upon detection, need to be distinguished from HCC. US has problems with detecting smaller lesions (less than 2 cm) and also establishing the nature of recognized lesions. As such, further confirmatory imaging is usually necessary once a suspicious lesion is detected. These have traditionally taken the forms of abdominal computed tomography (CT) scan and hepatic angiography. However, in recent studies conventional CT scan showed similar performance characteristics as US, detecting only 40-68% of HCC.

Recent innovations of helical CT scan and magnetic resonance imaging (MRI) have improved HCC detection. Helical contrast enhanced CT has resulted in increased sensitivity and specificity for HCC detection, of 80% and 90% respectively. (6) The use of MRI-angiography has better sensitivity for small HCC (1-2 cm) compared with CT. (7) The difficulty in detecting “subcentimeter” (< 1cm) lesions has not been resolved where up to 70% may be missed by all modalities of imaging.

Summary and the future
Current screening still relies on the combined modality of US and AFP performed at regular intervals in at-risk individuals. Innovations in imaging, such as helical CT and MRI, have allowed improved evaluation of lesions detected in screening. DCP and AFP-L3 are newer tumour markers but are not sufficiently superior to AFP for the purposes of cancer screening. Novel markers are being added to those currently available, largely through advances in proteomics, gene expression microarray and tumour immunology. These will have to undergo exploratory, validation and prospective studies before their worth is established.

Dr Lui Hock Foong
Consultant
Department of Gastroenterology
Singapore General Hospital

References

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