EDITORIAL

Diagnosis and Staging of HepatocellularCarcinoma Prior to Transplantation: Expertise orFailureMaria Varela, Alejandro Forner, and Jordi Bruix*Barcelona Clinic Liver Cancer group, Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain

Received June 27, 2006; accepted July 2, 2006.

See Articles on Pages 1504 and 1519

Liver transplantation is an effective treatment for hep-atocellular carcinoma (HCC), and for years there hasbeen a major effort to define which patients were theoptimal candidates for this intervention. Several stud-ies conducted in the early years of transplantation evi-denced that patients with advanced HCC (defined aslarge/multifocal tumors or by the presence of vascularinvasion) should be excluded from the procedure be-cause of almost universal recurrence in the shortterm.1 The seminal work by Mazzaferro et al.,2 togetherwith data from Paris, Barcelona, and Berlin, as well asfrom other groups, demonstrated that the best resultsin terms of survival with minimal recurrence wereachieved in patients with tumors diagnosed at an earlystage and defined as single HCC �5 cm in diameter orup to 3 nodules �3 cm in diameter.1 This definition iscurrently the accepted criteria for candidate selectionin most countries. Proposals for expansion have beenraised, but new limits have not been properly validatedin enough number of cases prospectively recruited.Larger size is associated with a high rate of vascularinvasion3,4 and, ultimately, tumor recurrence. In addi-tion, recent data on live donation show that expansionshould be carefully defined to avoid less than optimalresults.5,6 In any case, the current clinical challenge isnot how many more patients could be enlisted for trans-plantation, but how to accurately diagnose HCC, how todefine the extent of the disease and, finally, how to

establish priorities to guarantee a fair and equativedistribution of the scarce number of available livers.Fortunately, the clinical research conducted up to nowhas been fruitful in exposing the successes and failuresof different strategies and allowed a steady improve-ment of our knowledge of the disease. Thus, severalstudies have pointed out which concepts or approachesshould be abandoned or at least largely improved. Themanuscripts by Kemmer et al.7 and by Freeman et al.8

published in this issue of Liver Transplantation are im-portant additions in that regard.

Kemmer et al. analyzed the United Network for OrganSharing (UNOS) database to assess whether a concen-tration of alpha-fetoprotein (AFP) increasing beyond500 ng/mL is a valid criterion to indicate liver trans-plantation because of HCC suspicion, even if imagingtechniques are negative. Such a scenario depicts astressful clinical dilemma that several transplantgroups have faced: Is it justified to transplant a cir-rhotic patient for whom the HCC suspicion may not beconfirmed, or it is better to adopt a “wait and see”approach that may finally demonstrate a massive HCCnot suitable for transplantation? The reduced sensitiv-ity of old imaging techniques could have justified theproposal of transplantation because of increasing AFPin the absence of positive imaging findings. At the timeof old imaging techniques, the majority of patients withincreased AFP would ultimately have been proven tobear HCC if explored by laparoscopy or necropsy. To-day, however, the sensitivity of imaging techniques for

Abbreviations: HCC, hepatocellular carcinoma; UNOS, United Network for Organ Sharing; AFP, alpha-fetoprotein; MELD, model forend-stage liver disease.Supported in part by a grant of the Instituto de Salud Carlos III (grant 03/02) and the grant PI050150 also of the Instituto de SaludCarlos III (2006-2008). M.V. was also supported by a grant from the Fundacion Cientıfica de la Associacion Espanola Contra el Cancer,and A.F. was supported by a grant of the Instituto de Salud Carlos III.Address reprint requests to Jordi Bruix, MD, BCLC Group, Liver Unit, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain. Telephone: 34 932279803; FAX: 34 93 227 5792; E-mail: bruix@ub.edu

DOI 10.1002/lt.20909Published online in Wiley InterScience (www.interscience.wiley.com).

LIVER TRANSPLANTATION 12:1445-1447, 2006

© 2006 American Association for the Study of Liver Diseases.

detection and characterization of hepatic nodules hassignificantly improved, and the likelihood of missing aclinically significant HCC in patients with increasedAFP is reduced. The data collected by Kemmer et al.unequivocally show that the AFP enlistment criterion isnot adequate and that in most cases the suspicion ofHCC will not be confirmed. Accordingly, usage of AFP asan indicator of the presence of HCC in the absence ofunequivocally positive imaging findings has resulted inincorrect transplant indications. Only a quarter of thepatients within the UNOS database were ultimatelyproven to bear HCC, and this should be considered apoor service to patients and a misuse of the limitednumber of livers that are available. It could be arguedthat the explanted livers may not have been properlysliced to detect HCC, but this seems highly unlikely asany physician who would have indicated transplanta-tion because of suspected HCC would have requested adetailed examination of the whole liver by a concernedpathologist if explant examination was negative at firstsight.

Of course, an increasing AFP concentration may raisethe suspicion of HCC, but several studies have shownthat in the absence of a positive imaging finding theexistence of malignancy is not the rule.9,10 There is noneed to list the extrahepatic diseases that may presentincreased AFP values, but it is well known that flares ofinflammation associated with viral replication may re-sult in AFP increases even beyond 500 ng/mL.10-12

Furthermore, even if a tiny nodule is detected, it maynot correspond to HCC. Cirrhotic livers may containlarge regenerative or dysplastic nodules, and HCC di-agnosis should be established only if a specific dynamicpattern (intense contrast uptake in the arterial phasefollowed by washout in the venous/delayed phase) isobserved.10 If the nodule is not vascularized or thecontrast pattern is not specific, any other diagnosis isfeasible. It should be noted that there are reports ofmetastatic liver involvement with increased AFP andthat cholangiocarcinoma may also present with in-creased AFP concentration. Finally, it could be arguedthat increased AFP concentration is a predictor of HCCdevelopment during follow-up10 and, hence, transplan-tation could be indicated to prevent cancer develop-ment and, ultimately, death. However, HCC develop-ment and clinical recognition deserving treatment maytake years, and transplantation should not be regardedas a risk-free procedure. The accumulated knowledgein the field of prostate cancer and the clinical manage-ment of prostate-specific antigen increases represent-ing a very early cancer stage should be kept in mind toavoid overtreating patients with liver disease. In sum-mary, the data by Kemmer et al. provide further proofthat AFP is not a good tool for HCC diagnosis. Diagnosisshould be based either on biopsy or well-defined non-invasive imaging criteria as depicted in the recentlypublished American Association for the Study of LiverDiseases guidelines.10 In fact, the guidelines do notsupport the use of AFP as a screening tool for HCC dueto poor sensitivity and specificity, and now this lack ofaccuracy has been evidenced in the transplant setting.

Accordingly, it seems clear that the AFP enlistmentcriteria should be dropped, and UNOS surely will con-sider taking action in that direction.

In the study by Freeman et al., the area investigatedrefers to the capacity of imaging techniques to properlyassess the existence and extent of HCC prior to trans-plantation. This issue is critical to ensuring that pa-tients enlisted for liver transplantation really presentsuch a cancer, but at the same time, it is relevant toproperly establish whether the patient fits into the ac-cepted criteria for liver transplantation with optimalresults, or if the limits are exceeded and the patientshould be denied any priority according to the currentpolicy, or even excluded from transplantation. One ofthe major concerns of the study is the 21% of cases inwhom no tumor was found in the explanted liver. Again,absence of tumor may mean that the patient was trans-planted without need and/or given a priority that wasnot deserved. While this false-positive diagnosis shouldbecome a major concern, the data about staging arealso provoking. Patients were understaged and over-staged with equal frequency, and this fact disables thepotential fairness of any priority policy based on stag-ing. As a whole, the results of Freeman et al. indicatethat with the current methodology for diagnosis andstaging, the patients evaluated for liver transplantationare not properly managed. The authors give some po-tential explanations for their disappointing data, but inaddition to the flaws associated to any retrospectiveinvestigation, the most important reason should be thelack of common methodology for liver imaging togetherwith the absence of well-established imaging criteria toestablish HCC diagnosis and its extent. Noninvasivediagnostic criteria based on dynamic imaging were pro-posed years ago by the European Association for theStudy of the Liver13 and more recently by the AmericanAssociation for the Study of Liver Diseases.10 In bothinstances it is stressed that HCC diagnosis by imagingtechniques can be made only if the dynamic pattern ofa nodule detected within a cirrhotic liver presents in-tense arterial uptake with contrast washout in the ve-nous/delayed phase. Nodules larger than 2 cm in sizemay be diagnosed with a single imaging technique, butin nodules smaller than 2 cm, having 2 coincidentalreports by 2 of the available dynamic modalities (con-trast ultrasound, computed tomography, and magneticresonance imaging) is recommended. If the reports byexperienced radiologists do not offer conclusive results,a biopsy is considered mandatory to avoid an incorrectdiagnosis. It is important to note that HCCs � 2 cmseldom present a characteristic dynamic imaging pat-tern; thus, avoidance of biopsy in the absence of acharacteristic vascular profile will likely translate intomisdiagnosis. Undoubtedly this has happened, and thestriking data presented by Freeman et al. should triggerthe wide use of validated diagnostic criteria.

Nonetheless, consensus definitions for staging are notyet available. It is well known that cirrhotic livers maypresent large nodules without intense contrast uptake ortiny hypervascular spots only seen during the arterialphase of computed tomography or magnetic resonance

1446 EDITORIAL

LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

imaging.14 Lipiodol computed tomography is hamperedby false-positive and false-negative results15 and shouldnot be used, but very likely it has been responsible forsome of the mistakes described by Freeman et al. In anycase, accurate distinction between additional tumor sitesand insignificant findings is not feasible even in experthands; thus, all studies with correlation of imaging find-ings with explant analysis show some degree of overstag-ing and understaging. Nevertheless, the magnitude of thewrong assessment does not usually reach the figures ex-posed by Freeman et al. with a mere 50% accuracy. Theauthors suggest that centers with better results have ma-jor expertise and that their findings reflect real life innonreferral units. While accumulated expertise in referralcenters is a valid explanation, the lack of accuracy innonexpert centers should not be accepted as a given andunavoidable fact. Liver transplantation is not a routineprocedure, and it should be performed in centers withstate-of-the-art human and technical resources. Thus, tohave suboptimal radiology for the evaluation of the indi-cation of a complex procedure to be performed in referralcenters is an unacceptable opening for poor clinical deci-sions with misuse of valuable resources. Interestingly, theauthors report major differences according to UNOS re-gions, and these differences reflect varying skills andmethodology. Some transplant groups have the necessaryexpertise, while others need to improve or modify theirclinical management process. As a whole, major effortsshould be made to implement homogenous methods anddefinitions, as it is the sole way to ensure an optimalhealth care delivery and avoid unfair enlistment and man-agement of patients considered for transplantation. Fur-thermore, equative priority policy for the waiting list iscritical, and if staging plays a role in the points allocation,it is the key to ensuring that all patients will be managedaccording to the same measurements using the sametools with the same criteria. It is well known that in theso-called model for end-stage liver disease (MELD) era,the priority for receiving a liver is ranked according to ascore reflecting liver function impairment. This systemhas been embraced by several countries because of itssimplicity, but major aspects within it need to be fixed.Management of patients with HCC is of utmost relevance.Currently, HCC patients are given MELD points accord-ing to tumor stage, aiming to make their risk of progres-sion and death with equal to non-cancer patients’ risk ofdeath. Previous analyses have shown that point allocationmay give too much or too little priority to cancer patients.But even with continuous refinement it will be impossibleto prevent the consequences of the fact that MELD pointsof non-cancer patients vary from region to region. Thus,while on a large-scale basis the point allocation to HCCpatients according to stage may appear to offer a balanceddistribution of organs, the center- or region-based analy-sis may disclose a skewed situation. Certainly, MELD willbe refined and will evolve into a more complex system withpriority models for each major group of patients. In themeantime, it is mandatory to ensure that all patients arestaged according to the same methodology to avoid theperpetuation of the situation depicted by Freeman et al.Obviously, the sole way to achieve this aim is to have

patients with suspected or proven HCC properly evalu-ated in centers with state-of-the-art resources and makesure that the findings in “real life,” during the evaluationof candidates for liver transplantation, correspond to re-ality and priority granting based on facts and not on sub-jective interpretation of imaging techniques.

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EDITORIAL 1447

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