This study demonstrated that patients with AP or CP have a higher risk of developing PC compared to the control group. Among the subgroups of pancreatitis, RAP and CP with AP groups showed a higher and more prolonged risk of PC compared to SAP and CP without AP groups. Based on these findings, we suggest that the strategy of cancer surveillance should be individualized based on the specific subgroups of pancreatitis.
The increased risk of PC has been reported in patients with CP with significant variation.3–9,18−21 In Lowenfels et al.’s multinational study, the cumulative incidence of PC in CP patients was 1.8% at 10 years.6 An European cohort study revealed an incidence of PC in CP patients of 0.2% per year.18 A Veterans study in USA revealed the cumulative incidence of 1.04% in the CP group, which was higher than the 0.20% in the control group.3 Recent studies conducted in South Korea reported the cumulative PC incidences of 2.20% in a hospital based study 22 and 0.68% in a population based study.23 Another study on patients who underwent surgery for CP showed a higher cumulative incidence of PC with rates of 1.48% at 3 years, 2.63% at 6 years, and 3.71% at 9 years after surgery.2
In this study, the cumulative incidences of PC at 10 years were strikingly different in the four subgroups of pancreatitis. They were 1.42% in the RAP group and 1.37% in the CP with AP group, which were compatible or slightly lower than previous results. However, they were very low in the CP without AP group (0.26%) and SAP group (0.29%), which were slightly higher than the control group (0.20%).
In this study, the risk of PC was found to be higher in patients with CP with AP compared to those with CP without AP. CP with AP has been reported to exhibit a higher symptom burden and a greater number of flares than CP without AP.12 These patients are often active smokers and have alcohol-related etiology for their CP. The increased risk of PC in these individuals could be attributed to the “injury-inflammation-cancer” pathway.24 Recurrent pancreatic injuries lead to a pro-inflammatory environment characterized by various immune cells, cytokines, chemokines, growth factors, and altered extracellular matrix, thereby promoting prolonged inflammatory and chronic conditions. Inflammation and oncogenes collaborate as key promoters of these diseases.25
Another plausible mechanism is the alcohol related diseases as the primary cause of CP with AP. Previous study has observed an independent association between inflammatory complications and alcoholic etiology.14 However, several studies focusing on AP or CP have reported that the risk of PC does not differ based on alcoholic or non-alcoholic pancreatitis.6,11,20 Furthermore, the higher proportion of smokers in our CP with AP cohort aligns with previous findings that most alcohol users are concurrent smokers.26 It is important to note that smoking is a risk factor for both CP and PC.
The association between AP and PC remains a topic of controversy.2 While some studies have reported a positive association between AP and PC,8 7,11,27 others have found weak or no relation.2 In this study, the risk of PC in SAP group increased by 32% compared to the control group, and this increase persisted for the first 3 years. These findings are consistent with a recent study conducted using a large veterans cohort.11
Regarding RAP, the magnitude of PC risk is still debated. Some studies have reported a 2.4-fold increased risk of PC in RAP compared to SAP,7 while others have not identified a significant difference in PC risk among different subgroups of pancreatitis.8 RAP is considered an intermediate stage in the pathogenesis of CP, and a subset of RAP patients may transit to CP during the natural course of the disease.28 In this study, the shared clinical characteristics of patients with RAP or CP preceding AP, such as higher prevalence of alcohol consumption or smoking, are consistent to a previous study.12 The risk of PC in the RAP group was 4.5-fold higher compared to the control group, while in the SAP group, it was a 1.32-fold higher than the control group. These findings suggest that both RAP and CP with AP are part of the same disease spectrum. These findings are consistent with a recent study that reported that PC risks are related with the number of recurrence in RAP and CP with AP.11 A recent study conducted in South Korea also reported that CP patients with parenchymal calcification have a low risk of PC.22 Based on these findings, including our own results, it is suggested that PC risks are determined by inflammation in the pancreas rather than chronicity.
The risk of PC in patients with CP has been found to decline over time but remains persistent more than 10 years, as observed previous studies, including this one.7,8,10,11,29 In SAP, the risk of PC disappears after 3 years, and in CP without AP, it disappears after 4 years. However, in RAP group and CP with AP group, the increased risk persists for more than 8 years. Based on these findings, it is suggested that the duration of cancer surveillance should be individualized by the specific subgroups of pancreatitis.
Previous studies have reported conflicting findings regarding the risk of PC in AP or CP between males and females.7,10,20,30 A recent study utilizing the UK Biobank cohort reported that males with AP had a higher risk of PC than females, while females with CP had a higher risk of PC than males.29 However, in this study, females showed a higher risk of PC in RAP, CP with AP, and SAP groups, and similar risk in CP without AP group compared to males. Although the exact reasons are not clearly defined, it is possible that males with pancreatitis exhibit more frequent additional risk factors for PC, such as hepatic fibrosis/cirrhosis, alcoholic liver disease, gallstones, hepatic dysfunction, diabetes, smoking, and alcohol drinking. Consequently, the impacts of pancreatitis on the development of PC might be lower in males compared to females.
In this study, a 2-year lag time was applied to account for the possibilities of misdiagnosis of PC as pancreatitis. Because many patients with CP are asymptomatic, they often visit the hospital due to abdominal pain, which can be associated with PC. The risk of misdiagnosis is high due to the similarities in clinical, radiological, and biochemical nature of these diseases.31,32 To address this issue, most studies have utilized a lag time period of 1 or 2 year, as the short-term association between CP and PC risk is most likely due to the initial misdiagnosis of PC as CP.31 However, it is important to note that applying a lag time period carries the risk of excluding a significant number of PC cases from the study. In this study, for example, 96% of PC cases were excluded by the 2-year lag period. The determination of the appropriate lag time is closely related to the accuracy of the differential diagnostic between PC and CP. Therefore, a close follow-up should be conducted in the first two years following a CP diagnosis to avoid overlooking a potential PC cases.
In this study, PC cases diagnosed in pancreatitis group were found to be young and had a better prognosis compared to those in the control group. These findings are consistent with previous studies that found patients with a recent AP were diagnosed with PC at younger age and trended to be diagnosed at an earlier stage compared to PC patients without AP.3,27 The implementation of surveillance among pancreatitis patients may contribute to the earlier detection of PC, which in turn leads to better prognosis. However, it is important to conduct further research to validate these findings and to identify other potential factors that may contribute to the improved survival outcome in PC cases among patients with pancreatitis.
In this study, several risk factors associated with PC were adjusted for analysis. Among patients with pancreatitis, smoking was found to be a significant risk factor for PC having a 1.17-1.60-fold increased risk of PC, showing a dose-response correlation. These findings are consistent to previous research.33,34 Smoking is a known risk factor for PC as well as for disease progression in CP.35 Furthermore, this study revealed that overweight, prediabetes or diabetes, gallstone disease, and hepatic fibrosis/cirrhosis were associated with an increased risk of PC among patients with pancreatitis, which is in line with a previous study.36 However, alcohol consumption was not identified as a risk factor of PC in this study or in previous studies, despite it being a known risk factor for pancreatitis and a common characteristics of patients with RAP and CP with AP.3,6 On the other hand, physical inactivity and high cholesterol levels did not show an association with the risk of PC in this study.
The proportion of CP cases preceding AP can vary among different study populations. In our study, patients with CP who had preceding AP accounted for only one-fifths of CP cases. This proportion differs from previous studies that reported proportions of 40%11 or 60%.12 Additionally, in our study, CP without AP was diagnosed at a younger age compared to CP with AP. This finding contrasts with previous result that showed a younger age in CP with AP.12 Our data provide reliable information regarding the similar age at initial AP diagnosis in different subgroups (such as SAP, RAP, CP with AP). These inconsistent results among studies may be attributed to the differences in the study population evaluated.
The strength of this study are as follows. Firstly, we adjusted for most lifestyle or metabolic factors known to be associated with PC, such as smoking, alcohol consumption, obesity, and diabetes.37 Additionally, we controlled for hepatic dysfunction, alcoholic liver disease, hepatic fibrosis/cirrhosis, and gallstone diseases. This adjustment helps to account for potential confounding variables and strengthens the validity of our findings. Secondly, our study included a large sample size and had a sufficient duration of follow-up. The large cohort provides robust statistical power and increases the generalizability of our results. Moreover, the adequate follow-up duration allows us to assess the long-term risk of PC in different subgroups of pancreatitis.
However, this study also has certain limitations. Firstly, we were unable to identify other potential confounding factors associated with PC, such as a family history of the disease. This missing information may introduce some degree of confounding bias into our results. Secondly, we acknowledge that the survey responses relied on the participants' memories, which could introduce recall bias. Inaccurate recall of smoking duration, intensity, and cessation may affect the accuracy of our smoking-related risk estimates.
In conclusion, this study provides valuable insights into the magnitude and duration of PC risk among different subgroups of pancreatitis. We suggest that an optimized strategy for PC surveillance should be implemented, considering the specific subgroups of pancreatitis. To improve the prognosis of PC, it is crucial to identify patients who are suitable candidates for surveillance, particularly those with RAP or CP with AP and other risk factors for PC.