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EDITORIAL HcpatO'Uastroentcrol. 28 (1981) 1 -5 Liver Tumours -- New Aspects A. Noumayr, W. Weiss First Medical Department, KA.Rudolfstiftung, Vienna Introduction cently, a possible cause for this discrepancy was seen in a in J849, Rokitansky (27) was the first to make a clear dis tinction between primary and secondary liver carcinoma; he considered the former to be the more frequent of the two. The interest of the clinician in primary liver carcinoma ; (PLC), however, was until recently, on account of the in adequate diagnostic and therapeutic possibilities, only slight. Only in the last few years has renewed interest been protective effect of the female hormones or a greater ex posure of males to carcinogens (15, 40). Drew et al., (31 have drawn attention to some interesting relationships between parental, reaction to hepatitis B virus (HBV) and the sex distribution of their progeny. This observation might possibly be of significance for the selective "pref erence" of liver carcinoma for the male sex. shown in this tumour, stimulated by the observed increase Completely unexplained is the observation that in Den in incidence and also exciting new discoveries in the fields mark, Iceland, Chile and Colombia, PLC is found more of aetiology and pathogenesis, together with the develop frequently in females. ment of more effective diagnostic and therapeutic proce dures. ji\k In most cases PLC is preceded by a chronic hepatic t disease, A chronic hepatic injury appears to offer hepato- In recent times, the theoretical basis for successful preven 5 Carcinogens favourable conditions to develop their effect, tive measures has also been discussed. AT Thanks to the improved methods of detecting HBV, in j! ] many countries of Africa and South East Asia a formerly Frequency and epidemiology .^unknown high degree of infection of the population with In numerous countries in Asia and Africa, PLC is the most frequently observed cancer: Mozambique (70 % of all carcinomas), Senegal (67 %), Bantu in South Africa (51 %), Hong Kong (45 %), Malaysia (41 %), India, China, Taiwan and the Philippines (20 % each) head the list of these countries. In Europe, PLC is not uncommon in the Medi terranean countries (Greece 13 %, Spain 10 %). (15, 20, 22, 24, 26, 39). In Middle European countries and in the USA, where there is a close coincidence of liver cirrhosis and PLC, a quoted figure of 2.5 % for the relative frequen cy of this condition is almost certainly too low; with the appropriate awareness on the part of the clinician and path ologist, PLC is found as a late complication in 30 % of all patients with a long standing liver cirrhosis. On the basis of the continously increasing number of cases of cirrhosis, PLC is already counted among the ten most fre quent forms of cancer in Austria. Similar observations HBV has been documented in recent years. At the same time a remarkable parallelism in the geographical distribu tion of viral hepatitis and PLC has also been discovered. In countries with a high incidence of PLC, serological HBV markers were found in 80 to 90 % of all hepatoma patients. This would suggest a causal relationship between these two diseases (22). Epidemiological studies carried out in recent years have shown that infection with HBV in the early part of life considerably increases the risk of later contracting PLC. Already by way of perinatal infect ion of the newborn by HBsAg-positive mothers (vertical transmission), the ground is often prepared for subsequent chronic, usually insidious, anicteric liver disease. Hepatitis with a peracute course and massive necroses of the hepato- j cytes represents a smaller risk of subsequent PLC develop1 ment, probably because the predisposing liver cells are ` I largely eliminated. have also been made in Switzerland, Poland and Hungary In patients with PLC in a liver previously damaged by HBV. (39). || fllijow HBsAg litres and high anti-HBc titres are characteristic Just as variable as the geographical distribution of incident l|f`ndin8s- ^.^elyrare detection of anti-HBs might ce is the average age of the patient with a tumour of the. ; Iffe* "? of a disorderedimmune response (22) As a rule, liver: The higher the rate of incidence, the lower the age. antlSen "lackinS whjle- `"contrast, >s not In Africa and Asia, PLC is found predominantly in patient* |f fCOmmon- The expression of HBC antigen in tumour in the third decade, in Middle Europe, in contrast, in the |ff ^Kue 1S t0 sma t0 treasured. 6th to 7th decade. : Mi The detection of a HBV genome in the DNA of PLC cells i I^B'has been interpreted as a sign of a direct carcinogenic Aetiology v^tfj^otency of the HB viruses, although the exact oncogenic a) Individual (endogenous) factors: - Distribution by sex: In general, PLC is seen four times more frequently in males than in females. Until quite re* mechanism, at least for the time being, remains unexplained 24, 32, 40). .^ '. VS; 0300--970X/81 0132-0001 S 02.00 1981 Georg Thieme V*rlfl, Stuttgart - Naw York R&S 000834 2 Hepato-Gustroenterol. 28 0981) A. Neumayr, W. Weiss Small hepato-cellular (he) PLC in non-alcohol-induced liver cirrhosis and no serological signs of contact with HBV might be interpreted as a late complication of chronic non-A/non-B hepatitis (22). Although it is possible that, in Middle Europe and the too, HBV diseases and PLC might be associated, they an quantitatively of very little significance (23). In 80 case* of PLC confirmed at autopsy, we established serological evi dence for HBV contact in 6.3 %,- the figure for chronic liver disorders without PLC was 6.8 % (39); these obser vations have, in the meantime, been repeatedly confirmed both in Europe and in the USA (12, 23, 33). The basis for the development of PLC in Europe is pre dominantly alcohol-induced hepatic cirrhosis. Alcohol leads to an increase in the carcinogen-activating enzymes, which indicates a relationship between alcohol and carcinoma (34). In Austria, PLC is found particularly frequently in wine growing areas. The increasing sale of alcohol is reflected in a continuous increase in the incidence of liver cirrhosis and PLC (39). In Chile, however, despite a high incidence of al coholic liver cirrhosis, PLC is remarkably rarely observed (26). It is known that other chronic diseases of the liver, such as haemochromatosis or porphyria cutanea tarda, are asso ciated with a high risk of subsequent PLC, and similar re marks may be made for the rare condition hypertyrosiOM- mia or hepatic damage due to a lack of at antitrypsin (40), - Genetic disposition: Reports on familial accumulation of PLC and HBV conditions suggest the presence of genetic aetiological factors. Larouze (18) is of the opinion that family members of hepatoma patients have an approxima tely 60 times greater risk of themselves contracting this tumour. Other working groups investigating HLA antigen*; however, have found no evidence for a genetic disposition(16). - In the previous year, attention was drawn for the first time to a new aetiological variant: chronic typhoid carriers contract PLC six times more frequently than do healthy controls. A satisfactory explanation for this remarkable observation has not yet been offered (43). b) Exogenous environmental influences - The degree of contamination of food with mycotoxins, such as aflatoxin Bt or sterigmatocystin, bears a direct relationship to the frequency of PLC. At the present state of our knowledge, however, a direct carcinogenic effect on the liver seems to be improbable: Rather, mycotoxins appear to have a negative effect on the cell-mediated immunity and, in this way, prepare the ground for HBV pathology. Accordingly, mycotoxins should be considered co-carci nomas (19). The low content of aflatoxin B, in the food in Egypt might possibly be the reason for the low incidence of PLC there, although, in this country HBV is extremely pro* valent (44). - In China, extreme differences in the incidence of PLC were found in adjacent areas of the country sharing an equal prevalence of HBV and ingestion of mycotoxin*, Only recently it has been established that Chinese who4: obtain their drinking water from stagnant bodies of wat#r, moTe frequently develop PLC; to date, however, the car cinogen in stagnant water has not been identified (4). - Such parasites, as for example, Clonorchis sinensi apparently favour the development of choiangio-cellular (chc) hepatic carcinomas, but in Middle Europe, of course, such parasites are certainly without any significance. - Iatrogenic injuries a)-In the USA in areas with a petrochemical industry, a marked accumulation of PLC cases has been registered. Pesticides, such as DDT, also favour the development of malignant tumours of the liver (20). b) Chronic arsenic and copper poisoning, as also exposure to thorotrast and vinyl chloride, lead to quite characteristic changes in the liver tissue, which frequently reveal a ten dency to subsequently develop into an angiosarcoma, but also PLC (25). c) Attention has already been drawn to the importance of alcohol abuse in the development of PLC in Middle European countries. But smoking might also have a carcinogenic effect on the liver by way of enzyme induction (5). d) Drugs: An influence on the development of PLC has been confirmed only for drugs with a steroid structure: - Long-term therapy with anabolic androgenous steroids, as employed for the treatment of Fanconi's anaemia, or the misuse of anabolic agents by competitive athletes can result in the development of PLC and angiosarcomas (29). - Today it is believed that the long-term ingestion of contraceptives is associated with a dose-dependent and time-dependent risk of contracting hepatic tumours. In the USA, the annual incidence is estimated to be three to five per 100.000. It is probable that the number of undetected cases is disproportionately higher (28, 35). In the initial phase so-called "focal nodular hyperplasia" and benign adenomas develop. A malignant transforma tion tends to be rare and is never associated with an in creased synthesis of on fetoprotein (AFP). When the oral contraceptives were discontinued, a spontaneous regression of adenomas, but also the continued growth of hepatic tumours have been observed (30). - Recently, an above-average incidence of adenomas after the establishment of a portosystemic shunt has been reported and the increased serum oestrogen level of these patients has been thought responsible (38). Pathogenesis (22, 24, 40) The pathogenesis of PLC is multifactorial and also multiphasic. The close coincidence of liver cirrhosis and PLC suggests that these conditions are two dose-dependent, differing reactions of the hepatic tissue to the same noxae (40). Only a few environmental toxins or drugs have a primarily carcinogenic effect. Only as a consequence of bio-transformation do bioactive metabolites - the so-called "ultimate carcinogens" - develop. R&S 000835 Livi: Tumours - new Aspects Hcpalo-Gjiirocntcrol. 2M 11VM11 i Dietary factors (amount of fat in the food), viral infections, pesticides, drugs such as phenobarbital or steroids, and also alcohol and smoking, have an effect on the hepatic biotransformation system by way of enzyme induction or modulation, and are thus of considerable importance in the carcinogenesis of hepatic tumours. Proliferating hepatocytes, with their high mitotic rate, re present, as selective cell populations, a vulnerable "target". An interesting alternative pathogeneiic model was developed by Farber (7). On the basis of the fact that chemical car cinogens usually inhibit cell proliferation and that, initially, the development of a cancer in a given organ is focal, he postulated that hepatocytes which are resistent to carcino genic effects, react with unbounded proliferation, and that, paradoxically, liver cancer originates in the cells which are not susceptible to hepatic carcinogens! Finally, the bio-active secondary carcinogens are bound to the DNA of the nuclear chromatin, although the possible role of genetic control mechanisms is, at present, still contro versial (16, 18). PLC's, hepatic metastases and non-carcinumutous malig nant liver tumours (angiosarcoma, etc.), have no increase in AFP production (10, 21, 42), In so-called "high risk areas" with a high incidence of PLC, the average normal level of serum AFP in the healthy , population is three to four times higher than that seen in Middle Europe (42). A possible explanation for this may be the observation, made in recent years, that an increase in AFP can be triggered by viral infections (HBV, cytomegaly) (36). It is now known that PLC associated with renewed AFP production represents a poor prognosis. Thus, the deter mination of the AFP titre in the serum is a valuable para meter for assessing the efficiency of therapy. The halflife of the postoperative drop in titre is now considered determinative for the indication, duration and dosage of post-operative chemotherapy (42). For screening purposes we have developed a procedure which provides a positive result only in the presence of AFP values above 100 ng/ml (42). Nucleases have the task of removing the modified DNA, so that the nuclease capacity of the liver determines the further course of hepato-carcinogenesis. Under normal cir cumstances, this capacity is large enough to eliminate all carcinogens from the liver. Eliminated carcinogens can, however, give rise to carcinomas in other organs. The liver of the newborn has a lower nuclease capacity and thus re acts more sensitively to the effects of carcinogens. Morphologically, dysplasia hepatocytes represent the first link in the carcinogenic chain. They are characterized by the lack of stored iron, storage of glycogen and of a modi fied gamma-glutamyl transpeptidase. Under the electron microscope, changes can be shown at the cell surface and in the organelles even in the pre-neoplastic stage (24). The next stage in the development is focal nodular hyperplasia which gives rise to benign adenomas and, finally, hepato b) In future, as a valuable supplement to the determination of AFP, consideration might well be given to the serum level of ferritin, which has been found to be elevated in 70 to 85 % of all hepato-cellular PLC patients without the renewed synthesis of AFP especially in the early stages of the tumour (13). c) Whether a combination of several serological procedures Can appreciably improve the diagnostic efficiency, as re cently suggested by Waka-Bayashi et al. (37), (AFP, CEA and the iso-enzymes of alkaline phosphatase or gammaglutamyl transpeptidase were determined) is doubtful, since this approach would appear limited by inadequate sensitiv ity and considerable costs. cellular PLC. It is known that in patients with steroid-in duced adenomas this course of development is reversible up to a point so far unknown (30). 2) Morphological diagnosis In addition to well proven techniques such as angiography, with the aid of which even the smallest tumours - provid Diagnosis ed that they are adequately vascularized - can be recog nized with certainly, or laparoscopy, the diagnostic im While as little as ten years ago, a diagnostic accuracy of portance of which is largely dependent upon the personal the clinician of 10 % with respect to PLC was quoted in experience of the examiner, sonography coupled with . collective statistics, today, thanks to more recent examina- trageted fine needle biopsy and computed tomography arc j tion techniques, the correct diagnosis can be established becoming more and more important clinically (15,22,40). i Intra vitam in 90 % of the cases (41). I New aspects in the morphological diagnosis of PLC have ! 1 j Serological diagnosis resulted from multi-step scintigraphy of the liver using 99 m-tc colloidal sulphur and 67-gallium citrate (67-Ga), a) At the present time, the determination of oq fetopro- which examinations have proved an ideal supplementation | tein (AFP) is the only serological examination method of the AFP determination. In particular hepatocellular PLC i which, on account of its considerable "organ affinity", unaccompanied by an increased synthesis of AFP, and ! lias proved its value in practice as a screening procedure cholangio-cellular PLC, manifest an intensive uptake of gal for the early recognition of hepato-cellular PLC and lium. In 80 autoptically proven cases of PLC, which had embryonic germinal cell tumours. been investigated with AFP and 67 -Ga, the correct clinical Eighty to 85% of all hepato-cellular PLC's show an increas diagnosis was established in 99 % (41). ed new synthesis of AFP and represent the "target group" A decisive new impetus may be expected from initial of serological diagnostic efforts. The remaining hepato attempts to localize tumours using monoclonal tumour- cellular PLC's, and also all mixed and cholangio-cellular specific antibodies (10). R&S 000836 i 1:1 (b 4 Hcpato-Gastiocntctol. 2H (1981) A. Ncumavr, W. Weis, Therapy while, on the other hand, the application ol illil' a) The only curative therapy for PLC is radical surgical removed of the tumour-infected lobe of the liver. At centres with appropriate experience, the incidence of iurgical resection is 20 to 50 %. The post-operative mortality rate is surprisingly low at 7 to 16 %, and the five-year survival rates (SR) at 9 to 19 % are of an order of magnitude comparable to the results of gastric carcinoma surgery. In children subjected to surgery for PLC, indeed, vaccine in a large-scale vaccination programme would, theoretically, result in a drastic reduction of the PLC incidence in 'high risk areas" (18, 45). The realiza tion of such ideas, however, must be viewed with scepti cism, not least since the number of HBsAg-posmve people throughout the world is estimated at 176 millions, and the funds needed to vaccinate such an immense num ber of people are hardly likely to be forthcoming. a five-year SR of more than 50 % has been reported (8,9, 40). With the introduction of special surgical techniques these results may be expected to improve further, as a References study that achieved a three-year survival rate of 88 % has 1 Ballou, B., T.R. Hakala, G. Levine, D. Solter: Tumor Location shown (9). In view of these results, a "therapeutic nihilism" would no longer seen justifiable in PLC patients. In contrast, Detected with Radioactively Labeled Monoclonal Antibody and External Scintigraphy. Science 206 (1979) 844 2 Caine, R.Y.: Lcbertransplantation. Chirurg 51 ( 1980) 271 the indication for liver transplantation in PLC patients is 3 Drew, J.S., W.T. London, E.D. Lustbader, J.E. Hesser, B.S. no longer accepted by Starzl (31) although this opinion is by no means shared by all the experts (2). Blumberg: Hepatitis U virus and sex ratio of offspring. Science 201 (1978) 687 4 Editorial; Liver Cancer Something in the Water'.' Lancet I (1980) 747 b) Attempted palliative treatment employing chemotherapy has, to date, not beeen particularly promising, and is all the 5 Everson, K.B.: Individuals transplacentally exposed to maternal smoking may be at increased cancer risk in adult lile. Lancet II (1980) 123 more to be rejected in view of the fact that survival rates of 6 years and more are certainly not uncommon in 6 Fatkson, G-, C,G. Moertel, l'. Lavin, F.J. Preiorius, P.P, Carbone; Chemotherapy Sludies in Primary Liver Cancer. A Prospective Randomized Clinical Trial. Cancer 42 (1978) 2 149 untreated PLC patients (22, 40). The results of a multi- 7 Farber, E., D. Soil, R. Cameron, B. Laishes, K. Ogawa, A. Med centre investigation supports such a point of view: In only 15 of 189 treated PLC cases was a partial remission achieved, line. Newer Insights Into the Pathogenesis ot Liver Cancer. Am. J. Path. 89 (1977) 477 8 Flatmark, A., B, Frethem, O. Knutrud, G. Lande Surgical 9 of the 15 observed "partial successes" having employed adriamycin as the cytostatic agent (6). Treatment of Primary Liver Carcinoma. Scand. J. Oasrroent. 12 (1977) 571 9 Fortner, J.G., D.K. Kim, B.J. MacLean, M.K. Barrett, S. Iwatsukt, It is possible that, in the future, on the basis of more suit able prognostic criteria, the indication for palliative measures A.D, Turnbull, W.S, Howland, E.J. Beattie: Major Hepatic Re section for Neoplasia. Personal Experience in 108 patients. Ann, Surg. 188 (1978) 363 may be more accurately established. Thus, for example, 10 Harada, T,, K. Shigeta, K. Noda, Y. Ftikumoto, ll. Nisltimura, i Lai et al. (17) attaches considerable importance to the histo M. Mizuta, T. Takemoto: Clinical Implications of AFP in Liver Cirrhosis: Five Year Follow-up Study. Hepato-Castroenterology logical assessment of hepatocytes, considering the absence of 27 (1980) 169 so-called "clear cells" as a reliable sign of a favourable prog nosis. 11 tshii, K., H. Shibata, H. Okabe: Inhibition of liver cirrhosis and liver cell carcinoma in rats by an anti-allergic agent. XL lnt. Kongr. Uastroent., Hamburg 1980 12 Johnson, P.J.: Hepatocellular Carcinoma and Hepatitis 1) Vir R&S 000837 c) We have just received an initial report on good results obtained with Interferon (14). For the present, the high Markers in Europe and USA. Lancet I (1979) 434 13 Kaneto, A., Y. Kubo, T. Koga, T, Tanikawa: Serum ferritin, a useful indicator in the early diagnosis of hepato-cellular costs of such a therapy are not calculated to justify too much optimism. In general, it would appear that measures carcinoma. XL lnt, Kongr. Castroent., Hamburg 1980 14 Kawanishi, //., IV.iV, Carter, J.N. Sheagren, J.M. Greenwood, R.P. McDermott, M, Ibrahim; Effect of human fibroblast to stimulate the immune reaction in PLC patients are the interferon on injury of HBSAG producing human hepatoma most worthy of recommendation, if a radical surgical procedure proves impossible (22). cells in vitro, (Abstr.) Gastroenterology 78 (1980) 1192 15 Kawata, H,: Retrospective Study on the Evaluation of Diagnostic Procedure for Hepatoma in Patients with Cirrhosi of the liver. Acta hepato-gastroent. 21 (1974) 106 : I Prevention 16 Kew, M.C., A.J. Gear, L Baumgarten, G.M. Dusheiko, G. Ma Histocompatibility Antigens in Patients with Hepatocellular a) In Middle Europe and the USA a reliable preventive effect could presumable be achieved by restricting alco Carcinoma and their Relationship to Chronic Hepatitis U Virus Infection in these Patients. Gastroenterology 77 (1979) 537 17 Lai, C.L., P.C. Wu, K,C, Lam, D. Todd: Histologic Prognostic hol abuse. The chances of realizing such an aim, however, are as illusory as the incurably optimistic hope of being able to achieve a reduction in the consumption of nicotine. Indicators in Hepatocellular Carcinoma. Cancer 44 (1979) 1677 18 Laroute, B.: Studies on the prevention ot primary hepatic car cinoma. Parental influences on the transmission of, and host response to, hepatitis B Virus. Cancer detect. Prev. 2 (1979) 65 b) In animal experiments it has already proved possible to inhibit the development of liver cirrhosis and hepatomas (11) using the antiallergic agent neurotropine. c) Since the causal role of HBV infections for the high incidence of PLC in Asia and Africa is well known, effective preventive measure are, at least theoretically, imaginable. On the one hand, by means of a hygiene clean-up project, infection with HBV could be reduced, 19 Lutwick, L.I.: Relation between aflatoxin, hepatitis-B virus, and hepatocellular carcinoma. Lancet 1 (1979) 755 20 Mason, T., F. McKay, R, Hoover et al.: Atlas of cancer mortality for U.S. counties: 1950--1969, DHEW Publication (Nil!) 75-80 U.S. Department of Health, Education and Welfare. 1976 21 Nolan, J.P.: Significance of a-Fetoprotein in Liver Disease. Gastro enterology 74 (1978) 953 22 Okuda, K., T. Nakashima: Hepatocellular Carcinoma. A Review of of the Recent Studies and Developments. In: H. Popper, F, Schaffner (eds.): Progress in Liver Diseases, Vol, VI, Grune & Stratton, New York (1979) 639-650 23 Omaia, M., M. Ashcavai, C.T. Lietv, R.L. Peters: Hepatocellular Carcinoma in the USA, Etiologic Considerations, Localization of Livcf Tumours - new Aspects Hepato-Gastroenterol. '8 (lyKII 5 Hepatitis I) Antigens. Gastroenterology 76 ( 1979) 279 24 Popper, H.: The Increasing Importance of Liver Tumors in H. Kemmer, H.M. Bolt, P. Bannasch, H. Popper (eds.): Primary Liver Tumors, MTP Press, Lancaster, 1978 25 Popper, H,, L.B. Thomas, N.C. Teller, II. Falk, l.J. Selikoff: Development of hepatic angiosarcoma in man induced by vinyl chloride, thorotrast and arsenic. Comparison with cases of unknown etiology. Am. J. Path. 91 (1978) 349 26 Kemmer. //.. H.M. Bolt, P. Bannasch, II. Popper (eds.): Primary Liver Tumors, MTP Press, Lancaster, 1978 2 7 Rokitansky, C.A.: Manual of pathological anatomy. Edward Pub lishing Company, London, 1849 28 Kooks, J.B., H.W. Ory, K. G Ishak, L.T. Strauss. J.R. Greenspan, A.P. Hill, C. IV. Tyler jr.. The Cooperative Liver Tumor Study Group: Epidemiology of Hepatocellular Adenoma: The Hole of Oral Contraceptive Use. JAMA 242 (1979) 644 29 Scheuer, A., IS. Uerdes, F.G, Lehmann: Anabotika und Lebertumoren. Dtsch. med, Wschr. 104 (1979) 779 30 Sherlock, S.: Hepatic Tumors and Sex Hormones. In: H. Remitter, H.M. Bolt, P. Bannasch, H. Popper (eds.): Primary Liver Tumors, MTP Press, Lancaster (1978) 201 31 Stars I, T.E., L.J. Koep, C.G. Halgrimson, J. Hood, G.P.J. Schroftr, K.A. Porter, R. Weil III; Fifteen Years of Clinical Liver Trans plantation. Gastroenterology 77 (1979) 375 32 Theodoropoulos, G.: The Relationship between Hepatitis Associated Antigen and the Development of Hepatocellular Cancer. Acta hepato-gastroenterol, 21 (1974) 430 33 Trichopoulos. D., R.J. Gererry, L. Sparros, E. Tabor, E. .Yiroucluiki, N. Munoz: Hepatitis B and Primary Hepato cellular Carcinoma in a European Population. Lancet II (1978) 1217 34 Tuyns, A.J.: Epidemiology of Alcohol and Cancer. Cancer Res. 39 (1979) 2840 35 Vana, J,, G.P, Murphy, B.L. Aronoff, H.W. Baker: Primary Liver Tumors and Oral Contraceptives, Results of a Survey JAMA 238 (1977) 2154 36 Wahren, B.: Fetal Proteins in Viral Infections: Review Article Acta Med. Scand. 205 (1979) 145 37 Wakabayashi, T,, N. Sasvabu, M. Nakagen, L. Ozaki, D. 1'oya, II. Sendai. N. Hatton, M. Ishii: immuno-biochemicat diagnosis of hepatocellular carcinoma in which serum ALP is lower or negative. XI. Int. Kongr. Gastroent., Hamburg, 1980 38 Webster, M. tv'., D.H. ion Thiel, K.M. Bron, E.L. Barnes. Hepatic Adenoma Associated with Portasystemic Shunting in Young Woman. Digestion 19 (1979) 328 39 Weiss, IV.. H. Hanak: Primary Liver Cancer in Austria, In: H. Remmer, H.M. Bolt, P. Bannasch, H. Popper (eds.): Primary Liver Tumors. MTP Press, Lancaster. 1978, 145 40 Weiss, IV. Das prtmare Leberkamnom. int. prax. 18 (1978) 243 41 IVeisr, IV., G. Eder, A. Krotss, P. Hahn, A. Xeumayr- Clinical Significance of Liver Scintigraphy Using o7-Gallium and AFPDetermination as Screening for Primary Cancer of the Liver. Scand. J. Immunol, 8 (1978) Suppl. 8/417 42 Weiss, W.: Klinische Relevanz der AI P-Dcsiimmung in) Serum Onkologie 1 (1978) 6 43 Welton, J.C., J.S. Marr, Sr.M. Friedman: Association between hepato-biliary cancer and typhoid carrier state. Lancet I (1979) 791 44 Ziegler, J.L.: National Institutes of Health International Workshop on Hepatitis B and Licer Cancer. Meeting Report. Cancer Res. 37 (1977) 4672 Prof, Dr. A. Neumayr, First Medical Department, KA Rudolfstiftung, Vienna, Juchgasse 25, A-10J0 Wien, Austria R&s 000838