CP is known as one of the major risk factors for pancreatic cancer. The SIRs of pancreatic cancer in patients with CP have been reported to be 7.6‒68.12–6. The age‒ and sex‒SIR in our study was 18.1 (95% CI, 10.4‒29.5), which also demonstrated that CP has higher risk for pancreatic cancer.
There have been several studies on the incidence and relative risk of pancreatic cancer in patients with CP. The reported incidence of pancreatic cancer varied from study to study at 0.68‒2.94%2,9,10,12,15. There are many causes for this variation, and approaches to select patients with CP and the included CPs are the main cause. Studies using a large amount of data are thought to be more suitable for determining the incidence of pancreatic cancer in that these studies can analyze a large number of patients with CP. However, retrospective studies in which patients are selected by only the diagnostic ICD codes for CP are limited in accurately identifying CP patients16. Such studies can enroll patients with other pancreatic diseases, such as acute pancreatitis, pancreatic cancer, pancreas cystic neoplasm, and intraductal papillary mucinous neoplasm (IPMN), which may be frequently mistaken for CP. In addition, even for CP, it is sometimes not clear whether it is definite, probable, or borderline. Therefore, patients with various degrees of CP may be included in the studies. In this case, the incidence of pancreatic cancer can also be affected. In general, probable or borderline CP does not have clear diagnostic criteria, and the incidence of pancreatic cancer is not high in patients with probable or borderline CP compared to those with definite CP. Therefore, it is more desirable to select patients with definite CP and determine how many develop pancreatic cancer7,11,12. In our study, all imaging tests of the patients, as well as diagnostic codes, were reviewed to find definite CP. A few previous studies evaluated only patients who underwent surgery or endoscopic management for CP3,9. These patients had complicated CPs and were followed up well. However, they did not represent general CP, and surgery or endoscopic treatment can lead to a change in pancreas condition affecting the development of pancreatic cancer. In a multicenter retrospective study, patients who underwent surgery for the treatment of CP had significantly lower incidences of pancreatic cancer5. A recent published study in South Korea registered patients using only ICD‒10 codes and reported a low pancreatic cancer incidence of 0.68%15. As observed in our study, a notable number of CP patients registered with only ICD code K86 might not have CP, and even if they had CP, the CP could be probable or borderline CP instead of definite CP. Thus, it was difficult to accurately identify the occurrence of pancreatic cancer in that study, and the incidence of pancreatic cancer would be lower than it really is.
Pancreatic cancer development time is another factor affecting the incidence of pancreatic cancer. Since both CP and pancreatic cancer can be found at the same time or pancreatic cancer can be mistaken for CP, newly developed pancreatic cancer in CP is usually defined as pancreatic cancer discovered 1‒2 years after the diagnosis of CP17. Previous studies had a different reference point of time; thus, interpreting these studies requires careful attention. In previous studies, the patient registration time was mainly at the time of outpatient visit, but in our study, patients were registered at the time when imaging studies confirmed pancreatic cancer‒free CP. Therefore, it is considered rare for CP and pancreatic cancer to exist together or be mistaken for CP initially, and we set a 1‒year washout period to reduce the confusion. In addition, our study showed that pancreatic cancer incidence remained relatively stable until 7 years. Pancreatic cancer and CP were diagnosed at the same time in 0.68% of CP patients, within a year in 0.41% of CP patients, at 1‒2 years in 0.69% of CP patients, at 2‒3 years in 0.71% of CP patients, at 3‒4 years in 0.70% of CP patients, at 4‒5 years in 0.30% of CP patients, at 5‒6 years in 0.78% of CP patients, and at 6‒7 years in 0.51% of CP patients. Since the incidence of pancreatic cancers remained steady over time and the incidence within 2 years was not significantly higher than that during other follow‒up periods, very few or no cases of pancreatic cancer are considered to exist when CP was diagnosed. In a meta‒analysis, the risk of pancreatic cancer was 6.09 after 1 year of diagnosis of CP, 16.16 after 2 years, 7.90 after 5 years, and 3.53 after 9 years, so the incidence of pancreatic cancer was high within approximately 5 years after diagnosis of CP18. Our study revealed that pancreatic cancer occurred within up to 6.5 years after diagnosis of CP. Based on the meta‒analysis and our study, more active surveillance is needed up to 5‒6 years after diagnosis.
Although the incidence of pancreatic cancer is high in among patients with CP, surveillance of all patients with CP is not recommended because the incidence of pancreatic cancer itself is not high enough for surveillance. The 2020 International Consensus Guidelines also did not recommend screening all patients with CP for pancreatic cancer14. Therefore, it is recommended to select and monitor a subgroup of patients with CP with a higher risk of pancreatic cancer. International Consensus Guidelines recommend screening tests in patients with hereditary CP with PRSS1 gene mutation. Unfortunately, the guidelines did not present other subgroups who should be monitored. Since the majority of CP cases are sporadic, not hereditary, it is necessary to identify which factors are associated with a high risk of pancreatic cancer in patients with sporadic CP and specify the subject for follow‒up. The following risk factors for pancreatic cancer have been suggested: metabolic syndrome, Helicobacter pylori infection, obesity, alcohol use, and red meat consumption have a low risk (relative risk 1.1‒1.5); family history, long‒term diabetes, and smoking have a moderate risk (relative risk 1.5‒2.0); and hereditary pancreatitis, germline mutation, and CP have a high risk (relative risk > 2.0)14. However, the risk in patients with CP is a lifetime risk and is not high on an annual basis. Therefore, it is necessary to determine subgroups with a high annual incidence of pancreatic cancer. Patients with newly developed diabetes are a high‒risk group for pancreatic cancer, but similar to CP, screening for pancreatic cancer is not recommended for all new‒onset diabetes patients. Therefore, it is necessary to know the subgroup that requires pancreatic cancer surveillance among patients with new‒onset diabetes. A previous study identified groups for high‒risk pancreatic cancer using the enrich new‒onset diabetes for pancreatic cancer (ENDPAC) score model19. In the validation cohort including 1,096 new‒onset diabetes patients, 9 patients developed pancreatic cancers over 3 years (overall 0.82% and 0.27% per year), and 7 patients developed pancreatic cancers among the 197 patients with 3 or more ENPAC scores (overall 3.6% and 1.2% per year). Therefore, the study concluded that it is appropriate to monitor new‒onset diabetes patients with ENPAC scores of 3 or higher. If this is applied to CP, selecting a subgroup with an annual incidence of pancreatic cancer of 1% or more would allow detect pancreatic cancer to be efficiently in patients with CP while reducing unnecessary tests and economic burdens. In our study, the incidence of pancreatic cancer was 0.49% per year in all CP patients; however, the annual incidences of pancreatic cancer in patients with significant risk factors, such as age greater 60 years, no parenchymal calcification, pancreatic duct stricture, and CA 19‒9 levels greater than 100 U/mL increased the incidence of pancreatic cancer to 0.98%, 1.13%, 0.96%, and 4.75, respectively, which is close to or greater than 1%. Even except for the CA 19‒9 level, if two or more factors were satisfied, the incidence of pancreatic cancer increased to 1.74‒2.35%, and if all three factors were satisfied, the incidence of pancreatic cancer was as high as 3.80%. Therefore, it is necessary to perform surveillance for CP subgroups that have each risk factor, and in particular, if two or more risk factors are satisfied, a more careful follow‒up is needed.
There are some limitations in this study. First, the data were collected in a retrospective manner. Therefore, some data were missing or could not be analyzed. It is almost impossible to conduct a prospective study that requires a large number of patients with CP and long‒term follow‒up. Accordingly, all previous studies were performed in a retrospective manner. To reduce bias and ensure the quality of the data, we reviewed all patients' imaging studies. Second, we did not evaluate exocrine insufficiency due to a lack of available data on it, although it is included in the diagnostic criteria of definite CP. Additionally, the association between pancreatic cancer and lifestyle habits such as alcohol and tobacco use was not demonstrated due to the same reason. These should be supplemented by future research. Third, a few accompanied or confusing IPMN in the pancreas can be included in our study, since imaging studies cannot clearly distinguish between IPMN and CP. In some patients who underwent surgery, histologic findings revealed both IPMN and CP or IPMN instead of CP.