In total, 8,440 adult symptomatic cholelithiasis admission cases were selected from one million random samples of NHIRD data between January 2005 and December 2009. Cases (n = 101) that had undergone ES/EPBD, CCY, or lithotripsy in 2004 or before the diagnosis of cholelithiasis (n = 101) and cases (n = 74) diagnosed with pancreatic cancer, benign neoplasm of pancreas, or anomalies of the pancreas before index admission were excluded. We selected 8,265 cholelithiasis patients who had none of these exclusion criteria from January 2005 to December 2009 as the study group. The control group was drawn at a 1:1 ratio from cases without cholelithiasis but matching the study group in age, gender, and CP and PCD risk. The 8,265 patients in the cholelithiasis group had a mean age of 61 ± 16.98 years, and those in the control group had a mean age of 61 ± 17.29 years. Males accounted for 51.25% of the subjects in both the cholelithiasis and control groups.
Our use of age, gender, and CP and PCD risk to establish the control group without cholelithiasis minimized the risk factors of pancreatic cancer, which could confound the results. The age distribution was also similar in both groups. The cholelithiasis group had significantly higher pancreatic cancer risk factors, such as CHB (9.35% vs. 2.47%), CHC (7.48% vs. 2.06%), HP infection (1.58% vs. 0.59%), DM (32.56% vs. 17.29%), and end stage renal disease (ESRD; 3.04% vs. 1.06%). Some of these risk factors are also risk factors for cholelithiasis38.
The cholelithiasis group contained 86 (1.04%) cases diagnosed as pancreatic cancer, while the control group had 8 (0.10%) (p < 0.001). Exclusion of pancreatic cancer cases occurring in the first 6 months after index admission still revealed a significantly higher subsequent pancreatic cancer rate in the cholelithiasis group (0.22%) than in the control group (0.05%) (p = 0.003). These comparisons are shown in Table 1. The cumulative risks of cholelithiasis group and control group for pancreatic cancer (Panel A) and subsequent pancreatic cancer (Panel B) are demonstrated in Fig. 2.
Table 1
Demographic data of the study and control group
| Cholelithiasis group N = 8265 | Control group N = 8265 | p value |
N | SD; % | N | SD; % | |
Age, mean (SD) Age, years | 61.00 | 16.98 | 61.00 | 17.29 | 1.000 0.364 |
18–49 | 2118 | 25.63 | 2197 | 26.58 | |
50–69 | 3038 | 36.76 | 3013 | 36.45 | |
> 70 | 3109 | 37.62 | 3055 | 36.96 | |
Gender | | | | | 1.000 |
Male | 4236 | 51.25 | 4236 | 51.25 | |
Female | 4029 | 48.75 | 4029 | 48.75 | |
Follow up time (months), mean (SD) | 43.69 | 22.75 | 51.30 | 18.63 | < 0.001 |
Risk factors for pancreatic cancer | | | | | |
CHB | 773 | 9.35 | 204 | 2.47 | < 0.001 |
CHC | 618 | 7.48 | 170 | 2.06 | < 0.001 |
HP | 131 | 1.58 | 49 | 0.59 | < 0.001 |
DM | 2691 | 32.56 | 1429 | 17.29 | < 0.001 |
ESRD | 251 | 3.04 | 88 | 1.06 | < 0.001 |
CP | 141 | 1.71 | 141 | 1.71 | 1.000 |
PCD | 32 | 0.39 | 32 | 0.39 | 1.000 |
Pancreatic cancer | | | | | |
Number (rate) | 86 | 1.04 | 8 | 0.10 | < 0.001 |
Follow up time (months), mean (SD) | 17.11 | 23.35 | 19.93 | 19.15 | < 0.001 |
Pancreatic cancer after first 6 months | | | | | |
Number (rate) | 18 | 0.22 | 4 | 0.05 | 0.003 |
Follow up time (months), mean (SD) | 34.63 | 23.77 | 35.93 | 12.94 | < 0.001 |
SD = standard deviation, MBS = minimum basic salary, CHB = chronic hepatitis B, CHC = chronic hepatitis C, HP = Helicobacter infection, DM = diabetes mellitus, ESRD = end-stage renal disease, CP = chronic pancreatitis, PCD = pancreatic cystic disease |
Cholelithiasis cases that underwent ES/EPBD, CCY, ES/EPBD & CCY, or no intervention
Of the 8,265 patients with index cholelithiasis, 572 underwent ES/EPBD, 3,518 underwent CCY, 388 underwent ES/EPBD & CCY, and 3,787 received supportive care without further intervention. The average age was 67.00 ± 15.55 years in the ES/EPBD group, 56.00 ± 16.14 years in the CCY group, 60.00 ± 15.95 years in the ES/EPBD & CCY group, and 65.00 ± 16.69 years in the no-intervention group. Patients were statistically younger in the CCY and ES/EPBD & CCY groups, and these groups had a higher proportion of patients aged 18–49 years. The follow-up time was the shortest for the no-intervention group because of the clinical comorbidity condition in this group. The CCY group had the highest proportion of females, at 52.73% vs. 47.27%, and we believe the higher prevalence of gallbladder stones in females can explain this result.
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 significantly 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 first 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 significance. The incidence of subsequent pancreatic cancer was 0.070 (0.003–0.344) per 1000 person-years in the CCY group (p = 0.223), 0.598 (0.030–2.950) in the ES/EPBD & CCY group (p = 0.225), and 0.911 (0.479–1.584) in the no-intervention group (p < 0.001). 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 significantly 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.