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REVIEW ARTICLE Table of Contents   
Year : 2004  |  Volume : 1  |  Issue : 1  |  Page : 140-152
Hepatitis B associated hepatocellular carcinoma: Epidemiology, diagnosis and treatment


Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Mumbai 400 012, India

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How to cite this article:
Mohandas K M. Hepatitis B associated hepatocellular carcinoma: Epidemiology, diagnosis and treatment. Hep B Annual 2004;1:140-52

How to cite this URL:
Mohandas K M. Hepatitis B associated hepatocellular carcinoma: Epidemiology, diagnosis and treatment. Hep B Annual [serial online] 2004 [cited 2019 Mar 22];1:140-52. Available from: http://www.hepatitisbannual.org/text.asp?2004/1/1/140/27923



  Summary Top


Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer deaths in the world. Chronic hepatitis B infection accounts for over 75% of all HCC. Incidence of HCC in India is low, even though over 42 million Indians are estimated to have chronic HBV infection. It was estimated that about 14,120 new patients will develop HCC in India in the year 2001. Most patients with HCC have advanced cirrhosis at diagnosis. Therefore, the end results of patients with symptomatic HCC is grim. Early diagnosis of small tumor may offer better chance for curative treatments. Newer imaging techniques have facilitated the diagnosis and treatment of HCC. Ultrasonography (US), multi slice triphasic computed tomography (CT), magnetic resonance imaging (MRI) and virtual angiography have made the diagnosis, staging and post treatment evaluation of HCC less invasive. Surgery and liver transplantation are useful in treating small sized HCC. Percutaneous ethanol injection (PET); percutaneous radiofrequency ablation (RFA] and Trans-arterial chemo-embolization (TACE) are used to ablate nonresectable small HCC some of which may be cured. These techniques are also used to shrink HCC before surgery and liver transplantation. In spite of all advances, symptomatic HCC remains a lethal disease. Primary prevention by vaccination appears to be the only means of reducing mortality from HCC despite the fact that it will be a very challenging task. Screening of 45 million Indians with chronic HBV infection is not feasible or cost-effective.

Epidemiology

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer related death worldwide.[1] In the year 2000, it was projected that there will be 430,000 deaths from HCC all over the world. The prevalence of HCC in autopsied Indians are low, and varies from 0.2% to 1.9%.[2] Age-adjusted incidence of HCC in rural and urban Indian populations are low when compared to those in China, Japan, and other South East Asian countries.[1],[2] The incidence is a little higher than in western countries [Table - 1]. The mean age adjusted incidence of HCC in 6 Indian populations is 2.77 males and 1.28 females per 100,000 people. We had earlier estimated that there will be 14,120 patients with HCC in India in 2001.[2] Since the mortality rates of HCC are almost the same as incidence rates, equal number of patients are expected to die from HCC.

The incidence of HCC in India peaks in the seventh decade, and this is in favor of horizontal transmission of HBV infection.[2] Hospital studies reveal high male:female ratio in India, but in the community the ratio varies between 3:1 and 2:1. Worldwide incidence of HBV associated HCC has started declining after the introduction of safe blood transfusions and widespread HBV vaccination, while the proportion of cases due to HCV are rising.[3] The population data from Mumbai reveals a small increase in the incidence of HCC in males and females over three decades.[2] The incidence of HCC in Indians in Singapore and New South Wales, Australia is much lower than that in South East Asians. However in the UK, the mortality ratio for HCC is significantly higher in Indian immigrants as compared to the native British population.[2]

Role of chronic Hepatitis B virus infection

Approximately, three fourths of all liver cancer deaths are attributed to hepatitis B infection worldwide. In India the hepatitis-B surface antigen (HBsAg) positivity in patients with HCC varies from 36% to 74% (mean of 47%).[2] Underestimation of HBV infection in Indian patients with cirrhosis is likely due to the wide variability in the testing methodology. The relative risk of developing HCC in Indian patients with chronic HBsAg infection was estimated to be 17.89 from various studies [Table - 2].

A small proportion of Indian patients with chronic liver disease or HCC have combined HBV and HCV infections. Contamination of food with Aflatoxin is common in tropics. Food stuffs commonly contaminated with Aflatoxin include maize, paraboiled rice, coconut kernel, and groundnuts. Aflatoxin has been associated with toxic hepatitis and Indian childhood cirrhosis but there are no Indian studies on its role in HCC. Studies from Taiwan suggests that Aflatoxin and HBV can act as co-factors in the development of HCC. The prevalence of cirrhosis in HCC patients range from 70% to 80% in autopsies, while in clinical studies the prevalence vary from 30% to 80%. Majority of the patients with HCC in autopsy studies had post necrotic cirrhosis due to infective etiology. Heavy alcohol ingestion has been noted in 20%-30% of patients with HCC. The population at risk of development of HCC is huge, with over 42 million Indians estimated to be infected with HBV.[4]

Pathogenesis of HBV related HCC

HCC develops regularly after laboratory infection of Woodchucks, without external co-carcinogen in chronic carriers of surface antigen. Hans Popper and colleagues identified recurrent necro-inflammation to act as an endogenous co-carcinogen or promoter and induce the clonal development of HCC.[5] Therefore it is important while managing HBV carriers to reduce liver cell inflammation. In a study of Alaskan Eskimo with HCC, the noninvolved parenchyma included precursor hepatocytic nodules, with phenotypic alterations, dysplastic hepatocytes and hepatitis B surface antigen-laden ground-glass hepatocytes. Parenchyma within 1 mm of the HCC exhibited confluent hyperplasia and conspicuous necro-inflammation associated with pericellular and periductular fibrosis. In a few specimens, a continuous transition from hyperplasia and dysplasia near the periphery of the tumor to increasing anaplasia in the center could be made out.[5]

Clinical features

The development of most HCC involves the inflammatory process and cirrhosis in the liver.[6] Cryptogenic cirrhosis is not uncommon in Indian patients with HCC. Recent molecular studies from India reveal that between 10% to 40% of all cryptogenic cirrhosis is caused by HBV infection. Most patients with HCC often have no previous history of liver disease. Some are diagnosed before the onset of symptoms during work up for other diseases or during screening. Progressive abdominal pain, weight loss, and abdominal lump are the commonest presenting symptoms.[6] Sudden unexplained deterioration of otherwise stable cirrhosis, fever of unknown origin are other relatively common presentations. Rarely, the HCC may present as an acute emergency due to rupture or hemorrhage of the tumor or as acute Budd Chiari syndrome. Metabolic manifestations are frequent in HCC; these include hypoglycemia, erythrocytosis, hypercalcemia, and hyperlipidemia. Physical examination reveals non-specific findings such as jaundice, tenderness over the liver, hepatomegaly, or ascites. Hepatic friction rub, arterial bruit and features of chronic liver disease may be present.

Biochemical tests are of little use in making a diagnosis. As most HCC develop in the setting of cirrhotic liver disease, the liver profile and prothrombin time are essential for planning treatment. Elevated levels of tumor marker serum alpha fetoprotein (AFP) over 400 g/L is diagnostic and seen in 30% to 60% of patients.[6] In another 30% the AFP is elevated but not diagnostic. Presence of high levels of AFP in non pregnant adults most often occurs in HCC and in some germ cell tumors. The AFP elevations may be absent in small early-stage HCC and in areas with low-prevalence. Elevation of des-carboxyprothrombin (prothrombin precursor) in serum is under evaluation as a marker for HCC.

Diagnostic Imaging

Imaging techniques are used in patients with HCC for both diagnostics and therapeutic purposes. [Table - 3]. Abdominal ultrasound (US), computed tomography (CT) and magnetic resonance (MR) imaging are important investigations for HCC.[7],[8],[9] US examinations by experienced ultrasonographer and tri-phasic spiral CT can help to detect small symptomatic HCC. CT and MR imaging is also useful in measuring the liver volume, vascular invasion and judging the resectablity. A Lipiodol-CT scan often gives characteristic findings of tumor. US screening is used for HCC screening in patients with chronic HBV carrier. It has lower specificity in patients with macronodular cirrhosis as small lesions are difficult to detect. Hepatic arteriography is an important investigation for HCC and is used to outline the vascular anatomy when surgery is planned. However helical CT scan or MRI with CT/MR Angiography have obviated the need for invasive angiography for diagnostic purposes.[7],[8],[9]

CT and MRI scans document the relationship of the tumor to the hepatic and portal veins (and occasionally involvement of these structures), delineating tumors for which the chances of surgical cure are remote. Laparoscopic evaluation is useful to detect metastatic disease, bilobar disease, or extensive cirrhosis in the remnant liver, and obviate the need for open surgical exploration.[9] Nevertheless, hepatic arteriography is also used extensively in therapy such as intra-arterial chemotherapy, embolization and chemo-embolization. Biopsy and aspiration cytology are low risk procedures and confirm the diagnosis in most of the patients when performed under US guidance. It is important that biopsies or FNAC are not performed until the possibility of liver resection is excluded to avoid needle tract seeding in potentially curable tumors.

Current management strategies

One of the primary difficulties in treating HCC is that over 85% of this cancer develops in a cirrhotic liver.[6],[10] In other words, HCC develops in end stage liver disease. Furthermore many patients have partial or complete portal venous thrombosis which compromises the hepatic blood flow. Because of these, patients are at great risk of developing liver failure after surgical resection. Other cancer therapies such as radiation and chemotherapy also damage the normal hepatocytes that surround the tumor and can aggravate or precipitate liver failure. The prognosis of patients diagnosed after the onset of symptoms is grim, and the different treatments employed are generally unsatisfactory. Surgical resection of the tumor with adequate margin provides the best results. This is possible in less than 5% to 10% of all cases. Patients with small-localized tumors diagnosed early have prolonged survival.

The choice of treatment Table A depends on several factors including previous treatment, presence of cirrhosis, and location of recurrence, hepatic function as well as individual patient considerations such as co-morbidity.[5],[10],[11] Resection may be considered when feasible. When resection is not possible, other options include liver transplantation for some and local ablative therapies such as trans arterial chemo-embolization (TACE), percutaneous ethanol injection (PEI), and other ablative modalities including microwave coagulation, radiofrequency ablation and photodynamic therapy.[7],[8],[9],[10],[11],[12] Chemotherapy and radiation therapy are usually performed in experimental protocol settings.[13] From the point of view of treatment, all HCC patients may be divided into three broad groups.

In patients with resectable HCC, the tumor is confined as a solitary mass in a portion of the liver and can be resected completely along with a margin of normal liver.[10],[11] The liver function tests are mostly normal and there is little evidence of advanced cirrhosis or active hepatitis. However, because the HCC is frequently multi-focal, the preoperative assessment should therefore include a search for multi-centric HCC and small extrahepatic metastases which would preclude liver resection. Less than 10% of HCC will have such localized resectable disease. Resection of the localized liver cancer varies from segmental resection to tri-segmental (80%) resection. In carefully selected patients, partial hepatectomy has resulted in a 5-year survival of 10% to 30%. Resection of more than a wedge of liver is associated with high mortality rate in patients with frank cirrhosis or chronic active hepatitis. Adjuvant therapy with intra-arterial iodine-131 labeled Lipiodol has shown to reduce recurrence and improve the overall survival following curative resection.[13],[14] Liver transplantation is today being used increasingly for small (<5 cm) HCC in patients with cirrhosis with 5-year survivals of 20% to 30%.[11] Recurrent HCC is the major limiting step following transplantation. Pre-transplant chemotherapy followed by transplant is also being attempted for improving the 5-year survival rates.[13],[15]

The second group consists of patients with localized tumore that are not resectable due to other reasons. In these patients with small tumors confined to the liver, surgical resection is not possible because of the anatomical location or due to severe medical illness such as cirrhosis, chronic hepatitis, cardiac disease etc. Selected patients with this such type of HCC may be considered for liver transplantation. Otherwise, patients can be treated with local tumor ablative therapies such as chemo-embolization, percutaneous injection of ethanol or acetic acid and coagulation by laser, microwave or radiofrequency current.[15],[16],[17],[18]

The third group consists of advanced HCC with cancer in both lobes of the liver or metastases to distant sites resulting in an overall median survival of 2 to 4 months. Multi-focal HCC is common in patients with cirrhosis or chronic hepatitis. Bone and lungs are the most common metastatic sites of HCC. Chemo-embolization and local ablative therapies may produce some beneficial results in selected patients who have no extrahepatic metastases and good liver function. Systemic chemotherapy is investigational. External radiation is effective for palliation of bone metastasis.[6]

A very large proportion of patients who are not suitable for surgery due to tumor location, concomitant medical condition, bilateral tumors, and distant metastasis, a variety of treatment modalities have been used for palliation. The modalities include chemo-embolization, cryosurgery, percutaneous ethanol injection, and radiofrequency ablation for cancers smaller than 5 cms.[12],[16],[17],[18] Use of systemic chemotherapy, regional chemotherapy, and/or labeled antibodies have been shown to induce remission of unresectable HCC. Embolization of the hepatic artery with sponge, steel coils, Lipiodol and chemo-embolization (TACE) (usually using Adriamycin or Cisplatinum) have been extensively investigated. These approaches produce tumor necrosis, reduction in tumor size, and relief of pain, but the benefits are only transient. Some non randomized trials have reported survivals equivalent to resection for localized small tumors. However, damage to arterial blood supply (including injury during arterial infusion chemotherapy) can be associated with significant morbidity. These therapies are contraindicated in the presence of severe portal hypertension, portal vein thrombosis, and clinical jaundice. External-beam radiation therapy and chemotherapy followed by radiolabeled polyclonal antiferritin antibody has been shown to produce tumor regression in up to 50% of patients with localized tumor.[6]

The prognosis for patients with HCC with progressing, recurring, or relapsing disease is poor. Although several investigators have attempted to prognosticate HCC, the Okuda clinical classification remains extremely useful. There is no standard therapy for very advanced, metastatic and recurrent HCC. Appropriate clinical trials should be considered whenever possible. Routine screening of high-risk individuals with annual ultrasound examination and serum AFP estimation may be beneficial in detecting small HCC but may not improve survival. Further studies from low incident regions such as India are necessary before routine screening can be recommended. Vaccination against HBV would benefit populations living in high HBV prevalence areas, and reduce the burden of chronic liver disease and prevent HCC.

Summary

The age standardised incidence rates of HCC in India is low. More than 90% of HCC patients present late, when the possibility of offering curative therapy is remote. The hepatologists should strive to improve the outcome of HCC by appropriate health education in prevention and early diagnosis. Longitudinal studies are required before we can recommend secondary prevention of HCC by ultrasound or AFP based screening as done in Japan and several western countries. Theoretically, the large proportion of HCC in India is preventable by immunization, safe blood transfusion and injection practices and life style changes. Selective surveillance of patients with chronic HBV and HCV induced cirrhosis with US examination twice a year may be of benefit This would help to diagnose small HCC which can be managed effectively by simple techniques such as PET or RFA. More epidemiological studies are needed to assess true risk of HCC in chronic liver disease of viral etiology and unravel some of the enigmas associated with the occurrence of HCC in India.

 
  References Top

1.Parkin DM, Whelan SL, Ferlay J, et al. Cancer Incidence in Five Continents, Vol. VII. Lyon: International Agency for Research on Cancer 1997.  Back to cited text no. 1    
2.Dhir V, Mohandas KM. Epidemiology of digestive cancer in India-III. Liver. Indian J Gastroenterol 1998;17:100-3.  Back to cited text no. 2    
3.Popper H, Thung SN, McMahon BJ, et al. Evolution of hepatocellular carcinoma associated with chronic hepatitis B virus infection in Alaskan Eskimos. Arch Pathol Lab Med 1988;112:498-504.  Back to cited text no. 3  [PUBMED]  
4.Chang MH, Chen CJ, Lai 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.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.Thyagarajan SP, Jayaram S, Mohanavally B. Prevalence of HBV in the general population of India. In: Sarin SK, Singal AK, Eds. Hepatitis B in India : Problems and prevention. New Delhi: CBS publishers. 1996 : p.5-16  Back to cited text no. 5    
6.Hepatocellular carcinoma. Lancet 1999;353:1253-7.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]
7.Mor E, Kaspa RT, Sheiner P, et al. Treatment of hepatocellular carcinoma associated with cirrhosis in the era of liver transplantation. Ann Int Med 1998; 129:643-53.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Karl RC, Morse SS, Halpert RD, et al. Preoperative evaluation of patients for liver resection: appropriate CT imaging. Annals of Surgery 1993;217:226-32.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]
9.Lo CM, Lai EC, Liu CL, et al. Laparoscopy and laparo-scopic ultrasonography avoid exploratory laparotomy in patients with hepatocellular carcinoma. Annals of Surgery 1998;227:527-32.   Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Dalla Palma L. Diagnostic imaging and interventional therapy of hepatocellular carcinoma. Br J Radiol 1998;71:808-18.  Back to cited text no. 10    
11.Tanaka K, Nakamura S, Numata K, et al. The long term efficacy of combined Transcatheter arterial embolization and percutaneous ethanol injection in the treatment of patients with large hepatocellular carcinoma and cirrhosis. Cancer 1998;82:78-85.   Back to cited text no. 11  [PUBMED]  [FULLTEXT]
12.Yamamoto J, Iwatsuki S, Kosuge T, et al. Should hepatomas be treated with hepatic resection or transplantation? Cancer 1999;86:1151-8.   Back to cited text no. 12  [PUBMED]  [FULLTEXT]
13.Lau WY, Leung TW, Ho SK, et al. Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomized trial. Lancet 1999;353:797-801.   Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Lai EC, Lo CM, Fan ST, et al. Postoperative adjuvant chemotherapy after curative resection of hepatocellular carcinoma: a randomized controlled trial. Arch Surg 1998;133:183-8.   Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Livraghi T, Goldberg SN, Lazzaroni S, et al. Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology 1999;210:655-61.   Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Tanaka K, Nakamura S, Numata K, et al. The long term efficacy of combined Transcatheter arterial embolization and percutaneous ethanol injection in the treatment of patients with large hepatocellular carcinoma and cirrhosis. Cancer 1998;82:78-85.   Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Shimada M, Takenaka K, Taguchi K, et al. Prognostic factors after repeat hepatectomy for recurrent hepatocellular carcinoma. Annals of Surgery 1998;227:80-5.   Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Liovet JM, Real MI, Montana X, et al. Arterial embolization or chemotherapy versus symptomatic treatment in patients with unresectable hepatocellular carcinoma randomized trial. Lancet 2002;359:1734-9.  Back to cited text no. 18    

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Correspondence Address:
K M Mohandas
Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Mumbai 400 012
India
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Source of Support: None, Conflict of Interest: None


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[Table - 1], [Table - 2], [Table - 3], [Table - 4]



 

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