Development of upper gastrointestinal cancer in patients with symptomatic gallstones,cholecystectomy,and sphincterotomy: A nationwide cohort study

Abstract

Background and objective:

Exposures of gallstones and treatments thereof in relation to development of cancer have not been explored before in long-term follow-up studies. Our objective was to determine whether symptomatic gallstones, cholecystectomy, or sphincterotomy were associated with development of upper gastrointestinal cancers.

Methods:

This is a nationwide cohort study of persons born in Denmark 1930–1984 included from age 30 years with long-term follow-up (1977–2014). Exposures were hospital admissions with gallstones, cholecystectomy, and sphincterotomy. Time-varying covariates were included in analyses to allow the impact of exposures to change with time. Follow-up periods were 2–5 and > 5 years. Hazard ratios (HR) with 95% confidence intervals (CI) were reported.

Results:

A total of 4,465,962 persons were followed. We found positive associations between sphincterotomy and biliary (>5 years HR 4.34, CI [2.17–8.70]), gallbladder (2–5 years HR 20.7, CI [8.55–50.1]), and pancreatic cancer (2–5 years HR 3.68, CI [2.09–6.49]). Cholecystectomy was positively associated with duodenal (2–5 years HR 2.94, CI [1.31–6.58]) and small bowel cancer (2–5 years HR 2.75, CI [1.56–4.87]). Inverse associations were seen for cholecystectomy and biliary (>5 years HR 0.60, CI [0.41–0.87]), pancreatic (>5 years HR 0.45 CI [0.35–0.57]), esophageal (>5 years HR 0.57, CI [0.43–0.74]), and gastric cancer (>5 years HR 0.68, CI [0.55–0.86]) and for gallstones and pancreatic cancer (>5 years HR 0.66, CI [0.47–0.93]). Gallstones were positively associated with gallbladder (>5 years HR 3.51, CI [2.02–6.10]) and small bowel cancer (2–5 years HR 3.21, CI [1.60–6.45]).

Conclusions:

A positive association between sphincterotomy and biliary cancer was identified. Cholecystectomy seems to be inversely associated with biliary, pancreatic, esophageal, and gastric cancer. Associations should be explored in similar large cohorts.

Keywords

Cholangiopancreatography endoscopic retrograde cholelithiasis epidemiology ERCP follow-up studies

Context and Relevance

Specific exposures of gallstones, cholecystectomy, and sphincterotomy in relation to development of upper gastrointestinal cancer have not been explored before in long-term follow-up studies. In this nationwide cohort study including persons born in Denmark 1930–1984, we find a positive association between sphincterotomy and biliary cancer after more than 5 years of follow-up. Cholecystectomy seems to be inversely associated with biliary, pancreatic, esophageal, and gastric cancer.

Introduction

Gallstones and possible derived treatments have shown to be associated with occurrence of several gastrointestinal cancers.^1,2 Previous smaller clinical studies have suggested associations for cancer and sphincterotomy^3–5 and larger cohorts also for cholecystectomy,² but have been unable to explore whether it is the presence of gallstones or their treatments that cause development of gastrointestinal cancers. This may be due to unavailability of lifelong follow-up data, not exploring the impact of sphincterotomy, and for not including the changing exposures for gallstones and treatments in time-to-event analyses with long-term follow-up. There is a need for exploring potential harmful effects of specific gallstone treatments.

Gallstones are highly prevalent in general populations and their associated clinical conditions lead them to be among the most frequent gastrointestinal diagnoses for hospital admissions causing high health care costs and burden.^6,7 Standard treatment for symptomatic gallstones is cholecystectomy.⁸ Laparoscopic cholecystectomy is the most frequent surgical procedure of the gastrointestinal system in Scandinavian countries, and frequencies are on the rise in other European countries.^9,10 Endoscopic retrograde cholangiography (ERC) is performed when common bile duct stones are suspected with the aim of performing therapeutic sphincterotomy and stone extraction.⁸ ERC rates have been rapidly increasing within the recent decade in North America.^11,12

The sequence of clinical events in persons with gallstones may include a period from diagnosis of symptomatic gallstones to the performance of surgical treatments, which may be years apart. This causes a long period with changing exposures of gallstones, sphincterotomy, and cholecystectomy. All hospital contacts for Danish residents are registered centrally with diagnose and intervention codes, enabling long-term and complete follow-up.¹³ Thereby, the full impact of gallstones, sphincterotomy, cholecystectomy, and the changing exposures throughout a lifetime on incidence of gastrointestinal cancers may be explored.

The objective was to determine whether hospital admissions with gallstones, cholecystectomy, or sphincterotomy were associated with development of site-specific upper gastrointestinal cancer divided into biliary, gallbladder, hepatic, pancreatic, esophageal, gastric, duodenal, and small bowel cancer in a nationwide population cohort with long-term follow-up.

Methods

This is a nationwide cohort study including all persons born in Denmark in the years 1930–1984. Persons were included when turning 30 years of age as this was considered relevant for gallstone formation and for established socioeconomic conditions. Persons were followed until occurrence of upper gastrointestinal cancer, death, hepatic metastasis, or were censored if moving out of the country, whichever came first. Hepatic metastasis may be the debuting sign of disseminated gastrointestinal cancer without a site-specific cancer of origin ever being identified, and therefore these cases were censored if occurring before a site-specific gastrointestinal cancer. Persons were excluded if the explored cancers or liver metastasis had occurred before the age of 30 years. A varying number of persons may therefore have been included at baseline in analyses of site-specific cancer outcomes. When exploring gallbladder cancer, we censored patients that had cholecystectomy performed.

Persons were followed-up through Danish national registers. The Danish Central Person Registry contains daily updated information on vital status and migration of the entire nation. A unique personal registration number enables linkage to other registers.¹³ The National Patient Registry contains data on all hospital admissions from the year 1977 and emergency room visits from 1995. It includes diagnose codes according to the International Classification of Disease (ICD 8 or ICD 10—ICD 9 was never used in Denmark) and surgical intervention codes according to the Nordic Classification of Surgical Procedures. Codes are registered at the time of discharge from the hospital.¹⁴ The Danish Register of Causes of Death contains one underlying cause of death with up to three contributory causes according to the ICD since 1970.¹⁵ The National Patient Registry and The Danish Register of Causes of Death were used for identification of cancer outcome diagnoses, and The National Patient Registry was used to assess gallstone and treatment exposures. Statistics Denmark was used to obtain data on socioeconomic conditions. The National Patient Registry was updated at the end of 2014, The Danish Register of Causes of Death at the end of 2015, and The Danish Central Person Registry and Statistics Denmark in 2016. All registers have been used frequently in epidemiological research.^13–15

The outcome of interest was site-specific upper gastrointestinal cancer divided into biliary, gallbladder, hepatic, pancreatic, esophageal, gastric, duodenal, and small bowel cancer. Exposure variables included cholecystectomy, sphincterotomy, presence of both interventions performed, or gallstones without interventions performed. For detailed definitions of exposures and outcomes see Table 1.

Table 1.

Intervention and diagnosis codes.

	ICD-8	ICD-10	Nordic Classification of Surgical Procedures before 1996	Nordic Classification of Surgical Procedures after 1996
Exposure^a
Cholecystectomy			47360, 47365, 47420	KJKA20, KJKA21
Sphincterotomy			47860, 47870	KJKE00, KJKE02
Gallstones	57400-57509	K80-81
	57601	K82.3
	57605, 5761	K83.3
		K85.1
Cancer outcome^b
Biliary	15519-15589	C22.1
	15610-15699	C24
Gallbladder	15609	C23
Hepatic	15509	C22.0
		C22.2-22.9
Pancreatic	15709-15799	C25
Esophageal	15000-15009	C15
Gastric	15109-15199	C16
Duodenal	15209	C17.0
Small bowel	15280-15299	C17.1-17.9
Hepatic metastasis^c	19779	C78.7

ICD: International Classification of Disease.

Exposure diagnoses or interventions were identified in the National Patient Registry.

Outcome diagnoses were identified in the National Patient Registry or the Danish Register of Causes of Death.

Occurrence of hepatic metastasis were censored and not explored as an outcome.

Socioeconomic variables were included as covariates in multivariable models and served as proxy for lifestyle and anthropometric data, as both gallstones and gastrointestinal cancer may be associated with these. Socioeconomic variables were assessed once when the person was 30 years of age where possible. Covariates included sex (female/male), socioeconomic status (employee, self-employed/manager, retired, student, temporary transfer income/on leave, transfer income/unemployed), civil status (married/registered partner, unmarried, widowed, divorced), level of education (high school/elementary school, vocational training, short/medium-term education, higher university education), and personal annual income (DKK). Primary sclerosing cholangitis is highly associated with biliary cancer when compared with the risk in the general population.¹⁶ Sensitivity analyses were, therefore, performed to explore the possible confounding pathway for primary sclerosing cholangitis, sphincterotomy, and biliary cancer. The study was reported according to the STROBE statement.

Ethical approval for performing the study was given through the Danish Data Protection Agency and the Capital Region of Denmark (journal number CSU-FCFS-2017-007, I-Suite number 05575). As no new human data were collected, no participants provided informed consent was required.

Statistical analyses

Competing risk analyses¹⁷ were used with age as the underlying timescale. Death was used as the competing cause when analyzing the occurrences of the site-specific cancer outcomes. We modeled the cause-specific hazard functions using the Cox proportional hazards model¹⁸ with time-varying covariates to allow the impact of the different exposures to change with time. Time periods of 0–2 years, 2–5 years, and more than 5 years since exposure was used. Unexposed persons served as the controls. Based on the cause-specific hazard models, we computed cumulative incidence functions to quantify exposure effects on the probability scale. We did not report results from the period of 0–2 years since exposure to avoid prevalent cancers. We report number of outcome cases, total persons in exposure category, person years, incidence rate as cases per 100,000 person years, crude cumulative incidence curves, and hazard ratios (HR) with 95% confidence intervals (CI) both unadjusted and adjusted for baseline covariates. Significance level is set as a 95% CI not including one. Statistical software R with the “survival” package was used for analyses.

Results

The nationwide cohort included 4,465,962 persons in the period 1977–2014. For baseline characteristics, see Table 2. During follow-up, the most frequently occurring cancers were pancreatic, gastric, and esophageal. The rarest occurring cancers were duodenal, gallbladder, and small bowel. Hepatic and biliary cancers occurred with frequencies in between (Table 3).

Table 2.

Baseline characteristics of the study population born 1930–1984 (n = 4,465,962^a).

Sex	n (%)	Female	2,183,750 (48.9)
		Male	2,282,212 (51.1)
Socioeconomic status	n (%)	Employee	2,681,443 (60.0)
		Self-employed/manager	316,893 (7.1)
		Retired	45,763 (1.0)
		Student	321,595 (7.2)
		Temporary transfer income/on leave	81,951 (1.8)
		Transfer income/unemployed	557,118 (12.5)
		Missing observations	461,199 (10.3)
Civil status	n (%)	Married/registered partner	2,187,280 (49.0)
		Unmarried	1,438,131 (32.2)
		Widowed	28,987 (0.7)
		Divorced	275,620 (6.2)
		Missing observations	535,944 (12.0)
Level of education	n (%)	High school/elementary school	1,418,262 (31.8)
		Vocational training	1,427,486 (32.0)
		Short/medium-term education	709,854 (15.9)
		Higher university education	252,210 (5.7)
		Missing observations	658,150 (14.7)
Personal annual income	Mean (SD)	DKK	193,016 (144,958)
	n (%)	Missing observations	402,025 (9.0)

SD: standard deviation.

This is the maximum number of persons included in analyses. Due to censoring persons with occurrence of the specific cancer outcome either before the age of 30 years or before inclusion into the study population, some analyses include fewer persons in study populations.

Table 3.

Gallstones and treatments thereof in relation to development of upper gastrointestinal cancers.

Cancer	Exposure	Cases	Person years	Total	Incidence rate^a	Unadjusted HR [95% confidence interval]		Adjusted^b HR [95% confidence interval]
Cancer	Exposure	Cases	Person years	Total	Incidence rate^a	2–5 y	>5 y	2–5 y	>5 y
Biliary	Unexposed	3704	101,732,394	4,442,772	3.64	Ref.	Ref.	Ref.	Ref.
	Gallstones	253	635,631	146,068	39.8	2.47 [1.49–4.10]	1.27 [0.82–1.95]	1.96 [1.09–3.55]	1.04 [0.64–1.71]
	Cholecystectomy	115	1,623,118	129,265	7.09	0.99 [0.55–1.78]	0.58 [0.40–0.84]	0.88 [0.46–1.69]	0.60 [0.41–0.87]
	Sphincterotomy	391	75,652	22,080	516.8	11.2 [6.34–19.7]	4.12 [2.06–8.26]	10.6 [5.84–19.1]	4.34 [2.17–8.70]
	Cholecystectomy and sphincterotomy	48	157,960	17,091	30.4	2.98 [1.24–7.15]	1.20 [0.50–2.89]	3.21 [1.33–7.71]	1.31 [0.55–3.16]
Gallbladder	Unexposed	769	101,758,422	4,442,959	0.76	Ref.	Ref.	Ref.	Ref.
	Gallstones	95	636,909	146,310	14.9	3.76 [1.56–9.08]	3.76 [2.21–6.40]	3.89 [1.61–9.40]	3.51 [2.02–6.10]
	Sphincterotomy	55	77,089	22,744	71.3	20.2 [8.35–48.8]	2.21 [0.31–15.7]	20.7 [8.55–50.1]	2.29 [0.32–16.3]
Hepatic	Unexposed	5063	101,705,574	4,442,590	4.98	Ref.	Ref.	Ref.	Ref.
	Gallstones	136	635,407	146,120	21.4	1.45 [0.84–2.50]	1.09 [0.74–1.60]	1.54 [0.87–2.71]	1.07 [0.71–1.63]
	Cholecystectomy	94	1,623,158	129,388	5.79	0.64 [0.36–1.16]	0.63 [0.47–0.85]	0.67 [0.35–1.29]	0.76 [0.55–1.03]
	Sphincterotomy	78	76,742	22,564	101.6	1.99 [0.64–6.16]	1.85 [0.77–4.45]	1.98 [0.64–6.16]	1.93 [0.80–4.65]
	Cholecystectomy and sphincterotomy	20	158,612	17,277	12.6	1.21 [0.39–3.74]	0.50 [0.16–1.55]	1.46 [0.47–4.54]	0.64 [0.21–2.00]
Pancreatic	Unexposed	13.511	101,593,121	4,442,070	13.3	Ref.	Ref.	Ref.	Ref.
	Gallstones	264	634,122	145,446	41.6	0.82 [0.52–1.30]	0.63 [0.46–0.88]	0.90 [0.57–1.43]	0.66 [0.47–0.93]
	Cholecystectomy	153	1,618,051	128,555	9.46	0.32 [0.19–0.54]	0.44 [0.35–0.55]	0.27 [0.15–0.50]	0.45 [0.35–0.57]
	Sphincterotomy	370	73,854	20,245	501.0	3.85 [2.23–6.63]	0.67 [0.25–1.78]	3.68 [2.09–6.49]	0.72 [0.27–1.91]
	Cholecystectomy and sphincterotomy	55	157,619	16,884	34.9	1.00 [0.45–2.22]	0.50 [0.24–1.04]	1.11 [0.50–2.46]	0.49 [0.22–1.08]
Esophageal	Unexposed	8981	101,670,345	4,442,528	8.83	Ref.	Ref.	Ref.	Ref.
	Gallstones	112	635,872	146,216	17.6	0.58 [0.31–1.08]	0.79 [0.57–1.09]	0.68 [0.36–1.26]	0.93 [0.67–1.29]
	Cholecystectomy	82	1,623,628	129,484	5.05	0.44 [0.26–0.74]	0.41 [0.32–0.53]	0.50 [0.29–0.89]	0.57 [0.43–0.74]
	Sphincterotomy	21	76,998	22,766	27.3	0.98 [0.32-3.04]	0.55 [0.18-1.69]	0.96 [0.31-2.99]	0.57 [0.18-1.75]
	Cholecystectomy and sphincterotomy	9	158,668	17,297	5.67	0.21 [0.03–1.48]	0.42 [0.18–1.02]	0.25 [0.04–1.81]	0.55 [0.23–1.33]
Gastric	Unexposed	10.044	101,666,007	4,442,388	9.88	Ref.	Ref.	Ref.	Ref.
	Gallstones	160	635,251	146,032	25.2	1.02 [0.66–1.58]	0.65 [0.47–0.91]	1.14 [0.72–1.78]	0.73 [0.52–1.03]
	Cholecystectomy	129	1,621,951	129,326	7.95	0.62 [0.41–0.94]	0.54 [0.44–0.67]	0.65 [0.41–1.04]	0.68 [0.55–0.86]
	Sphincterotomy	26	76,902	22,731	33.8	0.56 [0.14–2.24]	0.93 [0.42–2.07]	0.56 [0.14–2.26]	0.81 [0.34–1.96]
	Cholecystectomy and sphincterotomy	12	158,615	17,288	7.57	0.55 [0.18–1.71]	0.37 [0.15–0.88]	0.66 [0.21–2.04]	0.46 [0.19–1.10]
Duodenal	Unexposed	649	101,759,604	4,442,962	0.64	Ref.	Ref.	Ref.	Ref.
	Gallstones	31	636,623	146,376	4.87	2.21 [0.71–6.87]	0.25 [0.04–1.81]	2.35 [0.76–7.33]	0.27 [0.04–1.93]
	Cholecystectomy	23	1,624,518	129,542	1.42	2.72 [1.22–6.08]	0.72 [0.36–1.45]	2.94 [1.31–6.58]	0.78 [0.39–1.57]
	Sphincterotomy	33	77,098	22,811	42.8	3.58 [0.50–25.5]	1.92 [0.27–13.7]	3.61 [0.51–25.7]	1.96 [0.28–14.0]
	Cholecystectomy and sphincterotomy	9	158,766	17,308	5.67	2.62 [0.37–18.6]	2.94 [0.95–9.17]	2.74 [0.39–19.5]	3.11 [0.997–9.69]
Small bowel	Unexposed	1391	101,754,031	4,442,915	1.37	Ref.	Ref.	Ref.	Ref.
	Gallstones	71	636,413	146,340	11.2	2.93 [1.46–5.88]	1.44 [0.79–2.61]	3.21 [1.60–6.45]	1.44 [0.77–2.69]
	Cholecystectomy	56	1,624,378	129,560	3.45	2.46 [1.40–4.35]	1.03 [0.68–1.55]	2.75 [1.56–4.87]	1.15 [0.76–1.74]
	Sphincterotomy	15	77,102	22,821	19.5	0.00 [0.00–∞]	1.10 [0.15–7.80]	0.00 [0.00–∞]	1.15 [0.16–8.19]
	Cholecystectomy and sphincterotomy	6	158,754	17,310	3.78	3.92 [1.26–12.2]	0.52 [0.07–3.71]	4.21 [1.35–13.1]	0.57 [0.08–4.05]

HR, hazard ratio; y, years; Ref., reference group.

Cases/100,000 person years.

Adjusted for sex (female, male), socioeconomic status (employee (ref.), self-employed/manager, retired, student, temporary transfer income/on leave, transfer income/unemployed), civil status (married/registered partner, unmarried, widowed, divorced), level of education (high school/elementary school (ref.), vocational training, short/medium-term education, higher university education), personal annual income.

When inspecting the crude cumulative incidence curves, patients with gallstones have higher incidence of biliary and gallbladder cancer than controls, whereas patients after sphincterotomy have much higher incidence of biliary, gallbladder, hepatic, and pancreatic cancer. Patients with both cholecystectomy and sphincterotomy have higher incidence of biliary and pancreatic cancers. Patients with cholecystectomy have lower incidence of pancreatic and gastric cancer than controls (Fig. 1).

Fig. 1.

Cumulative incidence curves for cancer outcomes.

Estimates for unadjusted and adjusted analyses were very similar regarding significance level in both exposure periods, except for gastric cancer (Table 3).

Patients with gallstones significantly more often developed biliary and small bowel cancer at 2–5 years of follow-up and gallbladder cancer at above 5 years compared with controls. An inverse association for gallstones and pancreatic cancer at above 5 years follow-up was seen. Those with cholecystectomy significantly more often developed duodenal and small bowel cancer at 2–5 years. Sphincterotomy caused both gallbladder and pancreatic cancer development significantly more often at 2–5 years. Sphincterotomy caused biliary cancer development significantly more often at above 5 years. Those with both cholecystectomy and sphincterotomy had significant associations for biliary and small bowel cancer at 2–5 years. Inverse associations for cholecystectomy and biliary, pancreatic, esophageal, and gastric cancer at above 5 years were found (Table 3).

Sensitivity analysis for biliary cancer with addition of primary sclerosing cholangitis to the multivariable adjusted model did not change estimates substantially (Supplemental Material).

Discussion

Through long-term follow-up of a nationwide population sample and with time-varying exposures for symptomatic gallstones and treatments thereof, we found associations for sphincterotomy and biliary, gallbladder, and pancreatic cancer. Cholecystectomy was associated with duodenal and small bowel cancer. Gallstones were associated with gallbladder and small bowel cancer. Inverse associations were found for cholecystectomy and biliary, pancreatic, esophageal, and gastric cancer and for gallstones and pancreatic cancer.

We define strong and precise associations as statistically significant estimates with narrow confidence intervals and as being present after 5 years of follow-up. Such associations were identified for sphincterotomy and biliary cancer, for gallstones and gallbladder cancer, and the inverse association for cholecystectomy and pancreatic cancer. The association for sphincterotomy and biliary cancer was not altered with the inclusion of primary sclerosing cholangitis in the multivariable model indicating no issues with confounding. Both gallstones and cholecystectomy were associated with small bowel cancer. Associations did not persist beyond 5 years of exposure and it may therefore be difficult to interpret whether gallstones or cholecystectomy caused cancer development.

Another study based on the National Health Insurance Research Database in Taiwan suggested associations for sphincterotomy or sphincter of Oddi balloon dilatation and biliary cancer and also the inverse association for cholecystectomy and biliary cancer when compared with controls with gallstones.¹⁹ The study is not consistent with our study as no general population controls without gallstones or treatments were used, adjusted time-to-event analysis were not performed, the study population was much smaller, and changing exposures were not accounted for. A population-based cohort study from Sweden identified gallstones to be associated with development of biliary cancer²⁰ consistent with our study. The study also found that cholecystectomy reduced the risk of biliary cancer back to the level of the background population with time after cholecystectomy based on similar standardized incidence ratios. The authors suggested mechanisms of chronic biliary inflammation in presence of gallstones which may be altered by cholecystectomy.²⁰ Another study finds gallstones associated with pancreatic cancer when compared with population controls, but finds no significant associations following cholecystectomy.²¹ These results are not consistent with our findings of an inverse association for cholecystectomy and biliary or pancreatic cancer when compared with the general population, but they do suggest a protective mechanism of cholecystectomy in patients with gallstones. The association for gallstones and gallbladder cancer has been reported several times before.² To our knowledge, this is the first study to report an inverse association for cholecystectomy and pancreatic cancer as well as the other inverse associations for cholecystectomy in patients with gallstone treatments when compared with the background population.

Cholecystectomy causes a continuous bile flow into the bowel^22,23 and an altered microbiota with increased bacterial dehydroxylation of primary bile acids into secondary bile acids^23,24 with the latter being carcinogenic.^25,26 Secondary bile acids and the bacteria producing them are also found in higher amounts in persons with gallstones and gallbladders in situ compared with persons without gallstones,^27–30 suggesting similar pathophysiological mechanisms in the non-cholecystectomy state. Sphincterotomy eliminates the function of the sphincter of Oddi and removes the common bile duct to duodenal pressure gradient which is believed to cause reflux of duodenal content into the common bile duct and pancreatic duct.³¹ Following sphincterotomy, a number of changes in bile and common bile duct are found, including colonization with bowel bacteria,³² higher amounts of secondary bile acids and cytotoxic agents, histological chronic inflammation,³³ and atypical cells indicating cell proliferation.³⁴ These experimental observations indicate a plausible and coherent cancer transformation mechanism seen with gallstones and sphincterotomy for gallbladder and biliary cancer. Reflux with chronic biliary inflammation has also been suggested as mechanism for biliary cancer transformation in smaller clinical series following patients with sphincterotomy.^3,5 The suggested mechanisms may also explain the possible mechanisms for duodenal and small bowel cancer development following cholecystectomy. No apparent mechanisms may be suggested to explain the inverse associations for cholecystectomy and cancer of the more oral sites as found in this study. Further studies are awaited.

The strength of this study is that it is the first cohort study to explore associations for specific and changing exposures of gallstones, treatments thereof, and cancer outcome in the general population. The comprehensiveness of the databases used in this study enabled all exposure treatments and occurrences of cancer to be registered nationwide without loss. The study population was also the largest reported in cohort studies exploring gallstones, treatments thereof, and cancer at the time of publication. Symptoms from a cancer may be clinically misinterpreted as gallstones as suggested earlier.³⁵ To avoid such diagnostic mimicry and risk of detection bias and to secure temporal associations, we did not include estimates during the first 2 years of follow-up. Limitations of this study include that only symptomatic gallstones causing hospital admission were identified. We know from a previous cohort study of screen-detected gallstones found in a population with systematic ultrasound screening, that clinically identified gallstones leading to hospital admission are only accountable for about one-fifth of persons with gallstones. Furthermore, specific characteristics determine symptomatic gallstones.^36,37 The true gallstone prevalence is therefore underestimated in this study with risk of potential differential misclassification bias. This could cause both significant and nonsignificant estimates when the gallstone exposure was explored, and these results should therefore be interpreted with caution. Estimates for sphincterotomy and cholecystectomy do not have such risk. Anthropometric data were not available which could cause residual confounding, but we included socioeconomic variables as proxy in models to minimize the impact of such potential bias. Due to differences in initiation dates of the registries used in this study, persons may have been older than 30 years when included. This baseline difference was addressed through having age as the underlying timescale.

The strong and precise association for sphincterotomy and biliary cancer found in this large nationwide population-based cohort with long-term and advanced follow-up analyses suggest a causal association. The association’s consistency should be explored in future cohort studies including similarly large populations and design. ERC with sphincterotomy is presently the most utilized treatment for common bile duct stones.³⁸ Alternatives for therapeutic common bile duct stone extraction without the use of sphincterotomy are available and have comparable clinical outcomes.³⁹ For now, caution with performance of sphincterotomy is advised and especially in younger patients.

In conclusion, this large nationwide population-based cohort study identified a novel association for endoscopic sphincterotomy and development of biliary cancer after more than 5 years of follow-up. Caution with use of sphincterotomy in younger patients may be advised until further studies are performed. Cholecystectomy seems to be inversely associated with biliary, pancreatic, esophageal, and gastric cancer. These associations should be explored in larger cohort studies with similar designs in the future.

Supplemental Material

sj-docx-sjs-10.1177_14574969221116941 – Supplemental material for Development of upper gastrointestinal cancer in patients with symptomatic gallstones, cholecystectomy, and sphincterotomy: A nationwide cohort study

Supplemental material, sj-docx-sjs-10.1177_14574969221116941 for Development of upper gastrointestinal cancer in patients with symptomatic gallstones, cholecystectomy, and sphincterotomy: A nationwide cohort study by Daniel M. Shabanzadeh, Torben Martinussen and Lars T. Sørensen in Scandinavian Journal of Surgery

Footnotes

Acknowledgements

The authors give credit to Sofie Korn and Frederik Mølkjær Andersen for performing data management and analyses, to Karin Mønsted Shabanzadeh for linguistic edit, and to Torben Jørgensen for his insights and help with the manuscript.

Author contributions

D.M.S. contributed to the study design, performing analyses, interpretation of results, drafting, and final acceptance of manuscript. T.M. contributed to performing analyses, interpretation of results, critical review, and final acceptance of manuscript. L.T.S. contributed to study design, interpretation of results, critical review, and final acceptance of manuscript.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by The Faculty of Health and Medical Sciences at the University of Copenhagen. The University of Copenhagen had no role in the study design or in the collection, analysis, and interpretation of data.

ORCID iD

Daniel M. Shabanzadeh

Supplemental material

Supplemental material for this article is available online.

References

Shabanzadeh

Sorensen

Jorgensen

: Association between screen-detected gallstone disease and cancer in a cohort study. Gastroenterology 2017;152:1965–1974.e1961.

Chen

Yeh

Lin

, et al: Cancer risk in patients with cholelithiasis and after cholecystectomy: A nationwide cohort study. J Gastroenterol 2014;49(5):923–931.

Fujimoto

Tsuyuguchi

Sakai

, et al: Long-term outcome of endoscopic papillotomy for choledocholithiasis with cholecystolithiasis. Dig Endosc 2010;22:95–100.

Tanaka

Takahata

Konomi

, et al: Long-term consequence of endoscopic sphincterotomy for bile duct stones. Gastrointest Endosc 1998;48(5):465–469.

Hakamada

Sasaki

Endoh

, et al: Late development of bile duct cancer after sphincteroplasty: A ten- to twenty-two-year follow-up study. Surgery 1997;121(5):488–492.

Shaffer

: Gallstone disease: Epidemiology of gallbladder stone disease. Best Pract Res Clin Gastroenterol 2006;20(6):981–996.

Peery

Crockett

Barritt

, et al: Burden of gastrointestinal, liver, and pancreatic diseases in the United States. Gastroenterology 2015;149:1731–1741.e1733.

European Association for the Study of the Liver: EASL clinical practice guidelines on the prevention, diagnosis and treatment of gallstones. J Hepatol 2016;65(1):146–181.

NOMESCO: Health Statistics for the Nordic Countries 2017, 2017, https://norden.diva-portal.org/smash/get/diva2:1148509/FULLTEXT05.pdf

10.

Bray

Balcaen

Baro

, et al: Increased incidence of cholecystectomy related to gallbladder disease in France: Analysis of 807,307 cholecystectomy procedures over a period of seven years. J Visc Surg 2019;156(3):209–215.

11.

Moffatt

Yie

, et al: Trends in utilization of diagnostic and therapeutic ERCP and cholecystectomy over the past 25 years: A population-based study. Gastrointest Endosc 2014;79(4):615–622.

12.

Parikh

Gupta

Thota

, et al: Temporal trends in utilization and outcomes of endoscopic retrograde cholangiopancreatography in acute cholangitis due to choledocholithiasis from 1998 to 2012. Surg Endosc 2018;32(4):1740–1748.

13.

Schmidt

Pedersen

Sorensen

: The Danish Civil Registration System as a tool in epidemiology. Eur J Epidemiol 2014;29(8):541–549.

14.

Lynge

Sandegaard

Rebolj

: The Danish National Patient Register. Scand J Public Health 2011;39:30–33.

15.

Helweg-Larsen

: The Danish Register of causes of death. Scand J Public Health 2011;39:26–29.

16.

Boonstra

Weersma

van Erpecum

, et al: Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology 2013;58(6):2045–2055.

17.

Andersen

Geskus

de Witte

, et al: Competing risks in epidemiology: Possibilities and pitfalls. Int J Epidemiol 2012;41(3):861–870.

18.

Cox

: Regression models and life-tables. J Roy Stat Soc B Met 1972;34:187–220.

19.

Wang

Tsai

Sung

, et al: Risk of cholangiocarcinoma in patients undergoing therapeutic endoscopic retrograde cholangiopancreatography or cholecystectomy: A population based study. World J Gastrointest Oncol 2019;11:238–249.

20.

Nordenstedt

Mattsson

El-Serag

, et al: Gallstones and cholecystectomy in relation to risk of intra- and extrahepatic cholangiocarcinoma. Br J Cancer 2012;106:1011–1015.

21.

Wang

Tseng

, et al: Symptomatic cholelithiasis patients have an increased risk of pancreatic cancer: A population-based study. J Gastroenterol Hepatol 2021;36(5):1187–1196.

22.

Pomare

Heaton

: The effect of cholecystectomy on bile salt metabolism. Gut 1973;14(10):753–762.

23.

Malagelada

Summerskill

, et al: Bile acid secretion and biliary bile acid composition altered by cholecystectomy. Am J Dig Dis 1973;18(6):455–459.

24.

Hepner

Hofmann

Malagelada

, et al: Increased bacterial degradation of bile acids in cholecystectomized patients. Gastroenterology 1974;66(4):556–564.

25.

Cook

Kennaway

: Production of tumors in mice by deoxycholic acid. Nature 1940;145:627.

26.

Hill

Drasar

Williams

, et al: Faecal bile-acids and clostridia in patients with cancer of the large bowel. Lancet 1975;1:535–539.

27.

Keren

Konikoff

Paitan

, et al: Interactions between the intestinal microbiota and bile acids in gallstones patients. Environ Microbiol Rep 2015;7(6):874–880.

28.

Berr

Kullak-Ublick

Paumgartner

, et al: 7 alpha-dehydroxylating bacteria enhance deoxycholic acid input and cholesterol saturation of bile in patients with gallstones. Gastroenterology 1996;111(6):1611–1620.

29.

Wells

Berr

Thomas

, et al: Isolation and characterization of cholic acid 7alpha-dehydroxylating fecal bacteria from cholesterol gallstone patients. J Hepatol 2000;32(1):4–10.

30.

Mamianetti

Garrido

Carducci

, et al: Fecal bile acid excretion profile in gallstone patients. Medicina 1999;59(3):269–273.

31.

Geenen

Toouli

Hogan

, et al: Endoscopic sphincterotomy: Follow-up evaluation of effects on the sphincter of Oddi. Gastroenterology 1984;87(4):754–758.

32.

Gregg

De Girolami

Carr-Locke

: Effects of sphincteroplasty and endoscopic sphincterotomy on the bacteriologic characteristics of the common bile duct. Am J Surg 1985;149(5):668–671.

33.

Bergman

van Berkel

Groen

, et al: Biliary manometry, bacterial characteristics, bile composition, and histologic changes fifteen to seventeen years after endoscopic sphincterotomy. Gastrointest Endosc 1997;45(5):400–405.

34.

Kalaitzis

Vezakis

Fragulidis

, et al: Effects of endoscopic sphincterotomy on biliary epithelium: A case-control study. World J Gastroenterol 2012;18:794–799.

35.

Goldacre

Wotton

Abisgold

, et al: Association between cholecystectomy and intestinal cancer: A national record linkage study. Ann Surg 2012;256(6):1068–1072.

36.

Shabanzadeh

Sorensen

Jorgensen

: A prediction rule for risk stratification of incidentally discovered gallstones: Results from a large cohort study. Gastroenterology 2016;150(1):156–167.

37.

Shabanzadeh

Sorensen

Jorgensen

: Determinants for clinical events in gallstone carriers unaware of their gallstones. J Gastroenterol Hepatol 2017;32(3):721–726.

38.

Wandling

Hungness

Pavey

, et al: Nationwide assessment of trends in choledocholithiasis management in the United States From 1998 to 2013. JAMA Surg 2016;151:1125–1130.

39.

Pan

Chen

, et al: The safety and efficacy of laparoscopic common bile duct exploration combined with cholecystectomy for the management of cholecysto-choledocholithiasis: An up-to-date meta-analysis. Ann Surg 2018;268(2):247–253.

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