Hepatocellular carcinoma — History, current status and perspectives

LEADING ARTICLE

DIGESTLIVERDIS 2002;34:613-6

Hepatocellular carcinoma and perspectives K. Okuda

hwm Department of Medicine, Chiba University Schoolof Medicine, Chibe,Japan.

-*cuny##kruu Ruf. K. Okuda,first Department of Medicine, ChibaUniversityS&o/ of Medicine, 1-8-I Inohene,Chuo-ku,Chibe, 26l-b8677 Japan. fax: +8143-2262088. E-mail: Okuda@mad, m. chiba-u.ac.jp

- History,

current

status

Hepatocellular carcinoma (HCC) is one of the most malignant and most common killer cancers in the world. So many investigators have been engaged in the elucidation of the mechanism of hepatocarcinogenesis, pathophysiological characterisation, early diagnosis and management, and so much is now known about this condition, yet no significant improvement in the overall survival of patients has been achieved. To grasp the current status of our knowledge of basic aspects and actual clinical practice for management, one needs to review the background of the disease carefully starting with the history. When Eggel, in Germany, surveyed the world literature for HCC autopsies in 1910, there were only 163 cases including one of his own, and he came up with his gross anatomical classification ‘. It was learned then that European cases were far out numbered by those outside Europe. In 1911, Yamagiwa 2 then proposed a new classification based on the cancer cell origin, hepatocellular and cholangiocellular, with the suggested terminology of “Hepatoma” and “Cholangioma”. It was a reasonable classification, but, subsequently, these terms were used to include benign lesions, and semantic confusion ensued. It was Berman 3 who in 1951 aroused world attention with his monograph to the extremely high HCC incidence among young Mozambican males (>500 times as common as among North European counteparts), and subsequently Higginson studied the global epidemiology confirming Berman’s report. Studies by Edmondson, the present author (Chiba) with Peters (Los Angeles) and Simson (Pretoria) 4 , Steiner (Chicago) 5, Nakashima (Kurume) ‘j, unequivocally showed that there is a great regional difference in pathology, and that HCC does not represent a single disease. The HCC bearing liver weighs more than 4 kg at autopsy among South African blacks 3 and less than 2 kg in Japan 6. The liver does not present a chronic progressive disease in Mozambique and cancer cells are poorly differentiated 5 perhaps reflecting the major carcinogenic factor, aflatoxin, as opposed to cirrhosis caused by viral infection in many non-African countries where hepatitis B virus (HBV) is the major aetiologic factor. The fact that fibrolamellar carcinoma which is common among young Caucasians is virtually non-existent in the Far East, clearly points to the congenital or ethic difference in chromosomal make-up. Fibrolamellar carcinoma provides good material for the study of non-viral carcinogenesis. The present author is also being credited for predicting hepatitis C virus (HCV) infection as the major cause of hepatocarcinogenesis in Japan, and for the elucidation of an acute rise in HCV-associated HCC in this country 8 where HBV-associated HCC has steadily declined in incidence. Colombo et al. 9 were the first to recognise a similar increase in HCV-associated HCC in Italy. It is interesting to note that Spain also has a similar trend in HCC epidemiology. When compared with Northern European countries such as Sweden, where the lancet used for smallpox vaccination was changed for each child in the distant past, it seems that smallpox vaccination rather than intramuscular injection of vaccine was the important iatrogenic factor for HCV infection and HCV-associated HCC in these countries where the same lancet was used repeatedly for vaccination. Worldwide, HCC is increasing in many countries including the USA. It is not clear whether the increase in 613

Hepatocellular carcinoma - History, current status and perspectives

HCV infection accounts for such temporal epidemiological changes in these countries, or an increase in chemical carcinogens in the environment has an additive effect on viral oncogenesis. HCV now seems to possessoncoviral properties; about 30% of cholangiocarcinoma patients in Japanhave HCV infection, and a similar proportion of non-Hodgkin B-cell lymphoma patients have HCV infection in this country lo. It is not known how hepatitis virus infection induces hepatocarcinogenesis,but a leading theory suggests,basedon transgenic mouse studies, that HCV core protein and HBX-protein play a pivotal oncogenic role ‘I. In 1965, Japanesesurgeonsformed a group to study the outcome of surgical treatment, and this group has expanded to include internists, pathologists and radiologists now reaching 829 participating institutes with more than 17,500 cases of primary liver malignancies compiled yearly. This study group greatly contributed to the progressin the diagnosis and managementof HCC and to the analysis of prognostic factors with the data basedon large numbersof cases12.Clinically and pathologically small and early HCC was most extensively studied by Japanesehepatologists/radiologists.They developed the early detection (screening) programme in which ultrasound and alpha foetoprotein (AFP) measurementare carried out at regular intervals 13.It has become an international strategy for early diagnosis. AFP has a limited diagnostic value for small HCC, and the measurementof des-y-cat-boxyprothrombin (DCP, PIVKA-II) somewhat improves diagnostic accuracy14.Major progresswas made in biochemical diagnosis with the subsequentdevelopment of L3 fraction measurement based on studies of molecular subspeciesof AFP in Japan15.Although early detection does prolong survival with early selection of appropriate treatment modality, how much early diagnosisreally prolongs the survival of patients remains to be determined. Arakawa et al., including myself have shown that an early HCC lesion frequently developswithin an adenomatoushyperplastic nodule, and that during carcinogenic transformation 16, these cells in the nodule undergo certain morphologic changes. However, pathological studies were mostly basedon haematoxylin & eosin (HE) stain sections,and objective histologic markers were lacking that would clearly separatebenign and malignant cells. Molecular biology now dicitates that carcinogenesisis a multistep process involving a number of genetic changes as shown by Vogelstein and Fearon I7 with colon cancer. Despite extensive studies on chromosome genetic changesin HCC tissue, as yet, no definite and consistent changeshave been found for hepatocarcinogenesis. Individual HCCs vary histopathologically so much, perhaps due to differing aetiology, that no consistent genetic changeshave been identified. There is a distinct difference in genetic changes between 614

HBV and HCV induced HCC. One possible approach to this problem would be to study cirrhotic nodules from a resectedliver bearing HCC for genetic analysis, a study Taiwanese investigators are conducting at the moment. Eventually, DNA chips and new DNA analytic techniques will prove useful in such a pursuit, but there is still a possibility that each HCC has a different combination of genetic changes and such an approach may prove futile. With the new imaging techniques, hepatologists/radiologists are studying the transition of benign nodules to malignant nodules. Using colour Doppler ultrasound, power Doppler, helical computed tomography, harmonic imaging and angio-multidetector CT, it has been shown that the blood vessels supplying a hyperplastic nodule change from portal veins to arteries and the draining vessels from hepatic veins to portal veins during the transformation process 18.Such an imaging study now assists in early diagnosis. About one half of adenomatoushyperplastic (dysplastic) nodules, which are monoclonal and detected by imaging, turn malignant, but, at the moment, no prediction of the outcome of the nodule is possible. For treatment, Japanesehepatologists developed Lipiodol-assisted chemoembolisation, and our group at Chiba started percutaneous ethanol injection (PEI) therapy in 1983 19,an idea to kill cancer cells locally (local ablation). It was followed by other techniques using heat and, currently, radiofrequency ablation therapy *Ois the most popular. Due to tumour recurrence, local ablation therapy rarely provides complete cure. Surgery is the best choice, if the patient can tolerate it. Transplantation for early HCC is the most certain curative measure21,but availability of donor livers is very limited. Living-related liver donation has been the leading procedure in Japan; Tanaka et al., at Kyoto University, developed a technique to use the right lobe of the donor liver for adult HCC 22,and 48 adult HCC caseshad been transplantedup to April 2002 with good results. The current procedure in harvesting embryonic stem cells for tissue production strongly suggests that liver transplantation may, someday,be replaced by stem cell derived liver cells. A number of methods will be developed for the use of in vitro and in vivo produced hepatocytes derived from stem cells. Liver cells injected into the spleen settle in the centrilobular area of the acinus. Artificial livers have been so improved 23 that they may keep the patient alive long enough to permit procedures to use in vitro propagated hepatocytes. Semitotal hepatectomy may become possible using cultured cells rather than transplantation. There are many other possibilities of using propagated hepatocytes for treatment while preventing hepatic failure. Since the background liver has cirrhosis, removal of HCC only enhancesthe possibility of new tumour evo-

K. Okuda

lution (generally called recurrence) from preexisting nodules. In my opinion, all efforts should be directed to prevention of HCC. As far as HBV-associated HCC is concerned,Taiwan’s success24in reducing the incidence of childhood HCC caused by germ-line genetic changes induced by familial vertical HBV transmission, is a prototype of prevention; it is expected that HBV-related HCC will decrease in developed countries with universal vaccination. It will be a matter of time. Prevention of HCC may be achieved in 4 steps. The primary prevention is to avoid hepatitis virus infection and exposureto hepatocarcinogenens.HBV infection is preventable whereas, for HCV, no vaccine is available and prospects are bleak. Exposure to environmental carcinogens is something that has attracted little attention. Judging from the large difference in the frequency of HCC development in patients with chronic HCV infection between Japan25,where practically all those who have HCV induced cirrhosis develop HCC within 15 years or so, and USA 26,Ireland 27and East Germany28where HCV seldom causesHCC, I believe that the difference comes from non-viral carcinogens. Perhaps Japanesepeople are exposed to greater concentrations of non-viral carcinogens in the environment, that boost the viral hepatocarcinogenesis.A very clear case of chemical carcinogenesiscomes from China, in the Quidong and Haimen provinces, where the farmers who dependedupon stagnant water for drinking, had a mortality rate of over 100/105/year. The incidence decreasingin the areaswhere deep wells have been dug. The offending chemicals were microcystin and other blue alga toxins 29. Thus there are many chemical hepatocarcinogensother than aflatoxins that have to be studied. We need more information on this aspect. The secondary prevention is to avoid acute viral hepatitis (B, C) from becoming chronic, and the third prevention is to stop chronic hepatitis from progressing to cirrhosis. Use of interferon has been successful, to some measure,in these steps. The fourth step is to prevent a cirrhotic liver from developing HCC. Japanesehepatologists have now shown that the use of interferon has a certain effect in this process3o31. Purely chemical prevention is rarely successful. Besides the acyclic carotenoid developedby Muto et al. at G ifu University 32who successfully used this agent for the prevention of frequent post-operative recurrence, dependablechemicals capableof preventing hepatocarcinogenesishave yet to be developed. I List of abbreviations ~ AFP: alpha foatoprotain; DCP: das-y-carboxy prothrombin; HBV: haI patw ” El virus; HCC: hapatocallular carcinoma; HCV: hepatitis C ~ virus; HE: haamatoxylin & aosin; PEI: percutaneous ethanol injection. :

References ’ Eggel H, Ueber das prim&-e Carcinom der Leber. Beitr z path Ana z allg Path 1910;30:506-604 * Yamagiwa K. Zum Kenntniss des prim%ren parenchymatosen Leberkarzinoms (“Hepatoma”). Virchows Arch Path Anat 1911;203:75-131. 3 Berman C. Primary carcinoma of the Liver. London: Higginson Lewis; 19.51. 4 Okuda K, Peters RL, Simson IW. Gross anatomical features of hepatocellular carcinoma from three disparate geographic areas. Proposal of new classification. Cancer 1984;54:2165-73. 5 Steiner PE. Cancer of the liver and cirrhosis in trans-SaharanAfrica and the United States of America. Cancer 1960;13:1085-166. h Nakashima T, Okuda K, Kojiro M, Jimi A, Yamaguchi R, Sakamoto K, et al. Pathology of hepatocellular carcinoma in Japan. 232 consecutive cases of autopsies in ten years. Cancer 1983;51:863-77. ’ Okuda K. Natural history of hepatocellular carcinoma including fibrolamellar and hepato-cholangiocarcinoma variants. J Gastroenterol Hepatol2002;17:(in press). 8 Okuda K, Fujimori I, Hanai A, Urano Y. Changing incidence of hepatocellular carcinoma in Japan. Cancer Res 1987;47:4967-72. 9 Colombo M, de Franchis R, Ninno ED, Sangiovanni A, De Fazio C, Tommasini M, et al. Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med 1991;325:675-80. lo Okuda K, NakanumaY, Miyazaki M. Cholagiocarcinoma. Recent progress. J Gastroenterol Hepatol 2002;17: 1049-63. ” Koike K. Role of hepatitis viruses in multistep hepatocarcinogenesis. Digest Liver Dis 2001;33:2-6. ” Okuda K, The Liver Cancer Study Group of Japan. Primary liver cancer in Japan. Cancer 1980;45:2663-9. I3 Okuda K. Early recognition of hepatocellular carcinoma. Hepatology 1986;6:729-38. I4 Okuda H, Nakashima T, Takatsu K, Saito A, Hayashi N, Watanabe K, et al. Measurement of serum levels of des-y-carboxy prothrombin in patients by a revised enzyme immunoassay kit with increased sensitivity. Cancer 1999;85:812-8. I5 Shiraki K, Takase K, Tameda Y, Tameda Y, Harada M, Kosaka Y, et al. A clinical study of lectin-reactive alpha-fetoprotein as an early indicator of hepatocellular carcinoma in the follow-up of cirrhotic patients. Hepatology 1995;22:802-7. I6 Arakawa M, Kage M, Sugihara S, Nakashima T, Suenaga M, Okuda K. Emergence of malignant lesions within an adenomatous hyperplastic nodule in a cirrhotic liver. Observations in five cases. Gastroenterology 1986;91: 198-208. ” Fearon ER. Molecular genetics of colorectal cancer. Ann NY Acad Sci 1995;768:101-10. ‘* Kudo M. Imaging diagnosis of hepatocellular carcinoma and premalignant/borderline lesions. Semin Liver Dis 1999; 19:297-307. I9 Sogiura N, Takara K, Ohto M, Okuda K, Hirooka N. Treatment of small hepatocellular carcinoma with ultrasound guide ethanol injection. Acta Hepatol Jpn 1983;24:920. ‘O Rossi S, Fomari F, Buscanini L. Percutaneous ultrasound-guided radiofrequency electrocauthery for the treatment of small hepatocellular carcinoma. J Inter-vent Radio1 1993;8:97-103. *I Mazzaferro V, Regallia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinoma in patients with cirrhosis. N Engl J Med 1996;334:693-9. 22Tanaka A, Tanaka K, Kaihara S, Ueda M, Uemoto S, Kiuchi T, et al. Liver transplantation for hepatocellular carcinoma. Nippon Rinsho 2001;6(Suppl):705-16.

Hepatocellular carcinoma - History, current status and perspectives

23Patzer JF. Advances in bioartificial liver assist devices. Ann NY Acad Sci 2001;944:320-33. 24Chang M, Chen CJ, Lai MS, Hsu HM, Wu TC, Kong MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997;336:1855-9. 25Ikeda K, Saito S, Koida I, Arase Y, Tsubota A, Chayama K, et al. A multivariate analysis of risk factors for hepatocellular carcinoma: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 1993; l&47-53. 26Seeff LB, Hollinger B, Alter H, Wright GC, Cain CMB, Buskell ZJ, et al. Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: a national heart, lung and blood institute collaborative study. Hepatology 2001;33:455-63. *’ Barrett S, Goh J, Coughlan B, Ryan E, Stewart S, Cockram A, et al. The natural course of hepatitis C virus infection after 22 years in a unique homogeneous cohort spontaneous viral clearance and chronic HCV infection. Gut 2001;49:423-30. 28Wiese N, Berr WM, Porst LM, Oessen U for the East German

COMMENTARY

lnfliximab J. Simmons,

Hepatitis C Study Group. Low frequency of cirrhosis in a hepatitis C (genotype lb) single-source outbreak in Germany: a 20-year multicenter study. Hepatology 2000;32:91-6. 29Yu SZ. Primary prevention of hepatocellular carcinoma. J Gastroenterol Hepatol 1995;10:673-82. ” Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, Nakajima S, et al. Randomized trial of effects of interferon-a on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 1995;346:1051-5. 3’Yoshida H, Shiratori Y, Moriyama M, Arakawa Y, Ide T, Sata M, et al. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhosis and noncirrhotic patients with chronic hepatitis C in Japan. Ann Intern Med 1999;131:174-81. 32Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, Takasaki KT, et al. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med 1996;344:1561-7.

DIGESTLIVERtttti 2002;34:616-8

for ulcerative

colitis

D.l? JewelF

The action of tumour necrosis factor (TNF) is diverse and has been implicated in many pathological processes and disease states; it is thought to be one of the key cytokines involved early in the inflammatory cascade. TNF seems central to the pathogenesisof inflammatory bowel disease (IBD) and in particular Crohn’s disease (CD). Elevated levels of TNF are detected in the inflamed mucosa in IBD * and changes in mucosal TNF levels, over time, can predict future clinical relapse *. A chimaeric monoclonal antibody raised against TNF, infliximab, has proven to be an effective therapy in patients with CD and has also proven to be useful both in steroid resistant active disease and in those with fistulas 3-5.This representsthe first step towards more rational specific therapies for IBD, which have traditionally involved non-specific anti-inflammatories and immunosuppressives. Following this remarkable successin treating CD with infliximab, a number of groups have investigated the effect of this agent in patients with refractory ulcera-

tive colitis (UC). Though TNF is classically seen as a Thl cytokine involved in the pathogenesis of CD, a number of lines of evidence suggest that TNF may also be important in the pathogenesisof UC. Increased levels of TNF have been detected in the intestinal mucosa, stool, rectal dialysate and in the plasma of patients with active UC. The cotton-top tamarin is probably the closest animal model of UC, spontaneously developing severe diarrhoea and wasting, which responds to corticosteroids. The pathology of this colitis closely mimics the chronic inflammation seen in UC and these animals also develop the complications of UC, such as colonic adenocarcinoma.TNF levels are increased in these animals and treatment with a chimaeric monoclonal antibody to TNF (CDP571) led to an improvement in symptoms and weight gain 6. The first study to examine the effects of anti-TNF therapy in UC used the CDP571 antibody and was published by Evans et al. in 1977 7. They enrolled 15 patients with mild to moderate UC of whom most had left-sided rather than extensive diseaseand only 6 were described as steroid-resistant. Patients were followed for 8 weeks following a single infusion of antibody.