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Year : 2019  |  Volume : 15  |  Issue : 1  |  Page : 153-156

Prospective observational study on cholelithiasis in patients with carcinoma gall bladder in a tertiary referral hospital of Eastern India

1 Department of Surgery, IPGMER/SSKM Hospital, Kolkata, West Bengal, India
2 Department of Surgery, IPGMER/SSKM Hospital; Department of Surgical Oncology, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India

Date of Web Publication13-Mar-2019

Correspondence Address:
Prof. Prosanta Kumar Bhattacharjee
Flat No. 5, 4th Floor, “Suryatoran Apartment”, 114/A, Barasat Road, Kolkata - 700 110, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_939_17

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 > Abstract 

Context: Gallbladder carcinoma (GBCA) is the fifth most common types of gastrointestinal malignancy and is the most common malignancy of the biliary tract. Cholelithiasis, gallbladder polyps, porcelain gall, and choledochal cysts are common known associations with GBCA. Because of the better understanding of the etiopathogenesis, the traditional nihilistic attitude toward the prognosis has, over the years, given way to greater interest and hope for treating the disease. Long-term survival has been reported in patients with resectable lesions in the hands of expert hepatobiliary surgeons.
Objective: This prospective observational study was conducted at a tertiary referral hospital of Eastern India on patients with the diagnosis of GBCA. The main objective was to assess the incidence of gallstones in patients with GBCA, and the relationship, if any, between the size and number of stones and GBCA in our patient cohort.
Materials and Methods: This prospective observational study was conducted, over a period of 2 years, at a tertiary referral hospital of Eastern India which caters to patients from all the neighboring districts. A total of 54 patients with the diagnosis of GBCA were included in the study. Data on their demographic and clinical profile, the incidence of associated gallstones, their size (<3 or ≥3cm), and number (solitary or multiple) were collected. Known predisposing factors of GBCA, if any, in those presenting without stones were noted.
Results: GBCA was found to afflict females 2.4 times as frequently as males. Patients, irrespective of their sex, were mostly in their sixth decade. Approximately three-fourth of the cases had associated cholelithiasis. The number of stones had no correlation with the disease. However, contrary to available published data, stones <3 cm were significantly more common in our study cohort.
Conclusion: The results of this study reaffirm that cholelithiasis is a strong predisposing factor for GBCA and females with gallstones in their sixth decade, are more at risk. Although number of stones was not found to be an independent risk factor, patients with stones <3 cm (mostly multiple) were found to be more at risk in our study.

Keywords: Cholelithiasis, gallbladder carcinoma, stone number, stone size

How to cite this article:
Bhattacharjee PK, Nanda D. Prospective observational study on cholelithiasis in patients with carcinoma gall bladder in a tertiary referral hospital of Eastern India. J Can Res Ther 2019;15:153-6

How to cite this URL:
Bhattacharjee PK, Nanda D. Prospective observational study on cholelithiasis in patients with carcinoma gall bladder in a tertiary referral hospital of Eastern India. J Can Res Ther [serial online] 2019 [cited 2020 Aug 6];15:153-6. Available from: http://www.cancerjournal.net/text.asp?2019/15/1/153/244243

 > Introduction Top

Gallbladder carcinoma (GBCA) is uncommon cancer in the west, with an estimated incidence and mortality in the US of 11,420 and 3710, respectively, in 2016.[1] On the contrary, it is one of the common and lethal malignancies encountered in women of Northern and Central India. The disease is showing an increasing trend among both genders, in Northern and Eastern India.[2],[3]

Conventionally, the disease was associated with a poor prognosis as may be evident from what Alfred Blalock wrote in 1924, “in malignancy of the gallbladder when the diagnosis can be made without exploration, no operation should be performed, since it only shortens the patient's life.”[4] This was mainly because of late presentation and diagnosis.

A better understanding of the etiopathogenesis and the widespread availability of improved imaging modalities are helping in earlier diagnosis of this dreaded entity. The widespread acceptance of laparoscopic cholecystectomy and expertise in advanced liver resection has improved the overall grim prognosis of the disease, and long-term survival has now been reported.[5]

Although GBCA is not uncommon in Eastern India, there is a paucity of published data about the disease. In this prospective observational study, we have sought to document the demographic and clinical profile of patients with GBCA attending our referral university hospital, with special reference to associated gallstones, their size and number with the ultimate aim of creating red flags while dealing with patients of gallstone disease which forms a considerable portion of our surgical workload.

 > Materials and Methods Top

This prospective observational study was conducted over a period of 2 years from April 2015 to March 2017 at a tertiary government teaching hospital of Eastern India. The database included patients, hailing from neighboring districts, who were either treated as outpatients or admitted in the surgical wards, under unit IV surgery, with the diagnosis of GBCA.

Inclusion criteria were patients of either sex with the diagnosis of GBCA attending the study area within the above-mentioned timeline and willing to take part in this study. Patients not willing were excluded from the study.

The diagnosis of GBCA was based on a combination of clinical, imaging, cytological, and postoperative histopathological information. Patients with GBCA presented in either of the following ways: as an incidental histopathological finding following cholecystectomy done for chronic cholecystitis, incidental unexpected finding during surgery, GB mass detected preoperatively on imaging, advanced cases with GB mass and jaundice apparent clinically and proven by guided aspiration cytology or with locally recurrent disease (with missed diagnosis of cancer during initial histopathology).

A total of 54 consecutive patients with the diagnosis of GBCA were included in this study. Parameters studied were the demographic and clinical profile of these patients; the incidence of gallstones among them, number of stones, and their size and whether there is any statistically significant relationship between the number and the size of the stones and GBCA. In patients without gallstones, the pathological nature of the growth was noted. For analyzing the stone size, stones were measured using calipers and grouped under two heads, those <3 cm and those ≥3 cm; and for analyzing their numbers they were grouped as solitary or multiple. In case of multiple stones, the size of the largest was taken into consideration for group distribution.

All the accumulated data were analyzed using standard statistical tests. The descriptive statistical analysis was used to describe the basic features of the collected data, i.e., frequencies and percentages for categorical data and mean with corresponding standard deviations for continuous data. Test of proportions was used to find standard normal deviate (Z) to compare sample proportions for determining whether the hypothesized difference between them is statistically significant. Chi-square test was used to find whether there is a significant association between variables. Corrected Chi-square test was used when one of the cell frequencies was less than zero. Student's t-test was used to compare the mean. Odds ratio (OR) with 95% of confidence interval (CI) was calculated to measure the different risk factors. The significance level was set at 0.05 and CI at 95% level. P < 0.05 was taken to be statistically significant.

 > Results Top

Our observational database constituted of 54 patients of either sex, all above the age of 12 years. The mean age of our patient cohort was 53.00 ± 10.40 years (range = 32–75 years). Test of proportion showed that the proportion of patients in their sixth decade (42.6%, n = 23) was significantly higher than the other age groups (Z = 2.48; P = 0.0131). About 9.3% (n = 5) of our patients belonged to the two extreme age groups considered in our study, i.e., 30–39 years and 70–79 years.

The female patients significantly outnumbered the males, the male/female ratio was 1.0: 2.4 (Z = 5.76; P < 0.0001). The gender-wise breakup of the affected age group showed no significant difference between the mean age group of affection between males and females (t52= 1.62; P = 0.1113).

About 74.1% (n = 40) of our patient cohort had gallstones. Test of proportion showed that the proportion of patients with cholelithiasis was significantly higher than those without stones (Z = 10.39; P < 0.0001). Corrected Chi-square test showed that there was no significant association between the age of patient and risk of cholelithiasis (P = 0.54).

The risk of a patient with GBCA having gallstones was 8.48 times more among females as compared to males (OR = 8.48; 95% CI 2.16–33.19; P = 0.0009). Chi-square test showed a significant association between gender and cholelithiasis (P = 0.0009).

Nearly 45% (n = 18) of our patient cohort had a single stone, whereas 55% (n = 22) had multiple stones. This difference was not found to be statistically significant (Z = 1.41; P = 0.1585). Test of proportion showed that significantly higher number of patients had stone size <3 cm (70%, n = 28) as compared to those with stone(s) ≥3 cm (Z = 5.65; P < 0.0001). Incidentally, multiple stones were mostly <3 cm in diameter while single stones were ≥3 cm in size, the association was statistically significant (P < 0.0001).

Among the 14 patients of GBCA without cholelithiasis, eight patients had hypoechoic mass obscuring the GB lumen which showed increased flow on color Doppler with or without infiltration into the adjacent liver, 5 had an intraluminal broad-based polypoidal mass >1 cm in size, and 1 was a case of missed diagnosis at primary surgery who presented with locally recurrent disease after 8 months of cholecystectomy. The patient initially had diffusely thickened gallbladder wall on imaging and dysplastic changes of mucosa on subsequent histopathology.

 > Discussion Top

Gallstone disease and GBCA share same risk factors such as female gender, increased age, fecundity, and obesity. Long-standing gallstone disease is the most important risk factor for the development of GBCA.[6] Gallstone disease is prevalent in 10%–15% of the adult population, but only 0.5% of these patients develop GBCA over 20 years.[7] However, 75%–92% of cases of GBCA are associated with gallstones.[8],[9],[10]

All over the world, the incidence of gallbladder cancer parallels the prevalence of gallstone disease. Mohandas et al., in their study, had found a definite reduction in GBCA mortality in women of Northern India following cholecystectomy even for asymptomatic gallstones disease.[11]

Most western literatures suggest a rising incidence of GBCA with age with sixth and seventh decades being the most common age group affected.[10]

Both gallstone disease and GBCA are more common in women than in men and have a rising incidence with increasing age.[10],[12] Patients having gallstone size >3 cm have ten times more risk of GBCA than those with stones <1 cm.[8],[10] Lowenfels et al. in their study on 1676 interracial female patients with GBCA, found the relative risk for GBCA in patients with stones ≥3 cm was 9.2 compared with patients with stone size <1 cm.[13] Similarly, Diehl, in his case–control study, on gallstone size and risk of GBCA on 81 patients found the OR was 10.1 for stone sizes >3 cm as compared to stones <1 cm.[14] Csendes et al. in their prospective study on 592 patients with asymptomatic, symptomatic gallstones, and GBCA, had found significantly more patients with multiple stones (more than 11, P < 0.01) and significantly larger stones regardless of their numbers (P < 0.001) as independent risk factors for GBCA.[12] They postulated that the increase in the number and size of the stones among patients with GBCA could simply a reflection of the long-term presence of stones in the gallbladder.[12] These findings have important implications in the approach toward management of asymptomatic gallstone disease. Moerman et al. and Roa et al. in their respective studies found no relationship between stone size and GBCA.[15],[16]

Observed results from accrued data available from our cohort of 54 patients with GBCA had some similarities with those available from western literature. Female preponderance (2.4:1), the incidence of associated gallstones (74.1%), and prevalence in the sixth decade (42.6%) were the similarities.

However, our findings regarding the association between the size of stones and risk of GBCA were not in accordance with most of the published data. We found that significantly higher number of patients had stones measuring <3 cm (Z = 5.65; P < 0.0001). It is expected that the proportion of small stones will decrease and large stones will increase over time. Since 70% of our patient cohort had small stone size, i.e., <3 cm it reflects a relatively short duration of their presence in the gallbladder. A higher incidence of GBCA in these patients indirectly indicates the influence of some chemical or physical factors, other than gallstones, in the pathogenesis of GBCA in this part of our country.

Although a significant number of our patients with multiple stones (22 out of 40) had stones measuring <3 cm in diameter, we did not find any significant relationship between the number of stones, i.e., single or multiple, and the risk of GBCA. This was contrary to the findings of Csendes et al. However, in most studies, this relationship is not clear.[12],[17]

Conclusions on comparative associations such as the size/number of gallstones and GBCA from case series based studies like ours have their limitations. A broader population-based study, taking into consideration multiple other risk factors for GBCA, would have given more accurate information regarding the predominant regional factors associated with GBCA. Our study has some other inherent limitations like small sample size and geographically limited catchment area of the patients enrolled. This study may be further enriched by making it a muticentric one, thereby widening the geographical area of patient inclusion, increasing the sample size and include more variables to find other possible risk factors associated with GBCA in this region.

 > Conclusion Top

This study was conducted with the aim at finding associations if any between gallstones, their number and the size, and GBCA. The results of our study reaffirm that gallstone disease is a strong predisposing factor for GBCA. A higher incidence of GBCA in patients in small stones indirectly indicates some factors, other than gallstones, may also have a role to play in the pathogenesis of GBCA in this part of our country.

Females in their sixth decade presenting with gallstones, irrespective of the size and number of the stone(s), should receive priority for cholecystectomy given the significantly higher risk of GBCA in this group. It may also be concluded that even silent gallstone disease in elderly females should be addressed given the higher prevalence of GBCA in association with gallstones, in this part of the country.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

American Cancer Society. Cancer Facts and Figures 2016. Atlanta, GA: American Cancer Society; 2016.  Back to cited text no. 1
Murthy NS, Rajaram D, Gautham MS, Shivaraj NS, Nandakumar BS, Pruthvish S, et al. Risk of cancer development in India. Asian Pac J Cancer Prev 2011;12:387-91.  Back to cited text no. 2
Kapoor VK. Advanced gallbladder cancer: Indian “middle path”. J Hepatobiliary Pancreat Surg 2007;14:366-73.  Back to cited text no. 3
Blalock A. A statistical study of 888 cases of biliary tract disease. John Hopkins Hosp Bull 1924;35:391-409.  Back to cited text no. 4
Fong Y, Jarnagin W, Blumgart LH. Gallbladder cancer: Comparison of patients presenting initially for definitive operation with those presenting after prior noncurative intervention. Ann Surg 2000;232:557-69.  Back to cited text no. 5
Zatonski WA, Lowenfelds AB, Boyle P, Maisonneuve P, Bueno de Mesquita HB, Ghadirian P, et al. Epidemiologic aspects of gall bladder cancer: A case-control study of the SEARCH programme of the International Agency for Research on Cancer. J Natl Cancer Inst 1997;89:1132-8.  Back to cited text no. 6
Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: Geographical distribution and risk factors. Int J Cancer 2006;118:1591-602.  Back to cited text no. 7
Contreras CM, Choi EA, Abdalla EK. Hepatobiliary cancers. In: Feig BW, Ching CD, editors. The MD Anderson Surgical Oncology Handbook. 5th ed. Philadelphia: Lippincott William & Wilkins; 2012. p. 416-71.  Back to cited text no. 8
Gore RM, Yaghmai V, Newmark GM, Berlin JW, Miller FH. Imaging benign and malignant disease of the gallbladder. Radiol Clin North Am 2002;40:1307-23, vi.  Back to cited text no. 9
Kapoor VK, McMichael AJ. Gallbladder cancer: An 'Indian' disease. Natl Med J India 2003;16:209-13.  Back to cited text no. 10
Mohandas KM, Patil PS. Cholecystectomy for asymptomatic gallstones can reduce gall bladder cancer mortality in Northern Indian women. Indian J Gastroenterol 2006;25:147-51.  Back to cited text no. 11
[PUBMED]  [Full text]  
Csendes A, Becerra M, Rojas J, Medina E. Number and size of stones in patients with asymptomatic and symptomatic gallstones and gallbladder carcinoma: A prospective study of 592 cases. J Gastointest Surg 2000;4:481-5.  Back to cited text no. 12
Lowenfels AB, Walker AM, Althaus DP, Townsend G, Domellöf L. Gallstone growth, size, and risk of gallbladder cancer: An interracial study. Int J Epidemiol 1989;18:50-4.  Back to cited text no. 13
Diehl AK. Gallstone size and the risk of gallbladder cancer. JAMA 1983;250:2323-6.  Back to cited text no. 14
Moerman CJ, Lagerwaard FJ, Bueno de Mesquita HB, van Dalen A, van Leeuwen MS, Schrover PA, et al. Gallstone size and the risk of gallbladder cancer. Scand J Gastroenterol 1993;28:482-6.  Back to cited text no. 15
Roa I, Ibacache G, Roa J, Araya J, de Aretxabala X, Muñoz S, et al. Gallstones and gallbladder cancer-volume and weight of gallstones are associated with gallbladder cancer: A case-control study. J Surg Oncol 2006;93:624-8.  Back to cited text no. 16
Rathanaswamy S, Misra S, Kumar V, Chintamani, Pogal J, Agarwal A, et al. Incidentally detected gallbladder cancer- the controversies and algorithmic approach to management. Indian J Surg 2012;74:248-54.  Back to cited text no. 17


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