Gallbladder Cancer In India Research Articles

Epidemiology of gallbladder cancer in India 2018–2023

ABSTRACT India is a high-incidence area for gallbladder cancer (GBC), contributing approximately 10% of the global GBC burden. Within the country, the incidence is notably high in North, North-East, Central, and Eastern regions, whereas it is less common in South and West India. The incidence has been steadily rising in both genders. Patients often present with advanced disease, which carries a dismal prognosis. Unlike the West, GBC in India typically affects younger patients in their fifth and sixth decades of life. Gallstones are present in 80% of Indian GBC patients, increasing the vulnerability of the gallbladder to mucosal injury. However, the incidence of GBC is disproportionate to the prevalence of gallstones in the country. Additional cofactors such as older age, lower socioeconomic status, chronic Salmonella typhi infection, Helicobacter pylori infection, exposure to pollutants, heavy metals, chemicals, adulterated mustard oil, and smoking in patients with gallstones have been identified as promoters of carcinogenesis. These risk factors act additively, resulting in a higher incidence of GBC and accelerating its development. Environmental risk factors, including soil and water contamination by industrial wastes, agricultural effluents, and human sewage, have also been identified as putative risk factors. The combination of a toxic environment, a vulnerable gallbladder, and a susceptible host plays a key role in the pathogenesis of GBC in India. Large multicentric comprehensive studies are required to assess the attributable risk of each identified putative risk factor. This will aid in formulating cost-effective national strategies to prevent GBC-related mortality in the country. Meanwhile, maintaining a high index of suspicion to detect incidental GBC and improving access to health-care facilities for appropriate management of gallstones will help reduce GBC-related mortality.

The Role of Gallstones in Gallbladder Cancer in India: A Mendelian Randomization Study.

Past history of gallstones is associated with increased risk of gallbladder cancer in observational studies. We conducted complementary observational and Mendelian randomization (MR) analyses to determine whether history of gallstones is causally related to development of gallbladder cancer in an Indian population. To investigate associations between history of gallstones and gallbladder cancer, we used questionnaire and imaging data from a gallbladder cancer case-control study conducted at Tata Memorial Hospital, Mumbai, Maharashtra, India (cases = 1,170; controls = 2,525). We then used 26 genetic variants identified in a genome-wide association study of 27,174 gallstone cases and 736,838 controls of European ancestry in an MR approach to assess causality. The association of these genetic variants with both gallstones and gallbladder cancer was examined in the gallbladder cancer case-control study. Various complementary MR approaches were used to evaluate the robustness of our results in the presence of pleiotropy and heterogeneity, and to consider the suitability of the selected SNPs as genetic instruments for gallstones in an Indian population. We found a strong observational association between gallstones and gallbladder cancer using self-reported history of gallstones [OR = 4.5; 95% confidence interval (CI) = 3.5-5.8] and with objective measures of gallstone presence using imaging techniques (OR = 2.0; 95% CI = 1.5-2.7). We found consistent causal estimates across all MR techniques, with ORs for gallbladder cancer in the range of 1.3-1.6. Our findings indicate a causal relationship between history of gallstones and increased risk of gallbladder cancer, albeit of a smaller magnitude than those found in observational analysis. Our findings emphasize the importance of gallstone treatment for preventing gallbladder cancer in high-risk individuals.

Incidence of gall bladder cancer in India and the scope of social work practice in the modification of lifestyle factor

Incidence of gall bladder cancer in India and the scope of social work practice in the modification of lifestyle factor

Management of gallbladder cancer in India

Gallbladder cancer is a highly aggressive disease with variable prevalence across the globe. Particularly the Indo-Gangetic belt in Northern India has an incidence as high as 21/100,000. Majority of cases are detected either incidentally on pathological evaluation of cholecystectomy specimens or present with advanced disease. Radical surgery remains the mainstay of cure but only a small subset of patients is operable at presentation, and even with curative surgery recurrence rates remain high. Much debate surrounds the management of gallbladder cancer, with continuously evolving standards regarding the extent of hepatic resection and lymphadenectomy, curative resection in patients presenting with jaundice, routine excision of bile duct, and the role of neoadjuvant chemoradiotherapy. In this review we present a synopsis of currently available evidence and emerging approaches in the management of gallbladder cancer in India.

Epidemiology of gallbladder cancer in India.

India is a high incidence area for gallbladder cancer (GBC) and contributes to about 10% of the global GBC burden. Within India, the incidence is high in North, North-East, Central and Eastern India, and less common in South and West India. The incidence has been on a steady rise in both genders. The presentation is often with advanced disease and carries dismal prognosis. GBC in India usually affects younger patients in the 5th and 6th decade in contrast to the west. Gallstones are present in 80% of the Indian patients with GBC and its presence increases the vulnerability of the GB to mucosal injury. The incidence of GBC is out of proportion to the prevalence of gallstones in the country. Additional co-factors such as older age, lower socio-economic status, chronic Salmonella typhi (S. typhi) infection, Helicobacter pylori (H. pylori) infection, exposure to pollutants, heavy metals, chemicals, adulterated mustard oil and smoking in patients with gallstones have been identified which promote carcinogenesis. These risk factors act in tandem in an additive manner resulting in higher incidence of GBC as well as hasten the development of GBC. Environmental risk factors such as soil and water contamination by industrial wastes, agricultural effluents and human sewage have been identified as putative risk factors. Combination of a toxic environment, vulnerable GB and a susceptible host play a key role in the pathogenesis of GBC in the country. Large multicentric comprehensive studies are required in India to assess the attributable risk of each of the identified putative risk factors. This will help in formulating cost effective national strategies in preventing GBC related mortality in the country. Meanwhile a high index of suspicion to pick up incidental GBC, and improved access to healthcare facilities to manage GS appropriately will help in reducing GBC related mortality.

Common genetic variation and risk of gallbladder cancer in India: a case-control genome-wide association study

Gallbladder cancer is highly lethal, with notable differences in incidence by geography and ethnic background. The aim of this study was to identify common genetic susceptibility alleles for gallbladder cancer. In this case-control genome-wide association study (GWAS), we did a genome-wide scan of gallbladder cancer cases and hospital visitor controls, both of Indian descent, followed by imputation across the genome. Cases were patients aged 20-80 years with microscopically confirmed primary gallbladder cancer diagnosed or treated at Tata Memorial Hospital, Mumbai, India, and enrolled in the study between Sept 12, 2010, and June 8, 2015. We only included patients who had been diagnosed less than 1 year before the date of enrolment and excluded patients with any other malignancies. We recruited visitor controls aged 20-80 years with no history of cancer visiting all departments or units of Tata Memorial Hospital during the same time period and frequency matched them to cases on the basis of age, sex, and current region of residence. We estimated association using logistic regression, adjusting for age, sex, and five eigenvectors. We recruited samples for a replication cohort from patients visiting Tata Memorial Hospital between Aug 4, 2015, and May 17, 2016, and patients visiting the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India, between July, 2010, and May, 2015. We used the same inclusion and exclusion criteria for the replication set. We examined three of the most significant single-nucleotide polymorphisms (SNPs) in the replication cohort and did a meta-analysis of the GWAS discovery and replication sets to get combined estimates of association. The discovery cohort comprised 1042 gallbladder cancer cases and 1709 controls and the replication cohort contained 428 gallbladder cancer cases and 420 controls. We observed genome-wide significant associations for several markers in the chromosomal region 7q21.12 harbouring both the ABCB1 and ABCB4 genes, with the most notable SNPs after replication and meta-analysis being rs1558375 (GWAS p=3·8 × 10-9; replication p=0·01; combined p=2·3 × 10-10); rs17209837 (GWAS p=2·0 × 10-8; replication p=0·02; combined p=2·3 × 10-9), and rs4148808 (GWAS p=2·4 × 10-8; replication p=0·008; combined p=2·7 × 10-9). Combined estimates of per-allele trend odds ratios were 1·47 (95% CI 1·30-1·66; p=2·31 × 10-10) for rs1558375, 1·61 (1·38-1·89; p=2·26 × 10-9) for rs17209837, and 1·57 (1·35-1·82; p=2·71 × 10-9) for rs4148808. GWAS heritability analysis suggested that common variants are associated with substantial variation in risk of gallbladder cancer (sibling relative risk 3·15 [95% CI 1·80-5·49]). To our knowledge, this study is the first report of common genetic variation conferring gallbladder cancer risk at genome-wide significance. This finding, along with in-silico and biological evidence indicating the potential functional significance of ABCB1 and ABCB4, underlines the likely importance of these hepatobiliary phospholipid transporter genes in the pathology of gallbladder cancer. The Tata Memorial Centre and Department of Biotechnology.

Place of birth and risk of gallbladder cancer in India.

Within India, the incidence of gallbladder cancer (GBC) is characterized by marked geographical variation; however, the reasons for these differences are unclear. To evaluate the role of place of birth, length of residence, and effect of migration from high- to low-risk region on GBC development. Population-based cancer registries (PBCRs); case-control study. Data of PBCRs were used to demonstrate geographical variation in GBC incidence rates. A case-control study data examined the role of birth place, residence length, and effect of migration in etiology of GBC. Rate ratios for different PBCRs were estimated using Chennai Cancer Registry as the reference population. Odds ratios (ORs) for developing GBC in a high-risk region compared to a low-risk region and associated 95% confidence interval (CI) were estimated through unconditional logistic regression models using case-control study. GBC shows marked variation in incidence with risk highest in Northeast regions and lowest in South India. OR of 4.82 (95% CI: 3.87-5.99) was observed for developing GBC for individuals born in a high-risk region compared to those born in a low-risk region after adjusting for confounders. A dose-response relationship with increased risk with increased length of residence in a high-risk region was observed (OR lifetime 5.58 [95% CI: 4.42-7.05]; Ptrend ≤ 0.001). The risk persisted even if study participant migrated from high- to low-risk region (OR = 1.36; 95% CI: 1.02-1.82). The present study signifies the importance of place of birth, length of stay, and effect of migration from high- to low-risk region in the development of GBC. The data indicate role of environmental and genetic factors in etiology of disease.

Need for Prophylactic Cholecystectomy in Silent Gall Stones in North India

One of the criteria for recommending cholecystectomy for silent gall stones, is gall stones in regions with high incidence of gall bladder cancer. Both gall stones and gall bladder cancer are common in North India. All tertiary care centres in India report high rates of gall bladder cancer (GBC) incidence and poor treatment outcomes in the majority of cases due to advanced stage of presentation. Csendes of Chile has reported very high incidence of gallbladder cancer in Chile and Bolivia and advocated prophylactic cholecystectomy in asymptomatic patients. Incidence rate of gall bladder cancer in Indian males is equal to that of Chile, whereas in females, the rates are almost double the rates of Chile. Indians have also been found to have high concentrations of heavy metals in gall bladder wall, and antibodies to tumor suppressor genes. In India, gall bladder cancer is the commonest GI cancer in women and fourth commonest cancer overall in the female population. In view of the epidemiology and clinical scenario of gall bladder cancer and proven safety of laparoscopic cholecystectomy, there is a need to act before it is too late in the current rates of gall bladder cancer. This study looks at the evidence correlating gall stones and gall bladder cancer, in relation to India. There is pressing evidence today to justify a strategy of prophylactic cholecystectomy in silent gall stones in North India. Data for this study was selected through an internet based search for literature concerning gall stones and gall bladder cancer in India, and for prophylactic cholecystectomy.

DCC (deleted in colorectal carcinoma) gene variants confer increased susceptibility to gallbladder cancer (Ref. No.: Gene-D-12-01446)

Background and aimGBC is a lethal and multifaceted disease. Deleted in colorectal carcinoma (DCC) is a well known tumor suppressor gene. Recently a small genome-wide association study (GWAS) identified DCC to be significantly associated with gallbladder cancer (GBC) susceptibility in a Japanese population sample. However, the study sample size was small and lacked independent replication. Therefore, the present study was carried out to replicate the association of two GWAS identified DCC SNPs (A>Grs4078288, C>Trs7504990) and two other SNPs (C>Grs2229080 and A>Grs714) previously associated with various cancers. MethodologyThe study was accomplished in 406 GBC cases and 260 healthy control samples from North India. Genotyping was carried out by PCR-RFLP and Taqman genotyping assays. Statistical analysis was performed by using SPSS ver16 and functional prediction of these variants was carried out using Bioinformatics tools (FAST-SNP, F-SNP). ResultWe did not observe association with GWAS-identified SNPs of DCC but other SNPs showed significant association. In addition, a DCC haplotype Grs2229080-Ars4078288-Crs7504990-Ars714 conferred high risk of GBC in India. The haplotype associated risk was independent of gallstone, sex or tobacco usages which are well-known modifiers of GBC risk. Further analysis suggested DCC A>Grs714 as a major risk conferring SNP in the Indian population. ConclusionThis study re-affirms the role of plausible tumor suppressor DCC variants, in gallbladder carcinogenesis and the risk haplotype may be explored as a useful marker for GBC susceptibility.

Significance of cytomorphological and microbiological examination of bile collected by endoscopic cannulation of the papilla of vater

Bile analysis yields important information such as "biliary microlithiasis" and biliary tract colonization by microorganisms like Salmonella typhi or paratyphi, Escherichia coli, etc., which may progresses to cholelithiasis and have been found to have a role in the development of gallbladder cancer in India. To perform microscopic, cytomorphological and microbiological examination of bile collected during endoscopic retrograde cholangiopancreatography in patients with benign and malignant lesions of the gallbladder. Bile was collected from 48 patients by a catheter inserted through the cystic duct during endoscopic retrograde cholangiopancreatography. Direct microscopy and grading of crystals was performed. Smears prepared from centrifuged deposits were stained with Giemsa, Papanicolaou stain and Gram's stain for cytological and microbiological examination. Special staining for Helicobacter pylori was performed using Loeffler's Methylene blue and Warthin Starry stain. The rest of the sample was used for culture and complete microbiological examination. Thirty-six patients had inflammatory lesions while 12 had malignant lesions. Crystals were observed in 93% of the cases, 13 (28.8%) had only cholesterol crystals, three (6.6%) had bilirubinate and 29 (64.4%) had both cholesterol and bilirubinate crystals. Smears from the centrifuged deposit mainly showed coccoid or cocobacillary bacteria on Gram's staining (81.3%). Five of 12 (41.6%) malignant cases showed epithelial atypia while none of the benign or inflammatory lesions showed such a change in hematoxylin and eosin and Pap-stained smears. Microbiologic analysis showed Staphylococcus aureus (14%), S. saprophyticus (5.5%), Peptococcus (5.5%), Peptostreptococcus (5.5%), Proteus mirabilis (5.5%), E. coli (17%), Enteorbacter cloacae (5.5%) and H. pylori (2.8%). Complete microscopic and microbiological examination of bile directly obtained from the common bile duct during endoscopic retrograde cholangiopancreatography yielded good results as fresh samples could be analyzed. It may help in diagnosis of many gallbladder lesions in early stages, thereby reducing the morbidity and mortality.

Is there a role for estrogen and progesterone receptors in gall bladder cancer?

Background/Aims. The concept of metaplastic and non-metaplastic types of gall bladder cancer and the likelihood of hormone receptor expression in the nuclei of tumour cells raised the possibility of a potential role for anti-estrogen therapy in gall bladder cancer. This study was carried out to determine the hormone receptors (ER/PR) expression level in gall bladder cancer using specific immunohistochemical assays and correlate it with patient and tumour histopathological characteristics. Patients and methods. Histopathological tumour specimens of 62 patients who underwent a radical cholecystectomy were analysed. Pronase pretreatment and primary monoclonal antibodies were used to perform immunohistochemical analysis for ER and PR. Results. The histology was adenocarcinoma – predominantly, moderately to poorly differentiated (91%). Gallstones were present in 90% of the individuals. Of the 62 specimens analysed, 62 (100%) and 61 (98%) were negative for ER and PR, respectively. Conclusion. The high incidence of gallstone-related gall bladder cancer in India is associated with metaplasia and a tendency to poorer differentiation in the tumour histology. These tumours are consequently less likely to express hormone receptors. Thus, there does not seem to be a role for anti-hormone therapy in patients with histogenesis similar to that seen in India.

Successful immunological treatment of gallbladder cancer in India—Case report

Gallbladder cancer has a poor outcome because of its anatomy and location. Often, the diagnosis is made very late due to its silent course. Post-operated cases do respond to chemotherapy but the survival is counted in months and the quality of life is further hampered due to toxicity of drugs. Immunotherapy holds good promise in non-responding cancers treated by conventional chemotherapeutic agents. Among various therapies, dendritic cell therapy is growing at rapid pace due to its acceptable rationale. It has been utilized in treating successfully resected stage III (T2, N1, M0) gallbladder cancer in one of our patients. A 48 years old lady treated with this therapy is free of metastasis with ten doses of autologous dendritic cell vaccine constructed by utilizing resected tumor lysate antigen. She has received ten doses of therapy in 14 months of her treatment. This therapy has proven to be safe and without apparent side effects. The positive clinical response obtained supports that autologous dendritic cell-based immunotherapy is a promising therapeutic approach for refractory gallbladder cancers.

Gallbladder cancer in India: A dismal picture

Gallbladder cancer (GBC) is one of the most common gastrointestinal malignancies. The data regarding GBC are, however, limited. Records of 634 patients with GBC over a 10-year period were examined with regard to the clinical presentation, investigative findings, treatment, operative findings and outcome. The mean age of patients was 51 +/- 11 years and men : women ratio was 0.36:1.00. Pain, jaundice and hepatomegaly were seen in 81.0%, 76.0% and 61.5% patients, respectively. On imaging, a mass replacing the gallbladder was seen in 73% patients. Gallstones were present in 54% patients. Surgery was carried out in 291 (46%) patients and endoscopic treatment in 72 (19%) patients but no intervention was carried out in the remaining patients because of disseminated disease. Among the patients who were operated on, 2.0% had stage I GBC, 3.4% stage II, 17.5% stage III, 47.0% stage IVa and 29.8% stage IVb. Radical resection was possible in 133 (46%) patients. The 30-day mortality was 10% with most (90%) deaths in patients with stage IV disease. The median survival after simple cholecystectomy and radical surgery was 33.5 and 12.0 months, respectively. However, among those who underwent debulking, palliative bypass or exploratory laparotomy alone, the survival ranged between 1 and 3 months. Logistic regression analysis showed that only radical resection improved the long-term survival (P < 0.05). The majority of patients with GBC in India have advanced unresectable disease. Detection of GBC at an early stage is incidental and rare but is associated with long-term survival. Radical surgery, when feasible, is the only option for achieving long-term survival.