Gallbladder cancer cases increasing in Karachi for past two decades

Gallbladder carcinoma (GC) was first described by Maximilian Stoll in 1777, and more than 200 years later, it is still considered to be a highly malignant disease with a poor survival rate. The clinical presentation of GC is nonspecific. It is often recognised late, with the diagnosis being established during advanced stages of the disease. Survival is less than five years in 90 percent of the cases. The incidence of GC in any population varies widely among various geographic regions and ethnic groups ranging from one to 23 per 100,000. There have been reports of rising incidences of GC from Northern India and Southern Pakistan over the past two decades. GC is the second commonest malignancy of gastrointestinal origin in Pakistani women. It is the most common cause of gastrointestinal cancer related mortality in females in the region.
While the etiology of GC remains obscure, it seems that more than one factor plays a role in the pathogenesis. A strong association is observed between gallstones and GC, suggesting that it is the most important risk factor. In addition, genetic factors, diet, parity, obesity, bacterial infection, poverty, benign neoplasm of gallbladder, congenital abnormalities and porcelain gallbladder are also postulated to the pathogenesis of GC. The aim of this case-control study was to identify the risk factors of GC, comparing patients with cholelithiasis and gallbladder cancer patients to patients with cholelithiasis but no cancer on histopathology.

METHODS: It was a retrospective case-control study conducted at the Aga Khan University Hospital. In this review, we included patients with cholelithiasis and gallbladder cancer and patients with cholelithiasis without gallbladder cancer over a period of 19 years – 1988 to 2007. All the patients with cholelithiasis and histologically proven gallbladder cancer were retrieved through the hospital’s electronic database system using ICD-9 coding system. There were 60 patients in this group and were selected as cases for the study (Group A). For these cases, controls were selected of those patients who have gallstones without gallbladder cancer on histology (Group B). A total of 120 patients were selected as controls in Group B (case-control – 1:2).
Group B controls were selected through computer generated software, which had randomly selected seven patients from every year (from 1988 to 2007), who underwent cholecystectomy for cholelithiasis (a total of 133 patients for 19 years). After reviewing these 133 patients’ records, 13 were excluded from the study due to selected exclusion criteria, so 120 patients were included in the study as controls. In Group A, all adult patients of age 18-75 years with gallbladder cancer with gallstones were included in the study. Patients with gallbladder cancer without gallstones, missing and/or incomplete records and patients with other concomitant malignancy were excluded from the study.
In Group B, all adult patients (18-75 years), who underwent laparoscopic cholecystectomy for gallstone disease, were included in the study. Patients who underwent laparoscopic cholecystectomy without gallstones (polyp, biliary dyskinesia), any history of previous malignancy and those with incomplete and/or missing record were excluded from the study.
After selecting cases and control groups, patients’ medical records were reviewed retrospectively and information was recorded on a predefined Performa. This Performa included all basic demographic details, clinical spectrum and information regarding documented risk factors for gallbladder cancer (parity, body mass index [BMI], alcohol, smoking, family history, oral contraceptive pill use, typhoid carrier state, stone number and size, etc). As this was a retrospective review of medical records without any intervention, approval of the hospital’s ethical review board was not taken.
Both the groups were compared for the following risk factors: age of diagnosis (age more than 55 being a risk factor), BMI (BMI of more than 23kg/m2 being a risk factor), parity (multiparity being a risk factor), number of stones (solitary stones being a risk factor) and size of stones (size more than 1cm being a risk factor). The number and size of stones were recorded from the initial ultrasound report. As in our institution, stone numbers are being reported as either single or multiple, so the actual number of stones was not available to calculate the mean or median number of stones. For stone size, the size of the largest stone documented on preoperative ultrasound was used.
Data was entered and analysed using SPSS version 14. Age was calculated in means and medians. Frequency tables were used to compare basic demographic, clinical and other desired characteristics. Comparison of characteristics between two groups was done using the chi square test. Factors which came out to be different with statistical significance, multivariate regression analysis was used to calculate odd ratio (OR), confidence interval and p values. CI of 95 percent and p value of less than 0.05 was considered statistically significant.

RESULTS: There were 60 patients in Group A and 120 patients in Group B. The mean age of diagnosis in Group A patients was 57±2.4 years, whereas the mean age of diagnosis in Group B patients was 48±1.35 years. Sixty seven percent of the cancer group patients were female as compared to 78 percent females in the non-cancer group. In Group A, 69 percent of the female patients were multiparous (parity of more than five), whereas 43 percent of the Group B patients were multiparous. For BMI, both groups were not very different in our study population, that is around 78 percent patients in each group has BMI of more than 23kg/m2. Other documented risk factors of gallbladder cancer like typhoid carrier state, oral contraceptive pill use, smoking, alcohol, family history were also tried to be analysed, but for these risk factors, data was either insufficient or difference between the two groups was too small.
Preoperative ultrasound findings were used to collect information regarding stone characteristics, that is the number and size of the stones. In Group A, 37 percent (n=22) have solitary stones as compared to 15percent (n=18) in Group B. Similarly, Group A patients have larger stone size as compared to Group B, that is 59 percent (n=36) patients in Group A have stones of more than 1cm when compared to 35 percent (n=41) patients in Group B. The mean stone size in Group A patients was 2.2cm as compared to Group B patients, in which the mean stone size was 0.8cm.
After comparing both groups for basic demographic characteristics and risk factors for gallbladder cancer, the differences between the two groups were calculated using the chi square test. After the initial comparison, age, BMI, parity, stone size and number of stones showed significant and/or marginal insignificant values. So, these variables were included in the multivariate regression analysis.
After using the multivariate regression analysis, age more than 55 years (OR: 7.27, p value <0.0001), solitary stone (OR: 3.33, p value: 0.002) and stone of more than 1cm (OR: 2.73, p value: 0.004) were found to be independent risk factors for development of gallbladder cancer. CONCLUSION: This study found statistically significant positive correlation of gallbladder carcinoma with large sized and solitary gallstones. Multiparity and increased age seem to play an important role in causation of GC. Based on the results of the present study, a case could be made for prophylactic cholecystectomy as a preventive strategy in a high-risk group of patients with asymptomatic gallstones. Early elective cholecystectomy for symptomatic gallstones might reduce the chances of gallbladder carcinoma in countries where high incidence of GC is reported, including Southern Pakistan (Karachi). However, a population based study is required to calculate the true incidence of GC in Karachi and a multicentre study is needed to produce strong evidence for screening and prophylactic cholecystectomy in high-risk patients. Extracted from A Rehman Alvi, Nadeem Ahmed Siddiqui and Hasnain Zafar’s research paper ‘Risk factors of gallbladder cancer in Karachi: a case-control study’ published in the World Journal of Surgical Oncology.