Primary hepatocellular carcinoma (a review of 74 cases).
Primary hepatocellular carcinoma (HCC) holds a unique position among all the human neoplasms because of its striking difference in racial and geographical distribution and its association with chronic liver disease as well as certain biological markers like alpha-feto proteins and Hepatitis B virus surface antigen (HBsAg).
The material on which this study is based consists of 42 autopsied cases and 32 surgical biopsy cases of proved hepatocellular carcinoma at Topiwala National Medical College, Bombay, during 1971 to 1981. The gross and microscopic features, as well as the clinical data and other records were reviewed. The histological material was re-evaluated by studying following sections:
1. Routine sections stained by H. and E.
2. Reticulin stain.
3. Orcein (Shikata) staining by technique of Deodhar et al to study the presence of HBsAg in the liver tissue.
4. Masson's trichrome stain to study the presence of intracytoplasmic hyaline bodies.
A total of 1065-9 autopsies were done at T.N. Medical College, during a period of 1.1 years. Out of these, there were 42 cases of HCC showing an incidence of 0.394 per cent. The mean age was 50.35 years, the range extending from 11 to 80 years.
[Table - 1]. The maximum incidence was noted in the fifth decade (32.432 per cent) and the lowest incidence was seen between 11 and 20 years of age (2.703 per cent). There were 40 males and 2 females in the autopsy group and 26 males and 6 females in the surgical group. Out of 74 cases, 17 gave history of consuming alcohol for a period of over 15 years. Nine patients (12.162 per cent) gave history of jaundice in the past. Cirrhosis was seen in 38 cases at autopsy (90.48 per cent) and 7 cases at biopsy (21.93 per cent). All the alcoholic patients had cirrhosis except one. The commonest clinical presentation was that of abdominal pain (47 cases), abdominal distension (25 cases), jaundice (21 cases), anorexia (16 cases), fever (15 cases), oedema feet (13 cases), vomiting (12 cases), weight loss (8 cases) and haematemesis (8 cases). Seven patients presented with a lump in the abdomen and 15 patients came in a state of hepatocellular failure. On examination, 48 patients were found to have hepatomegaly, 35 had ascites, 23 had oedema feet, 17 had icterus and 8 had splenomegaly.
The relevent investigations included serum bilirubin, SGOT, SGPT and alkaline phosphatase studies. The records were available only in 35 cases and the above mentioned parameters were increased in all of them. Ascitic fluid tapping done in 9 cases, was found negative for malignant cells. Alpha feto proteins estimated in 2 cases were within normal limits. Liver scan was done in 8 cases; 5 of these showed a cold area in the left lobe and one in the right lobe, whereas 2 cases showed multiple cold areas. All these cases were positive for malignancy at biopsy and/or autopsy. Exploratory laparotomy was performed in 7 cases. All patients revealed multiple nodules in the liver. In one case, hemoperitoneum was found due to rupture of two such nodules. Biopsy from the nodules confirmed the diagnosis of HCC.
Gross examination of the liver done at autopsy showed marked increase in the weight of the liver in all cases. A solitary lesion was detected in the right lobe in 11 cases, and in the left lobe in 5 cases. A diffuse lesion was noted in 26 cases. Micro nodular cirrhosis was present in 13 cases and macronodular in 29 cases. Necrosis was seen in 11 cases. Distant organs were examined for metastasis. Out of 42 autopsy cases, 8 showed extrahepatic involvement, the commonest site being lungs (7 cases), lymph nodes (1 case) and brain (1 case).
Histological features of HCC seen in our series are shown in [Table - 2], which is self-explanatory. Reticulin stain showed loss of fibres within the tumor nodules as compared to persistence or even increase in these fibres in the cirrhotic nodules. Orcein stain was done for detection of HBsAg. Eleven cases out of 42 (26.19 per cent) at autopsy were positive, whereas only 2 out of 32 surgical biopsy cases were positive (6.25 per cent) for the sama. Bile secretion was found in 8 cases (19.05 per cent) at autopsy. Intracytoplasmic hyaline bodies were not detected in any of these cases.
Hepatocellular carcinoma is a leading cause of death beyond infancy and childhood in some of the most populous areas of the world, notably China, South East Asia and most of the tropical Africa, the common factor being tropical or subtropical environment and rural poverty. In India, though it is a relatively uncommon disease, some increase is suspected in South India. Reddy et al have reported an incidence of 1.6 per cent from Madras in an autopsy study of liver cell cancer. Recently, a high incidence of HCC has been reported from the East Coast of India. The incidence in India corresponds to that of the Western Countries. The increase may be due to improved treatment and longer survival of the cirrhotic patients, as well as better facilities for its detection among patients.
In almost all parts of the world, the males are affected more than the, females. In our series, male to female ratio was 8.25:1. In the present series, 38 cases (90.48 per cent) showed associated cirrhosis at autopsy, whereas, it was seen in only 23.93 per cent of biopsy cases. This is probably due to the small amount of tissue Obtained at biopsy, which may consist only of tumourous areas. Out of these, 29 cases (69.05 per cent) showed cirrhosis of macro-nodular type. Divekar et at reported an incidence of cirrhosis in 50 per cent cases of HCC.
A well defined tumour mass was seen in 16 cases, 11 (26.19 per cent) being in the right lobe. Lai et al also reported 38 per cent dominant right lobe involvement.
To some extent, degree of differentiation of liver cell cancer determines the frequency of extrahepatic metastasis. The more undifferentiated variants tend to disseminate more readily. Liver cell carcinoma has a marked tendency for spread via intrahepatic veins-both hepatic and portal. Thrombosis of these vessels by tumour and blood clot is a characteristic finding at autopsy. The commonest site of metastasis is lungs, followed by bones, lymph nodes and brain. One of the patients showed only three tiny nodules in the liver with widespread dissemination to distant organs. Spontaneous and traumatic rupture of hepatoma has been reported by Nagasue and Inokuchi.
Histologically, the most useful diagnostic criteria were resemblance of cytoplasm of the tumour cells to that of normal hepatic parenchymal cells, bile production by the tumour cells, increased N: C ratio, nuclear hyperchromasia, enlarged nucleoli and decreased reticulin within the tumour nodules. At the same time, the type of cellular arrangement and blood vessel invasion were looked for. At biopsy, in a significant number of cases (34.37 per cent), it was not possible to classify the tumour into any one particular type, as the tissue obtained was too small and consisted of necrotic material and groups of malignant cells only, hence, the term `undefined' was denoted. Orcein stain was done for the detection of HBsAg. This is also possible by electron microscopy, immunofluorescence and immunoperoxidase techniques. However, a comparative study of different methods by Sumithran showed orcein stain to be the method of choice for routine use. The Shikata staining carried out in this study is not only specific, but relatively inexpensive, easily performed and stains out distinct cytoplasmic inclusions even in stored formalin fixed liver, old paraffin blocks and autolysed livers. Nuclear staining has been never observed with orcein. A positive association between HCC and positive Hepatitis B test was reported by Anand and Malaviya. In the present series, HBsAg was detected in 26.19 per cent cases at autopsy and only 6.25 per cent cases at biopsy. The low incidence at biopsy is due to the presence of the HBsAg in the non-tumourous hepatocytes, which is rarely included in the biopsy material. However, in two cases, we found orcein positive material in the tumour mass. The highest incidence of the same in the tumour cells has been reported by Nayak et al (8 per cent) in Indian patients. It was more easily detectable at the periprery of the tumour nodules suggesting that infection of the neoplastic cells may be an expression of variable metabolic environment. Alternatively, normal hepatocytes may become enmeshed in the growing edge of the tumour, hence, these cells pick up the stain. Cohen et al detected orcein positive material in 36 per cent cases of HCC.
To summarise, primary hepatocellular carcinoma was common in males above 50 years of age and was associated with cirrhosis of macronodular type in 90.48 per cent cases. Detection of HBsAg in 26.10% cases denotes the oncogenic role of hepatitis B virus.
We are thankful to Dr. B. R. Kalke, Dean, T.N. Medical College, for allowing us to publish this data.