A review of 352 patients with primary liver cell carcinoma treated by the author is presented. The poor rate of resectability (7 per cent) has necessitated various forms of treatment over the years. These are described in detail. Based on this experience, the current form of treatment for nonresectable carcinoma is summarized. Although it is too early to assess this form of treatment, initial results appear to be promising. A second report in the near future is planned.
Necropsies were performed on 285 consecutively unclaimed Orang Asli bodies from Gombak Orang Asli Hospital during an eight-year period from May 1967 to April 1975. Of the 25 malignant neoplasms, hepatocellular carcinoma was by far the commonest (36%). The nine patients with this neoplasm had coexistant macronodular cirrhosis. There were 20 cases of cirrhosis; 45% of these had coexistant hepatocellular carcinoma. The 53,000 Orang Aslis living in West Malaysia comprise three tribes, the Negrito, Senoi, and Melayu Asli (Proto Malays). The Sinoi appear to have a high predilection for liver cancer, all our nine cases occurring in this group. These aboriginal people live in the jungles where they practice shifting cultivation and maintain their own dietary and social customs. Detailed studies of their dietary habits may provide a clue to the etiology of liver cancer in these people.
The level of serum alpha-fetoprotein (AFP) was estimated by radioimmunoassay in 153 normal healthy Malysians of different ethnic groups. The mean level was 7.5 In1/ml (SD 2.28InU/ml). Among 330 patients with malignant tumors, 11 had increased levels of AFP. The only patient who had hepatoma had a very high level of serum AFP. High levels were also found in three of four patients with dysgerminoma of the ovary, in the only two patients with carcinoma of the testis, and in one patient with secondary carcinoma of the humerus of unknown origin. Lower, but significantly increased levels were observed in one patient (of 48) with breast carcinoma, one patient (of 8) with basal cell carcinoma of the nose, one patient (0f 27) with carcinoma of the lung, and one patient (of 59) with nasopharynegeal carcinoma.
Necropsy and clinical data show that primary hepatocellular carcinoma (PHC) is the commonest cancer among the Senoi (a Malaysian aboringine group). The other aboringine tribes do not appear to have this high predilection for liver cancer. In the necropsy series, PHS was present in 10 out of 22 Senoi patients with cirrhosis. All the 22 livers contained hepatocytes that stained with Shikata's orcein stain and specific immunoperoxidase and immunofluorescent stains for hepatitis B antigen (HBAg). This observation raises the strong possibility that hepatitis B may be an important etiologic factor in the development of cirrhosis and PHC in the Senoi. The reason for the high susceptibility of the Senoi for HB virus infection is not clear, and the role of aflatoxin in the pathogenesis of PHC in the Senoi has yet to be determined. That the Senoi are a numerically small community, maintaining their own unique dietary and social customs and living in readily accessible areas in the Malaysian jungle, makes them an ideal population for the study of factors in the etiology of liver cancer.
This is a preliminary report of 46 sera tested for alpha-fetoprotein (AFP) by the Counter immuno-electrophoresis technique in which biopsies for histopathology were also submitted. In 42 cases the needle biopsy of the liver was available. The material was divided into two groups on the basis of AFP positive and AFP negative sera and their histological diagnosis. The overall positivity rate in proven Primary liver cell carcinoma was 64.2 per cent.
An abnormal, fast-moving 5'-nucleotide phosphodiesterase isozyme was found in 90.0% of 20 Malaysian patients with primary hepatoma and in 23.5% of 391 Malaysian patients with various malignant diseases; it was also discovered in 42.9% of 14 Malaysian and American patients with clinically active hepatitis B infection; in 16.7% of 18 healthy American blood bank donors who were positive for hepatitis B surface antigen (HBsAg); in 13.9% of 287 healthy Malaysian blood bank donors, some positive for HBsAg; and in none of 160 healthy American donors who were negative for HBsAg. A correlation of this abnormal isozyme with hepatoma and with infectious hepatitis B is clearly evident.
The high incidence of primary liver cancer in Malaysian males is not observed in childhood, where it constitutes 0.16 per 1000 paediatric hospital admissions and 3.20/0 of all childhood malignancies at the University Hospital, Kuala Lumpur. This frequency is comparable to that reported from several developed countries. The commonest liver tumour in children is the hepatoblastoma which is probably of embryonal origin and has a similar world wide "incidence. The relative infrequency of hepatocellular carcinoma in childhood and its association with cirrhosis, the hepatitis B antigen and its prevalence in the older age group helps to substantiate an acquired environmental aetiology.
We present a study of 288 hepatic resections carried out in Malaysia for the past fifteen years. First, we describe our indications for hepatic resectins which are not limited to hepatic trauma and hepatomas, but also include hepatic abscesses, cysts, intrahepatic calculi and hemangiomas. Second, we give a simplified classification of hepatic resections using accurate terminology. Third, we describe the safety of hepatic resections in our hands which we believe is due to specially designed surgical instruments and the accurate decision making process at surgery. We have had minimum postoperative mortality and no intraoperative deaths so far. Finally, while analysing each indication we have drawn vignettes from our experience for the past fifteen years.
Two hundred eight-eight hepatic resections performed over the past 15 years are discussed. The safety and success achieved are attributed to the original work in Malaysia on the anatomy of the liver and its anomalies, the use of surgical instruments specially designed for hepatic resection, various types of resections devised and studies on aids to liver regeneration after resection. The diversity of the principles and practice of surgery in the Western countries compared with those in Malaysia is illustrated.
Twenty Malaysian patients with unresectable primary liver cell cancer were prospectively studied at the General Hospital, Kuala Lampur, and were compared for clinical features with an equal number each of African and American patients being studied by the Eastern Cooperative Oncology Group. The patients received intravenous 5-FU and oral MeCCNU which was used for the first time in an Asian country. Most of the Malaysian patients were Chinese, belonged to younger age groups, and presented with massive hepatomegaly, jaundice, and fever. Toxicity to MeCCNU invariably occurred in the form of leukopenia or thrombocytopenia, but none life threatening. Partial response was seen in 20% of Malaysians as compared to 16% in Americans and none in Africans. Malaysians achieved a median survival of 16 weeks compared to 28 weeks in Americans and only eight weeks in Africans. Malaysian Chinese patients were all HBc Ab + ve. Other factors which may have played an etiologic role in the induction of primary liver cancer included alcohol, Chinese herbal medicines, aflatoxin and habitual use of medicated rubbing oils.
In West Malaysia, hepatocellular carcinoma (HCC) is common in the Chinese and in the members of the Senoi aboriginal tribe, two racial groups with diametrically opposite life-styles. Certain fundamental differences exist between the liver tumors in the two races. In the Senoi, the tumor occurs in a younger age group and there is a greater male preponderance than in the Chinese. There is also a very close relationship between hepatitis B virus infection, chronic active hepatitis, cirrhosis, liver cell dysplasia, and HCC in the Senoi and the tumors generally present as multiple nodules studding both lobes of the liver. In the Chinese, although a relationship between hepatitis B virus infection, HCC, and cirrhosis exists, this association is not as strong as in the Senoi and the tumors are generally large and solitary. The data suggest that, although the hepatitis B virus is probably an important oncogenic agent in both racial groups, there may be a difference in the pathogenesis of HCC in the two races.
Hepatitis B virus (HBV) DNA in the serum of 31 patients with histologically confirmed primary hepatocellular carcinoma (PHC) from Malaysia and Indonesia was quantitated by densitometric scanning of autoradiograms obtained by Southern blot DNA hybridization, after electrophoresis using a 32P DNA cloned into plasmid pBR325 as a probe. This quantitation after electrophoresis is more informative than the usual spot hybridization technique. Five of the 31 sera were positive for HBV DNA. Levels ranged between 1.36 pq and 143.18 pq per ml of serum, and the levels of HBsAg, anti-HBs, anti-HBc, HBeAg and anti-HBe in the serum were serologically determined. All five sera positive for HBV DNA were also positive for HBsAg. Three of the five positive for HBV DNA were positive for HBeAg and negative for anti-HBe. Two of the sera positive for HBV DNA were negative for HBeAg but positive for anti-HBe. All sera negative for HBV DNA were also negative for HBeAg. Many sera which were negative for HBV DNA and HBeAg were positive for HBsAg. Of the 31 sera from PHC patients, 23 had at least one HBV marker positive (74.2%).
Based on data collected by the population-based Singapore Cancer Registry over the period 1968 to 1982, baseline epidemiological characteristics and incidence trends of primary liver cancer were described. This will facilitate the interpretation of future trends, especially in the light of new interventions such as hepatitis B immunisation. The primary liver cancer incidence is four times higher in males than in females, with the incidence peaked in the seventh decade. The incidence rate was higher in the Chinese than in Malays and Indians and marginally higher among foreign born than Singapore born Chinese. A general declining trend in liver cancer incidence was especially notable in the local born Chinese. Misclassification of metastatic carcinomas in the earlier years of cancer registration may have contributed to the initial higher incidence. Definitive decrease in incidence as a result of hepatitis immunisation will only be seen in another two to three decades.
In the 7-year period between 1980 and 1987, six cases of childhood primary hepatocellular carcinoma (PHC) were confirmed histologically in our institution. Hepatitis B surface antigen (HBsAg) seropositivity was confirmed in five of the cases, and tissue HBsAg was shown in four of these using the Shikata's orcein stain. An associated maternal HBsAg seropositivity was shown in two of the seropositive children. The youngest seropositive patient who developed PHC was 7 years old. The mother of this patient was also seropositive. These observations support a causal relation between childhood Hepatitis B virus infection and PHC. The importance of vertical or perinatal transmission of HBV in the causation of childhood PHC and the prophylactic role of childhood vaccination is emphasized. Attention is also drawn to the relative short malignant transformation time seen in some of these patients.
A case of primary hepatocellular carcinoma (PHC) developing in a 10 year old boy who contracted Hepatitis B virus (HBV) infection in the course of maintenance phase chemotherapy for acute lymphoblastic leukemia was seen at University Hospital, Kuala Lumpur. This case is of interest in that it (1) supports an etiological relationship between HBV infection and PHC, (2) manifested a distinctly short malignant transformation time, and (3) draws attention to the possible contributory role of chemotherapy in increasing the risk of developing PHC.
Serum alpha-fetoprotein (AFP) levels and its expression in liver tissue was studied in 50 cases of histologically confirmed hepatocellular carcinoma (HCC). Serum AFP levels were elevated (greater than 20iu/ml) in 35/50 (70%) of the cases, 28 of whom had levels greater than 500 iu/ml, which is highly suggestive of HCC. These results indicate that serum AFP, by itself, is a relatively insensitive diagnostic test for HCC. Although elevated levels in high risk patients provide a specific clue, a negative result does not exclude the diagnosis of HCC. Expression of AFP by tumour cells paralleled that of serum in the majority of cases. However, tissue AFP was negative in 7 patients who had markedly elevated serum AFP. This observation may be a reflection of preferential excretion of the tumour antigen or differential expression of the antigen by the tumour cells. None of the patients with normal serum AFP demonstrated a reaction for tissue AFP. There was no correlation between AFP production and tumour differentiation.
We studied the presence of Hepatitis C Virus (HCV) antibodies in a defined Malaysian population and examined the association, if any, between HCV and the Hepatitis B Virus (HBV), using sensitive recombinant DNA second generation Enzyme Immunoassay (EIA) test kits. This sero-prevalence study comprised 1,434 sera from eleven distinct groups comprising intravenous drug users (IVDU), haemophiliacs, male homosexuals, female prostitutes, healthy blood donors, staff of dialysis unit and laboratory personnel, chronic renal failure patients undergoing dialysis (CRFD), patients with liver cirrhosis, chronic active hepatitis, chronic persistent hepatitis and primary liver cancer. Except in laboratory personnel and dialysis staff, HCV antibodies were detected in each group of patients ranging from 3% in blood donors to 85% in IVDU. The main modes of HCV transmission identified were parenteral drug use, transfusion and/or dialysis related. The HBV was found to be the major viral etiological agent in 75% of chronic liver disease (CLD); while in 10% of cases both HCV and HBV were detected. HCV was implicated as the sole viral agent in only a small proportion (1.5%) of patients with chronic liver disease.
This study evaluates the usefulness of a combined cytological and histological approach to the diagnosis of hepatocellular carcinoma (HCC) when applied to fine needle biopsy specimens obtained under ultrasonic guidance. The material, aspirated from 51 focal liver lesions, was handled in such a way that there was sufficient material for both cytological and histological (cell block) assessment. Of the 29 cases of HCC studied, a confident cytological diagnosis was made in 23 (79%). In the remaining six cases, the cytological features were considered to be suspicious but not diagnostic of HCC. Examination of cell blocks in the six cases enabled a confident diagnosis of HCC to be made in all cases. This was due to the supplementary visual information provided by the histological features, particularly the pattern of arrangement of the tumour cells.
Chronic hepatitis B virus (HBV) infection constitutes a major public health problem particularly in developing countries in East Asia, South-East Asia, the Pacific Basin and Africa. In Malaysia, a developing nation in the South East Asian region, the chronic HBV carrier rate varies between < 1% to about 10% depending on the ethnic group studied. The highest frequency is seen among the Chinese, followed by the Malays and lastly the Indians, with a male preponderance of between 2 : 1 and 3 : 1. Exposure to the virus among the adult population is estimated to be about 15%, 26% and 36% among the Indians, Malays and Chinese respectively. Serological study of adult chronic HBV carriers showed a frequency of HBe antigenemia of about 35%, with a significant decreasing trend with age. HBV DNA status generally correlated with the HBe status. An atypical profile of anti-HBe associated with serum HBV DNA is found in some carriers; in most instances, this is related to seroconversion from HBe antigenemia to anti-HBe. Chronic complications of HBV infection include the development of hepatocellular carcinoma (HCC), the occurrence of which closely parallel that of HBsAg carrier rate. In Malaysia, HCC is the third most common malignant neoplasm and among the 10 leading causes of death. About 80% of our HCC cases are HBV associated. All 3 ethnic groups are afflicted, the highest frequency being among the Chinese. Males show a disproportionate risk with an odds ratio of 3.93 (p < 0.0001).