Symptomatic Cholelithiasis Patients Have Increased Pancreatic Cancer Risk- A Population Based Study

Background :Pancreatic cancer is a fatal disease, andthe current risk factor survey is not suitable for sporadic pancreatic cancerthat lacks obvious family history orgenetic analysis data.The aim of the present study was to evaluate the roles of cholelithiasis and cholelithiasis treatmentson pancreatic cancer risk. Methods: Symptomatic adult patients with an index admission ofcholelithiasis diagnosis were selectedfrom one million random samples of National Health Insurance Research Database (NHIRD)obtained between January 2005 andDecember 2009. Exclusion criteria included pancreatic cancer, benign neoplasm or anomalies of the pancreas, orendoscopic sphincterotomy/endoscopic papillary balloon dilatation (ES/EPBD), cholecystectomy (CCY) before 2004. The control group was matched in a 1:1 ratio for sex, age,chronic pancreatitis and pancreatic cystic disease. The study group was divided into ES/EPBD, CCY, ES/EPBD&CCY, and nointervention groupsfor subsequent pancreatic cancer evaluation. Results: Both the cholelithiasis group and the matched control group included 8,265 adult cases. The cholelithiasis group contained 86 (1.04%) cases of diagnosed pancreatic cancer and the control group contained8 (0.10%) cases (p<0.001). Exclusion of pancreatic cancer cases diagnosed in the rst 6 months still resulted in asignicantly higher pancreatic cancer rate in the cholelithiasis group (0.22%) thanin the control group (0.05%)(p=0.003). The subsequent pancreatic cancer rates weresimilar,at0.17%, 0.11%, 0.26%, and 0.29%, in the ES/EPBD, CCY, ES/EPBD&CCY, and no-intervention groups, respectively. Conclusion:Symptomatic cholelithiasis and regardless of the intervention of cholelithiasis. (ES) or endoscopic papillary balloon dilatation (EPBD) 33 . The recognition that pancreatic juice and bile reux in patients with pancreaticobiliary maljunction can lead to biliary malignancy 34, 35 led us to postulate a role for cholelithiasis, an increasing and high-prevalence disease worldwide, in pancreatic cancer. We conducted this retrospective database study to conrm whether symptomatic cholelithiasis or invasive interventions for cholelithiasis are risk factors for pancreatic cancer.

Pancreatic cancer is a fatal disease, and surgical resection is possible only in a small portion of patients 1 . Even in the patients who can undergo pancreaticoduodenectomy, the ve-year survival rate is less than 30 percent for patients with T1 tumors and only 10 percent for those with other resectable pancreatic cancers 2 . Today, R0 resection remains the only curative treatment and survival guarantee for pancreatic cancer 2 , but most symptomatic patients with pancreatic cancer have advanced, incurable disease at diagnosis. Therefore, R0 resection is a mission impossible, given the lack of an e cient screening policy.
The current screening policy focuses on familial pancreatic cancer, the presence of Peutz-Jeghers syndrome 3 , and individuals with a pancreatic cancer family history 4 . Pancreatic cancer is a genetic disease caused by inherited and acquired mutations in certain cancer-associated genes 5 that lead normal pancreatic cells to form precursor lesions or invasive carcinomas. This recognition has led to a new classi cation system of pancreatic neoplasms 6-8 ; however, the majority of newly diagnosed pancreatic cancer patients still cannot bene t from the current screening method.
Many risk factors have already been recognized in the existing literature, including hereditary risk factors 9 , germline mutations 10 , non-O blood type 11 , diabetes mellitus (DM) 12-14 , cigarette smoking 15-18 , obesity 19, 20 , physical inactivity 21, 22 , chronic hepatitis B (CHB) 23, 24 , chronic hepatitis C (CHC) 23, 25 , and Helicobacter pylori (HP) infection 26-28 , but the best-known and strongest risks are chronic pancreatitis (CP) 29, 30 and pancreatic cystic disease (PCD) 31,32 . A screening policy is hard to plan, except for CP and PCD patients, and gene analysis is too expensive for use as a screening method.
In our previous study, we found that patients with cholelithiasis have a higher cholangiocarcinoma risk when compared with the normal population, and this is especially true in patients who undergo endoscopic sphincterotomy (ES) or endoscopic papillary balloon dilatation (EPBD) 33 . The recognition that pancreatic juice and bile re ux in patients with pancreaticobiliary maljunction can lead to biliary malignancy 34, 35 led us to postulate a role for cholelithiasis, an increasing and high-prevalence disease worldwide, in pancreatic cancer. We conducted this retrospective database study to con rm whether symptomatic cholelithiasis or invasive interventions for cholelithiasis are risk factors for pancreatic cancer.

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This study was a population-based retrospective cohort study based on Taiwan's NHIRD and the study methods have been described in detail in our previous studies 33,36 . This study was approved by the local Institutional Review Board (IRB) and the IRB waived the need for informed consent in this study. All authors have declared no con icts of interest in this study.

Study design
Symptomatic patients more than 18 years old with an index admission with a diagnosis of cholelithiasis were selected from one million random samples of NHIRD data between January 2005 to December 2009 using Codes of International Statistical Classi cation of Diseases and Related Health Problems-9th Edition (ICD-9). We excluded patients who had undergone ES/EPBD, CCY, and lithotripsy in 2004. Patients with a diagnosis in 2004 of pancreatic cancer, benign neoplasm of pancreas, or anomalies of pancreas were also excluded. A control group was selected by matching in a 1:1 ratio by sex, age, and the strong pancreatic cancer risk factors of CP and PCD. The control group cases were de ned as individuals who had neither been diagnosed with cholelithiasis nor undergone a related medical procedure before January 2005. The variables of follow-up time and known risk factors (such as CHB, CHC, HP infection, DM, ESRD, CP, and PCD) were compared between the two groups. We calculated the number of pancreatic cancer cases and rates of pancreatic cancer after index admission and 6 months after ES/EPBD, CCY, and ES/EPBD & CCY intervention following index admission. We regarded pancreatic cancer that arose after the rst 6 months as subsequent pancreatic cancer, which is recommended for the evaluation of procedure-related pancreatic cancer. However, the patients with pancreatic cancer diagnosed within 6 months after index admission for cholelithiasis were more likely to have been misdiagnosed or to have a concurrent malignancy rather than a subsequent pancreatic cancer. Detailed information about the study design is shown in Fig. 1. The ICD-9 codes for the diseases listed above and their procedure codes are provided in the supplementary table.
We divided the study group further into cases who had undergone ES/EPBD, CCY, or ES/EPBD & CCY and cases who had not undergone any invasive intervention (the no-intervention group). The age, gender, previous known risk factors for pancreatic cancer, pancreatic cancer rate, and subsequent pancreatic cancer rate for these four subgroups are compared in Table 2. The incidence of subsequent pancreatic cancer in these subgroups was also compared with that in the control group, and the cumulative risk of subsequent pancreatic cancer was calculated for each subgroup and the control group. Evaluation of the subsequent pancreatic cancer risk revealed one subsequent pancreatic cancer in the ES/EPBD group, four in the CCY group, one in the ES/EPBD & CCY group, and 11 in the no-intervention group. Although the pancreatic cancer risk differed signi cantly among these groups, the subsequent pancreatic cancer rates were similar, at 0.17%, 0.11%, 0.26%, and 0.29% in the ES/EPBD, CCY, ES/EPBD & CCY, and no-intervention groups, respectively. The cumulative subsequent pancreatic cancer risks, shown in Fig. 3, are similar in all four groups (p = 0.492).
Evaluation of the previous pancreatic cancer risk factors indicated that CHB and HP infection were not statistically different in these groups. The no-intervention group had a higher proportion of patients having CHC, DM, and ESRD, whereas patients with CP and PCD were more frequent in the ES/EPBD (2.80% and 0.70%, respectively) or ES/EPBD & CCY (3.09% and 0.77%, respectively) groups.
Detailed information is shown in Table 2.

The incidence of subsequent pancreatic cancer
This was a retrospective study; therefore, the subsequent pancreatic risks may be confounded by different follow-up times. The incidences of pancreatic cancer after the rst 6 months (henceforth, subsequent pancreatic cancer) between patients who underwent ES/EPBD, CCY, ES/EPBD & CCY, no intervention for cholelithiasis, and the control group were compared using the incidence rate per 1000 person-years. The ES/EPBD group showed an incidence of subsequent pancreatic cancer of 0.495 (0.025-2.439) per 1000 person-years, which is 4-fold greater than the incidence in the control group, although this difference did not meet statistical The incidence of subsequent pancreatic cancer in the no-intervention group was 9-fold higher than in the control group, and this was the only subgroup that had a subsequent pancreatic cancer incidence, at 0.911 (0.479-1.584) per 1000 person-years, that differed signi cantly from the incidence in the normal population, at 0.113 (0.036-0.273) per 1000 person-years (p < 0.001). The incidence of subsequent pancreatic cancer was even higher for females in the no-intervention group, at 1.216 (0.532-2.404) per 1000 person-years. All these data are shown in Table 3. Discussion: The current surveillance and screening suggestions for pancreatic cancer are di cult to carry out in clinical practice. For this reason, we have attempted to identify a high risk group without resorting to complicated and costly genetic analysis. We noted that many well-known risk factors for cholangiocarcinoma, such as CHB, CHC 39, 40 ,DM 41, 42 , and HP infection 43, 44 , are coincidentally also risk factors for pancreatic cancer. We also recognized that cholelithiasis is an important risk factor for bile duct cancer 45, 46 ; therefore, we explored the possible relationship between cholelithiasis and pancreatic cancer and the in uences of invasive bile duct procedures on the subsequent pancreatic cancer rate. As reported here, we found that the pancreatic cancer rate is signi cantly higher in the cholelithiasis group than in the control group after adjustment for CP and PCD (1.04% vs. 0.10%, p < 0.001).
Because the previous known risk factors of pancreatic cancer, such as CHB, CHC, DM, HP, are higher in cholelithiasis group, the increased pancreatic cancer risk may be confound by these factors. We performed multivariate analysis between these risk factors to isolate the most important risk factors for pancreatic cancer and it revealed old age, symptomatic cholelithiasis (Odds ratio 9.971 [4.793-20.744], p < 0.001) and DM to be signi cant risk factors of pancreatic cancer after CP and PCD been excluded by our study design. Symptomatic cholelithiasis is the most important risk factors of pancreatic cancer in both cholelithiasis and control group, the details were shown in Table 4. In the second part of this study, we de ned pancreatic cancer newly diagnosed at least 6 months after index admission as subsequent pancreatic cancer as a way to exclude the possibility of misdiagnosis or concurrent pancreatic cancer during cholelithiasis treatment.
We evaluated the effect of invasive bile duct interventions, like ES/EPBD, CCY, and ES/EPBD & CCY, on the subsequent pancreatic cancer risk. Comparisons between patients with cholelithiasis and the control group revealed a signi cantly higher subsequent pancreatic cancer risk in the patients with cholelithiasis (0.22% vs. 0.05%, p = 0.003). Comparisons of the four subgroups in the cholelithiasis group revealed that the subsequent pancreatic cancer risk was only slightly higher in the no-intervention group, but the difference was not statistically signi cant. The different invasive procedures for cholelithiasis treatment therefore do not appear to affect the subsequent pancreatic cancer risk, according to our analysis.
Our study had several limitations. One was that this was a retrospective national cohort database study, so no laboratory data results or clinical images are presented. We can only rely on the diagnosis made by clinical physicians and cannot re-evaluate these patients to get better diagnoses. This is partly why we excluded pancreatic cancer diagnosed in the rst 6 months after index admission in our analysis of the procedure-related pancreatic cancer rates. However, the innate character of a national cohort database means that this selection also avoids patient loss at follow-up and missed diagnoses of pancreatic cancer, even in patients who underwent treatment at different hospitals. Another limitation is that the total pancreatic cancer occurrence was 86 patients in the cholelithiasis group and 8 patients in control group, but the subsequent pancreatic cancer occurrence was only one patient in the ES/EPBD and ES/EPBD & CCY groups, which makes any statistical signi cance di cult to detect. Further larger scaled retrospective or prospective studies are needed to evaluate the procedure-related subsequent pancreatic cancer risks. A third limitation is that the cholelithiasis group had higher proportions of some pancreatic cancer risk factors, such as CHB, CHC, HP, and DM. Although CHC and ESRD 47 can be explained by common risk factors of cholelithiasis itself, CHB, HP, and DM may slightly affect the pancreatic cancer risk between the cholelithiasis and control groups. For this reason, we have done the multivariate analysis in these risk factors of pancreatic cancer.

Consent for publication
There is no identifying images, other personal or clinical details of participants presented in our study. Because of the design of this de-link database article, consent to publish is not applicable to my manuscript.

Availability of data and materials
The datasets generated and analysed during the current study are not publicly available due to they come from NHIRD but are partially available from the corresponding author on reasonable request.
Supervision: M-C T All authors have read and approved the manuscript.

Figure 1
Flow chart for case selection from a database of one million nationwide representatives in Taiwan NHIRD = National Health Insurance Research Database, ES= endoscopic sphincterotomy, EPBD= endoscopic papillary balloon dilatation