This article reviews methodological issues around screeningfor hepatocellular carcinoma, and discusses selection of theat-risk group, which screening test to use, and how frequentlyit should be applied. Screening of patients at risk for hepato-cellular carcinoma should be undertaken using ultrasonogra-phy applied at six-month intervals. Patients at risk include allthose with cirrhosis, and certain non-cirrhotic patients with
chronic hepatitis B. In this population, screening has beenshown to reduce disease-specific mortality. Although data donot exist for other populations, screening is nonethelessadvised because small cancers can be cured with appreciablefrequency.
Key words: cancer screening, hepatocellular carcinoma
INTRODUCTION
SCREENING IS MUCH more than the application ofa screening test or tests. A number of criteria have to
be met before a screening program has any chance ofbeing effective. In addition, the choice of screening testis critical, as is the identification of the target populationfor whom the screening is intended, and the screeninginterval. All these considerations are discussed in thisarticle.
Criteria for successful programProrok1 defined the criteria for the successful develop-ment and execution of a screening program for anydisease. These include that:1 The disease must be common and have a severe
outcome.2 The screening test should be widely available and
non-invasive, inexpensive and easily applied.3 The at-risk population should be well defined, and
should accept the need for screening.4 The physicians looking after the at-risk population
should also accept the need for screening.5 There should be effective treatment available.
Screening for liver cancer meets these criteria tovarying extents. In the at-risk populations, hepatocellu-lar carcinoma (HCC) is common. In cirrhosis causedby hepatitis C or other causes, the incidence may be
3–11%/year,2–5 and in hepatitis B, including the cir-rhotic and non-cirrhotic population the incidence is0.2–0.6%/year.6–8
The ideal screening test has not yet been identified,but existing screening tests, which will be discussed inmore detail later, include ultrasound (US), and theserological tests alfa-fetoprotein (AFP), alfa-fetoproteinL3–total AFP (AFP–L3) ratio, and des-gamma-carboxyprothrombin (DCP). Of these tests, only mea-surement of AFP can be considered inexpensive (asscreening tests go). However, all are easily applied andare non-invasive. US and AFP are widely available, andin some countries DCP and AFP–L3 are also widelyavailable.
The target at-risk population is only partly defined.Although cirrhosis is the major risk factor for HCC, notall patients with cirrhosis are at immediate risk. Thereare no markers that might indicate a higher risk within adefined period. For example, any patient with cirrhosiscaused by chronic hepatitis C is at risk for HCC, butthere is no way of predicting whether the HCC mightdevelop within 1, 3, 5, 10 or more years. Ideally, sincethe risk of HCC increases over time (at a rate that is atpresent unquantifiable), we would like to avoid screen-ing when the risk of HCC is low, and institute screeningwhen the incidence exceeds a certain cut point or whena specified degree of risk is exceeded. Furthermore,among hepatitis B carriers the risk is not limited to thosewith cirrhosis, although they carry the highest risk. Thus,cirrhosis alone can not be used to determine risk in thisgroup. However, not all hepatitis B carriers requirescreening. A later section describes which hepatitis Bcarriers are at greatest risk.
Correspondence: Dr Morris Sherman, Toronto General Hospital, 200Elizabeth Street, Toronto, On M5G 2C4, Canada. Email:[email protected]
Hepatology Research 2007; 37 (Suppl. 2): S152–S165 doi: 10.1111/j.1872-034X.2007.00180.x
Whether the population at risk for HCC accepts theneed for screening is debatable. In the only randomizedcontrolled trial of HCC screening, compliance fell tobelow 30% after nine years.9 However, there are likelydifferences in compliance rates between those includedin population-based studies and individuals attendingthe physician’s office. In the latter situation, patients arelikely to be more compliant with screening. Neverthe-less, in our screening program, which has been runningsince 1989, less than 20% of patients have completed allscreening assessments.
The need for screening is generally accepted by phy-sicians who are expert in the management of cirrhosis,and by family practitioners who look after communitiesin which hepatitis B is common. However, the findingthat most HCCs still present at a late stage is testimonythere is still no widespread acceptance of the need toscreen.
Finally, although there is effective therapy available, itis really only for early stage disease. Liver transplanta-tion can only be offered to a small minority of patients,but resection and local ablation may be offered on awider scale, and for small lesions are effective therapies.
Assessments of screening efficacyAll diagnostic tests are evaluated for their performancein making the diagnosis by a series of statistical tests.These include the sensitivity, specificity, and positiveand negative predictive values, the Youden index andreceiver operating characteristic (ROC) curves.
Table 1 shows the calculation of some of the perfor-mance characteristics. Sensitivity is a measure of theproportion of patients who have the disease who have apositive test. Specificity is a measure of the proportion ofpatients without the disease who have a negative test.Positive predictive value is a measure of the proportionof positive tests that are correct, and negative predictivevalue a measure of the proportion of negative tests thatare correct. Sensitivity and specificity are independent ofthe frequency of the disease in the population, but the
positive and negative predictive values differ in differentpopulations depending on the prevalence of the diseasein question. Sensitivity and specificity are reciprocals. Asthe sensitivity increases, the specificity decreases and viceversa. The Youden index is (1 - sensitivity + specificity).The higher the Youden index the better the test. AYouden index greater than 0.8 is a good test. A test ofless than 0.7 is unacceptable. ROC curves (Fig. 1) areplots of sensitivity vs 1 - specificity over the whole rangeof test results. ROC curves provide a means of compar-ing the performance of two different tests. The greaterthe area under the curve, the better the test. In addition,the ROC curve provides the optimum value above orbelow which a test result can be considered abnormalfor that condition (but not necessarily in other condi-tions). This is also not necessarily the usual measure oftwo standard deviations from the mean of an averagepopulation. The optimum cut-off value is given by theapex of the curve.
It is important to recognize that the performance char-acteristics of screening tests used for diagnosis are dif-ferent from when the same test is used for screening. Toquote: “Nearly everything we know about the naturalhistory of cancers has derived from observation of clini-cally symptomatic cases – that is, the tip of the iceberg ofdisease that extends above the waterline. However,cancer is not an event, but rather a process of pathogen-esis that extends over decades. . . . Most of the naturalhistory of cancer is taking place below the waterline ofdetection. A screening test allows us to dip below thewaterline and detect numerous lesions. However, wecannot necessarily extrapolate the natural history of
Table 1 Calculation of test performance characteristics
HCC No HCC Total
Test positive A B A + BTest negative C D C + DTotal A + C B + D A + B + C + D
Figure 1 Receiver Operating Characteristic curve. AUC = areaunder the curve. AUC = 0.5 indicates a test that has no diag-nostic ability; AUC = 1.0 indicates a test that is 100% accurate.
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these newly discovered abnormalities to our experiencewith the traditional symptomatic cancers that break thewaterline”.10
There are data from studying other cancers that theperformance characteristics of screening tests improve asthe cancer develops from early to late stage. Therefore, atest that is used to diagnose cancer (e.g. AFP) is notnecessarily a good test to screen for cancer, because itmay not be able to detect premalignant lesions and earlysmall cancers.
The objective of cancer screening programs is todecrease mortality from the cancer. There are severalcauses of bias that make it difficult to assess whether ascreening program succeeds in its aims, including lead-time bias, length bias, and verification bias. Lead-timebias is the apparent increase in survival that is solely dueto early diagnosis. Patients diagnosed on screening willhave better survival from the time of diagnosis simplybecause the disease was found earlier, whether or not anintervention is applied, and whether or not the interven-tion makes any difference. Thus, in assessing trials inwhich lead time bias is not accounted for, no commentcan be made on either the efficacy of the screeningintervention or on the therapeutic intervention. Lengthbias is the bias introduced because slow growing tumorsare more frequently detected at a treatable stage thanrapidly growing tumors. Slow growing tumors also havea better prognosis, whether or not an intervention isapplied. Therefore, patients with screen-detected tumorswill apparently survive longer than non-screen detectedtumors, but in reality the comparison is not validbecause what is being compared is survival betweenslow growing and rapidly growing tumors. Verificationbias occurs when the screening test and the diagnostictest are the same, e.g. when computed tomography (CT)scanning is used for both screening and diagnosis.When the diagnosis is not made with complete certaintyverification bias exists.
There are several surrogate markers that have beendescribed to evaluate the efficacy of screening programs.These markers include stage shift, incidence of advancedcancer, case fatality rates, disease specific mortality ratesand all cause mortality rates. All of these surrogatemarkers will show improvement in a successful screen-ing program, but improvement in any of these markerscan also be caused by the biases described above. Stageshift must by definition accompany a cancer screeningprogram. Screening is designed to find earlier disease.However, stage shift alone does not necessarily translateinto decreased mortality. Similarly, a decrease indisease-specific mortality rates, case fatality rate, and
incidence of advanced cancer will all improve with effec-tive screening. However, these decreases can all becaused by verification and lead-time bias. This effect hasclearly been shown by analysis of the Surveillance, Epi-demiology and End Results (SEER) Program of theNational Cancer Institute (NCI), which demonstratedthat these endpoints did not correlate with a reductionin disease-specific mortality.11 Several studies haveshown that surveillance does detect earlier disease (stagemigration).12–15 However, as discussed above, this doesnot correlate well with reduction in disease-specificmortality. Uncontrolled studies, all subject to lead-timebias, have suggested that survival is improved aftersurveillance.12,15
Only a randomized controlled trial can eliminatethese biases.
Surveillance for hepatocellular carcinomaStrictly speaking, screening is the one-time applicationof a test to make a diagnosis, but surveillance is therepeated application of screening tests in a program-matic fashion. The two words however, are oftenused interchangeably. Surveillance for HCC, therefore,involves a program or a process in which screening testsand recall procedures have been standardized and inwhich quality control procedures are in place. Theprocess of surveillance also involves deciding what levelof risk of HCC is high enough to trigger surveillance, i.e.who should undergo surveillance, what surveillancetests to apply and how frequently (surveillance interval),and how abnormal results should be dealt with (diag-nosis and/or recall).
Until recently, although there was no evidence thatscreening was beneficial, screening and surveillancewere widely applied. However, a randomized controlledtrial of surveillance versus no surveillance in hepatitis Bcarriers has shown a survival benefit to a strategy ofsix-monthly surveillance with alfa-fetoprotein and US.9
The study, which was performed in China, recruited18 816 patients who had markers of either current orprior hepatitis B infection. Adherence to surveillancewas suboptimal but despite this, the HCC related mor-tality was reduced by 37% compared to the unscreenedgroup, a statistically significant result. These resultsprobably represent the minimum benefit that can beexpected from surveillance because of poor compliancewith surveillance, and because the only therapies offeredwere either resection or palliative care. An earlier study,also conducted in China, failed to show benefit, largelybecause patients who were diagnosed with HCC did notundergo appropriate treatment.16 The results of this
S154 M. Sherman Hepatology Research 2007; 37 (Suppl. 2): S152–S165
study can not be generalized to other causes of cirrhosisbecause the frequency of resection in hepatitis B is likelyto be greater than in other diseases, because, unlikeother diseases, HCC in hepatitis B can occur in non-cirrhotic patients. Therefore, ideally, these results shouldbe validated in other geographic areas and for othercauses of liver disease. However, this is unlikely tohappen. Such trials would be difficult to undertake.
Surveillance for HCC is widely practiced and despitethe lack of concrete evidence can generally be recom-mended for certain at-risk groups. HCC detected afterthe onset of symptoms has a dismal prognosis (0–10%5 years survival).17 In contrast, small HCCs can be curedwith an appreciable frequency.17–21 Five-year disease-freesurvival exceeding 50% has been reported for bothresection and liver transplantation.17,22–30 Patients surviv-ing free of disease for this duration must be consideredcured. For these patients it is highly likely that surveil-lance did decrease mortality.
Definition of at-risk populationThe decision to enter a patient into a surveillanceprogram is determined by the level of risk for HCC.Risk is related to the incidence of HCC. There are noexperimental data to indicate what level of risk or whatincidence of HCC should trigger surveillance. In theabsence of more definitive data, decision analysis hasbeen used to provide guidelines as to the incidence ofHCC at which surveillance may become effective. Ingeneral terms an intervention is considered effective ifit provides an increase in longevity of approximately100 days (~3 months).31 Although these levels were setyears ago, and may not be appropriate today, interven-tions that can be achieved at a cost of less than approxi-mately $USD 50 000/year of life gained are consideredcost-effective.32
There are now several published decision analysis/cost-efficacy models for HCC surveillance, which differin the nature of the theoretical population being ana-lyzed, and in the intervention being applied. Despitethese differences, these models all find that surveillanceis cost-effective, although in some cases only marginallyso. Most find that the efficacy of surveillance is highlydependent on the incidence of HCC. In a theoreticalcohort of patients with Child’s A cirrhosis, if the inci-dence of HCC exceeded 1.5%/year, surveillance resultedin an increase in longevity of approximately threemonths.33 However, if the incidence of HCC was 6%,the increase in survival was approximately nine months.This study did not include transplantation as a treat-ment option. In another study, which did include liver
transplantation,34 in a similar population of hepatitis Ccirrhotic patients with normal liver function, surveil-lance with either CT scanning alone or CT scanning plusUS became cost-effective when the incidence of HCCwas more than 1.4%. However, this study has to beinterpreted cautiously, because the performance charac-teristics of CT scanning were derived from diagnosticstudies, not surveillance studies. Lin et al.35 found thatsurveillance with AFP and ultrasound was cost effectiveregardless of HCC incidence. Thus, for patients withcirrhosis of varying etiologies, surveillance should beoffered when the risk of HCC is 1.5%/year or greater.Table 2 describes the groups of patients in which theselimits are exceeded.
The above cost efficacy analyses, which were restrictedto cirrhotic populations, can not be applied to non-cirrhotic hepatitis B carriers. These patients, particularlyin Asia and Africa, are also at risk for HCC. A costefficacy analysis of surveillance of hepatitis B carriersusing US and AFP levels suggested that surveillancebecame cost effective once the incidence of HCCexceeded 0.2%/year (Collier J., Sherman M., 1999,unpublished data). The subgroups of hepatitis B carriersin which the incidence of HCC exceeds 0.2%/year arealso given in Table 2.
HEPATITIS B
THE INCIDENCE OF HCC in hepatitis B carriersvaries between 0.2 and 0.6%.36–38 The annual
Table 2 Groups suitable for hepatocellular carcinomascreening
Hepatitis B carriersAsian males <~ 40 years (incidence ~0.4–0.6%/year)Asian females <~ 50 years (incidence ~0.2%/year)Africans >20 years (incidence unknown but likely
>0.2%/year)Cirrhosis (HCC incidence 3–5%/year)Family history of HCC, mainly Asian and AfricanTreated hepatitis B cirrhosis
Non-hepatitis B cirrhosisHepatitis CTreated hepatitis C cirrhosisIncidence of HCC ~3–5%/yearAlcoholic cirrhosisGenetic hemochromatosisAlfa1-antitrypsin deficiencyPrimary biliary cirrhosisAutoimmune hepatitis
HCC, hepatocellular carcinoma.
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incidence increases with age, so that in one study at age70 the incidence was 1%.36 The incidence in patientswith known cirrhosis was 2.5%/year.36 In comparisonwith those not infected with hepatitis B, the relative riskof HCC was approximately 100, i.e. hepatitis B carrierswere 100 times more likely to develop HCC than theuninfected. Sakuma et al.39 found the incidence of HCCin male Japanese railway workers was 0.4%/year. Mostof the populations in which incidence is well-describedare male and Asian, with the hepatitis B infection likelyacquired at birth or in early childhood. Uncontrolledprospective cohort studies in North America, where theepidemiology of hepatitis B is different, i.e. hepatitis isacquired later in life, have indicated that the incidenceof HCC in hepatitis B virus (HBV) carriers varieswidely.37,38,40 Villeneuve et al.40 found no tumors in acohort infected with HBV and followed-up for 16 years.McMahon et al.38 reported an incidence of HCC of0.26%/year in a study of HBV-infected individuals inAlaska. Sherman et al.37 described an incidence of0.46%/year in their cohort. In Europe, HCC in hepatitisB carriers occurs mainly in patients with establishedcirrhosis.41,42 Non-Asian chronic carriers who are anti-hepatitis B e-antigen (HBe) positive with long-terminactive viral replication and who do not have cirrhosisseem to have little risk of developing HCC.43–46 Whethersurveillance is worthwhile in this population is notclear. This is not true for Asian non-cirrhotic hepatitis Bcarriers, who remain at risk for HCC regardless of repli-cation status.43,47–49 Similarly, the risk of HCC persists inlong-term HBV carriers from Asia who lose hepatitis Bsurface antigen (HBsAg), and these patients should con-tinue to undergo surveillance.50 In Caucasian hepatitis Bcarriers who lose surface antigen, the risk of HCC seemsto decline dramatically.51,52
In Asian male hepatitis B carriers, although HCC doesoccur at a younger age, the annual incidence of HCConly starts to exceed 0.2% at approximately age 40.36
Therefore, Asian men should undergo surveillance fromage 40 onwards. The efficacy of providing surveillance toall carriers younger than age 40 is likely to be low. Theincidence of HCC in women is lower than in men,although age-specific incidence rates are hard to comeby. Nonetheless, it seems appropriate to start surveil-lance at approximately age 50 in Asian women. Since ahistory of HCC in a first degree relative of a hepatitis Bcarrier carries an increased risk of HCC at a youngerage,53 such a history should prompt earlier onset ofscreening, although what that age should be is hard todefine. Africans with hepatitis B seem to get HCC at ayounger age.54,55 Surveillance in these populations
should also start at a younger age. Whether this is true inblack people born elsewhere is uncertain. In non-cirrhotic Caucasian hepatitis B carriers51,52 the incidenceof HCC is probably too low to make surveillance worth-while. However, there are additional risk factors thathave to be taken into account, including older age, per-sistence of viral replication and coinfection with hepa-titis C or human immunodeficiency virus (HIV), or thepresence of other liver diseases.
More recent data indicate that the best predictor ofHCC was the HBV DNA, even measured 10 years ear-lier.56 The higher the HBV DNA, the higher the risk.Further, if the HBV declined over time the HCC risk alsodeclined. However, how this can be factored into thecalculation of risk requiring screening is not yet clear.
HEPATITIS C
THE RISK OF HCC in patients with chronic hepatitisC has mainly been established in clinic-based
studies, and is highest in patients who have establishedcirrhosis,57–60 in whom the incidence of HCC is 2–8%per year. There is a single prospective population-basedstudy of the risk of HCC in patients with hepatitis C.3 Inthis study of 12 008 men there was a 20-fold increase inrisk of HCC in the presence of anti-hepatitis C virus(HCV) compared to anti-HCV negative subjects. Thepresence or absence of cirrhosis was not evaluated. Non-cirrhotic hepatitis C infected individuals have a muchlower risk of developing HCC and do not require screen-ing.4 However, the transition from bridging fibrosis tocirrhosis can not be determined clinically, and the cli-nician can not easily determine when these patients startto develop a significant increase in risk of HCC. For thisreason, the first European Association for Study of theLiver conference on HCC recommended that screeningshould start in patients who had stage 3 fibrosis(METAVIR).61 However, the cost-efficacy of this recom-mendation has not been evaluated. It is not feasible torepeat biopsies periodically in these patients to identifythe point at which HCC risk increases.
There have been several attempts to develop non-invasive markers to predict the stage of fibrosis62–64 andif properly validated, these could be used to determinewhen to initiate surveillance. Similarly, several markershave been suggested to predict a significant risk of HCC.One such marker may be the platelet count. It has beensuggested that the incidence of HCC in hepatitis C cir-rhosis only increases substantially once the plateletcount is less than 100 ¥ 109/L,60,65–67 regardless of liverfunction. This association needs to be validated. Others
S156 M. Sherman Hepatology Research 2007; 37 (Suppl. 2): S152–S165
have attempted to develop predictive indices based onpanels of commonly performed serological tests such asalfa-2-macroglobulin, apolipoprotein A1, haptoglobin,bilirubin, gamma-glutamyl-transpeptidase, and theaspartate aminotransferase–alanine aminotransferase(AST/ALT) ratio.64,67 However, these indices still have tobe validated before entering general use and can not berecommended at present.
Therefore, whether patients with bridging fibrosisshould also undergo surveillance remains controversial.
CIRRHOSIS FROM CAUSES OTHER THANVIRAL HEPATITIS
THE INCIDENCE OF HCC in cirrhosis caused bydiseases other than viral hepatitis is, with some
exceptions, not accurately known. Most studies on theincidence of HCC in alcoholic cirrhotic patients datefrom before the identification of the hepatitis C virus.Given that hepatitis C is relatively frequent in alcohol-ics, most of the reported incidence rates in these earlierstudies must be overestimates. However, there is nodoubt that alcoholic liver disease is a risk factor forHCC, although the magnitude of that risk is at presentunknown. In one study, alcoholic liver diseaseaccounted for 32% of all HCCs.68 In an Austrian cohortwith HCC, alcoholic liver disease was the risk factor in35% of subjects.69 In the USA, the approximate hospi-talization rate for HCC related to alcoholic cirrhosis is8–9/100 000 per year compared to approximately7/100 000 per year for hepatitis C.70 This study did notdetermine the incidence of HCC in alcoholic liverdisease, but it does confirm that alcoholic cirrhosis is asignificant risk factor for HCC, probably sufficient towarrant surveillance for HCC.
Cirrhosis secondary to steatohepatitis is also likely tobe a risk factor for HCC. However, no study to date hasfollowed a sufficiently large group of such patients forlong enough to describe an incidence rate for HCC. Inone cohort study of patients with HCC,71 diabetes wasfound in 20% as the only risk factor for HCC. Whetherthese patients were cirrhotic was not noted. Non-alcoholic fatty liver disease (NAFLD) has been describedin cohorts of patients with HCC.72,73 Since the incidenceof HCC in cirrhosis caused by NAFLD is unknown, it isnot possible to assess whether surveillance might beeffective or cost efficient.
Patients with genetic hemochromatosis (GH) whohave established cirrhosis have an increased risk ofHCC.74–76 The relative risk of HCC is approximately 20.The standardized incidence ratio for of HCC in cirrhotic
GH is 92.9 (95% confidence interval [CI] 25–237.9).The incidence of HCC in cirrhosis from GH is suffi-ciently high (~ 3–4%/year) that these patients should beincluded in surveillance programs. Surveillance in thesepatients has become standard practice. Whether surveil-lance will reduce mortality from the disease is notknown. The incidence of HCC in primary biliary cirrho-sis is about the same as in cirrhosis caused by hepatitisC.77 For cirrhosis due to alfa 1-antitrypsin (AAT) defi-ciency,78,79 or autoimmune hepatitis, there are insuffi-cient data from cohort studies to accurately assess HCCincidence.
TREATED CHRONIC VIRAL HEPATITIS
Hepatitis B
THE EVIDENCE THAT interferon therapy reduces therisk of HCC is conflicting. Studies in Europe sug-
gested that interferon therapy for chronic hepatitis Bimproved survival and reduced the incidence ofHCC.59,80,81 A study from Taiwan also indicated that suc-cessful interferon therapy, i.e. the development of anti-HBe, was associated with a reduced incidence of HCC.82
However, in these studies the event rate was low, andthe sample sizes were relatively small. In contrast, anon-randomized, but matched controlled study fromHong Kong that included a larger cohort followed forlonger periods found that the incidence of HCC was notdecreased in the treated group.83 A single randomizedcontrolled trial suggests that lamivudine treatment ofchronic hepatitis B carriers with cirrhosis does reducethe incidence of HCC,84 but whether the risk reductionis sufficient that surveillance becomes unnecessary is notclear. Thus, it seems prudent to continue to offer sur-veillance to Asian hepatitis B infected individuals withcirrhosis, even after therapy-induced seroconversion.However, this may not be appropriate for non-cirrhoticCaucasian hepatitis B carriers.
Hepatitis CThere are a number of studies evaluating the effect oftreatment of chronic hepatitis C on the incidence ofHCC. A single randomized controlled trial in Japan sug-gested that the incidence of HCC was reduced in bothresponders and non-responders to interferon.85 Theseresults could not be confirmed in a second randomizedcontrolled trial from France.86 The results of thesestudies and other studies were summarized in a meta-analysis, which concluded that the benefit is mainlyseen in those who were successfully treated, i.e. had a
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sustained virological response, and even then, the effectwas small.87 However, even non-responders appeared toshow some risk reduction after interferon therapy. Anumber of studies in Japan compared the incidenceof HCC in treated patients with that in historicalcontrols.4,88–94 These studies suggested that there is areduced incidence of HCC in treated patients. It seemsthat treating or eradicating hepatitis C reduces, butdoes not completely eliminate, the risk for HCC. Thus,patients with hepatitis C and cirrhosis who haveachieved viral clearance on therapy should continue toundergo surveillance.
Patients with treated or spontaneously inactivatedchronic hepatitis B or C may show regression of fibrosissufficient to suggest reversal of cirrhosis. The risk ofHCC in these patients probably does not decrease pro-portionately with the improvement in fibrosis. There aremany theories about the pathogenesis of HCC in thesepatients, but one common factor seems to be thatrepeated rounds of necrosis and regeneration are neces-sary. The steps required to initiate the carcinogenicpathway probably occur many years before the diseasebecomes inactive, and so the threat of HCC remainseven if fibrosis decreases. Regressed fibrosis is not areason to withhold surveillance.
OTHER PREDICTIVE FACTORS FOR HCC
THERE ARE A number of factors associated with anincreased risk of HCC that are seen in patients at risk
for developing HCC. These factors include elevated AFPconcentration,94–96 presence of macroregenerative nod-ules,97 small and large cell dysplasia on biopsy,60,98,99
irregular regeneration (irregular margins to regenerativenodules),100 and increased labeling index for proliferat-ing cell nuclear antigen or silver staining of the nucle-olar organizing region.101–105 Although such patients areat more immediate risk of developing HCC, they willlikely already be in surveillance programs because ofother recognized risk factors such as cirrhosis or chronichepatitis B. The increased risk, however, does notrequire a change in surveillance protocol.
Surveillance tests
The development of a cancer screening test involvesseveral stages before the test can be fully validated as aneffective cancer screening test. First, the test has to beshown to be associated with the cancer in laboratorystudies. Next the test has to be positive in serum ofpatients known to have cancer. Then, retrospective
studies should show that the test becomes positivebefore clinical detection of the cancer. A randomizedcontrolled study should show that the test decreasesmortality compared to no screening, or more than thepre-existing test. Finally, the screening test should showan effect on cancer control. Of the available screeningtests, none have been fully validated according to thisalgorithm.
Screening tests fall into two categories, serological andradiological. Of the serological tests, the performancecharacteristics of AFP have been best studied.37,106–109
ROC analysis of AFP used as a diagnostic test suggeststhat a value of approximately 20 ng/mL provides theoptimal balance between sensitivity and specificity.106
However, at this level the sensitivity is only 60%, i.e.AFP surveillance would miss 40% of HCC if a value of20 ng/mL were used as the trigger for further investiga-tion. This sensitivity is inadequate for general use. If ahigher cut-off is used, a progressively smaller proportionof HCCs will be detected. If the AFP cut-off is raised to,e.g., 200 ng/mL the sensitivity drops to 22%. Con-versely, reducing the cut-off means that more HCCswould be identified, but at the cost of a progressiveincrease in the false-positive rate. This analysis was per-formed in a case control study where the prevalence ofHCC was artificially set at 50%. At this prevalence thepositive predictive value of an AFP of 20 ng/mL was84.6%. However, if the HCC prevalence rates were morelike those seen in most liver clinics, i.e. about 5%, thepositive predictive value of an AFP of 20 ng/mL is only41.5%, and even at a cut-off of 400 ng/mL, the positivepredictive value (PPV) is only 60%. In cohorts undergo-ing surveillance, the incidence of HCC may be evenlower than 5%, depending on the criteria for entry intosurveillance. For example, in non-cirrhotic hepatitis Bcarriers infected at birth the incidence of HCC is usuallyless than 1%.
Therefore, AFP is an inadequate screening test.110 AFPstill has a role in the diagnosis of HCC, since in cirrhoticpatients with a mass in the liver, an AFP greater than200 ng/mL has a very high positive predictive value forHCC.106 Further, a persistently elevated AFP has beenclearly shown to be a risk factor for HCC.94,95 Thus, theAFP can be used to help define patients at risk, butappears to have limited utility as a screening test.
Another serological test used to diagnose HCC isDCP, also known as prothrombin induced by Vitamin Kabsence II (PIVKA II).109,111–114 Most reports on the use ofDCP have evaluated the use of this test in a diagnosticmode, rather than for surveillance. Although there arereports of its use in a surveillance mode, these do not yet
S158 M. Sherman Hepatology Research 2007; 37 (Suppl. 2): S152–S165
provide sufficient justification for routine use of thismarker. There are also reports that DCP is a marker forportal vein invasion by tumor.115 If confirmed, thiswould also suggest that DCP is not a good screening test.A screening test should be able to identify early disease,not late disease. Other tests that have been reported asscreening tests included the ratio of glycosylated AFP(L3 fraction) to total AFP,116–123 alfa fucosidase124,125 andglypican-3.126,127 Other potential markers have also beendescribed, e.g. GP73, a resident Golgi glycoprotein.127
None of these new markers have been adequately inves-tigated and can not be recommended as screening tests.Proteomic profiling may aid to develop more accuratemarkers.128
The radiological test most widely used for surveillanceis ultrasonography (US). A small HCC on ultrasoundmay take on one of several different appearances. Thesmallest lesions may be echogenic, because of the pres-ence of fat in the tumor cells. Other lesions may behypoechoic, or show a “target lesion” appearance. Noneof these appearances is specific. US has been reportedto have a sensitivity of 65–80% and a specificitygreater than 90% when used as a screening test.15
However, the performance characteristics have not beenas well defined in nodular cirrhotic livers undergoingsurveillance.129–131 These performance characteristics,although not ideal, are considerably superior to any ofthe serological tests. The main drawback to using US forHCC surveillance is that it is very operator dependent.In addition, scanning is difficult in obese subjects.
Strategies such as alternating AFP and US at intervalshave no theoretical basis. The guiding principle shouldbe that the best available screening test should bechosen, and it should be applied regularly. Combineduse of AFP and US increases detection rates, but alsoincreases costs and false-positive rates.132 AFP-only sur-veillance had a 5.0% false-positive rate, US alone had a2.9% false positive rate, but in combination the false-positive rate was 7.5%. US alone costs approximately$USD 2000 per tumor found, where the combinationcost was approximately $USD 3000 per tumor found.132
Some reports suggest the use of CT scanning as a screen-ing test for HCC.131,133–135 This is problematic for severalreasons. First, a screening test is not usually also thediagnostic test of choice. Second, the performance char-acteristics of CT scanning have been developed indiagnostic/staging studies and the performance charac-teristics of CT scanning in HCC surveillance areunknown. If CT scanning is to be used as a screening testi.e. every 6–12 months over many years, there is signifi-cant radiation exposure to be considered. Practical
experience suggests that the false-positive rate will bevery high.
Therefore, screening should be with US alone. Sero-logical tests do not add much to the sensitivity, anddetract from other performance characteristics. Indeed,it is hard to see how serological testing detects earliertumors when US is capable of detecting lesions smallerthan 1 cm, which are very early HCC. Such small lesionshave a very low likelihood of secreting enough of anyserological marker to be detectable in serum.
Surveillance intervalThe ideal surveillance interval is not known. A surveil-lance interval of 6–12 months has been proposed basedon tumor doubling times. A single randomized con-trolled trial9 used a six-month interval with positiveresults. However, a retrospective study has reported thatsurvival is no different in patients screened at six- or12-month intervals.136 Another study in HCV infectedhemophiliacs without cirrhosis suggested that the like-lihood of finding HCC at the single nodule stage (asopposed to multinodular HCC) was the same with six-and 12-month surveillance intervals.137 Thus, the sur-veillance interval remains controversial. Most expertsuse a six-month interval, but there are no clear data tosuggest that six months is better than 12 months. Thesurveillance interval is determined by the tumor growthrates and not by the degree of risk. This is an importantconcept because it means that the surveillance intervalneed not be shortened for patients who are thought tobe at higher risk. However, it is important to make thedistinction between patients undergoing surveillance,i.e. those in whom, although high risk is recognized, donot have any a priori reason to suspect HCC, and thosein whom surveillance tests have been abnormal andthere is a concern that HCC is already present. Suchpatients are, strictly speaking, not candidates for surveil-lance, but should be receiving enhanced follow-up (seelater).
Recall policiesRecall policies are the policies instituted to deal with anabnormal screening test result. The first step is to definean abnormal result.106 It has been recommended thatAFP no longer be used, so I will not consider the level ofAFP that should trigger recall. A new mass on US in apatient who has been undergoing surveillance previ-ously is clearly abnormal. A mass which enlarges is alsoabnormal, even if previously considered to be benign.However, more problematic is the nodular cirrhoticliver. Early HCC can be difficult to distinguish from
Hepatology Research 2007; 37 (Suppl. 2): S152–S165 Screening for hepatocellular carcinoma S159
background nodularity. Some cirrhotic nodules can beas large as 2 cm. However, most nodules smaller than1 cm are not HCC.138 Therefore, in a cirrhotic liver anynodule larger than approximately 1 cm should be con-sidered an abnormal screening result warranting furtherinvestigation. Lesions smaller than approximately 1 cmcan be followed at short intervals to monitor growth. Itis also important to note that although classically HCCis described as hypoechoic on ultrasound, HCC can alsobe isoechoic with a halo, hyperechoic, or of mixedechogenicity. Description of the further investigation ofthese nodules is beyond the scope of this article.
SUMMARY
SCREENING OF PATIENTS at risk for HCC should beundertaken using ultrasonography applied at six-
month intervals. Patients at risk include all those withcirrhosis, and certain non-cirrhotic patients with chronichepatitis B. In this population, screening has beenshown to reduce disease-specific mortality. Althoughdata do not exist for other populations, screening isnonetheless advised because small cancers can be curedwith appreciable frequency.
CONFLICT OF INTEREST
NO CONFLICT OF interest statement has beenreceived from the author.
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