Incidence of Pancreatic Cancer in Chinese Patients with Chronic Pancreatitis

Original Paper Received: January 22, 2010 Accepted after revision: November 19, 2010 Published online: February 10, 2011

Pancreatology 2011;11:16–23 DOI: 10.1159/000322982

Incidence of Pancreatic Cancer in Chinese Patients with Chronic Pancreatitis Wei Wang a Zhuan Liao a Gang Li b Zhao-Shen Li a Jie Chen a Xian-Bao Zhan a Luo-Wei Wang a Feng Liu a Liang-Hao Hu a Yan Guo a Duo-Wu Zou a Zhen-Dong Jin a  

 

 

 

 

 

 

 

 

 

 

 

Chronic Pancreatic Study Group, Department of Gastroenterology, and b Department of Hepato-Pancreato-Biliary Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, China  

 

Key Words Pancreatic cancer ⴢ Chronic pancreatitis ⴢ Standardized incidence ratio

Abstract Background and Aim: It is suggested that patients with chronic pancreatitis (CP) have a markedly increased risk of pancreatic cancer compared with the general population. This study was designed to determine the rate of pancreatic cancer in CP patients in China. Methods: This was a semiprospective, single-center study including 420 consecutive CP patients (285 males and 135 females, median age at onset 39.5 years), with the median follow-up time being 102.3 months (range 24–419 months). We calculated the standardized incidence ratio (SIR) based on the pancreatic cancer incidence in the general population of China. Results: Four cases of pancreatic cancer (0.9% of patients) were observed in 3,591 patient-years (expected number of cases 0.15; SIR 27.2, 95% CI 7.4–69.6). Similar results were seen in alcoholics and non-alcoholics, and in smokers and non-smokers. When patients lost to follow-up were considered to be followed up until the end point without having developed pancreatic cancer (4,280 patient-years), SIR was 22.8 (CI 6.2–58.4). Based

© 2011 S. Karger AG, Basel and IAP 1424–3903/11/0111–0016$38.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/pan

on the Cox model, with inserting factors being sex, age at the time of CP clinical onset, type of pancreatitis, and presence or absence of diabetes, calcification, alcohol use and smoking status, only age was found to correlate positively with the occurrence of pancreatic cancer (150 years, hazard ratio, 1.8 8 0.5; p = 0.044). Conclusion: The risk of pancreatic cancer is markedly increased in CP patients in China compared with the general population, especially in older patients. Copyright © 2011 S. Karger AG, Basel and IAP

Introduction

The etiology of pancreatic cancer remains largely unknown, hampering the development of effective approaches to prevention and therapy of this disease. Perhaps the best-defined environmental risk factor for pancreatic cancer is tobacco smoking, which increases the risk for pancreatic cancer by 2- to 3-fold [1–4]. In addition, up to 10% of pancreatic cancer cases are associated

W.W., Z.L. and G.L. contributed equally to this work.

Zhao-Shen Li, Prof. PhD, Head Department of Gastroenterology, Changhai Hospital The Second Military Medical University, 168 Changhai Road Shanghai, 200433 (China) Tel. +86 21 8187 3241, E-Mail zhaoshenli @ hotmail.com

Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.213.236.110 - 6/17/2013 12:40:16 PM

a

Pancreatic Cancer and Chronic Pancreatitis

Patients and Methods Patients All consecutive patients enrolled in this study had at least one hospitalization in Changhai Hospital between January 1997 and August 2007, and met all the diagnosis criteria for CP. Patients with a follow-up period of less than 2 years, a diagnosis of pancreatic cancer established during the first 2 years of follow-up, or diagnosed within 2 years of CP diagnosis were excluded from the study to rule out the possibility of pancreatitis revealing pancreatic cancer [6, 14]. The duration of follow-up was defined as the period from the onset of the disease (or symptoms, or when diagnosis was first established) to the last contact or the date of diagnosis of pancreatic cancer [14]. CP was diagnosed on the basis of a typical history and the presence of any of the following findings during the first hospitalization: (1) typical CP histology of an adequate surgical pancreatic specimen; (2) pancreatic calcification confirmed by plain radiography, abdominal ultrasonography, computerized tomography, or echoendoscopy, and (3) moderate-to-marked pancreatic ductal lesions on pancreatography obtained by endoscopic retrograde or magnetic resonance pancreatography (Cambridge classification) [18]. CP was considered to be due to alcohol when alcohol intake exceeded 60 g/day for at least 2 years in the absence of other causes, and CP was considered ‘idiopathic’ when no obvious causes were found [14]. Hereditary CP was diagnosed when two first-degree relatives, or three or more second-degree relatives suffered from recurrent acute pancreatitis or CP without any apparent precipitating factors [19]. The diagnosis of pancreas divisum was based on the presence of ductal abnormalities demonstrated by endoscopic retrograde cholangiopancreatography (ERCP) [20]. A serum triglyceride level of more than 1,000 mg/dl (11.1 mmol/l) was considered an identifiable risk factor for CP [21]. The date of clinical onset of CP was defined as the date when the first manifestation clearly attributable to CP occurred. The final diagnosis of pancreatic cancer was confirmed in all cases by histological examination of surgical specimens or by fine-needle biopsy. Special attention was paid to exclude pancreatic cancer arising on intraductal papillary mucin-producing tumors. Study Design and Data Collection In February 2005, a program that prospectively collected clinical information on all patients seen in our hospital was installed. The Institutional Review Board of Changhai Hospital approved this chart review and computer-based study. The data on patients admitted to our hospital before 2005 were retrospectively collected and then prospectively followed up after 2005. Patients were seen at a regular follow-up as an outpatient at least once a year, or in an unscheduled visit (as outpatients or hospitalized) when the disease became symptomatic or if complications occurred. Special attention was paid to signs or symptoms suggestive of pancreatic cancer such as pain, weight loss, jaundice, and abdominal mass. Abdominal imaging and laboratory tests were performed when necessary. Patients were considered lost to follow-up when they failed to attend the follow-up visit for more than 1 year after all attempts by the investigators to contact the patients, such as repeated phone calls, e-mail, and registered mails, were made. Person-years (one person-year was the observation time contributed by 1 patient followed for 1 year) were calculated from the date

Pancreatology 2011;11:16–23

17

Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.213.236.110 - 6/17/2013 12:40:16 PM

with inherited disorders, including abnormalities in protease, serine 1 (PRSS1), cystic fibrosis transmembrane conductance regulator (CFTR), serine protease inhibitor, Kazal type 1 (SPINK1) and breast cancer 2 (BRCA2) [3, 4]. Whether or not alcohol intake is related to pancreatic cancer has not been established [2, 5, 6]. However, alcohol consumption may induce chronic pancreatitis (CP) and diabetes mellitus; both are well-known risk factors for pancreatic cancer [4]. The various metabolic effects of alcohol can interact with other risk factors (genetic, dietary, environmental, and lifestyle factors), which ultimately affect the multistep process of carcinogenesis and lead to the development of pancreatic cancer [7, 8]. Alcoholics indeed have a greater risk (by 30–60%) of pancreatic cancer relative to nondrinkers [9–11]. Since inflammation is indicated in cancer development, there is an increasing interest in determining the relationship between CP and pancreatic cancer. The incidence of pancreatic cancer in the course of CP appears to be greater that in the general population, as shown in a cohort study of 1,552 patients from seven centers of six countries, which found a 14.4-fold increased risk in CP patients within a 5-year follow-up period [12]. Two additional studies from Italy and France supported the notion, reporting a standardized incidence ratio (SIR) of 18.5- and 26.7-fold with the mean follow-up period being 9.2 and 10 years, respectively [13, 14]. The Fourth International Symposium of Inherited Diseases of the Pancreas classifies CP as moderate (5- to 10-fold) risk for developing pancreatic cancer [15]. On the other hand, the information on pancreatic cancer in patients with CP in China is rather sparse, considering that the CP incidence has recently been rising rapidly in China. As the largest country in the world in terms of population, China faces many challenges in public health, especially with increasing chronic metabolic syndromes and chronic disorders, such as cancer and diabetes. Interestingly, the association between heavy alcohol intake and CP is not as strong as that reported in Western countries [16, 17]. If alcohol is indeed a risk factor for pancreatic cancer and if the established risk factors (genetics, smoking) for the disease in China are similar to those seen in Western countries, the risk for pancreatic cancer in patients with CP in China would be expected to be lower than that in Western countries. We therefore conducted a cohort study to determine the incidence of pancreatic cancer in our single center of consecutive patients with proven CP. This may represent the first attempt to determine the link between CP and pancreatic cancer in China.

Suspected CP patients (n = 557)

Confirmed CP patients (n = 514) Excluded Patients followed up (n = 445) Excluded Patients analyzed (n = 420)

Patients who could not be followed up (n = 69) Lost in follow-up (n = 66) Refused interviews (n = 3) Follow-up period for less than 2 years after onset of CP (n = 18) Diagnosed with pancreatic cancer (n = 7) Being followed up (n = 11) Pancreatic cancer diagnosed within 2 years of diagnosis of CP (n = 7)

Died (n = 21, 5.0%) From pancreatic cancer (n = 4) From nonpancreatic cancer (n = 5) From sepsis (n = 1) From gastrointestinal bleeding (n = 2) From complications of diabetes mellitus (n = 3) From unknown causes (n = 5)

Fig. 1. Patient participation and fol-

low-up.

Statistical Analysis Differences were analyzed using the Student’s t or MannWhitney U tests as appropriate for continuous data and the (Pearson) ␹2 or Fisher’s exact tests for categorical data. To determine the expected number of cases of pancreatic cancer in the cohort, we used age-stratified (according to 10-year age groups) and sexspecific data on the incidence of cancer in China in 2005, provided by the National Office for Cancer Prevention and Control of China [22]. The ratio of the observed number of cases of pancreatic cancer in the cohort of CP patients to the expected number of cases (standardized incidence ratio, SIR) was calculated and used to estimate the relative risk for pancreatic cancer in this cohort. The 95% CI for the SIR was calculated, assuming that the observed cases of pancreatic cancer followed a Poisson distribution. For the multivariate analysis of estimates of potential prognostic factors in the CP patients, the Cox’s proportional-hazards regression model was used, performing backward stepping of variables with pre-assigned p = 0.05 controlling the stepping removal [14]. The data and statistical analyses were accomplished with SAS 9.13 (SAS Institute Inc., Cary, N.C., USA). All statistical tests were two sided. Statistical significance was considered when p ! 0.05.

18

Pancreatology 2011;11:16–23

Results

Patient Characteristics Among the 557 patients with suspected CP attending the hospital, 514 fulfilled the diagnostic criteria of CP, and were studied retrospectively and prospectively. Sixtysix patients were lost to follow-up, 3 refused interviews, and 18 were followed up for less than 2 years after the onset of CP; all of these patients were excluded from the present analysis. Seven (histological evidence of CP, n = 3; pancreatic calcifications, n = 2; pancreatic duct abnormalities on ERCP, n = 2) of the 18 patients were later diagnosed with pancreatic cancer. In addition, 7 patients with pancreatic cancer diagnosed within 2 years of diagnosis of CP were also excluded, with two pancreatic cancers diagnosed by histological examination of surgical specimens and five cancers by the clinical course and positive laboratory and/or radiologic findings. All of the 7 patients had pancreatic calcifications on imaging examination, and the mean duration of CP (from the onset to the confirmation of pancreatic cancer) was 98.3 months (range 26–145 months) (fig. 1). Table 1 presents the characteristics of the remaining 420 patients, with 3,591 patient-years of follow-up. There were no significant differWang /Liao /Li /Li /Chen /Zhan /Wang / Liu /Hu /Guo /Zou /Jin  

 

 

 

 

 

 

 

 

 

 

 

Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.213.236.110 - 6/17/2013 12:40:16 PM

of clinical onset of CP to either the end point of the study, the last personal contact, the date of diagnosis of pancreatic cancer, the date of total pancreatectomy, or death. This method was the same as reported previously [14].

Table 1. Clinical characteristics of the 420 patients with CP

Patients in 1997–2005 (n = 202) Median age at CP onset, years 39.4818.4 Median age at CP diagnosis, years 43.4817.7 Median age at the time of last contact or the date of diagnosis of pancreatic cancer, years 49.8817.7 Median duration of follow-up, months 125.2858.1 Males, n (%) 130 (64.4) Alcoholic CP, n (%) 49 (24.3) Duration of symptoms, months 44.4852.9 Duration of symptoms, n (%)# <5 years 139 (69.2) 5–10 years 39 (19.4) 10–15 years 19 (9.5) >15 years 4 (2.0) Duration of CP diagnosis, months 40.7852.8 Duration of CP diagnosis, n (%)# <5 years 146 (72.6) 5–10 years 35 (17.4) 10–15 years 16 (8.0) >15 years 4 (2.0) Alcohol consumption, g/day 36.7868.0 Alcohol consumption, n (%) 0 g/day 100 (49.5) <20 g/day 31 (15.4) 20–120 g/day 54 (26.7) >120 g/day 17 (8.4) Tobacco consumption (pack-years) 11.9820.0 Tobacco consumption, n (%) 105 (52.0) 0 pack-years* <10 pack-years 20 (9.9) 10–40 pack-years 62 (30.7) >40 pack-years 15 (7.4) Smokers, n (%) 50 (51.6) Alcoholic CP† 47 (48.5) Non-alcoholic CP† 112 (55.5) Pancreatic calcifications, n (%)‡ 55 (27.2) Diabetes mellitus, n (%)‡ 30 (14.9) Insulin requirement‡ 115 (56.9) Bouts of acute pancreatitis, n (%)‡ 37 (18.3) Pseudocysts, n (%)‡ 0 Duodenal stenosis, n (%)‡ 0 Portal vein occlusion, n (%)‡ 7 (3.5) Liver cirrhosis, n (%)‡ 45 (22.3) Cholelithiasis, n (%)‡ 81 (40.1) Elective surgery for CP, n (%)‡ 15 (7.4) Uncomplicated CP, n (%)‡, § Deaths, n (%) 14 (6.93)

Patients in 2005–2007 (n = 218)

p value

39.7817.2 43.7816.5

0.7971 0.8199

46.5816.7 81.8851.1 155 (71.1) 67 (30.7) 43.7850.1

0.0717 0.0000 0.139 0.138 0.7908 0.836

155 (71.4) 35 (16.1) 23 (10.6) 4 (1.8) 38.6847.4 163 (74.8) 34 (15.6) 18 (8.3) 3 (1.4) 41.5862.1 108 (49.5) 23 (10.6) 60 (27.5) 27 (12.4) 15.4832.5

0.7880 0.914

0.5674 0.324

0.2459 0.573

102 (46.8) 29 (13.3) 67 (30.7) 20 (9.2) 63 (54.3) 53 (45.7) 136 (62.4) 51 (23.4) 22 (10.1) 137 (62.8) 32 (14.7) 2 (0.9) 4 (1.83) 5 (2.3) 25 (11.5) 67 (30.7) 32 (14.7) 7 (3.2)

0.687 0.687 0.148 0.366 0.139 0.216 0.315 0.172 0.053 0.471 0.003 0.045 0.018 0.081

Pancreatic Cancer and Chronic Pancreatitis

Pancreatology 2011;11:16–23

19

Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.213.236.110 - 6/17/2013 12:40:16 PM

* Patients who had smoked <100 cigarettes during their lifetime. # Percentage totals exceed 100% because of rounding. † Smokers in alcoholic CP versus smokers in nonalcoholic CP, p = 0.000. ‡ At any time during the course of CP. § No acute pancreatitis, pseudocysts, duodenal stenosis, biliary liver disease, splenic or portal vein occlusion, need for pancreatic surgery, or insulin.

Table 2. Characteristics of CP patients who developed pancreatic cancer Age at CP onset years

Age at CP diagnosis years

F M M M

48 56 59 70

50 61 61 71

Alcohol intake g/day

0 20–120 0 <20

Smoking Etiology pack(pancreatic years calcification)

0 >40 0 <10

idiopathic (yes) alcoholic (no) idiopathic (yes) idiopathic (yes)

Duration of symptoms months

Duration Diabetes of mellitus diagnosis months

Steatorrhea

Symptoms revealing pancreatic cancer

Survival after diagnosis of pancreatic cancer, months

30 51 17 1

30 51 17 1

yes no no no

pain, weight loss, jaundice pain, weight loss, jaundice pain, weight loss pain, weight loss, jaundice

46 9 7 2

ences in clinical characteristics, including age at onset, age at diagnosis, sex, duration of symptoms to diagnosis, alcohol and tobacco consumption, calcifications, diabetes mellitus, pseudocysts, bouts of acute pancreatitis, duodenal stenosis, portal vein occlusion, liver cirrhosis and deaths, between the patients whose first hospitalization in our hospital was before February 2005 (n = 202) and those after February 2005 (n = 218). Mean alcohol consumption of drinkers at the time of diagnosis of CP was 77.6 g/day. Mean cumulative tobacco consumption of smokers at the time of diagnosis of CP was 27.1 packyears. The causes of nonalcoholic CP were hereditary CP (n = 3), inflammatory bowel disease (n = 2), hyperlipidemia (n = 1), trauma (n = 2), choledochal cysts (n = 1), and pancreas divisum (n = 22); CP was classified as ‘idiopathic’ in the remaining 273 (65%) cases, with 54 (19.8%) of them being complicated cholelithiasis. The 69 patients (13.4%) who were lost to follow-up or refused to be interviewed did not differ from the remaining CP patients in their characteristics, except for a longer duration of follow-up (median follow-up 121.7 months; CI 108.6–134.7; range 29–273, data not shown in table 1). Risk of Pancreatic Cancer Twenty-one patients (5.0%) died within the follow-up period: 1 from sepsis, 2 from gastrointestinal bleeding (one happened after drinking, another happened after pseudocyst disruption), 3 from complications of diabetes mellitus, and 5 from unknown causes. Five patients (1.2%) died from nonpancreatic cancer (esophageal, stomach, nasopharyngeal, lung, and leukemia). Four patients (0.9%) died from pancreatic cancer; none of them had a family history of pancreatic cancer, hereditary CP, or cholecystectomy (fig. 1; table 2). The expected number of cases of pancreatic cancer was 0.15, yielding an SIR of 27.2 (95% CI 7.4–69.6). Similar results were seen in alcoholics and nonalcoholics, and in smokers and nonsmokers (table 3). The cumulative incidence of pancreatic can20

Pancreatology 2011;11:16–23

yes yes no no

Table 3. Comparison of SIR of pancreatic cancer in CP patients: smokers versus nonsmokers and alcoholics versus nonalcoholics Cancer Person- Cancer SIR observed years expected (O/E)

All Alcohol abuse Alcoholic Nonalcoholic Smoking Smokers Nonsmokers

95% CI

4

3,591

0.15

27.17 7.40–69.56

2 2

1,846 1,745

0.08 0.07

26.43 3.20–95.46 28.00 3.39–100.98

2 2

1,781 1,810

0.07 0.07

27.39 3.32–98.94 26.95 3.26–97.36

Smokers were defined as subjects who had smoked ≥100 cigarettes during their lifetime [10].

cer was 0.2% at 5 years and 1.6% at 10 years. The SIR was 22.8 (CI 6.2–58.4) when patients who refused or were lost to follow-up were considered to be followed up until the end point without the occurrence of pancreatic cancer (4,280 patient-years; expected number of cases of pancreatic cancer, 0.18). By means of the Cox model, with inserting factors, such as demographic variables (sex, age at the time of clinical onset), clinical variables (the type of pancreatitis and the presence or absence of diabetes, calcification), and lifestyle variables (alcohol use and smoking status) [12], only age was found to correlate positively with the occurrence of pancreatic cancer (150 years, HR 1.8; SE 0.5; p = 0.044).

Discussion

In this single-center, semiprospective cohort study, we demonstrated that the risk of pancreatic cancer was markedly increased in CP patients in China, compared Wang /Liao /Li /Li /Chen /Zhan /Wang / Liu /Hu /Guo /Zou /Jin  

 

 

 

 

 

 

 

 

 

 

 

Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.213.236.110 - 6/17/2013 12:40:16 PM

Sex

sis between CP and pancreatic cancer should be made in these patients. Determining the underlying mechanisms of CP contributing to pancreatic cancer may lead to the development of pancreatic cancer prevention strategies for highrisk individuals. But the mechanisms are still not clear, even though a number of cellular and genetic mechanisms (prolonged inflammation, genetic susceptibility, alcohol abuse and smoking) have been identified [31, 33– 35]. Recent studies reveal that the SPINK1 mutations are more evident in nonalcoholic CP and may be associated with young-onset pancreatic cancer [36, 37], while the PRSS1 is not associated with pancreatic cancer [38, 39]. In our series, 3 of 4 pancreatic cancer patients had nonalcoholic CP and half of them were nonsmokers. Since Chinese pancreatic cancer patients may have different K-ras and p53 expressions, and Chinese CP patients have different PRSS1 and SPINK1 mutations than other populations [40, 41], it seems reasonable to speculate that genetic factors are likely to play an different role in the causes of CP and the development to pancreatic cancer in the Chinese population. Further investigations focusing on genetic factors and/or their interaction with environmental risk factors are needed. About 1% of our CP patients developed pancreatic cancer and the overall 10-year cumulative frequency of pancreatic cancer in these patients was 1.6%. It is clear that unstructured screening of all patients with CP is unlikely to be of benefit, as early diagnosis to distinguish pancreatic cancer from CP is still difficult [33, 42, 43]. For this reason, a routine procedure of pancreatic cancer screening in CP patients may not be advocated [14]. However, since patients with CP are at high risk of pancreatic cancer in the long run, the screening of pancreatic cancer with approaches of serum markers, genetic markers, and specific imaging studies may be justified in the future, especially in older (1 40–50 years) patients with CP [2, 43–46]. The main limitation of our study was the ‘semiprospective’ nature which might introduce inherent bias in the patient selection and the recall bias. In particular, information on some patients was not collected in a standardized fashion directly from the patients themselves. However, these biases may have minimally affected our results. The study subjects were identified from those whose clinical information was recorded in a computerized database system and half of the patients were followed up ‘prospectively’. In addition, there was no significant difference in the clinical data between the patients admitted during 1997–2005 and those during

Pancreatic Cancer and Chronic Pancreatitis

Pancreatology 2011;11:16–23

21

Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.213.236.110 - 6/17/2013 12:40:16 PM

with the general population. During the 102 months of follow-up, approximately 1% of the patients died from the pancreatic cancer, in keeping with the findings from some previous studies [12–14], but only to certain degree of agreement with others [5, 23–27]. Although the causes for the discrepancy are not known, it is most likely that the differences in the length of follow-up and selection bias may explain the variations in the incidence of pancreatic cancer among various populations. However, it has been clearly demonstrated that CP patients in China have a high risk of pancreatic cancer, regardless of their status of smoking or alcohol consumption. Smoking, an accepted risk factor for pancreatic cancer, was more frequent among alcohol abusers in our series and in previous studies [28, 29], but the consumption of tobacco and alcohol in our series was lower than that in patients from Western countries [12–14]. From the analysis conducted using the Cox model, the only risk factor for pancreatic cancer to emerge in the course of CP was age, whereas smoking, alcohol intake, and diabetes mellitus were not considered as risk factors in this model, a finding similar to the results of previous studies [12, 13, 30]. This may indicate that the risk factors for pancreatic cancer are independent of the underlying causes of CP [31], that there are confounding factors in this type of study, such as small sample size, and/or that the risk of smoking, alcohol intake, and diabetes mellitus for pancreatic cancer is too small, which, from the statistical standpoint, makes it hard to identify them as risk factors for pancreatic cancer. The inclusion criteria of cases of pancreatic cancer in the final analysis of risk for pancreatic cancer (SIR calculation) would dramatically affect the final results and the interpretation. In the present study, we excluded any cases of pancreatic cancer diagnosed within 2 years of clinical CP onset, as in a previous study [13]. To achieve maximum certainty, pancreatic cancers diagnosed within 2 years of diagnosis of CP were also excluded [14], even if their duration was more than 98 months, they all had pancreatic calcifications on imaging examination, and the pancreatic cancer was diagnosed by histological examination. After exclusion of these cases, the observed incidence of pancreatic cancer still showed approximately a significant 27.2-fold increase, compared with the expected incidence. Moreover, a fraction of patients with pancreatic cancer were eliminated from the study, similar to the results of previous findings [12, 32], suggesting that a large fraction of pancreatic cancer may have been masqueraded as CP, that the original diagnosis of CP should be cautious, and that major efforts to differential diagno-

2005–2007. Of note, all the pancreatic cancer patients died after February 2005 and their diagnoses were confirmed. Thus, the data appeared complete and reliable. Another limitation may be that only a small number of cancer patients were included in the analysis, which may overestimate the incidence of pancreatic cancer. Therefore, studies with a larger number of patients and a longer follow-up period are needed to verify our findings. Additionally, we did not carry out genetic testing or analysis of individual dietary items in the present study, which limited our ability to identify the genetic and/or environmental factors among the patients who developed pancreatic cancer. Finally, although two recent studies failed to find protective benefits from fruit and vegetable consumption [47, 48], adherence to a so-called Mediterranean diet seemed to lower the risk of pancreatic cancer, when fruits and vegetables were included as part of a ‘healthy lifestyle’ [49]. Future studies are needed to clarify the protective roles of such intervention approaches, including changes in diet and lifestyle.

In summary, the risk of pancreatic cancer is markedly increased in patients with either alcoholic CP or non-alcoholic CP in China, especially in older patients. Further investigation focusing on genetic or environmental risk factors is needed to confirm our findings and to uncover the underlying mechanisms for the association between CP and pancreatic cancer.

Acknowledgements The authors thank Medjaden Bioscience Limited for assisting in the preparation of the manuscript. Supported in part by the National Natural Science Foundation of China No. 30800510.

Disclosure Statement No conflict of interest to declare.

References

22

9 Ye W, Lagergren J, Weiderpass E, et al: Alcohol abuse and the risk of pancreatic cancer. Gut 2002;51:236–239. 10 Hassan MM, Bondy ML, Wolff RA, et al: Risk factors for pancreatic cancer: case-control study. Am J Gastroenterol 2007; 102: 2696–2707. 11 Tramacere I, Scotti L, Jenab M, et al: Alcohol drinking and pancreatic cancer risk: a metaanalysis of the dose-risk relation. Int J Cancer 2010;126:1474–1486. 12 Lowenfels AB, Maisonneuve P, Cavallini G, et al: Pancreatitis and the risk of pancreatic cancer: International Pancreatitis Study Group. N Engl J Med 1993;328:1433–1437. 13 Talamini G, Falconi M, Bassi C, et al: Incidence of cancer in the course of chronic pancreatitis. Am J Gastroenterol 1999; 94: 1253– 1260. 14 Malka D, Hammel P, Maire F, et al: Risk of pancreatic adenocarcinoma in chronic pancreatitis. Gut 2002;51:849–852. 15 Brand RE, Lerch MM, Rubinstein WS, et al: Advances in counselling and surveillance of patients at risk for pancreatic cancer. Gut 2007;56:1460–1469. 16 Wang LW, Li ZS, Li SD, et al: Prevalence and clinical features of chronic pancreatitis in China: a retrospective multicenter analysis over 10 years. Pancreas 2009;38:248–254.

Pancreatology 2011;11:16–23

17 Wang W, Liao Z, Li ZS, et al: Chronic pancreatitis in Chinese children: etiology, clinical presentation and imaging diagnosis. J Gastroenterol Hepatol 2009; 24:1862–1868. 18 Axon AT, Classen M, Cotton PB: Pancreatography in chronic pancreatitis: international definitions. Gut 1984;25:1107–1112. 19 Witt H, Sahin-Toth M, Landt O, et al: A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Nat Genet 2006;38:668–673. 20 Spicak J, Poulova P, Plucnarova J, et al: Pancreas divisum does not modify the natural course of chronic pancreatitis. J Gastroenterol 2007; 42:135–139. 21 Yadav D, Pitchumoni CS: Issues in hyperlipidemic pancreatitis. J Clin Gastroenterol 2003;36:54–62. 22 Yang L, Parkin DM, Ferlay J, et al: Estimates of cancer incidence in China for 2000 and projections for 2005. Cancer Epidemiol Biomarkers Prev 2005;14:243–250. 23 Ekbom A, McLaughlin JK, Karlsson BM, et al: Pancreatitis and pancreatic cancer: a population-based study. J Natl Cancer Inst 1994; 86:625–627. 24 Gullo L, Pezzilli R: Pancreatitis and the risk of pancreatic cancer. Pancreas 1997; 14: 105– 107. 25 Karlson BM, Ekbom A, Josefsson S, et al: The risk of pancreatic cancer following pancreatitis: an association due to confounding? Gastroenterology 1997; 113:587–592.

Wang /Liao /Li /Li /Chen /Zhan /Wang / Liu /Hu /Guo /Zou /Jin  

 

 

 

 

 

 

 

 

 

 

 

Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.213.236.110 - 6/17/2013 12:40:16 PM

1 Ji BT, Chow WH, Dai Q, et al: Cigarette smoking and alcohol consumption and the risk of pancreatic cancer: a case-control study in Shanghai, China. Cancer Causes Control 1995; 6:369–376. 2 Malfertheiner P, Schütte K: Smoking – a trigger for chronic inflammation and cancer development in the pancreas. Am J Gastroenterol 2006; 101:160–162. 3 Lowenfels AB, Maisonneuve P: Epidemiology and risk factors for pancreatic cancer. Best Pract Res Clin Gastroenterol 2006; 20: 197– 209. 4 Raimondi S, Maisonneuve P, Lowenfels AB: Epidemiology of pancreatic cancer: an overview. Nat Rev Gastroenterol Hepatol 2009;6: 699–708. 5 Bansal P, Sonnenberg A: Pancreatitis is a risk factor for pancreatic cancer. Gastroenterology 1995;109:247–251. 6 Talamini G, Bassi C, Falconi M, et al: Alcohol and smoking as risk factors in chronic pancreatitis and pancreatic cancer. Dig Dis Sci 1999;44:1303–1311. 7 Go VL, Gukovskaya A, Pandol SJ: Alcohol and pancreatic cancer. Alcohol 2005;35:205– 211. 8 Welsch T, Kleeff J, Seitz HK, et al: Update on pancreatic cancer and alcohol-associated risk. J Gastroenterol Hepatol 2006; 21(suppl 3):S69–S75.

Pancreatic Cancer and Chronic Pancreatitis

34 Greer JB, Whitcomb DC: Inflammation and pancreatic cancer: an evidence-based review. Curr Opin Pharmacol 2009;9:411–418. 35 Landi S: Genetic predisposition and environmental risk factors to pancreatic cancer: a review of the literature. Mutat Res 2009; 681:299–307. 36 Hucl T, Jesnowski R, Pfützer RH, et al: SPINK1 variants in young-onset pancreatic cancer. J Gastroenterol 2007; 42:599. 37 Masamune A, Kume K, Shimosegawa T: Differential roles of the SPINK1 gene mutations in alcoholic and nonalcoholic chronic pancreatitis. J Gastroenterol 2007; 42(suppl 17):135–140. 38 Rebours V, Boutron-Ruault MC, Schnee M, et al: Risk of pancreatic adenocarcinoma in patients with hereditary pancreatitis: a national exhaustive series. Am J Gastroenterol 2008;103:111–119. 39 Rebours V, Boutron-Ruault MC, Jooste V, et al: Mortality rate and risk factors in patients with hereditary pancreatitis: uni- and multidimensional analyses. Am J Gastroenterol 2009;104:2312–2317. 40 Dong M, Nio Y, Tamura K, et al: Ki-ras point mutation and p53 expression in human pancreatic cancer: a comparative study among Chinese, Japanese, and Western patients. Cancer Epidemiol Biomarkers Prev 2000; 9: 279–284. 41 Chang YT, Wei SC, L PC, et al: Association and differential role of PRSS1 and SPINK1 mutations in early-onset and late-onset idiopathic chronic pancreatitis in Chinese subjects. Gut 2009;58:885.

42 Howes N, Neoptolemos JP: Risk of pancreatic ductal adenocarcinoma in chronic pancreatitis. Gut 2002;51:765–766. 43 Gemmel C, Eickhoff A, Helmstädter L, et al: Pancreatic cancer screening: state of the art. Expert Rev Gastroenterol Hepatol 2009; 3: 89–96. 44 Wong T, Howes N, Threadgold J, et al: Molecular diagnosis of early pancreatic ductal adenocarcinoma in high risk patients. Pancreatology 2001;1:486–509. 45 Brand R, Mahr C: Risk factors for pancreatic adenocarcinoma: are we ready for screening and surveillance? Curr Gastroenterol Rep 2005;7:122–127. 46 Yan L, McFaul C, Howes N, et al: Molecular analysis to detect pancreatic ductal adenocarcinoma in high-risk groups. Gastroenterology 2005;128:2124–2130. 47 Michaud DS, Skinner HG, Wu K, et al: Dietary patterns and pancreatic cancer risk in men and women. J Natl Cancer Inst 2005;97: 518–524. 48 Vrieling A, Verhage BA, van Duijnhoven FJ, et al: Fruit and vegetable consumption and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 2009;124:1926–1934. 49 Jiao L, Mitrou PN, Reedy J, et al: A combined healthy lifestyle score and risk of pancreatic cancer in a large cohort study. Arch Intern Med 2009;169:764–770.

Pancreatology 2011;11:16–23

23

Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.213.236.110 - 6/17/2013 12:40:16 PM

26 Arvanitakis M, Van Laethem JL, Parma J, et al: Predictive factors for pancreatic cancer in patients with chronic pancreatitis in association with k-ras gene mutation. Endoscopy 2004;36:535–542. 27 Bracci PM, Wang F, Hassan MM, et al: Pancreatitis and pancreatic cancer in two large pooled case-control studies. Cancer Causes Control 2009; 20:1723–1731. 28 Bien TH, Burge R: Smoking and drinking: a review of the literature. Int J Addict 1990;25: 1429–1454. 29 Frulloni L, Gabbrielli A, Pezzilli R, et al: Chronic pancreatitis: report from a multicenter Italian survey (PanCroInfAISP) on 893 patients. Dig Liver Dis 2009;41:311–317. 30 Rocca G, Gaia E, Iuliano R, et al: Increased incidence of cancer in chronic pancreatitis. J Clin Gastroenterol 1987; 9:175–179. 31 Whitcomb DC, Pogue-Geile K: Pancreatitis as a risk for pancreatic cancer. Gastroenterol Clin North Am 2002;31:663–678. 32 Thuluvath PJ, Imperio D, Nair S, et al: Chronic pancreatitis: long-term pain relief with or without surgery, cancer risk, and mortality. J Clin Gastroenterol 2003;36:159– 165. 33 Vitone LJ, Greenhalf W, McFaul CD, et al: The inherited genetics of pancreatic cancer and prospects for secondary screening. Best Pract Res Clin Gastroenterol 2006; 20: 253– 283.