Our results demonstrate a marked strong association for pancreatic cancer with pancreatitis diagnosed within 3 years prior to the pancreatic cancer diagnosis. In addition, modest increased risk estimates for pancreatic cancer that decreased over time were observed both for those with a diagnosis of pancreatitis 3–10 years and more than 10 years before their cancer diagnosis. The observed association may reflect pancreatitis as an initiator of pancreatic cancer and/or a consequence of pancreatic cancer. These results require confirmation and should be interpreted conservatively given that the CIs overlapped for the individual categories representing the longer latencies, and the CI for the longest duration category included unity. Our results also support further evaluation in larger pooled studies to determine whether other risk factors (sex, early onset, gallbladder disease, and smoking) modify the association between pancreatitis and pancreatic cancer and thus better define at-risk subgroups of patients.
Similar to our results, other studies that have examined the temporal association between pancreatitis and pancreatic cancer have reported an elevated risk estimate for pancreatic cancer diagnosed within the first few years following the diagnosis of pancreatitis [27
]. However, the differences in study designs and end-point measurements and the lack of mutually exclusive groups used in duration analyses have resulted in substantial variation in reported effects [27
]. Our results are consistent with those of a large Swedish retrospective cohort study of patients discharged with an initial diagnosis of pancreatitis between 1965 and 1983 [29
]. In this cohort study, the standardized incidence ratio (SIR) of pancreatic cancer decreased from 5.0 for 1–4 years of follow-up after pancreatitis diagnosis to 1.5 for 10–24 years of follow-up [33
]. Interestingly, a persistent excess risk 10 years after pancreatitis was observed only among patients who also had been diagnosed as alcoholics [33
]. Although our data also showed an increased risk estimate that persisted more than 10 years after pancreatitis diagnosis, the effect was not different from chance possibly due to the limited number of study participants in this category.
Our results differed from those reported for a medical records-based case–control study conducted through the department of Veteran Affairs (VA) in the US, although differences in computation of duration complicated the direct comparisons of results. Results from the VA study showed that ORs for pancreatic cancer decreased from 2.3 for pancreatitis diagnosed ≥1 year before the diagnosis of pancreatic cancer to 2.0 for pancreatitis diagnosed 7–22 years before pancreatic cancer diagnosis [27
]. However, because the VA analyses did not estimate risk using mutually exclusive categories for duration (e.g. mean length of follow-up was 8.2 years in the group followed up for >1 year), it is not possible from the published report to determine whether the observed decrease in their risk estimates is directly comparable to that observed in our study or in the Swedish study.
In contrast to our results, a hospital-based study in Italy reported that risk estimates for pancreatic cancer were higher for those whose duration between pancreatitis and pancreatic cancer diagnoses was five or more years compared with those whose duration was less than 5 years [30
]. The duration cut-point of 5 years used in this Italian study prohibits a direct comparison of their results with ours and does not provide sufficient evidence to determine the effect of duration >10 years on pancreatic cancer risk estimates in their population. Similarly, the results from an international clinic/hospital-based study among patients with chronic pancreatitis estimated risk with person-years cumulated for >2 and >5 years since pancreatitis diagnosis [35
]. Although there was some evidence among patients with non-alcoholic chronic pancreatitis that risk may decrease with increasing duration, long-term duration was not assessed [35
Multiple possible explanations for the observed association between pancreatitis and pancreatic cancer have been suggested including misclassification of pancreatic cancer as pancreatitis, mechanical effects of the tumor due to infiltration of the pancreas and/or obstruction of the pancreatic duct, and inflammation. Differentiation of signs and symptoms of pancreatic disease due to pancreatic cancer and those due to pancreatitis can be challenging and may have affected the specificity of pancreatitis diagnosis more often in cases with pancreatic cancer than among controls, leading to differential misclassification of the pancreatitis history. Medical record confirmation was not obtained for patients who reported a physician-diagnosed episode of pancreatitis to support the specificity of the pancreatitis diagnosis. The effect of misclassification of pancreatitis diagnosis and the possible differential in misdiagnosis between cases and controls, if present, is unknown. If the observed associations were due to a mechanical effect related to underlying pancreatic cancer, pancreatitis would be a manifestation rather than a pathogenic step in the development of pancreatic cancer. Finally, inflammation may be due to the pancreatitis and thus a pathogenic step towards the development of pancreatic cancer, or it may be a consequence of the pancreatic cancer itself.
The inflammatory-related mechanisms that may cause, promote, or be a consequence of pancreatic cancer have not been established. Normal inflammation is limited by the release of anti-inflammatory cytokines. However, under conditions of chronic inflammation, the factors that control the inflammatory response are dysfunctional, thereby allowing inflammation to continue [41
]. Chronic inflammation can promote DNA damage and cell proliferation via release of inflammatory mediators such as cytokines, chemokines, and reactive oxygen species. The inflammatory mediators that are commonly released during pancreatitis, NF-KB, IL-8, COX-2, and TNF-alpha, play a role in cell growth, proliferation, and apoptosis and also are highly expressed in pancreatic cancer [54
]. The involvement of NF-KB is of particular interest as it is important in both inflammatory and oncogenic pathways [54
]. Interestingly, in an earlier analysis of our data, we used DNA obtained from study participants to determine genetic susceptibility for pancreatic cancer associated with polymorphisms in inflammatory-related genes, including TNF-alpha and the chemokines, RANTES and CCR5 [55
]. Our results showed that pancreatitis modified the association between pancreatic cancer and polymorphisms in TNF-alpha
such that risk estimates for pancreatic cancer were increased among those who carried the variant alleles for polymorphisms in these genes and also had a history of pancreatitis. The exact significance of these polymorphisms as markers of risk estimates and/or pathogenic factors requires validation and exploration in functional studies.
We investigated statistical interaction with other exposures and factors that have been associated with pancreatitis and with pancreatic cancer including gallbladder disease and smoking. Although intriguing, evidence to support that these factors modified the association between pancreatitis and pancreatic cancer was weak. Smoking and gallbladder/biliary disease may promote an inflammatory milieu that could contribute to pancreatitis and pancreatic cancer [56
]. Interestingly, gallbladder conditions have been associated with biliary pancreatitis which in turn has been correlated with acute rather than chronic pancreatitis [57
]. This relationship may partly explain our observed higher risk of pancreatic cancer among pancreatitis patients without a history of gallbladder disease and with the lower risk among women, who are more likely than men to have biliary pancreatitis. However, our results suggesting that gallbladder disease history, smoking, and sex may modify the association between pancreatitis and risk of pancreatic cancer should be interpreted conservatively as they were based on a small number of exposed participants, were imprecise and remained elevated regardless of the factor level. The low frequency of pancreatitis limited our ability to conduct further detailed analyses but emphasizes the need to continue to investigate these complex associations in larger pooled studies.
One advantage of the current combined pooled analyses is the large sample size allowing for a detailed investigation of pancreatitis that was not possible in the individual studies. Additionally, participants in our two studies were interviewed in-person, thus minimizing the reporting bias associated with proxy interviews [58
]. Further, we had a very low patient-refusal rate of 8% at the population-based UCSF site and 6% at the clinic-based MDACC site, and the study hypotheses were unknown to the participants and to the interviewers.
Possible limitations common to case–control studies also should be considered when interpreting our results. Recall bias is possible but is likely to have been diminished by requesting that participants report “physician-diagnosed pancreatitis”. Similar to other population-based studies of pancreatic cancer, a large number of patients had died prior to initial contact due to the aggressive nature of the disease, despite use of rapid case ascertainment methods at UCSF and enrollment of cases at diagnosis at MDACC. Comparison of SEER abstract demographic data for interviewed and non-interviewed cases identified as part of the UCSF study showed that non-interviewed cases tended to be slightly older, with a slightly greater proportion of women than men, somewhat more minorities, fewer known tumor characteristics, and a shorter survival time [46
]. It is possible that cases diagnosed in proximity to their pancreatic cancer diagnosis may have incorrectly reported their pancreatitis diagnosis. Although this misclassification of pancreatitis may have been differential between cases and controls and resulted in an overestimate of the association with pancreatic cancer in the years closest to their cancer diagnosis, the practical implications of our results remain clinically important. Given the magnitude of the risk estimate for the shortest duration and the consistently elevated risks for longer duration, the association of long-term pancreatitits with pancreatic cancer risk requires further exploration.
In conclusion, results from our analyses in this large pooled dataset provide support for the hypothesis that some pancreatitis may be a clinical marker for early manifestation of pancreatic cancer or a pathogenic step towards the development of pancreatic cancer. Further investigation in larger pooled studies is required to confirm our results and to assess the joint effects with other risk factors that may contribute to pancreatic inflammation such as smoking and gallbladder disease. In addition, larger pooled analyses that include multiple case–control studies are needed to determine whether additional characteristics of pancreatitis such as age at pancreatitis onset, the number of episodes, chronic or acute disease, duration by sex, and family history of pancreatitis are related to the observed association with pancreatic cancer.