Epidemiology of Gallbladder Cancer in the Unites States

A Population-Based Study

Motasem Alkhayyat; Mohannad Abou Saleh; Thabet Qapaja; Mohammad Abureesh; Ashraf Almomani; Emad Mansoor; Prabhleen Chahal


Chin Clin Oncol. 2021;10(3):25 

In This Article


Our population-based study of 56 million patients showed that the 20-year period prevalence rate of GBC is 8.5 per 100,000 among the US population. In our cohort, patients with GBC were more likely to be elderly (age >65) and females.

Our study was consistent with previous epidemiologic studies in the US that showed a higher prevalence of GBC in women compared to men.[22,37] GBC is considered one of the few cancers where the incidence is higher in women than men,[5] this is thought to be due to a higher prevalence of gallstones in women.[38] After adjusting for several factors in the multivariate analysis, we found that female gender is an independent risk factor for GBC. In our cohort, gallstone was the single most important risk for GBC, which is consistent with prior studies.[5] Moreover, it is believed that the geographic pattern of GBC correlates with the prevalence of gallstones.[7] Gallstone size is believed to influence the risk of GBC with larger stones (>3 cm) carrying a higher risk compared to smaller stones.[39] However, despite the increased risk, the development of GBC in patients with gallstone disease remains rare.[40–42] It is proposed that cholelithiasis leads to GBC through chronic inflammation and metaplasia.[40] Chronic inflammation can also lead to the deposition of calcium in the gallbladder wall, a condition called porcelain gallbladder. Historically, porcelain gallbladder was an absolute indication for cholecystectomy due to the risk of GBC. However, today, the association between GBC and porcelain gallbladder is controversial.[43,44]

The data on obesity as a risk factor for GBC is conflicting. Our study however, is in agreement with the previous studies that showed an increased risk of GBC in obese patients including a cohort of 181,000 individuals by Larsson et al..[45] In a systematic review of eight studies, obesity and body mass index (BMI) were significantly associated with GBC. The increased risk is thought to be related to increased predisposition to form gallstones. On the contrary, other studies have showed no association between obesity and GBC.[46] Previous studies found an association between diabetes and GBC, but it was unclear whether this association was independent or mediated by obesity.[47] We found that DM is independently associated with increased risk of GBC. Similarly, a recent European cohort study showed that diabetes was associated with a higher risk of GBC independent of obesity.[48] Cigarette smoking and heavy alcohol use were also associated with GBC. In a prospective study conducted in Japan, there was a positive linear association observed between the risk of GBC and the number of cigarettes smoked. The study showed a linear association between alcohol drinking and risk of GBC among men as well but not in women.[16] In a meta-analysis investigating the association of alcohol and risk of 23 types of malignancy, the relative risk of GBC among heavy drinkers was 2.64 (95% CI: 1.62–4.30).[17]

Emerging data suggest that chronic HBV and HCV infections may also play a role in extrahepatic bile duct cancers. One Taiwanese study found that HBV and HCV infections were associated with increased risk of several extrahepatic malignancies including the risk of gallbladder and extrahepatic bile duct cancer compared to the general population.[49] Similarly, a Chinese population-based study concluded that patients with chronic HBV have increased risk of extrahepatic bile duct cancer.[50] In our study, we found a higher risk of developing GBC in HBV or HCV infection. Moreover, PSC was significantly associated with higher risk of GBC with a seven-fold increased risk compared to the general population. It is well-known that PSC is associated with an increased risk of several neoplasms, mainly cholangiocarcinoma, GBC, liver cancer, and colorectal neoplasm, with nearly 50% of deaths in patients with PSC being due to cancer.[51]

The indolent and non-specific presentation of GBC along with a paucity of early screening methods, and predictive radiological features often preclude early detection of GBC. Therefore, that results in difficulty in implementing curative intent surgical resection and subsequently reflects negatively on the overall prognosis. GBC remains a highly fatal cancer, with only 10% of cases presenting at a surgically resectable stage with an overall 5-year survival of 60% for localized tumors, 30% for regional spread, and 2% for distant spread.[52] Despite the importance of obtaining accurate prognostic information in helping physicians to make better clinical decisions, there are limited prognostic data in GBC at the current time. In a Chinese study, Bai et al. proposed a nomogram to predict the overall survival after GBC resection.[53] The nomogram suggested that the absence of jaundice, lower preoperative CA19-9 levels, lower TNM stage, and incisional margins without tumor cells correlated well with a long survival time. Using the SEER database, Wang et al. formulated two nomograms that would help predict survival for GBC receiving chemoradiotherapy.[54,55] On multivariate regression analysis, the model showed that age, sex, papillary histology, stage, and adjuvant radiotherapy were significant predictors of overall survival. In a systemic review evaluating the prognostic value of DM on the survival of patients with GBC, a meta-analysis of 10 studies concluded that diabetic patients had a higher mortality of GBC.[56] Extrapolating data from other cancers, smoking and alcohol abuse have detrimental effect post-cancer diagnosis as well as increased mortality.[57,58]

This study has few limitations, mostly related to the use of a large database. Accurate prevalence rates of diagnoses might be affected as the database is generated from those who sought medical care. Given the de-identified nature of Explorys database, we were not able to obtain individual data regarding imaging reports and laboratory values, therefore we were not able to include patients with porcelain gallbladder or pathological data on gallbladder biopsies. Despite these limitations, the major strengths of this study lie in that it is one of the largest population-based studies to ever address GBC epidemiology and risk factors to our best knowledge. Explorys captures electronic medical record data of more than 50 million patients from all different regions of the US. In addition, SNOMED-CT allows for more concepts to be coded per clinical document compared to ICD making it more accurate in terms of documenting diagnoses and pertinent patient information. It is important to highlight that Explorys has been validated previously as a database[59] and in different specialties including gastroenterology.[26–36,60,61]