Incidence and risk of pancreatic cancer in patients with chronic pancreatitis: defining the optimal subgroup for surveillance

Abstract

We aimed to present the incidence and risk factors for pancreatic cancer in a multicenter retrospective cohort of patients with chronic pancreatitis (CP). Patients with ICD‒10 codes for CP (K86.0, K86.1) who underwent abdominal CT or MRI between January 2010 and December 2021 in seven academic hospitals were analyzed. After exclusions, we identified 727 patients with definite CP with a median follow‒up of 3.6 years (range 1.0‒12.9). During 3,290 person‒years of observation, pancreatic cancers were diagnosed in 16 patients (2.20%, 0.49% per year) after a median follow‒up of 2.4 years (range 1.4‒6.6), with an age‒ and sex‒standardized incidence ratio of 18.1 (95% CI 10.4‒29.5). The underlying CPs in the 16 pancreatic cancers were classified as chronic obstructive pancreatitis (10, 63%), chronic obstructive and calcifying pancreatitis (4, 25%), chronic calcifying pancreatitis (1, 6%), and autoimmune pancreatitis (1, 6%). Factors associated with pancreatic cancer development included age (HR 4.830, p = 0.006), parenchymal calcification (HR 0.213, p = 0.003), pancreatic duct stricture (HR 2.706, p = 0.048), and serum CA 19‒9 level (HR 22.49, p < 0.001). After adjustment, age greater 60 years (HR 5.580, p = 0.007) and serum CA 19‒9 levels greater 100 U/mL (HR 25.56, p < 0.001) were independent risk factors for pancreatic cancer.

Introduction

Pancreatic cancer is one of the cancers with the worst prognosis and has the lowest 5‒year survival rate among all cancers, at around 10%. The cancer death rates of lung cancer, prostate cancer, breast cancer, and colon cancer, which have higher cancer death rates than pancreatic cancer in the United States, have all been declining over times. However, the cancer death rate for pancreatic cancer has increased slightly (by 0.2% per year) since the mid‒2000s according to the American Cancer Society, Cancer Facts & Figs. 2022. The mortality of pancreatic cancer is predicted to increase over time, reaching the second‒highest overall cancer mortality rate in the United States by 2030¹. Although much effort has been made to improve the low survival rate of patients with pancreatic cancer, no tangible progress has been made yet. The most effective method for survival improvement to date is the early detection of pancreatic cancer through screening tests. Therefore, it is important to identify and monitor high‒risk groups for pancreatic cancer.

Patients with chronic pancreatitis (CP) is one of the major risk groups for pancreatic cancer, and the relative risk of pancreatic cancer in patients with CP has been reported to be as high as 7.6‒68.1 times^2–6. The incidence of pancreatic cancer in patients with CP has been mainly investigated in Western countries, where it was reported to be 1.0‒2.6%^4,7−10. In a small number of studies in Asia, the incidence of pancreatic cancer was found to be 0.9‒2.9%^11–13. The incidence and standardized incidence ratio (SIR) of pancreatic cancer in patients with CP have rarely been reported in South Korea. In the 2020 International Consensus Guidelines on Surveillance for Pancreatic Cancer in CP, it was not recommended to monitor for pancreatic cancer in all sporadic CP cases because the prevalence of pancreatic cancer is not high enough¹⁴. According to international guidelines, patients with CP accompanied by serine protease 1 gene (PRSS1) mutation are recommended to undergo regular follow‒up for pancreatic cancer detection. However, others conditions required for surveillance in patients with CP were not presented, and additional related research is still necessary. To date, several studies have suggested that risk factors for pancreatic cancer in CP include newly developed diabetes, obesity, pancreatic duct dilatation, old age, and current smoker^3,8−11. However, these risk factors need to be verified, and risk groups of patients with CP for surveillance should be selected using risk factors for pancreatic cancer.

Therefore, we aimed to determine the incidence of pancreatic cancer in patients with CP and to obtain age‒ and sex‒standardized incidence ratios (SIRs) using the incidence of pancreatic cancer in the general population. In addition, we wanted to present subgroups of patients with CP who should be followed up for pancreatic cancer by analyzing which factors are related to the development of pancreatic cancer in CP and the incidence of pancreatic cancer according to risk factors.

Results

Discussion

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 7.6‒68.1^2–6. 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 cancer^7,11,12. 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 CP^3,9. 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.

Conclusion

Patients with CP had a high risk of developing pancreatic cancer. CP patients aged 60 years or older at CP diagnosis and with CA 19‒9 levels greater than 100 U/mL warrant careful surveillance for pancreatic cancer, and active surveillance is needed up to 5‒6 years after the diagnosis of CP.

Methods

Declarations

Data availability statement

The datasets generated or analyzed during the current study are not publicly available due to privacy policies but are available from the corresponding author on reasonable request.

Funding

This research was supported by the Institute of Clinical Medicine Research of Bucheon St. Mary's Hospital, South Korea (Research Fund, BCMC22BD08).

Author contributions

J.H.C. conceived and designed the study. J.H.C., H.S.K, and S.H.P. analyzed and interpreted the data. J.H.C. and H.S.K wrote the manuscript. T.G., T.H.K, and C.W.K. supervised the study and made critical revisions. All authors reviewed and approved the manuscript.

Competing interests

The authors declare no competing interests.

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