Focus

AFP was first described by Abelev et al. in the early 1960s [1Abelev G.I. Chramkova N.I. Postnikova Z.A. The antigenic structure of mouse hepaticas. I. Organ-specific antigens of the liver and immuno-electrophoretic study of their occurrence in hepatomas].Neoplasma. 1962; 9 ([in Russian]): 123-130PubMed Google Scholar, 2Abelev G.I. Assecritova I.G. Kraevsky N.A. Perova S.D. Perevodchikova N.I. Embryonal serum alpha-globulin in cancer patients. Diagnostic value.Int J Cancer. 1967; 2: 551-558Crossref PubMed Scopus (272) Google Scholar]. Over the next 30 years, and before the introduction of modern imaging techniques, AFP measurement was frequently used for screening of patients at risk, confirmation of diagnosis of hepatocellular carcinoma (HCC), and even surveillance. However, in the past decade, it became progressively clear that serum AFP measurements do not correlate reliably with tumor size, stage, and prognosis in HCC [[3]Trevisani F. D’Intino P.E. Morselli-Labate A.M. Mazzella G. Accogli E. Caraceni P. et al.Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status.J Hepatol. 2001; 34: 570-575Abstract Full Text Full Text PDF PubMed Scopus (600) Google Scholar]. At a cutoff of 20 μg/ml, AFP has a 60% sensitivity and 91% specificity as a diagnostic tool for HCC with positive and negative predictive values of 25% and 98%, respectively (at an HCC prevalence of 5%) [[4]Gupta S. Bent S. Kohlwes J. Test characteristics of alpha-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C. A systematic review and critical analysis.Ann Intern Med. 2003; 139 (1): 46Crossref PubMed Scopus (354) Google Scholar]. These data lead to a 2001 Editorial published in this Journal by M. Sherman entitled: “Alpha-feto protein: an obituary”, who suggested “bidding a fond adieu to AFP as a test for diagnosis and surveillance of HCC” [[5]Sherman M. Alphafetoprotein: an obituary (Edt).J Hepatology. 2001; 34: 603-605Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar]. Consequently, the recent AASLD guidelines for the management of HCC adopted this policy verbatim and excluded the recommendation for testing and monitoring of AFP levels for diagnosis and surveillance of HCC in patients at risk [[6]Bruix J. Sherman M. American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1022https://doi.org/10.1002/hep. 24199Crossref PubMed Google Scholar]. Despite these reservations, many clinicians still check AFP in their routine clinical practice, knowing that markedly elevated AFP levels are a poor prognostic sign in HCC. Therefore, at present, AFP testing remains at best only a confirmatory test in patients with a liver mass detected by an up to date imaging technique. However, even then, it cannot be used as an absolute diagnostic biologic marker for HCC, due to the differential diagnosis suggested by such a finding. In the present issue of the Journal, Merani and co-workers provide evidence supporting a new application for AFP testing [[7]Merani S. Majno P. Kneteman N.M. et al.The impact of waiting list alpha-fetoprotein changes on the outcome of liver transplant for hepatocellular carcinoma.J Hepatology. 2011; PubMed Google Scholar]. They propose to use AFP monitoring in those HCC patients who secrete AFP, for prediction of outcome in HCC candidates for liver transplantation (LT). Special emphasis is given to forecasting prognosis in patients who underwent a pre-transplant down-staging procedure (mainly ablation), provided the last AFP measurement is determined close to LT. The Canadian and Swiss investigators used the US Scientific Registry of Transplant Recipients database of 6817 HCC listed patients between 2003 and mid 2009. Intent to treat (ITT) analysis included evaluation of AFP and total tumor volume (TTV) at time of listing and at time of transplantation, expressed also as AFP and TTV velocity. Serum AFP >400 ng/ml was detected in 8.2% of the evaluated cohort. Based on current guidelines, almost all patients fulfilled the Milan criteria and 35.5% of 5481 patients with available information underwent a pre-LT ablation procedure, while 59% did not receive any anti-tumor therapy. The main results of this interesting study indicate that HCC patients with initial AFP levels >400 ng/ml at listing, in whom loco-regional therapy led to a drop in AFP levels <400 ng/ml, had better survival as compared to patients failing to reduce AFP. Specifically, overall ITT survival from listing in patients downstaged to AFP levels <400 ng/ml compared to patients with AFP >400 ng/ml was 81% vs. 48%, respectively, at 3 years post LT. The authors suggest that AFP monitoring in HCC transplant candidates (with special emphasis on treatment response in those patients with AFP >400 ng/ml) may be used as a new tool for assessment of prognosis in patients undergoing pre-transplant loco-regional ablation therapy. This report adds new fuel to the currently ongoing debate concerning extension of the referral rules for LT in HCC patients beyond the Milan criteria, as previously suggested by several investigators [8Majno P.E. Adam R. Bismuth H. Castaing D. Ariche A. Krissat J. et al.Influence of preoperative transarterial lipoidol chemoembolization on resection and transplantation for hepatocellular carcinoma in patients with cirrhosis.Ann Surg. 1997; 226: 688-701Crossref PubMed Scopus (480) Google Scholar, 9Yao F.Y. Kerlan Jr., R.K. Hirose R. Davern III, T.J. Bass N.M. Feng S. et al.Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis.Hepatology. 2008; 48: 819-827Crossref PubMed Scopus (432) Google Scholar, 10Ravaioli M. Grazi G.L. Piscaglia F. Trevisani F. Cescon M. Ercolani G. et al.Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria.Am J Transplant. 2008; 8: 2547-2557Crossref PubMed Scopus (303) Google Scholar, 11Chapman W.C. Majella Doyle M.B. Stuart J.E. Vachharajani N. Crippin J.S. Anderson C.D. et al.Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation.Ann Surg. 2008; 248: 617-625PubMed Google Scholar]. On the one hand, it seems that referral for LT of successfully downstaged patients may be an acceptable solution for a new subgroup of HCC patients with a similar predictable outcome as compared to LT candidates within the Milan criteria. Such an approach based on the presented data, seems logic for patients in whom downstaging by loco-regional treatment is indeed confirmed by suppression of AFP <400 ng/ml and obviously also by imaging studies. On the other hand, incorporation of new rules into currently accepted guidelines may augment the already congested waiting lists worldwide for patients awaiting LT and indirectly contribute to further extension of the waiting time for non-HCC candidates for LT. The report of Merani et al. has a number of limitations including its retrospective evaluation and the fact that only 9% of surveyed patients had hepatitis B derived chronic liver disease, which is much more prevalent in Africa and Asia. Furthermore, in the present study, the cut-off level for statistical analysis of successful down staging was arbitrarily set at an AFP level of 400 ng/ml. It appears that at this threshold, assessment of successful down staging through monitoring of falling AFP levels (in addition to imaging follow-up) is relatively reproducible. However, it is not known whether this threshold is indeed fixed or flexible along a wider range of AFP levels. Finally, almost the entire study cohort was listed according to the Milan criteria. Consequently, the studied population does not necessarily represent the target population for down-staging beyond the Milan criteria. Repeating this analysis in an independent cohort of down-staged HCC patients beyond the Milan criteria to be studied prospectively, will require a very large sample size and is not foreseen in the near future. Thus, despite some limitations, this report, based on information extracted from a large database, provides evidence for a proof of principle as well as a wealth of details on the role and effects of down-staging in patients with HCC. This information is therefore an important addition to the limited available data to support extension of selection criteria beyond Milan and should be the focus of future discussion of this “hot” topic. Thus, until the identification of a better biologic marker for HCC, it seems pre-mature to kiss goodbye to AFP in this selected group of patients with HCC. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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