Table 1.

Results.

Author, date of publication, journal and country	Study type and level of evidence	Patient group	Outcomes	Key results	Additional comments
LOWENFELS et al. [2], 1989, International Journal of Epidemiology, USA	Retrospective cohort study, level III	The study included 1676 female patients. 25 of them identified to have gallbladder cancer. They used histopathology reports for patients whom surgery had been performed for cholelithiasis, and/or gallbladder cancer during the seven-year period 1979–1985	To investigate the relation between stone size and gallbladder cancer	They found a strong relationship between gallstone size and gallbladder cancer. Large stones (>3 cm) were found in 40% of patients with gallbladder cancer. The relative risk for gallbladder cancer in subjects with stones ≥3 cm was 9.2 compared with subjects with stones <1 cm. (95% confidence interval: 2.3–37)	Multicentre, large sample size, interracial, restricted to female patients and 3 races (white, black, native Americans), study was reported based on histopathology reports for symptomatic patients only
Csendes et al. [3], 2000, Journal of gastrointestinal Surgery, Chile	Prospective case control study, level IV	The study included 592 female patients divided into three groups: (A) 78 asymptomatic patients with gallstones; (B) 365 symptomatic patients with gallstones and (C) 149 patients with gallbladder carcinoma, during 1995–2000	To determine the number and the size of gallstones in patients with gallbladder carcinoma compared to asymptomatic and symptomatic female patients with gallstones	Patients with gallbladder carcinoma had significantly larger stones, regardless of the number of stones present (P < 0.001)	Single centre, large sample size, restricted to female patients
VITETTA et al. [4], 2000, ANZ Journal of Surgery, Australia	Retrospective Cohort Study, level III	Study consisted of 439 patients who underwent a cholecystectomy for gallstone disease. 14 patients (3.2%; 95%CI: 1.8–5.3) were diagnosed with gall bladder carcinoma, of which there were 11 women and three men, 1980–1994	Study reviewed the occurrence of gall bladder carcinoma in patients who underwent a cholecystectomy for gallstone disease	The author postulated that gall bladder carcinoma may be intimately associated with large or numerous cholesterol gallstones	Multicentre, large sample size, the study did not address the relation between acalculous gall bladder and gallbladder cancer
Diehl et al., 1983 [5], JAMA, USA	Case control study, level IV	The study included three controlled groups. 81 gallbladder cancer, 80 benign gallbladder controls, 66 non gallbladder controls. during 1976–1980	The purpose of this study was to determine risk factors that might interact with gallbladder stones to identify a high-risk subgroup for gallbladder cancer	Persons with large gallstones were found to be at increased risk for cancer. Stone diameter of 2.0–2.9 cm the odds ratio was 2.4; for stones >3 cm or larger the ratio was 10.1	Multicentre, the finding was not hypothesized before the study, small sample size, some selectively missing data which can raise potential bias, not sure that some of the patients in non-gallbladder controls have actually gallstone disease “as they can be asymptomatic”
Andrea et al. [6], 2015, Annals of surgery, Italy	Case Control study, level IV	The study Compared data from 2942 patients with benign biliary tract disease with those of 75 patients with gallbladder cancer, 20-year long study	The purpose of this study was to identify the high-risk group patients to develop gallbladder cancer which could benefit from preventive cholecystectomy	Patients with large gallstone of more than 3 cm at increased risk to develop gallbladder cancer. The increased risk odds ratio of developing gallbladder cancer has been reported to be 10.1 for gallstones larger than 3 cm versus stones smaller than 1 cm	Small sample size, a letter to editor has been found instead of a full article
Moerman et al. [7],1993, Scandinavian Journal of Gastroenterology, Netherlands	Case control study, level IV	43 cases and 98 controls with stones that could be classified by size were included in the analysis, cases were defined as patients with a surgical diagnosis gallbladder cancer while control defined as patients who underwent a cholecystectomy for a benign gallbladder disorder excluding carcinoma in situ, between 1983 and 1989	the relationship between stone size and gallbladder cancer	no association was found between the size of the largest stone within the gallbladder and gallbladder cancer in a matched hospital-based case-control study of surgical patients	Multicentre, small sample size, the patient group is mostly female and white ethnicity, Since a substantial number of patients with gallbladder cancer will not undergo surgery, the present findings cannot be generalized without caution to all patients with gallbladder cancer, relied on ultrasound for the size of gallstones