Indian J Gastroenterol (January–February 2014) 33(1):35–40 DOI 10.1007/s12664-013-0373-7
ORIGINAL ARTICLE
Profile of hepatocellular carcinoma in a tertiary care hospital in Punjab in northern India Ajit Sood & Vandana Midha & Omesh Goyal & Prerna Goyal & Neena Sood & Suresh Kumar Sharma
Received: 9 March 2013 / Accepted: 28 July 2013 / Published online: 6 September 2013 # Indian Society of Gastroenterology 2013
Abstract Purpose/Aim Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality in all parts of the world. We analyzed the clinical presentation, etiology, and tumor characteristics of HCC presenting to our hospital. Methods All patients diagnosed to have HCC from September 2007 to August 2010 were prospectively enrolled. HCC was diagnosed according to EASL criteria—USG/CT/MRI of the abdomen and/or serum alpha-fetoprotein and/or histology (where indicated). Detailed clinical and laboratory parameters were noted. Barcelona Clinic Liver Cancer (BCLC) staging was done. Results One hundred and twenty-eight patients (22 females, mean±SD; age, 49.8±10.2 years) were diagnosed to have HCC. Underlying cirrhosis was present in 99.2 %. Hepatitis C virus infection, alone (21.9 %) or with alcohol (22.9 %) was the most common etiological factor, followed by alcohol alone; 33.6 % of the patients had more than one etiological factor. Most patients (83.5 %) presented with features of A. Sood (*) : O. Goyal Department of Gastroenterology, Dayanand Medical College and Hospital, Tagore Nagar, Ludhiana 141 001, India e-mail: [email protected] V. Midha : P. Goyal Department of Medicine, Dayanand Medical College and Hospital, Tagore Nagar, Ludhiana 141 001, India N. Sood Department of Pathology, Dayanand Medical College and Hospital, Tagore Nagar, Ludhiana 141 001, India S. K. Sharma Department of College of Nursing, Dayanand Medical College and Hospital, Tagore Nagar, Ludhiana 141 001, India
decompensated cirrhosis. HCC leading to decompensation of cirrhosis was the first presentation of the liver disease in nearly one third of the cases. Serum alpha-fetoprotein was >200 ng/mL in 67.2 % of the patients, while it was normal in 18.7 % of the patients. The mean±SD size of HCC was 5.3±2.9 cm. HCC was multicentric in 57 %, and portal vein thrombosis was present in 34.4 %. About 66 % of the patients belonged to BCLC stage C or D. Conclusions Hepatitis C virus infection was the most common cause of HCC in Punjab. One-third of the patients had multiple etiological factors and almost all had underlying cirrhosis and presented at advanced stage. Keywords Alcohol . Hepatitis B virus . Hepatitis C virus . Liver cancer
Introduction Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer death [1]. In 2002, the estimated number of new cases of HCC worldwide was 625,000 [2]. The incidence of HCC ranges from 4 cases per 100,000 population in USA to 150 cases per 100,000 population in parts of Africa and Asia [2, 3]. Over the last several decades, the incidence of HCC has shown an increasing trend in Japan and many Western countries [4–8]. In India, the mean incidence of HCC in four population-based registries has been reported to be 2.77 % for males and 1.38 % for females [9–11]. Overall, the prevalence of HCC in India varies from 0.2 % to 1.6 % [9, 10]. Despite India being in a low-incidence zone for HCC, the number of HCC patients in 2001 was estimated to be 12,750 [9]. The etiological profile of HCC is quite heterogeneous, depending largely on the prevalence of underlying risk factors in the general population in different geographical areas. Studies have reported that more than 80 % of patients with
36
HCC in high-incidence areas, such as East Asia and subSaharan Africa, were seropositive for hepatitis B surface antigen (HBsAg), where only 10 % to 15 % of the population is known to be HBsAg positive [12]. In areas with low HCC incidence, like Japan, Europe, and North America, chronic hepatitis C infection (CHC) is more commonly associated with HCC and is largely responsible for the increase in incidence of HCC in the last several decades [1, 12]. In India, chronic hepatitis B infection (CHB) has been reported to be the leading cause of HCC in studies from New Delhi, Chandigarh, and Hyderabad [13–16]. In contrast to the West, where majority of HCC are diagnosed at early stage during routine surveillance, most of the HCC cases in India are diagnosed at an advanced stage, ruling out curative treatment [17, 18]. Although HCC is a major health problem and a major cause of mortality in patients with chronic liver disease (CLD), data on the clinico-etiological profile of HCC in India are limited. The present study was designed to analyze the clinical presentation, etiological profile, and tumor characteristics of patients of HCC presenting to a tertiary care institute in Punjab, northern India and compare these with presentation of HCC in the rest of the country.
Patients and Methods This prospective observational study was carried out over a period of 3 years (September 2007 to August 2010) in a tertiary care teaching institute in northern India. During this period, all patients diagnosed to have HCC in the gastroenterology outpatient/inpatient departments of this institute were enrolled. Detailed history, clinical examination, and laboratory assessment including hemogram, liver and renal function tests, prothrombin time index, blood sugar, and α-fetoprotein were done. The diagnosis of cirrhosis was made on the basis of clinical, radiological, biochemical, and/or histological criteria. Child–Pugh score for the stage of cirrhosis was calculated. HCC was diagnosed by USG/CT scan/MRI of the abdomen, serum alpha-fetoprotein (AFP), and/or histology (where indicated), according to the Barcelona Clinic Liver Cancer (BCLC) criteria [18]. Staging of HCC was performed using the EASL criteria [18]. Etiology of cirrhosis was considered to be alcohol, if the alcohol consumption per day was 40–80 g for males and 20–40 g for females for >10 years. Markers for detecting current, past, or occult infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) were done in all patients of HCC. These included HBsAg (ELISCAN HBsAg, RFCL, Dehradun, India), total antibody to hepatitis B core antigen (HBcAg) (Vidas, bioMerieux, Craponne, France), HBV DNA (COBAS Taqman, Roche Molecular Systems, Branchburg, NJ, USA), anti-HCV antibody (ELISCAN HCV, RFCL, Dehradun, India), and HCV RNA (COBAS Taqman V2.0, Roche
Indian J Gastroenterol (January–February 2014) 33(1):35–40
Diagnostics Corporation, Indianapolis, IN, USA). Etiology of HCC was considered to be CHB if HBsAg, total antibody to HBcAg and/or serum HBV DNA were positive. CHC was considered as the etiological factor if anti-HCV antibody and/ or HCV RNAwere positive. Work up for autoimmune (AI) liver disease, Wilson's disease, nonalcoholic fatty liver disease (NAFLD), hemochromatosis, and Budd–Chiari syndrome (BCS) was done where indicated. Decompensation of cirrhosis was defined by the presence of ascites, jaundice, bleeding, or encephalopathy in a patient with cirrhosis. Quantitative data were presented as mean±SD or median (range) and qualitative data as percentages. The two-tailed Fisher's exact test was used to analyze categorical variables and student's t test to analyze continuous variables. The pvalue 5 cm) was seen in 9.3 % (n=12) of the patients while in 49.2 % of the patients, liver was not clinically palpable. Serum AFP was >200 ng/mL in 67.2 % of the patients, while it was normal in 18.7 % of the patients (Table 1). The etiological profile of patients with HCC is shown in Table 3. More than one etiological factor was present in 33.6 % (n=43) of the patients. Sixty-seven (52.3 %) patients were diagnosed to have CHC. Of these, 65 patients were antiHCV antibody positive, while 2 were anti-HCV negative but
Indian J Gastroenterol (January–February 2014) 33(1):35–40
37
Table 1 Baseline characteristics of patients with hepatocellular carcinoma (n=128) Baseline characteristics Age, mean±SD Median (range) Sex (male/female) Duration of new onset symptoms before HCC diagnosis 3 months Type of presentation of HCC In previously diagnosed cirrhotics (n=74) • Features of decompensation • HCC detected on surveillance In newly diagnosed cirrhotics (n=53) • Features of decompensation • Nonspecific symptoms
49.8±10.2 years 60 (32–86) years 4.8:1
59 55 4
*Patients with multiple etiological factors (33.6 %, n=43) have been included under all the factors HCV hepatitis C virus, HBV hepatitis B virus, NAFLD nonalcoholic fatty liver disease
64 10
Table 2 Baseline clinical and laboratory parameters of patients with hepatocellular carcinoma (n=128)
Abdominal distension Weakness Anorexia Abdominal pain Encephalopathy Jaundice Gastrointestinal bleeding Weight loss Asymptomatic Signs Ascites Icterus Hepatomegaly Splenomegaly Lab parameters Bilirubin, mg/dL (mean±SD) Albumin, g/dL (mean±SD) INR (mean±SD) AFP (median, range) 200 IU/mL
Number
Percentage
72
56.3
52 45 43 27 23 11 7 10
40.6 35.2 33.6 21 17.9 8.6 5.5 7.8
117 71 65 44 Value 4.6±7 2.7±0.49 1.67±0.8 791 (0.8–500,000) 24 18 86
Etiological factors*
Number (%)
HCV related (total) • HCV alone • HCV+alcohol • HCV+HBV • HCV+HBV+alcohol Alcohol (total) • Alcohol alone • Alcohol+HBV HBV related (total) • HBV alone
67 (52) 28 (21.9) 21 (16.4) 11 (8.6) 7 (5.5) 56 (43.8) 24 (18.8) 4 (3.1) 38 (29.7) 16 (12.5)
NAFLD Cryptogenic
8 (6.3) 9 (7.0)
43 10
HCC hepatocellular carcinoma
Symptoms
Table 3 Etiological profile of patients with hepatocellular carcinoma (n=128)
91.4 55.5 50.8 34.4
HCV RNA positive. Of the 65 anti-HCV positive patients, 44 were HCV RNA positive also, while 21 were HCV RNA negative. Fifty-seven (43.8 %) patients had a history of significant alcohol intake. Thirty-eight (29.7 %) had evidence of current/past infection with HBV. Of these, 12 patients were HBsAg positive (8 HBV DNA positive also); seven patients were HBsAg negative but HBV DNA positive, suggesting occult HBV infection, and 19 patients were positive only for total Ab to HBc (HBsAg and HBV DNA negative), indicating past infection with HBV. The etiological profile of cirrhosis among the total of 1,523 patients (mean age, 51.0±11.4 years; male/female ratio=3.36:1) who presented to our department over the 3-year study period is as follows: (a) alcohol, 59.2 % [alcohol alone, 45.3 %; alcohol and HCV, 12.3 %; alcohol and HBV, 1.1 %; alcohol, HCV, and HBV, 0.5 %]; (b) HCV, 38.6 % [HCV alone, 24.9 %; HCV and HBV, 0.9 %]; (c) HBV, 5.4 % [HBV alone, 2.9 %]; (d) NAFLD [3.1 %]; (e) AI [2.2 %]; (f) BCS [1.4 %]; (g) Wilson's disease [0.4 %]; and (h) cryptogenic [4.9 %]. Triphasic CT of the abdomen was done in all the patients. The average size of HCC was 5.3±2.9 cm. Small tumors (5 cm) tumors were present in 26.6 % (n=34) of the patients. HCC was multicentric in 57 % (n=73), and portal vein thrombosis (PVT) was present in 34.4 % of the patients. The median AFP value in patients with an HCC size 5 cm was 1,000 ng/mL. The BCLC staging of HCC in our patients is shown in Fig. 1.
Discussion The present study is one of the largest prospective crosssectional studies of HCC from India. Comparison of this study with other Indian studies on HCC [11, 13–16, 19–21] highlights some distinct regional differences in the clinical presentation, etiological profile, and tumor characteristics of patients with HCC. Almost all patients in the present study had underlying cirrhosis, and in nearly one third of the patients, HCC was the reason for the initial presentation of decompensated cirrhosis. Other major differences noted in our study were the different etiological factors, presence of multicentric lesions, and presentation at advanced stage of disease. The age-specific incidence of HCC is different in the different parts of the world, with peak age of onset of varying from 40 to 80 years depending on the geographic area studied and prevalence of different etiological factors there [1, 22]. Most studies from India and rest of the world report a peak incidence during the fifth and sixth decades [11, 13]. Our study has also shown a similar peak age of onset of HCC with 68.8 % of patients presenting between 41 and 60 years. In the present study, patients with HBV-related HCC had lower mean age as compared to those with HCV-related HCC, which is consistent with the results of various studies in this regard [11, 23, 24]. The younger age patients with HBV-related HCC
Fig. 2 Comparison of etiological profile of hepatocellular carcinoma at different Indian centers [13–16]
Indian J Gastroenterol (January–February 2014) 33(1):35–40
can be explained by the fact that 75 % of the HBV infection in India is acquired by horizontal spread during early childhood, and secondly, HBV is a more potent oncogenic stimulus for HCC [13, 25]. Patients with alcohol-related HCC had the highest mean age of presentation. The incidence of HCC has been reported to be higher in males than in females; the male/female ratio ranging from 1.4 to 3.3 [1, 12]. The male/female ratio is partly dependent on the etiological factor prevalent in a particular region. In areas where HBV-related cirrhosis is the major etiological factor, the male predominance tends to be more pronounced compared to areas with HCV as the main etiological factor [1]. Similar results were observed in the present study, as male predominance was higher among patients with HBV-related HCC (4.3:1) as compared to those with HCV-related HCC (1.8:1). The possible reason for the male predominance among cases with HBV related HCC may be that the spontaneous clearance of HBV is less likely in males compared to females. The etiological factors for HCC vary in different geographical regions. The most common reported risk factor for HCC worldwide is CHB, which accounts for 52.3 % of all HCC [1, 12, 26]. In Africa and East Asia, 60 % of the HCC cases are attributable to CHB, and Asia accounts for 76 % of all HCC cases worldwide [1, 12]. On the other hand, in Japan, Europe, and North America, CHC is the major etiological factor for HCC and only about 20 % of the cases can be attributed to CHB [1, 27]. The incidence of HCC in these countries had increased during the past few decades, largely due to a cohort effect [1]. For instance, as the cohort of people infected with hepatitis C (1) between the end of World War II (WWII) and 1970 in Europe, (2) in the 1960s and 1970s in North America, and (3) after WWII in Japan aged, the incidence of HCVrelated HCC increased [1]. In the USA, the incidence of HCC
Indian J Gastroenterol (January–February 2014) 33(1):35–40
increased two-fold, mainly due to hepatitis C but with a contribution from hepatitis B also [8]. In a retrospective survey of HCC referred to 13 liver disease centers in the USA, 700 cases were identified, 51.2 % of which were seropositive for HCV and 20.1 % for HBsAg (including 4.7 % who were seropositive for both) [12]. In the same study, when the patients were analyzed according to race, HBV was the most common etiology among Asians (55.1 %), while HCV was the most common cause among Whites and Blacks (55.1 % and 62 %, respectively). In India, HBV has been reported as the major etiological factor for HCC in most of the studies, accounting for 47.5 % to 73 % of the cases (Fig. 2) [11, 13–16, 19, 20, 28, 29]. However, a major difference in the etiological profile of HCC was observed in our study, in which HCV accounted for more than half of the cases of HCC and was far more common than HBV (52.3 % vs. 29.7 %, respectively). This profile resembles more with that of developed countries like Japan and the western world rather than the rest of Asia and other parts of India. A similar etiological profile of HCC has been reported from Pakistan (India's neighboring country which shares a part of its international border with Punjab) where HCV has been reported to as the etiological factor of HCC in 56.1 % to 85 % of the cases and HBV in 20 % to 34.1 % of the cases only [30, 31]. This difference in the etiological profile in this region of India can partly be explained by the difference in prevalence of HBV and HCV in the cirrhotic population in Punjab. In our patients with cirrhosis, as mentioned above, alcohol was the etiological factor in 59.2 %, HCV in 38.6 %, and HBV in 5.4 %. This data also indicate that the etiological association of HCV and HBV with HCC is stronger than that of alcohol, as the percentage of HBV cirrhotics developing HCC (23.2 %, 19/82) and HCV cirrhotics developing HCC (11.4 %; 67/587) was significantly higher than patients with alcoholic cirrhosis developing HCC (6.3 %; 57/901; p=0.0001 and 0.0007, respectively). However, this is in contrast to the results reported by Ramesh et al. from AIIMS, New Delhi, who found that the prevalence of antibodies to HCV was similar in patients with chronic liver disease and HCC (16.2 % and 15.1 %, respectively) [32]. Another important difference in the etiological profile of HCC noted in our study was that about one third (33.6 %) of the patients had greater than one etiological factor for HCC, which is much more than that reported in other Indian studies (9.5 % to 16.5 %) [13]. This may be the reason for the lower mean age of HCC patients in our study (49.8 years) as compared to that reported by Paul et al. and Kumar et al. [13, 14]. The presence of underlying cirrhosis in patients with HCC is variable. Up to 40 % of the patients with HBV-related HCC may not have cirrhosis, and more recently, development of HCC without cirrhosis in hepatitis C has also been documented [1]. Indian studies have reported cirrhosis in 30 % to 80 % of the HCC patients [21, 33, 34]. In a recent study from New
39
Delhi, a significant percentage (97.5 %) of patients with HCC had underlying cirrhosis [13]. In our study, almost all patients (99.2 %) had underlying cirrhosis. Out of these, only 57.8 % were known cirrhotics, while the rest (41.4 %) were diagnosed to have cirrhosis for the first time during their current presentation with HCC. Most of the patients in our study presented in advanced stage with large or multicentric tumors. The average size of HCC in our study was 5.3±2.9 cm. Sarin et al. [21] reported an average size of 6.8±3.4 cm, while Butt et al. [31] reported an average size of 7.8±8.1 cm in their patients with HCC. In the present study, multicentric tumors were present in 57 % of the patients. This is much greater than that reported by Sarin et al. (36 %) [21] and Paul et al. (31 %) [13] but closer to the results from a study from Pakistan (46 %) where the etiological profile is the same as in our population. Whether HCVrelated HCC presents more commonly with multicentric tumors needs to be evaluated in further studies. (All the above mentioned studies used triphasic CT). PVT was seen in 34.4 % of the patients in our study. The presence of vascular invasion with HCC has varied from 10 % to >50 % in different studies [11, 13, 30]. Our results are similar to those of Paul et al. who reported PVT in 40 % of the patients [13]. AFP value was >200 ng/mL in 67.2 % of the patients in our study; values were higher in patients with larger lesions. Saini et al. [15] reported AFP to be diagnostic only in 17 %, and Paul et al. reported AFP >400 ng/mL in 36 % [13]. Though the sensitivity of AFP for diagnosing HCC was higher in our study as compared to other studies, still it is much below than that of an ideal screening test. To conclude, CHC was the most common cause of HCC in Punjab. One third of the patients had greater than one etiological factor and almost all patients had underlying cirrhosis. HCC leading to decompensation of cirrhosis was the first presentation of the liver disease in nearly one third of the cases. AFP was diagnostic in two thirds of the cases. Most of the patients had multicentric disease and presented at advanced stage.
Conflict of interest None
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40 6. Deuffic S, Poynard T, Buffat L, Valleron AJ. Trends in primary liver cancer. Lancet. 1998;351:214–5. 7. Stroffolini T, Andreone P, Andriulli A, et al. Characteristics of hepatocellular carcinoma in Italy. J Hepatol. 1998;29:944–52. 8. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745–50. 9. Annual Report 1987. National Cancer Registry Programme. New Delhi, Indian Council of Medical Research, 1990 10. Jayant K, Rao RS, Nene BM, Dale PS. Rural cancer registry at Barshi—Report 1988–92. Rural Cancer Registry: Barshi; 1994. 11. Kumar R, Saraswat MK, Sharma BC, Sakhuja P, Sarin SK. Characteristics of hepatocellular carcinoma in India: a retrospective analysis of 191 cases. Q J Med. 2008;101:479–85. 12. Di Bisceglie AM. Hepatitis B and hepatocellular carcinoma. Hepatology. 2009;49:S56–60. 13. Paul SB, Chalamalasetty SB, Vishnubhatla S, et al. Clinical profile, etiology and therapeutic outcome in 324 hepatocellular carcinoma patients at a tertiary care center in India. Oncology. 2009;77:162–71. 14. Kumar M, Kumar R, Hissar SS, et al. Risk factors analysis for hepatocellular carcinoma in patients with and without cirrhosis: a case–control study of 213 hepatocellular carcinoma patients from India. J Gastroenterol Hepatol. 2007;22:1104–11. 15. Saini N, Bhagat A, Sharma S, Duseja A, Chawla Y. Evaluation of clinical and biochemical parameters in hepatocellular carcinoma: experience from an Indian center. Clin Chim Acta. 2006;371:183–6. 16. Joshi N, Kumar A, Rani MS, Chandra N, Ramanjaneyulu ER. Clinical and aetiological profile of hepatoma at a tertiary care centre. Trop Gastroenterol. 2003;24:73–5. 17. Sharma S, Sharma B, Chawla YK, et al. Comparison of 7 staging systems in north Indian cohort of hepatocellular carcinoma. Trop Gastroenterol. 2010;31:271–8. 18. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–36. 19. Durga R, Muralikrishna P. Viral markers in hepatocellular carcinoma. Indian J Gastroenterol. 1994;13:A57. 20. Kar P, Budhiraja S, Narang A, Das BC, Panda SK, Chakravorty A. Comparative evaluation of serology and polymerase chain reaction
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ORIGINAL ARTICLE
Profile of hepatocellular carcinoma in a tertiary care hospital in Punjab in northern India Ajit Sood & Vandana Midha & Omesh Goyal & Prerna Goyal & Neena Sood & Suresh Kumar Sharma
Received: 9 March 2013 / Accepted: 28 July 2013 / Published online: 6 September 2013 # Indian Society of Gastroenterology 2013
Abstract Purpose/Aim Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality in all parts of the world. We analyzed the clinical presentation, etiology, and tumor characteristics of HCC presenting to our hospital. Methods All patients diagnosed to have HCC from September 2007 to August 2010 were prospectively enrolled. HCC was diagnosed according to EASL criteria—USG/CT/MRI of the abdomen and/or serum alpha-fetoprotein and/or histology (where indicated). Detailed clinical and laboratory parameters were noted. Barcelona Clinic Liver Cancer (BCLC) staging was done. Results One hundred and twenty-eight patients (22 females, mean±SD; age, 49.8±10.2 years) were diagnosed to have HCC. Underlying cirrhosis was present in 99.2 %. Hepatitis C virus infection, alone (21.9 %) or with alcohol (22.9 %) was the most common etiological factor, followed by alcohol alone; 33.6 % of the patients had more than one etiological factor. Most patients (83.5 %) presented with features of A. Sood (*) : O. Goyal Department of Gastroenterology, Dayanand Medical College and Hospital, Tagore Nagar, Ludhiana 141 001, India e-mail: [email protected] V. Midha : P. Goyal Department of Medicine, Dayanand Medical College and Hospital, Tagore Nagar, Ludhiana 141 001, India N. Sood Department of Pathology, Dayanand Medical College and Hospital, Tagore Nagar, Ludhiana 141 001, India S. K. Sharma Department of College of Nursing, Dayanand Medical College and Hospital, Tagore Nagar, Ludhiana 141 001, India
decompensated cirrhosis. HCC leading to decompensation of cirrhosis was the first presentation of the liver disease in nearly one third of the cases. Serum alpha-fetoprotein was >200 ng/mL in 67.2 % of the patients, while it was normal in 18.7 % of the patients. The mean±SD size of HCC was 5.3±2.9 cm. HCC was multicentric in 57 %, and portal vein thrombosis was present in 34.4 %. About 66 % of the patients belonged to BCLC stage C or D. Conclusions Hepatitis C virus infection was the most common cause of HCC in Punjab. One-third of the patients had multiple etiological factors and almost all had underlying cirrhosis and presented at advanced stage. Keywords Alcohol . Hepatitis B virus . Hepatitis C virus . Liver cancer
Introduction Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer death [1]. In 2002, the estimated number of new cases of HCC worldwide was 625,000 [2]. The incidence of HCC ranges from 4 cases per 100,000 population in USA to 150 cases per 100,000 population in parts of Africa and Asia [2, 3]. Over the last several decades, the incidence of HCC has shown an increasing trend in Japan and many Western countries [4–8]. In India, the mean incidence of HCC in four population-based registries has been reported to be 2.77 % for males and 1.38 % for females [9–11]. Overall, the prevalence of HCC in India varies from 0.2 % to 1.6 % [9, 10]. Despite India being in a low-incidence zone for HCC, the number of HCC patients in 2001 was estimated to be 12,750 [9]. The etiological profile of HCC is quite heterogeneous, depending largely on the prevalence of underlying risk factors in the general population in different geographical areas. Studies have reported that more than 80 % of patients with
36
HCC in high-incidence areas, such as East Asia and subSaharan Africa, were seropositive for hepatitis B surface antigen (HBsAg), where only 10 % to 15 % of the population is known to be HBsAg positive [12]. In areas with low HCC incidence, like Japan, Europe, and North America, chronic hepatitis C infection (CHC) is more commonly associated with HCC and is largely responsible for the increase in incidence of HCC in the last several decades [1, 12]. In India, chronic hepatitis B infection (CHB) has been reported to be the leading cause of HCC in studies from New Delhi, Chandigarh, and Hyderabad [13–16]. In contrast to the West, where majority of HCC are diagnosed at early stage during routine surveillance, most of the HCC cases in India are diagnosed at an advanced stage, ruling out curative treatment [17, 18]. Although HCC is a major health problem and a major cause of mortality in patients with chronic liver disease (CLD), data on the clinico-etiological profile of HCC in India are limited. The present study was designed to analyze the clinical presentation, etiological profile, and tumor characteristics of patients of HCC presenting to a tertiary care institute in Punjab, northern India and compare these with presentation of HCC in the rest of the country.
Patients and Methods This prospective observational study was carried out over a period of 3 years (September 2007 to August 2010) in a tertiary care teaching institute in northern India. During this period, all patients diagnosed to have HCC in the gastroenterology outpatient/inpatient departments of this institute were enrolled. Detailed history, clinical examination, and laboratory assessment including hemogram, liver and renal function tests, prothrombin time index, blood sugar, and α-fetoprotein were done. The diagnosis of cirrhosis was made on the basis of clinical, radiological, biochemical, and/or histological criteria. Child–Pugh score for the stage of cirrhosis was calculated. HCC was diagnosed by USG/CT scan/MRI of the abdomen, serum alpha-fetoprotein (AFP), and/or histology (where indicated), according to the Barcelona Clinic Liver Cancer (BCLC) criteria [18]. Staging of HCC was performed using the EASL criteria [18]. Etiology of cirrhosis was considered to be alcohol, if the alcohol consumption per day was 40–80 g for males and 20–40 g for females for >10 years. Markers for detecting current, past, or occult infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) were done in all patients of HCC. These included HBsAg (ELISCAN HBsAg, RFCL, Dehradun, India), total antibody to hepatitis B core antigen (HBcAg) (Vidas, bioMerieux, Craponne, France), HBV DNA (COBAS Taqman, Roche Molecular Systems, Branchburg, NJ, USA), anti-HCV antibody (ELISCAN HCV, RFCL, Dehradun, India), and HCV RNA (COBAS Taqman V2.0, Roche
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Diagnostics Corporation, Indianapolis, IN, USA). Etiology of HCC was considered to be CHB if HBsAg, total antibody to HBcAg and/or serum HBV DNA were positive. CHC was considered as the etiological factor if anti-HCV antibody and/ or HCV RNAwere positive. Work up for autoimmune (AI) liver disease, Wilson's disease, nonalcoholic fatty liver disease (NAFLD), hemochromatosis, and Budd–Chiari syndrome (BCS) was done where indicated. Decompensation of cirrhosis was defined by the presence of ascites, jaundice, bleeding, or encephalopathy in a patient with cirrhosis. Quantitative data were presented as mean±SD or median (range) and qualitative data as percentages. The two-tailed Fisher's exact test was used to analyze categorical variables and student's t test to analyze continuous variables. The pvalue 5 cm) was seen in 9.3 % (n=12) of the patients while in 49.2 % of the patients, liver was not clinically palpable. Serum AFP was >200 ng/mL in 67.2 % of the patients, while it was normal in 18.7 % of the patients (Table 1). The etiological profile of patients with HCC is shown in Table 3. More than one etiological factor was present in 33.6 % (n=43) of the patients. Sixty-seven (52.3 %) patients were diagnosed to have CHC. Of these, 65 patients were antiHCV antibody positive, while 2 were anti-HCV negative but
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37
Table 1 Baseline characteristics of patients with hepatocellular carcinoma (n=128) Baseline characteristics Age, mean±SD Median (range) Sex (male/female) Duration of new onset symptoms before HCC diagnosis 3 months Type of presentation of HCC In previously diagnosed cirrhotics (n=74) • Features of decompensation • HCC detected on surveillance In newly diagnosed cirrhotics (n=53) • Features of decompensation • Nonspecific symptoms
49.8±10.2 years 60 (32–86) years 4.8:1
59 55 4
*Patients with multiple etiological factors (33.6 %, n=43) have been included under all the factors HCV hepatitis C virus, HBV hepatitis B virus, NAFLD nonalcoholic fatty liver disease
64 10
Table 2 Baseline clinical and laboratory parameters of patients with hepatocellular carcinoma (n=128)
Abdominal distension Weakness Anorexia Abdominal pain Encephalopathy Jaundice Gastrointestinal bleeding Weight loss Asymptomatic Signs Ascites Icterus Hepatomegaly Splenomegaly Lab parameters Bilirubin, mg/dL (mean±SD) Albumin, g/dL (mean±SD) INR (mean±SD) AFP (median, range) 200 IU/mL
Number
Percentage
72
56.3
52 45 43 27 23 11 7 10
40.6 35.2 33.6 21 17.9 8.6 5.5 7.8
117 71 65 44 Value 4.6±7 2.7±0.49 1.67±0.8 791 (0.8–500,000) 24 18 86
Etiological factors*
Number (%)
HCV related (total) • HCV alone • HCV+alcohol • HCV+HBV • HCV+HBV+alcohol Alcohol (total) • Alcohol alone • Alcohol+HBV HBV related (total) • HBV alone
67 (52) 28 (21.9) 21 (16.4) 11 (8.6) 7 (5.5) 56 (43.8) 24 (18.8) 4 (3.1) 38 (29.7) 16 (12.5)
NAFLD Cryptogenic
8 (6.3) 9 (7.0)
43 10
HCC hepatocellular carcinoma
Symptoms
Table 3 Etiological profile of patients with hepatocellular carcinoma (n=128)
91.4 55.5 50.8 34.4
HCV RNA positive. Of the 65 anti-HCV positive patients, 44 were HCV RNA positive also, while 21 were HCV RNA negative. Fifty-seven (43.8 %) patients had a history of significant alcohol intake. Thirty-eight (29.7 %) had evidence of current/past infection with HBV. Of these, 12 patients were HBsAg positive (8 HBV DNA positive also); seven patients were HBsAg negative but HBV DNA positive, suggesting occult HBV infection, and 19 patients were positive only for total Ab to HBc (HBsAg and HBV DNA negative), indicating past infection with HBV. The etiological profile of cirrhosis among the total of 1,523 patients (mean age, 51.0±11.4 years; male/female ratio=3.36:1) who presented to our department over the 3-year study period is as follows: (a) alcohol, 59.2 % [alcohol alone, 45.3 %; alcohol and HCV, 12.3 %; alcohol and HBV, 1.1 %; alcohol, HCV, and HBV, 0.5 %]; (b) HCV, 38.6 % [HCV alone, 24.9 %; HCV and HBV, 0.9 %]; (c) HBV, 5.4 % [HBV alone, 2.9 %]; (d) NAFLD [3.1 %]; (e) AI [2.2 %]; (f) BCS [1.4 %]; (g) Wilson's disease [0.4 %]; and (h) cryptogenic [4.9 %]. Triphasic CT of the abdomen was done in all the patients. The average size of HCC was 5.3±2.9 cm. Small tumors (5 cm) tumors were present in 26.6 % (n=34) of the patients. HCC was multicentric in 57 % (n=73), and portal vein thrombosis (PVT) was present in 34.4 % of the patients. The median AFP value in patients with an HCC size 5 cm was 1,000 ng/mL. The BCLC staging of HCC in our patients is shown in Fig. 1.
Discussion The present study is one of the largest prospective crosssectional studies of HCC from India. Comparison of this study with other Indian studies on HCC [11, 13–16, 19–21] highlights some distinct regional differences in the clinical presentation, etiological profile, and tumor characteristics of patients with HCC. Almost all patients in the present study had underlying cirrhosis, and in nearly one third of the patients, HCC was the reason for the initial presentation of decompensated cirrhosis. Other major differences noted in our study were the different etiological factors, presence of multicentric lesions, and presentation at advanced stage of disease. The age-specific incidence of HCC is different in the different parts of the world, with peak age of onset of varying from 40 to 80 years depending on the geographic area studied and prevalence of different etiological factors there [1, 22]. Most studies from India and rest of the world report a peak incidence during the fifth and sixth decades [11, 13]. Our study has also shown a similar peak age of onset of HCC with 68.8 % of patients presenting between 41 and 60 years. In the present study, patients with HBV-related HCC had lower mean age as compared to those with HCV-related HCC, which is consistent with the results of various studies in this regard [11, 23, 24]. The younger age patients with HBV-related HCC
Fig. 2 Comparison of etiological profile of hepatocellular carcinoma at different Indian centers [13–16]
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can be explained by the fact that 75 % of the HBV infection in India is acquired by horizontal spread during early childhood, and secondly, HBV is a more potent oncogenic stimulus for HCC [13, 25]. Patients with alcohol-related HCC had the highest mean age of presentation. The incidence of HCC has been reported to be higher in males than in females; the male/female ratio ranging from 1.4 to 3.3 [1, 12]. The male/female ratio is partly dependent on the etiological factor prevalent in a particular region. In areas where HBV-related cirrhosis is the major etiological factor, the male predominance tends to be more pronounced compared to areas with HCV as the main etiological factor [1]. Similar results were observed in the present study, as male predominance was higher among patients with HBV-related HCC (4.3:1) as compared to those with HCV-related HCC (1.8:1). The possible reason for the male predominance among cases with HBV related HCC may be that the spontaneous clearance of HBV is less likely in males compared to females. The etiological factors for HCC vary in different geographical regions. The most common reported risk factor for HCC worldwide is CHB, which accounts for 52.3 % of all HCC [1, 12, 26]. In Africa and East Asia, 60 % of the HCC cases are attributable to CHB, and Asia accounts for 76 % of all HCC cases worldwide [1, 12]. On the other hand, in Japan, Europe, and North America, CHC is the major etiological factor for HCC and only about 20 % of the cases can be attributed to CHB [1, 27]. The incidence of HCC in these countries had increased during the past few decades, largely due to a cohort effect [1]. For instance, as the cohort of people infected with hepatitis C (1) between the end of World War II (WWII) and 1970 in Europe, (2) in the 1960s and 1970s in North America, and (3) after WWII in Japan aged, the incidence of HCVrelated HCC increased [1]. In the USA, the incidence of HCC
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increased two-fold, mainly due to hepatitis C but with a contribution from hepatitis B also [8]. In a retrospective survey of HCC referred to 13 liver disease centers in the USA, 700 cases were identified, 51.2 % of which were seropositive for HCV and 20.1 % for HBsAg (including 4.7 % who were seropositive for both) [12]. In the same study, when the patients were analyzed according to race, HBV was the most common etiology among Asians (55.1 %), while HCV was the most common cause among Whites and Blacks (55.1 % and 62 %, respectively). In India, HBV has been reported as the major etiological factor for HCC in most of the studies, accounting for 47.5 % to 73 % of the cases (Fig. 2) [11, 13–16, 19, 20, 28, 29]. However, a major difference in the etiological profile of HCC was observed in our study, in which HCV accounted for more than half of the cases of HCC and was far more common than HBV (52.3 % vs. 29.7 %, respectively). This profile resembles more with that of developed countries like Japan and the western world rather than the rest of Asia and other parts of India. A similar etiological profile of HCC has been reported from Pakistan (India's neighboring country which shares a part of its international border with Punjab) where HCV has been reported to as the etiological factor of HCC in 56.1 % to 85 % of the cases and HBV in 20 % to 34.1 % of the cases only [30, 31]. This difference in the etiological profile in this region of India can partly be explained by the difference in prevalence of HBV and HCV in the cirrhotic population in Punjab. In our patients with cirrhosis, as mentioned above, alcohol was the etiological factor in 59.2 %, HCV in 38.6 %, and HBV in 5.4 %. This data also indicate that the etiological association of HCV and HBV with HCC is stronger than that of alcohol, as the percentage of HBV cirrhotics developing HCC (23.2 %, 19/82) and HCV cirrhotics developing HCC (11.4 %; 67/587) was significantly higher than patients with alcoholic cirrhosis developing HCC (6.3 %; 57/901; p=0.0001 and 0.0007, respectively). However, this is in contrast to the results reported by Ramesh et al. from AIIMS, New Delhi, who found that the prevalence of antibodies to HCV was similar in patients with chronic liver disease and HCC (16.2 % and 15.1 %, respectively) [32]. Another important difference in the etiological profile of HCC noted in our study was that about one third (33.6 %) of the patients had greater than one etiological factor for HCC, which is much more than that reported in other Indian studies (9.5 % to 16.5 %) [13]. This may be the reason for the lower mean age of HCC patients in our study (49.8 years) as compared to that reported by Paul et al. and Kumar et al. [13, 14]. The presence of underlying cirrhosis in patients with HCC is variable. Up to 40 % of the patients with HBV-related HCC may not have cirrhosis, and more recently, development of HCC without cirrhosis in hepatitis C has also been documented [1]. Indian studies have reported cirrhosis in 30 % to 80 % of the HCC patients [21, 33, 34]. In a recent study from New
39
Delhi, a significant percentage (97.5 %) of patients with HCC had underlying cirrhosis [13]. In our study, almost all patients (99.2 %) had underlying cirrhosis. Out of these, only 57.8 % were known cirrhotics, while the rest (41.4 %) were diagnosed to have cirrhosis for the first time during their current presentation with HCC. Most of the patients in our study presented in advanced stage with large or multicentric tumors. The average size of HCC in our study was 5.3±2.9 cm. Sarin et al. [21] reported an average size of 6.8±3.4 cm, while Butt et al. [31] reported an average size of 7.8±8.1 cm in their patients with HCC. In the present study, multicentric tumors were present in 57 % of the patients. This is much greater than that reported by Sarin et al. (36 %) [21] and Paul et al. (31 %) [13] but closer to the results from a study from Pakistan (46 %) where the etiological profile is the same as in our population. Whether HCVrelated HCC presents more commonly with multicentric tumors needs to be evaluated in further studies. (All the above mentioned studies used triphasic CT). PVT was seen in 34.4 % of the patients in our study. The presence of vascular invasion with HCC has varied from 10 % to >50 % in different studies [11, 13, 30]. Our results are similar to those of Paul et al. who reported PVT in 40 % of the patients [13]. AFP value was >200 ng/mL in 67.2 % of the patients in our study; values were higher in patients with larger lesions. Saini et al. [15] reported AFP to be diagnostic only in 17 %, and Paul et al. reported AFP >400 ng/mL in 36 % [13]. Though the sensitivity of AFP for diagnosing HCC was higher in our study as compared to other studies, still it is much below than that of an ideal screening test. To conclude, CHC was the most common cause of HCC in Punjab. One third of the patients had greater than one etiological factor and almost all patients had underlying cirrhosis. HCC leading to decompensation of cirrhosis was the first presentation of the liver disease in nearly one third of the cases. AFP was diagnostic in two thirds of the cases. Most of the patients had multicentric disease and presented at advanced stage.
Conflict of interest None
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