Best evidence topic: Does the presence of a large gallstone carry a higher risk of gallbladder cancer?

A best evidence topic has been constructed using a described protocol. The three-part question addressed was: In a patient with symptomatic gallstone disease does the presence of a large sized gallstone associated with a higher risk of gallbladder cancer? Using the reported search, 3876 papers were found. 6 studies were deemed to be suitable to answer the question. The outcome assessed was the relationship between the presence of large sized gallstones and the risk of gallbladder cancer. It appears from the current available evidence that there is a strong association of a large sized gallstones and gallbladder cancer. Larger stones (>3 cm) have the greatest risk to develop gallbladder cancer, especially in symptomatic gallstone disease patients. Authors recommend special care for this patient's group and to warrant cholecystectomy when the clinical condition allows.


Introduction
A Best Evidence Topic was constructed based on a structured protocol. This is described by the International Journal of Surgery [1].

Clinical scenario
You are a general surgery registrar, reviewing a patient with symptomatic gallstone disease in a general surgery outpatient clinic. You are discussing the ultrasound finding with him. The ultrasound scan shows the presence of a large gallstone which measures 3 cm. The patient asks you whether this finding is associated with higher risk of gallbladder cancer? What would you answer? The results were limited to English articles and human studies.

Search outcome
A total of 3876 papers were found using OVID and 316 using the PubMed interface. 2882 papers were identified after duplicates were removed. Out of these, 2874 papers were excluded because they were irrelevant based on titles and abstracts. 8 full-text articles were screened and assessed for eligibility. From these, six papers were identified that provided the best evidence to answer the question. Eligible articles were defined as those articles that compared large gallbladder stone and risk of gallbladder cancer. The search strategy process is detailed in Fig. 1.

Discussion
Gallbladder cancer is a rare malignancy and as a result of its rarity, it is understudied [8]. It has been established that the presence of gallstones is an important risk factor [9]. Diehl et al. [5] conducted a case control study in 1983 to determine the risk factors for gallbladder cancer. Surprisingly, without a structured hypothesis before the study, they concluded a strong association between the presence of a large sized gallstone and gallbladder cancer. Moreover, they found that a stone diameter of 2.0-2.9 cm is associated with the odds ratio of 2.4 while for stones of 3 cm or larger the ratio was 10.1 for cancer. In 1989, Lowenfels et al. [2] conducted a cohort retrospective study which included 1676 female patients. Twenty-five of them were identified to have gallbladder cancer. They used histopathology reports for patients whom surgery had been performed for cholelithiasis and/or gallbladder cancer. The authors 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).
In 2000, Csendes et al. [3] conducted a prospective case control study which 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. They concluded that Patients with gallbladder carcinoma had significantly larger stones, regardless of the number of stones present (P < 0.001).
In the same year, Vitetta et al. [4] concluded that gall bladder carcinoma may be intimately associated with large or numerous cholesterol gallstones after the retrospective cohort study they conducted.
In 2015, Andrea et al. [6] conducted a case control study which Compared data from 2942 patients with benign biliary tract disease with those of 75 patients with gallbladder cancer. They concluded that patients with large gallstones 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.
In contrast to all of the above-mentioned studies, Moerman et al. [7] conducted a case control study in 1993 which included 43 cases and 98 controls, cases were defined as patients with a surgical diagnosis of gallbladder cancer while control defined as patients who underwent a cholecystectomy for a benign gallbladder disorder excluding carcinoma in situ. They concluded that no association was found between the size of the largest stone within the gallbladder and gallbladder cancer.

Clinical bottom line
Five out of six studies have found a strong relationship between the large sized gallstones and gallbladder cancer. Larger stones (>3 cm) have the greatest risk to develop gallbladder cancer, especially in symptomatic gallstone disease patients. Authors recommend special care for this patient's group and to warrant cholecystectomy when the clinical condition allows.

Ethical approval
Not applicable.

Sources of funding
None.

Author contribution
TA: conducted the literature search, structured PRISMA chart and interpretated the results.
SA: conducted the literature search, interpretation of the results and wrote the paper.

Registration of research studies
1. Name of the registry: Not applicable. 2. Unique Identifying number or registration ID: 3. Hyperlink to your specific registration (must be publicly accessible and will be checked):

Consent
Not required.

Declaration of competing interest
None.