Gut Supplement, 1991, S104-S110 Advances in neoplastic disease of the liver and biliary tract P J Johnson, M L Wilkinson, J Karani The last 25 years have seen an explosion of interest in hepatic and biliary neoplasia reflecting not only the worldwide importance of these tumours, but also the fact that recent advances in serological and radiological diagnosis and the new techniques of molecular biology have all had a major impact. It seems hard to believe that in 1965, none of the hepatitis viruses had been identified and although 'Australian antigen' had just been described its significance was yet to be realised. Computerised tomography, ultrasono- graphy and ERCP were all unheard of. The idea of useful tumour markers was still the stuff of oncologists' dreams, alphafetoprotein having only been recognised in animal studies in the year the first liver transplant programme was started (1964). This review aims to summarise progress over the period in question and high- light some of the contributions and current areas of interest of the Institute over this period. Institute of Liver Studies, King's Coliege Hospital, London P J Johnson Gastroenterology Unit, United Medical and Dental Schools of Guy's and St Thomas's Hospitals, London M L Wilkinson Department of Radiology, King's College Hospital, London J Karani Correspondence to: DrP J Johnson. Historical overview In 1965 there were occasional perceptive sugges- tions that hepatocellular carcinoma might be aetiologically related to chronic infection with one of the hepatitis viruses. With the discovery of the association between 'Australia antigen' and hepatitis in 1967, however, the door was opened for a flood of papers soon to show an undoubted association of this tumour with hepatitis B virus infection.' The crowning epidemiological study was that of Beasley et al who, in an ongoing follow up study of over 22 000 male Chinese, clearly showed that those who were HBsAg seropositive were at a relative risk of over 100 for the development of hepato- cellular carcinoma.2 At about the same time there were several reports that integrated HBV-DNA could be detected in the genome of hepatoma cell lines and in some samples of human liver tumour tissue.' Another seminal observation was that certain animals, particularly woodchucks4 and Pekin ducks carried viruses (subsequently classified as 'hepadna' viruses) which are similar in genome size, morphology, and genome organ- isation to human hepatitis B virus. The wood- chuck frequently develops chronic hepatitis and hepatocellular carcinoma which contains inte- grated WHV-DNA sequences and is, therefore, an excellent model for the investigation of hepa- titis B virus related carcinogenesis. It is probably fair to say that molecular bio- logical investigations made rather less progress than expected over the next decade, in explain- ing the mechanism of hepatitis B virus carcino- genesis. Some workers made the startling observation that even among alcoholic cirrhotic patients developing hepatocellular carcinoma and subjects with no serum markers of hepatitis B virus infection, integrated HBV-DNA could be detected in tumour tissue.5 These observa- tions remain controversial, and others have been unable to confirm them.67 There is currently no evidence that the viral DNA contains a trans- forming gene - that is, an 'oncogene' - and analysis of integrated viral segments has failed to reveal any consistent site of integration or common deletions or duplications. The excitement over hepatitis B virus involve- ment overshadowed other possible aetiological factors particularly cirrhosis, the frequency of which amongst men with hepatocellular carci- noma had been commented upon for at least 50 years.8 In a large prospective follow up of 613 patients with different types of cirrhosis initiated in 1978 by Walter Melia and continued by Shams Zaman and Elizabeth Metivier, multivariate analysis showed that the major independent risk factors for the development of hepatocellular carcinoma were increasing age, 'non-UK' nationality and male sex.9 Interestingly, serum hepatitis B virus markers were not a significant risk factor implying that, in previous analyses, the risk associated with hepatitis B virus might have been confounded by the coassociation of hepatitis B virus infection with male sex and birth in areas of high incidence. The importance of cirrhosis as a major aetiological factor is now more widely accepted, at least in low hepato- cellular carcinoma incidence areas, but the inter- actions with other aetiological factors including hepatitis B virus infection remain controversial. SEX HORMONES AND LIVER CANCER It had been long established that, in certain mouse strains, administration of testosterone significantly increases the frequency with which chemically induced hyperplastic nodules pro- gress to hepatoma and castration of male animals decreases the frequency of this occurrence.'" In 1966 in a preclinical study of steroids to be used in oral contraceptive preparations it was recorded that, '. . . Dr Bosner reported to the Committee (on the Safety of Drugs) that dosage with mestranol was associated with the pro- duction of nodules in rats which histologically showed various stages of nodular hyperplasia and the production of hepatoma .. .'."I It should therefore perhaps, not have come as a surprise when Baum'2 and her colleagues described the development of hepatic adenomas in women taking oral contraceptive steroids, an association soon to become well accepted. The possible role of these agents in malignant liver disease was more controversial but an influential paper by James Neuberger in collaboration with Professor Richard Doll at Oxford suggested a small, but significantly increased, risk of hepatocellular S 104 on August 31, 2020 by guest. Protected by copyright. http://gut.bmj.com/ Gut: first published as 10.1136/gut.32.Suppl.S104 on 1 September 1991. Downloaded from
Transcript
Gut Supplement, 1991, S104-S110
Advances in neoplastic disease of the liver andbiliary tract
P J Johnson, M L Wilkinson, J Karani
The last 25 years have seen an explosion ofinterest in hepatic and biliary neoplasia reflectingnot only the worldwide importance of thesetumours, but also the fact that recent advances inserological and radiological diagnosis and thenew techniques ofmolecular biology have all hada major impact. It seems hard to believe that in1965, none of the hepatitis viruses had beenidentified and although 'Australian antigen' hadjust been described its significance was yet to berealised. Computerised tomography, ultrasono-graphy and ERCP were all unheard of. The ideaof useful tumour markers was still the stuff ofoncologists' dreams, alphafetoprotein havingonly been recognised in animal studies in theyear the first liver transplant programme wasstarted (1964). This review aims to summariseprogress over the period in question and high-light some of the contributions and current areasof interest of the Institute over this period.
Institute of Liver Studies,King's Coliege Hospital,LondonP J Johnson
Gastroenterology Unit,United Medical andDental Schools ofGuy'sand St Thomas'sHospitals, LondonM L Wilkinson
Department ofRadiology, King'sCollege Hospital,LondonJ KaraniCorrespondence to:Dr P J Johnson.
Historical overviewIn 1965 there were occasional perceptive sugges-
tions that hepatocellular carcinoma might beaetiologically related to chronic infection withone of the hepatitis viruses. With the discoveryof the association between 'Australia antigen'and hepatitis in 1967, however, the door was
opened for a flood of papers soon to show an
undoubted association of this tumour withhepatitis B virus infection.' The crowningepidemiological study was that of Beasley et alwho, in an ongoing follow up study of over
22 000 male Chinese, clearly showed that thosewho were HBsAg seropositive were at a relativerisk of over 100 for the development of hepato-cellular carcinoma.2 At about the same time therewere several reports that integrated HBV-DNAcould be detected in the genome ofhepatoma celllines and in some samples ofhuman liver tumourtissue.' Another seminal observation was thatcertain animals, particularly woodchucks4 andPekin ducks carried viruses (subsequentlyclassified as 'hepadna' viruses) which are similarin genome size, morphology, and genome organ-isation to human hepatitis B virus. The wood-chuck frequently develops chronic hepatitis andhepatocellular carcinoma which contains inte-grated WHV-DNA sequences and is, therefore,an excellent model for the investigation of hepa-titis B virus related carcinogenesis.
It is probably fair to say that molecular bio-logical investigations made rather less progressthan expected over the next decade, in explain-ing the mechanism of hepatitis B virus carcino-genesis. Some workers made the startlingobservation that even among alcoholic cirrhoticpatients developing hepatocellular carcinomaand subjects with no serum markers of hepatitis
B virus infection, integrated HBV-DNA couldbe detected in tumour tissue.5 These observa-tions remain controversial, and others have beenunable to confirm them.67 There is currently noevidence that the viral DNA contains a trans-forming gene - that is, an 'oncogene' - andanalysis of integrated viral segments has failedto reveal any consistent site of integration orcommon deletions or duplications.The excitement over hepatitis B virus involve-
ment overshadowed other possible aetiologicalfactors particularly cirrhosis, the frequency ofwhich amongst men with hepatocellular carci-noma had been commented upon for at least 50years.8 In a large prospective follow up of 613patients with different types of cirrhosis initiatedin 1978 by Walter Melia and continued by ShamsZaman and Elizabeth Metivier, multivariateanalysis showed that the major independent riskfactors for the development of hepatocellularcarcinoma were increasing age, 'non-UK'nationality and male sex.9 Interestingly, serumhepatitis B virus markers were not a significantrisk factor implying that, in previous analyses,the risk associated with hepatitis B virus mighthave been confounded by the coassociation ofhepatitis B virus infection with male sex andbirth in areas of high incidence. The importanceof cirrhosis as a major aetiological factor is nowmore widely accepted, at least in low hepato-cellular carcinoma incidence areas, but the inter-actions with other aetiological factors includinghepatitis B virus infection remain controversial.
SEX HORMONES AND LIVER CANCERIt had been long established that, in certainmouse strains, administration of testosteronesignificantly increases the frequency with whichchemically induced hyperplastic nodules pro-gress to hepatoma and castration of male animalsdecreases the frequency of this occurrence.'" In1966 in a preclinical study of steroids to be usedin oral contraceptive preparations it wasrecorded that, '. . . Dr Bosner reported to theCommittee (on the Safety of Drugs) that dosagewith mestranol was associated with the pro-duction of nodules in rats which histologicallyshowed various stages of nodular hyperplasiaand the production of hepatoma .. .'."I It shouldtherefore perhaps, not have come as a surprisewhen Baum'2 and her colleagues described thedevelopment of hepatic adenomas in womentaking oral contraceptive steroids, an associationsoon to become well accepted. The possible roleof these agents in malignant liver disease wasmore controversial but an influential paper byJames Neuberger in collaboration with ProfessorRichard Doll at Oxford suggested a small, butsignificantly increased, risk of hepatocellular
Advances in neoplastic disease ofthe liver and biliary tract
HCC 3
*-- Nucleosol-CytosolI-- HSA
SHBG
E boundx1010DHTx 109 (motIF1 )
Figure 1: Scatchard plots ofsex steroid binding in the cytosoland nucleosol ofhepatocellular carcinoma. Androgen receptorswere assayed using methyltrienolone as ligand and oestrogenreceptors using oestradiol (from ref 14). (Reproduced bycourtesy ofBr J Cancer.)
carcinoma after prolonged usage.'3 Such obser-vations, together with the previously noted pre-dominance of men among cirrhotic subjectsdeveloping hepatocellular carcinoma, focused onthe attention of many on the Unit to the role ofsex hormones in hepatic neoplasia.Jawed Iqbal and colleagues were the first to
show the presence of androgen receptors'4 inhuman liver tissue (Fig 1) which were identical toandrogen receptors found in prostatic tissue.'5These data have since been confirmed'6 as hasthe observation that human hepatocellularcarcinoma tissue exhibits much higher concen-trations of androgen receptors and Sa-reducedandrogens than normal liver tissue.'415 Duringthese studies a new circulating sex-steroid bind-ing protein, 'fetal steroid binding protein' wasdiscovered in human fetal liver and the serum ofhepatocellular carcinoma patients.'7 This proteinwas later purified and shown to be present innormal serum. While its role is uncertain, itslevels in hepatocellular carcinoma patientsappear to correspond with response to therapy.
DIAGNOSIS AND MONITORING RESPONSE TOTHERAPYFor all the work into serological tumourmarkers, alphafetoprotein, first described in theserum of a human with hepatocellular carcinomain 1964'1 is perhaps still the only one which iswidely used in clinical practice. In the presenceof a mass lesion in a cirrhotic liver a markedlyraised level is sufficient to establish the diagnosisof hepatocellular carcinoma and monitoring ofchanges in serum levels can be invaluable inassessing response to therapy (Fig 2).1920 None-theless, some of the initial enthusiasm for usingalphafetoprotein to screen high risk populationsfor early detection of hepatocellular carcinomahas subsided with the recognition that there issome overlap between levels of alphafetoproteinin hepatocellular carcinoma and uncomplicatedchronic liver disease, particularly while thetumour is small.The fibrolamellar variant of hepatocellular
carcinoma was described in detail in 1980 byCraig et al2 and for the first time a primarymalignant liver cell tumour with distinctivehistological features (deeply eosinophilic cyto-
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. 200-
X 1| Partial response'E100-
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Figure 2: Response ofalphafetoprotein during adriamycintherapy in relation to clinical response. Note that evidence ofsubsequent response can be seen after the first injection (fromref 19). (Reproduced by courtesy ofthe Lancet.)
plasm and pyknotic nuclei interspersed withparallel bundles of collagen resulting in fibroussepta) had a specific clinical counterpart. Itoccurs during adolescence, in a non-cirrhoticliver and is invariably alphafetoprotein sero-negative and unrelated to hepatitis B virusinfection. The prognosis is somewhat better thanwith other histological types although very fewpatients will survive more than five years fromdiagnosis. At the suggestion of Iain Murray-Lyon, vitamin B12 binding protein was measuredand in a series of 107 patients with hepatocellularcarcinoma was shown to be a specific marker forthis particular tumour variant.22
RADIOLOGYThe advent of clinical ultrasonography has had agreat impact.23 It is now the first line investiga-tion for screening high risk patients and monitor-ing response of liver tumours to therapy. Muchof the original impetus came from Japan reflect-ing the combination of technological expertiseand the high frequency of hepatocellular carci-noma and from where the concept of 'minute'carcinomas (usually defined as less than 3 cm indiameter), eminently suitable for resection,derived.24There is now an extensive literature from the
Far East on the role of lipiodol image enhance-ment in computed tomography diagnosis.25 Theaim of this technique is to opacify the liver on acellular, rather than a vascular basis. Lipiodol,an oily based contrast medium, is injected intothe hepatic artery at the time of arteriographyand sequential computed tomography scanningis carried out (Fig 3). Lipiodol is cleared fromnormal hepatic tissues but is said to accumulatein malignant tumours because of the 'leaky'character of neovascular tissue, coupled with thelack of lymphatic clearance from tumour tissue.
Figure 3: Lipiodol localised in an hepatocellular carcinoma after intraarterial injection.
Our current practice is that it should bereserved for smaller tumours, to confirm that alesion is solitary, or in patients with raisedalphafetoprotein, where conventional imaginghas failed to show a tumour. It is of little valuein patients with multicentric tumour, alreadyconfirmed on imaging.26 A recent study fromKing's has shown that combining describedradiological criteria27 with clinical and bio-chemical parameters, accurately predicts thetype of tumour, both benign and malignant, inover 90% of patients, when compared withsubsequent histology obtained at resection ofbiopsy.28 As smaller tumours are detected histo-logical proofofmalignancy becomes increasinglyimportant, and both computed tomography andultrasound guided biopsy have now becomeroutine procedures which have greatly increasedthe diagnostic accuracy and safety of percutan-eous biopsy.
In a notable paper Ulrich Raeth, who arrivedat the Institute in 1981 from Heidelberg with hisown 'state of the art' ultrasound machine, de-scribed an accurate ultrasonic method for cal-culating liver volume. This was probably theonly method which has been genuinely validatedby ultrasonic measurement of liver volume incadavers in the autopsy room and then by waterdisplacement after removal!29
Hepatic arterial embolisation, a refinement of
hepatic artery ligation, a technique investigatedby Iain Murray-Lyon a decade earlier30 waswidely used in the early 1980s and activelypursued in the radiology department by JohnLaws and Heather Nunnerly. Although used lessnow because there is little evidence of improvedsurvival the technique has proved valuable insymptomatic control, particularly with regard topain and the symptom of flushing and diarrhoeaassociated with carcinoid and other peptideproducing tumours.3' Heather Nunnerly waslargely responsible for the introduction of theiridium wire as a source of internal radiation forpatients with inoperable cholangiocarcinoma, atechnique which is now widely combined withstenting at endoscopic retrograde cholangiopancreatography.32
TREATMENT AND PROGNOSISThere is no doubt that treatment has been themost disappointing area, one which has seenmany false dawns. Other than those patients inwhom the tumour is detected incidentally orpresymptomatically as a result of screening, theoutlook has probably changed little for any oftheprimary liver tumours. Indeed the use of coeliacplexus block for pain and biliary stenting torelieve obstructive jaundice,33 although notaffecting survival, have probably done more forimprovement of quality of life than any of theother attempts at treatment.
SURGERY AND LIVER TRANSPLANTATIONSurgery remains the only hope of 'cure' inpatients with malignant liver tumours. Over thelast 25 years there has been a gratifying reductionin the operative mortality and an increase in thenumber of patients considered 'operable', par-ticularly in the Far East. This reflects a combi-nation of better surgical and anaesthetictechniques, in particular appreciation of thesegmental anatomy of the liver. About 40% ofhepatocellular carcinoma patients without cir-rhosis and in whom complete resection isobtained can now expect to live for five years,but this group represents only a small minority ofthe whole population of hepatocellular carci-noma patients. In the Far East surgeons arebecoming increasingly enthusiastic about resec-tion in the cirrhotic liver with a five year survivalrate of up to 50% being quoted but Westernexperience with the cirrhotic liver has, to date,been less favourable. Bismuth reported that only35 of 270 cirrhotic patients were operable and, ofthese, only 12 were alive at 16 months.34
Similarly, only a small percentage of tumoursin the high bile duct or at the bifurcation areamenable to curative surgical resection.Amongst this group, the development of endo-scopic stenting has been a major advance and isnow the treatment of choice in most instanceswhere it offers excellent palliation.35 Low malig-nant bile duct lesions may also be amenable toendoscopic stenting and a consensus is beingreached that this is the treatment of choice in theelderly, frail and ill. The stay in hospital may beshorter and the mortality less than for surgery36which should probably be reserved for youngerpatients with a longer life expectancy.
Surgery is also being increasingly used inpatients with metastatic colorectal metastasesand guidelines as to which patients will benefitmost are becoming available. For example, itappears that for a patient with one or twometastases from a Dukes grade B colonic carci-noma and a resection margin of greater than1 cm, the chances of five year survival reachalmost 50%.37
Early experience with liver transplantation forhepatocellular carcinoma was disappointing;whilst the patients did uniformly well in theshort term, tumour recurrence was the norm,38presumably reflecting spread of clinically un-detectable extrahepatic micrometastases toinvolve the new liver. Our more recent experi-ence, however, has shown that such disappoint-ing results are associated with large tumours and
Advances in neoplastic disease ofthe liver and biliary tract
that patients with small (<4 cm in diameter)and/or asymptomatic tumours, do much betterand seem to be one of the most suitable groups ofpatients for liver transplantation.
CYTOTOXIC AND ANTI-HORMONALCHEMOTHERAPYEarly studies on cytotoxic chemotherapy saw thefirst collaborative ventures between the RoyalFree, Charing Cross Hospital, and King's. Thefirst suggested a modest response rate of around25% with systemic arterial adriamycin'9 in aseries of 43 patients. Subsequent studies havenot always been able to achieve even such modestlevels reported but no other single drug orcombination of drugs seem to have fared anybetter. Recent studies have shown that it isfeasible to give full doses of adriamycin even inthe presence of hyperbilirubinaemia but theresponse rate is still disappointingly low.36Our current base line treatment for inoperablehepatocellular carcinoma, against which newtherapies should be compared, is to administerthree courses of adriamycin systemically at adose of 60 mg/mi (provided the serum bilirubinconcentration is below 30 ,umol/1) at threeweekly intervals. Where there is objectiveevidence of response in terms of a decrease intumour or liver size, or a fall in the serumconcentration of alphafetoprotein, the courseshould be completed (to a maximum dose of550 mg/M2) otherwise treatment should bewithdrawn.
After the detection of sex hormone receptorsin hepatocellular carcinoma a prospective ran-domised controlled trial comparing tamoxifenplus doxorubicin with doxorubicin alone wasundertaken. The first patient to enter the studyresponded dramatically and died, ofan unrelatedillness whilst in complete remission, three yearsafter. Over the next two years, however, we sawno further such dramatic responses and indeed,in the final analysis, there was no difference insurvival.39 A much more optimistic result usingtamoxifen alone has recently been reported'4with a survival at one year of 40% in thetamoxifen treated group compared with zero inthe untreated control group. If these results areconfirmed they represent an exciting advance.We have also tried the alternative approach ofusing the antiandrogen cyproterone acetate in 25cases. In all five patients with objective evidenceof a response there was an associated fall in free 5a-dihydrotestosterone.4'
SECONDARY TUMOURS AND THE INFUSAID PUMPSeveral early studies reported that intraarterialchemotherapy with FUDR led to high remissionrates in patients with metastases from colorectalcarcinoma but against this needed to be countedthe side effects of repeated vascular access. Withthe development of permanently implantablesystems such as the Infusaid pump these prob-lems seem to have been overcome and recentcontrolled studies confirm that high remissionrates are obtainable. Nonetheless it remains to beproved that these good remission rates are trans-latable into improved survival, particularly
100 @.-.--* Stage I (n=33)o---o Stage II (n=134)*2r-| . A - Stage III (n=62)
'E 50- 9Cj) I %
\ qcn -i's
024i 6 9 1'2 18 24Months
30 36 42
100- OBia'\ 0 ~~~~~Japan (n--850)|
2> 0, o---o Uganda (n=72)
bs
6 12 18 24 30 36 42Months after diagnosis
Figure 4: (a) Survival curvesfor 229 patients who received nospecific treatment. The median survival was 0 7 monthsforstage III patients, and 2 monthsfor 134 stage II patients, and8 3 monthsfor 33 stage I patients (from ref45). (b) Life tableanalysis ofsurvival ofpatients with hepatocellular carcinoma- comparison between patients in Uganda," and apan.45(Reproduced by courtesy ofBr J Cancer.)
because of the progression of extrahepaticmetastases.4'
CARCINOID TUMOURSThis period has seen major improvement in thesymptomatic control of carcinoid tumours.Although cytotoxic chemotherapy with strep-tozotocin and 5-fluorouracil is more effectivethan in hepatocellular carcinoma, it has not beenshown to improve survival.43 As noted above,however, arterial embolisation often givesdramatic symptomatic improval.3' Syntheticsomatostatin analogues have also led to dramaticimprovement in symptoms with less immediatecomplications than embolisation."4
PROGNOSISSurvival in patients with malignant liver diseaseis largely dependent on the size of the tumourand the amount of hepatic reserve. The simpleststaging classification for hepatocellular carci-noma is that of Okuda4 (Fig 4a). The prolongedsurvival of patients with stage I disease should benoted and indeed this is increasing as tumoursare being detected earlier by ultrasound or alpha-fetoprotein screening. It should also be notedthat the survival of Japanese patients with stageIII disease is similar to that reported fromAfricae (Fig 4b). This suggests that, rather thanhaving a particularly malignant form of thedisease as is sometimes suggested, Africanpatients with hepatocellular carcinoma probablypresent, or are detected, later than in othercountries.
Current areas of interestThe central theme ofmuch ofthe cancer researchat the Institute has been in the still controversialarea of the relationship between hepatocellular
carcinoma and cirrhosis.47 Our prospectivefollow up study of patients with cirrhosis nowinvolves over 1400 patients followed for up to 12years. To date 608 have died, 76 with hepato-cellular carcinoma. This unique database mayanswer some fundamental questions. Forexample: suppose the signal for progression tohepatocellular carcinoma occurred simultan-eously with that for the development ofcirrhosis? This might suggest that even if anti-viral therapy for hepatitis B virus infectionprevented progression to cirrhosis it might stillbe ineffective in avoiding hepatocellular carci-noma development.
ROLE OF THE HEPATITIS C VIRUSAfter identification and cloning ofthe hepatitis Cvirus which is responsible for most parenterallytransmitted non-A, non-B hepatitis an assay foranti-hepatitis C virus antibodies was devel-oped.41 Up to 80% of patients with hepatocellularcarcinoma were reported as seropositive instudies from Italy and Spain together with othertypes of cirrhosis previously categorised asalcoholic, hepatitis B virus related and auto-immune.49 Ian McFarlane must take much of thecredit for the early recognition that many of theso called positive results among patients withautoimmune chronic active hepatitis may well be'false positive', associated with hypergamma-globulinaemia.50We have recently shown similar results among
patients with hepatitis C virus and had theopportunity to test a new diagnostic systembased on synthetic peptides derived from boththe structural and non-structural part of thehepatitis C virus genome, and this also suggeststhat only between one and two thirds of theoriginal positive tests can be confirmed.Although these more specific tests have indeeddecreased the number of hepatocellular carci-noma patients testing positive for hepatitis Cvirus on the continent of Europe, a substantialproportion remain hepatitis C virus positive byall available tests. In the United Kingdom itseems likely that its most important implicationwill be as a cause of a substantial number of casesof 'alcoholic cirrhosis' rather than as a majoraetiological factor in hepatocellular carcinoma.
MORE SENSITIVE TUMOUR MARKERSOne of the major potential roles of serum AFPmeasurement, distinct from its use for diagnosisin symptomatic patients, lies in screeningasymptomatic cirrhotic patients with a view toearly diagnosis which, as noted above, does seemworthwhile when skilled surgery and/or trans-plantation are available. A problem soonbecame apparent, however, small, asympto-matic, tumours tended to have only mildly raisedconcentrations [in the range 20-500 ng/ml], atwhich there is some overlap with uncomplicatedchronic liver disease. Several studies showedthat alphafetoprotein derived from patients withchronic liver disease (or other non-malignantconditions such as fulminant hepatic failure orpregnancy) was qualitatively different from thatderived from hepatocellular carcinoma in terms
4
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-~4-o-o With lipiodol CY|-0 Without lipiodol -C 3R
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f ADR -' 00 02 04 06 08 1-0
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-A1 1ADR-OL ADR
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-OL
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Figure S: Pharmacokinetics ofadriamycin (ADR) and itsmajor metabolite adriamycinol (ADR-OL) after intraarterialadriamycin with and without lipiodol. The coadministrationoflipiodol appeared to have no significant effect (from ref54).(Reproduced by courtesy ofJournal of Hepatology.)
of binding to various lectins, particularly lentillectin. This implied increased fucosylation of theprotein and Winston Hutchinson and Ming QingDu have recently shown that such abnormalitiescould be detected even amongst hepatocellularcarcinoma patients who had concentrations ofalphafetoprotein below 400 ng/ml - that is,concentrations which are, quantitatively notconsidered diagnostic.5' They also showed thatthe underlying mechanism of these changes isprobably related to disturbances of enzymaticcontrol particularly involving fucosyltransfer-ases which are very active in both the serum andtissue of hepatocellular carcinoma patients.52
TARGETING OF CYTOTOXIC DRUGSIn attempts to increase selectivity, cytotoxicagents have been linked to polyclonal and mono-clonal antibodies and lipiodol, an agent which, aspreviously noted, localises in tumour tissuesafter arterial administration. Several groupsfrom Japan and the Far East have suggested thatthis is an ideal method for targeting cytotoxicdrugs, because it leads to increased concentra-tion of drug in the tumour and therefore toincreased clinical efficacy and might be expectedto decrease systemic toxicity. In an extensiveseries of studies, Cem Kalayci showed that thecoadministration of lipiodol had very little affecton the pharmacokinetics, toxicity or clinicalefficacy of adriamycin (Fig 5).534 It was con-cluded that previous favourable results were theresult of other methods of treatment adminis-tered at the same time as the lipiodol chemo-therapy, particularly arterial embolisation.
GROWTH FACTORSThe autocrine mechanism of cellular transform-ation is probably one of the most frequentinitiators of tumourigenesis.55 Cells that possessspecific receptors for the polypeptides theysecrete, produce either or both ligand and recep-tor in an uncontrolled fashion. Increased insulinlike growth factor II mRNA transcripts havebeen reported in the hepatocellular carcinomadeveloping in woodchucks infected withhepadna virus56 and recently, using in situhybridisation Carolyn d'Arville and KayhanNouri-Aria have shown that the expression ofinsulin like growth factor II mRNA is upreg-
Advances in neoplastic disease ofthe liver and biliary tract S109
ulated in hepatocellular carcinoma tissue wherethere is cirrhosis and when the patients arecarriers of the hepatitis B virus.5"
The futureAssuming that current vaccines remain effective,the eradication of hepatitis B (and later, perhapshepatitis C) could probably eliminate mosthepatocellular carcinoma in the East within 50years. In the West, control of excessive alcoholconsumption would probably be almost aseffective. To this extent medical science hasoffered the solutions - their implementation isdependent on financial considerations andpolitical will.The search for the mechanism by which
hepatitis B virus is oncogenic (if indeed it is!) isthe next great prize-there may well tuM out tobe several different mechanisms. At present itseems most likely that a cellular oncogene isactivated by integration of viral DNA and itspromoter sequence upstream from the onco-gene. Alternatively, viral DNA integration is anessential step but it is subsequently eliminatedfrom the site of action leaving a permanentdeletion-the so called 'hit and run' hypothesis.The concept of early diagnosis will perhaps
need to be redefined with respect to hepato-cellular carcinoma. The results of 'too late'diagnosis are only too well recognised; those of'too early' diagnosis are only just being recog-nised. There is probably just a brief window ofopportunity when the tumour is sufficientlylarge that we can be sure that it poses a significantthreat to its host and yet is small enough to besuccessfully resected. An important recent studysuggests that adenomatous hyperplasia may bethe true precancerous lesion but detection ofsuch foci will provide major therapeutic dilem-mas.58 Hilar cholangiocarcinoma remains amajor problem-often impossible to diagnose ortreat effectively.The role of screening high risk populations
with a view to early diagnosis remains conten-tious and its potential value in different countriesis being actively investigated. In the UnitedKingdom it seems unlikely to have a majorimpact, as the high risk groups (namely carriersof the hepatitis B virus and patients withcirrhosis) are seldom identified before thedevelopment of tumour.59
ConclusionsMany of the advances in the field of hepaticoncology have arisen from chance observationsin unrelated fields and progress seems to havebeen haphazard. More 'goal directed' research,exemplified by the cloning of the hepatitis Cvirus by commercial and pharmaceutical com-panies can be seen as a way of overcoming theprodigious expense of such research. The downside, however, including reluctance to publish inconventional scientific journals, and the patent-ing of genetic sequences has become all tooapparent. There is no such thing as a freediagnostic test or vaccine; the health service willultimately have to cover research costs.
If the potential for research in this important
and intellectually intriguing area is great, manyof those committed to research in a hospitalenvironment have not been reassured by recentGovernment attitudes which appear to under-value the role ofresearch as an integral part ofthehealth service. So much of what has been usefulin the Institute's contributions has resulted fromwide and free referral of patients even when, asis the case with hepatocellular carcinoma, nodefinitive therapy is available. The likely dele-terious impact of an internal market for patientson such free referral should not be under-estimated.
Finally, it is sobering to recall that behind allthe Institute's academic endeavour and publica-tions, each point on the accompanying figuresusually represents one person suffering fromthese devastating forms of cancer. These were allcared for as patients on our wards. The manage-ment of those whom we have no way to cure isperhaps the most demanding of all clinicaldisciplines, and the best reason for continuedresearch.
1 Beasley RP. Hepatitis B virus as the etiologic agent inhepatocellular carcinoma-epidemiologic considerations.Hepatology 1982; 2: 215-21.
2 Beasley RP, Hwang LY, Lin CC, Chein CS. Hepatocellularcarcinoma and hepatitis B virus. A prospective study of22 707 men in Taiwan. Lancet 1981; ii: 1129-32.
3 Shafritz D, Shouval D, Shermann HI, Hadzyiyannis SJ, KewMJ. Integration of hepatitis B virus DNA into the genome ofthe liver cells and in chronic liver disease and hepatocellularcarcinoma. NEnglJ3Med 1981; 305: 1067-73.
4 Summers J, Smolec JM, Snyder RL. A virus similar to humanhepatitis B virus associated with hepatitis and hepatoma inwoodchuck. Proc NatlAcadSci USA 1978; 75: 4533-7.
5 Brechot C, Nalpas B, Courouce AM, et al. Evidence thathepatitis virus has a role in liver cell carcinoma in alcoholicliver disease. N EnglJ Med 1982; 306: 1384-7.
6 Walter E, Blum HE, Meier P, et al. Hepatocellular carcinomain alcoholic liver disease: no evidence for a pathogenetic roleof hepatitis B virus infection. Hepatology 1988; 8: 745-9.
7 White YS, Johnson PJ, Davison F, Williams R. Frequency ofhepatic HBV-DNA in patients with cirrhosis and hepato-cellular carcinoma: relation to serum HBV markers.BrJ Cancer 1990; 61: 909-12.
8 Parker RGF. The incidence of primary hepatic carcinoma incirrhosis. Proc R Soc Med 1956; 50: 145-7.
9 Zaman SN, Melia WM, Johnson RD, Johnson PJ, WilliamsR. Risk factors for the development of hepatocellularcarcinoma in cirrhosis. A prospective study of 613 patients.Lancet 1985; i: 1357-60.
10 Andervont HB. Studies on the occurrence of spontaneoushepatomas in mice ofstrain C3B and CAB.J Natl CancerInst1952; 11: 581-91.
11 Leonard B. The use of rodents for studies of toxicity incontraceptive research. Acta Endocrinol 1974; 75: Suppl 185:34-64.
12 Baum JK, Holtz F, Bookstein JJ, Klein EW. Possibleassociation between benign hepatomas and oral contracep-tive. Lancet 1981; ii: 926-9.
13 Neuberger J, Forman D, Doll R, Williams R. Oral contracep-tives and hepatocellular carcinoma. Br Med J 1986; 292:1355-57.
14 Iqbal MJ, Wilkinson ML, Johnson PJ, Williams R. Sexsteroid receptor proteins in foetal, adult and malignanthuman liver tissue. BrJ Cancer 1983; 48: 791-6.
15 Wilkinson ML, Iqbal MJ, Williams R. Characterisation ofhigh affinity binding sites of androgens in primary hepato-cellular carcinoma. Clin Chim Acta 1985; 152: 105-13.
16 Nagasue N, Ito A, Yukaya H, et al. Androgen receptors inhepatocellular carcinoma and surrounding parenchyma.Gastroenterology 1985; 89: 643-7.
17 Wilkinson ML, Iqbal MJ, Williams R. A new sex-steroidbinding protein in foetal liver. ICRS Med Sci 1983; 11:1123-4.
18 Tatarinov YS. Detection of embryo specific-globulin in bloodserum ofa patient with primary liver cancer. VoprMed Khim1964; 10:90.
19 Johnson PJ, Williams R, Thomas H, Sherlock 5, Murray-Lyon IM. Induction of remission in hepatocellular carci-noma with doxorubicin. Lancet 1978; i: 1006-9.
20 Johnson PJ, Williams R. Serum alpha-fetoprotein estimationsand doubling time in hepatocellular carcinoma: Influence oftherapy and possible value in early detection. J Natl CancerInst 1980; 64: 1329-32.
21 Craig JR, Peters RL, Omata M. Fibrolamellar carcinoma ofthe liver: a tumour of adolescents and young adults withdistinctive cliico-pathologic features. Cancer 1980; 46:372-9.
22 Paradinas FJ, Melia WM, Wilkinson ML, et al. High serumvitamin B12 binding capacity as a marker ofthe fibrolamellarvariant of hepatocellular carcinoma. Br Med J 1982; 285:840-2.
23 Okuda K. Advances in hepatobiliary ultrasonography. Hepa-tology 1981; 1: 662-71.
24 Ebara M, Ohto M, Shinagawa T, et al. Natural history ofminute hepatocellular carcinoma smaller than three centi-metres complicating cirrhosis. Gastroenterology 1986; 90:289-98.
25 Yumoto Y, Jinno K, Tokuyama K. Intrahepatic administra-tion of lipiodol for detection of minute hepatocellularcarcinoma. Radiology 1985; 154: 19-24.
26 Raby N, Karani J, Michell M, Gimson A, Nunnerly H,Williams R. Lipiodol enhanced CT scanning in assessmentof hepatocellular carcinoma. Clin Radiol 1989; 40: 480-5.
27 Karani J. Tumours: benign: primary malignant. Imaging of theliver, pancreas and spleen. Wilkins R, Nunnerly HB, eds.Oxford: Blackwell 1990: 172-86.
28 Pain J, Karani J, Howard E. Clinical and radiological assess-ment of liver tumours: Is biopsy necessary? Clin Radiol 1991(in press).
29 Raeth U, Johnson PJ, Williams R. Ultrasound determinationof liver size and assessment of patients with malignant liverdisease. Liver 1984; 4: 287-93.
30 Murray-Lyon IM, Dawson JL, Parsons VA, et al. Thetreatment of secondary hepatic tumours by ligation ofhepatic artery and infusion of cytotoxic drugs. Lancet 1970;ii: 172-4.
31 Melia WM, Nunnerly HB, Johnson PJ, Williams R. Use ofarterial devascularization and cytotoxic drugs in 30 patientswith carcinoid syndrome. BrJ Cancer 1982; 46: 331-8.
36 Smith AC, Dowsett JF, Hatfield ARW, et al A prospectiverandomised trial of by-pass surgery versus endoscopicstenting in patients with malignant obstructive jaundice.[Abstract] Gut 1989; 30: A1513.
37 Hughes KS, Simon R, Songhorabodi S, et al. Resection of theliver for colonic carcinoma metastases: a multi institutionalstudyofindicationsfor resection. Surgery 1988; 103: 278-84.
38 O'Grady J, Poulsen RT, Rolles K, et al. Liver transplantationfor malignant liver disease. Ann Surg 1988; 207: 373-7.
39 Melia WM, Johnson PJ, Williams R. Controlled trial ofDoxorubicin and Tamoxifen versus Doxorubicin alone inhepatocellular carcinoma. Cancer Treat Rev 1987; 71:1213-6.
40 Farinati F, Salvagnini M, de Maria N, et al. Unresectablehepatocellular carcinoma: a prospective controlled trial withtamoxifen.JHepatol 1990; 11: 297-301.
41 Forbes A, Wilkinson ML, Iqbal MJ, Johnson PJ, Williams R.Response to cyproterone acetate treatment in primary
hepatocellular carcinoma is related to fall in free Sa-dihydro-testosterone. EurJ7 Cancer Clin Oncol 1987; 23: 1659-64.
42 Kemeny N, Daly J, Reichman B, et al. Intrahepatic orsystemic infusion of fluorodeoxyuridine in patients withliver metastases from colorectal carcinoma. Ann Intern Med1987; 107: 459-65.
44 Kvols LK. Treatment of the malignant carcinoid syndrome.Evaluation of a long acting somatostatin analogue. N EnglJ7Med 1986; 315: 613-16.
45 Okuda K, Ohtsuki T, Obata H, et al. Natural history ofhepatocellular carcinoma and prognosis in relation to treat-ment. Cancer 1985; 56: 918-28.
46 Primack A, Vogel CL, Kyalwazi SK, etal. A staging system forhepatocellular carcinoma: prognostic factors in Ugandanpatients. Cancer 1975; 35: 1357-64.
47 Johnson PJ, Williams R. Cirrhosis and the aetiology ofhepatocellular carcinoma. J Hepatol 1987; 4: 140-7.
48 Koo G, Choo Q-L, Alter HJ, et al. An assay for circulatingantibodies to a major etiologic virus of human non-A non-Bhepatitis. Science 1989; 244: 359-62.
49 Bruix J, Calvet X, Costa J, et al. Prevalence of antibodies tohepatitis C virus in Spanish patients with hepatocellularcarcinoma and hepatic cirrhosis. Lancet 1989; ii: 1004-6.
50 McFarlane IG, Smith HM, Johnson PJ, Bray G, Vergani D,Williams R: Hepatitis C virus antibodies in chronic activehepatitis: pathogenetic factor or false positive result?: Lancet1990; i: 754-7.
51 Hutchinson WL, Du M-Q, Johnson PJ, Williams R. Fucosyl-transferases: Differential plasma and tissue alterations inhepatocellular carcinoma and chronic liver disease. Hepato-logy 1991 (in press).
52 Du M-Q, Hutchinson WL, Johnson PJ, Williams R. Differ-ential alphafetoprotein lectin binding in hepatocellularcarcinoma: diagnostic utility at low serum levels. Cancer1991; 67: 476-80.
53 Kalayci C, Johnson PJ, Raby N, Metivier EM, Williams R.Intraarterial adriamycin and lipiodol for inoperable hepato-cellular carcinoma: A comparison with intravenousadriamycin. JHepatol 1990; 11: 349-53.
54 Johnson PJ, Klayci C, Dobbs N, et al. Pharmacokinetic andtoxicity of intraaterial adriamycin for hepatocellular carci-noma: effect of coadrniistration of lipiodol. J Hepatol 1991(in press).
56 Rogler CE, Hino 0, Su CY. Molecular aspects of persistentwoodchuck hepatitis virus and hepatitis B virus infectionand hepatocellular carcinoma. Hepatology 1987; 7: 74s-8s.
57 d'Arville CN, Nouri-Aria KT, Johnson PJ, Williams R.Regulation of insulin-like growth factor II gene expressionby hepatitis B virus in hepatocellular carcinoma. Hepatology1991; 13: 310-15.
58 Takayama T, Makuuchi M, Hirohashi S, et al. Malignanttransformation of adenomatous hyperplasia to hepato-cellular carcinoma. Lancet 1990; 336: 1150-2.
59 Zaman SN, Johnson PJ, Williams R. Silent cirrhosis inpatients with hepatocellular carcinoma. Implications forpopulation screening. Cancer 1990; 65: 1607-610.
