Albert B. Lowenfels, Patrick Maisonneuve, Giorgio Cavallini, Rudolf W. Ammann, Paul G. Lankisch, Jens R. Andersen, Eugene P. Dimagno, Ake Andren-Sandberg, Lennart Domellof, for The International Pancreatitis Study Group
Background The results of case-control studies and anecdotalreports suggest that pancreatitis may be a risk factor for pancreaticcancer, but there have been no studies of sufficient size andpower to assess the magnitude of the relation between thesetwo diseases.
Methods and Results We undertook a multicenter historical cohortstudy of 2015 subjects with chronic pancreatitis who were recruitedfrom clinical centers in six countries. A total of 56 cancerswere identified among these patients during a mean (±SD)follow-up of 7.4 ±6.2 years. The expected number of casesof cancer calculated from country-specific incidence data andadjusted for age and sex was 2.13, yielding a standardized incidenceratio (the ratio of observed to expected cases) of 26.3 (95percent confidence interval, 19.9 to 34.2). For subjects witha minimum of two or five years of follow-up, the respectivestandardized incidence ratios were 16.5 (95 percent confidenceinterval, 11.1 to 23.7) and 14.4 (95 percent confidence interval,8.5 to 22.8). The cumulative risk of pancreatic cancer in subjectswho were followed for at least 2 years increased steadily, and10 and 20 years after the diagnosis of pancreatitis, it was1.8 percent (95 percent confidence interval, 1.0 to 2.6 percent)and 4.0 percent (95 percent confidence interval, 2.0 to 5.9percent), respectively.
Conclusions The risk of pancreatic cancer is significantly elevatedin subjects with chronic pancreatitis and appears to be independentof sex, country, and type of pancreatitis.
Many epidemiologic studies have been performed to detect riskfactors for exocrine pancreatic cancer -- a common and usuallyfatal gastrointestinal tumor. Smoking and reduced consumptionof fruits and vegetables appear to be the best established riskfactors for this tumor1,2,3,4,5,6,7,8,9. However, case-controlstudies and case reports have also implicated pancreatitis,a disease often seen in heavy drinkers, as a possible cause.Because of the limited number of cases of pancreatitis in moststudies, the evidence linking these two pancreatic disordersis largely anecdotal3,6,10,11,12. In this report, we describethe results of a large historical cohort study of subjects withchronic pancreatitis from six countries, which we undertookto assess the risk of pancreatic cancer in such persons.
Methods
Subjects
Centers with experience in the management of chronic pancreatitiswere invited to join an international study group to investigatethe relation between pancreatitis and pancreatic cancer. Thefinal group included seven centers located in six countries:Denmark (Copenhagen), Germany (Gottingen-Luneburg), Italy (Verona),Sweden (Lund and Orebro), Switzerland (Zurich), and the UnitedStates (Rochester, Minn.). In each center, information was abstractedfrom the patients' clinical records or transferred directlyfrom existing computer files to a central data base. We wereable to obtain information on demographic characteristics andvital status; data referring to the diagnosis, management, andcomplications of pancreatitis; and data on the smoking and drinkinghistories of each patient. We were also able to ascertain whetherthe patients had other types of tumors.
The initial cohort consisted of 2015 subjects who fulfilledthe diagnostic criteria for chronic pancreatitis (see below).Person-years for this group were calculated from the date ofthe diagnosis of pancreatitis to the date of last patient contactor death. We then excluded 462 subjects who had been followedfor less than two years or who had been given a diagnosis ofpancreatic cancer during this period, as well as 1 subject whohad initially undergone a 95 percent pancreatectomy, leavinga total of 1552 subjects thought to be free of pancreatic cancerfor at least two years after the onset of pancreatitis. Forthe analysis of this group the calculation of person-years begantwo years after the diagnosis of pancreatitis. A final analysiswas performed on the 1160 subjects with at least five yearsof follow-up who were free of pancreatic cancer during thisinterval; for this analysis the calculation of person-yearsbegan five years after the diagnosis of pancreatitis. The recruitmentof patients began in 1946 and continued through 1989.
Diagnosis of Chronic Pancreatitis
All patients had been previously hospitalized in universityor tertiary hospitals. Criteria for the diagnosis of chronicpancreatitis have been published previously for five of theseven centers13,14,15,16,17,18. The diagnosis was based on acombination of the following criteria: symptoms of chronic epigastricpain, steatorrhea, or both (1530 patients); the presence ofpancreatic calcification (988 patients); evidence of pancreatitison diagnostic procedures (radiographic studies, 814 patients;ultrasonography, 561 patients; endoscopic retrograde cholangiopancreatography,545 patients; and computed tomography, 248 patients); and resultsof laboratory tests (secretin-pancreozymin or secretin-ceruleintest, fecal fat test, or fecal chymotrypsin assay, 999 patients).
Diagnosis of Pancreatic Cancer
Of the 29 patients with suspected pancreatic cancers that appearedtwo or more years after the diagnosis of pancreatitis, histologicconfirmation was obtained at either surgery or autopsy in 24(83 percent). In the remaining five patients, the diagnosiswas established by exploratory laparotomy in two patients andby the clinical course and positive laboratory or radiologicfindings in three patients.
Statistical Analysis
We used published age-stratified (according to five-year agegroups), sex-specific, and country-specific data on the incidenceof cancer to determine the expected number of cases of pancreaticcancer in the cohort19,20. For countries with more than onecancer registry, we selected the registry nearest to the center:for Switzerland, Zurich; for Germany, Hamburg; and for Italy,the province of Parma. For the United States we used data fromthe Surveillance, Epidemiology, and End Results study21. Thestandardized incidence ratio -- the ratio of observed to expectedpancreatic cancers -- was used to estimate the relative risk.The 95 percent confidence interval for the standardized incidenceratio was calculated on the basis of the assumption that theobserved cases of cancer followed a Poisson distribution. Alife-table method was used to estimate the cumulative probabilityof the development of pancreatic cancer once pancreatitis wasdiagnosed. For multivariate analysis of the simultaneous effectsof the study center, age, sex, and several clinical variablesassociated with pancreatitis, we used the Cox proportional-hazardsmodel. The final model contained terms for smoking status, drinkingstatus, clinical center, sex, and age. For smoking and drinkingstatus, the subjects were classified as either "ever" havingsmoked or drunk alcohol or "never" having smoked or drunk alcohol.For analyses of the age at diagnosis of pancreatitis we dividedthe subjects into the following groups: those 0 to 39 yearsof age (the reference category), those 40 to 59 years of age,and those 60 years of age or older. Data analysis was performedwith SAS procedures22.
Results
Fifty-six pancreatic cancers developed in the initial groupof 2015 subjects with pancreatitis, some of whom were followedfor less than two years. The expected number of tumors was 2.13,yielding a standardized incidence ratio of 26.3 (95 percentconfidence interval, 19.9 to 34.2).
Table 1 provides country-specific and overall characteristicsof the 1552 subjects who were followed for at least two years.The type of pancreatitis was listed as alcoholic in 1198 patients(77 percent), idiopathic in 261 patients (17 percent), hereditaryin 29 patients (1.9 percent), and due to other factors in 64patients (4.1 percent). The overall incidence of alcohol consumptionwas high: 981 subjects (63 percent) consumed five or more drinksper day ( 100 g of alcohol per day). Data on smoking statuswere available for all centers except that in Denmark: 1040smoked of 1207 whose smoking status was known (86 percent);651 of 922 subjects (71 percent) for whom specific informationabout cigarette smoking was available smoked one or more packsper day. Pancreatic calcification, diabetes, and cirrhosis ofthe liver were documented in 988 (64 percent), 728 (47 percent),and 108 (7 percent) subjects, respectively. A total of 712 subjects(46 percent) underwent surgery for chronic pancreatitis duringthe follow-up period.
Table 1. Country-Specific Characteristics of 1552 Subjects with Chronic Pancreatitis Who Were Followed for 2 Years.
Of the 1552 subjects, 29 (21 male and 8 female subjects) hadevidence of cancer of the pancreas 2 or more years after thediagnosis of pancreatitis during a mean (±SD) follow-upof 7.4 ±5.6 years. The expected number, adjusted forage, sex, and center, was 1.76, yielding a standardized incidenceratio of 16.5 (95 percent confidence interval, 11.1 to 23.7)(Table 2). The incidence ratios were elevated in all countries,and these country-specific estimates appeared to be homogeneous(P 0.90). When we restricted the analysis to the subjects witha minimum of five years of follow-up, the overall incidenceratio was slightly reduced (standardized incidence ratio, 14.4;95 percent confidence interval, 8.5 to 22.8), and all but oneof the country-specific incidence ratios remained significantlyelevated.
Table 2. Country-Specific and Overall Risk of Pancreatic Cancer in 1552 Subjects with Chronic Pancreatitis Who Were Followed for 2 Years.
The risk of pancreatic cancer in subjects with alcoholic pancreatitiswas compared with that in subjects with nonalcoholic pancreatitis(Table 3). The differences were not statistically significant,and the risks appeared to be homogeneous for subjects with aminimum of two or five years of follow-up.
Table 3. Risk of Pancreatic Cancer in 1198 Subjects with Chronic Alcoholic Pancreatitis and 354 Subjects with Chronic Nonalcoholic Pancreatitis.
Using the Cox proportional-hazards model, we studied the possibleeffects of several variables on the risk of developing pancreaticcancer. These included demographic variables (age, sex, andcountry), clinical variables (the type of pancreatitis and thepresence or absence of diabetes, calcification, and cirrhosis),and lifestyle variables (alcohol use and smoking status). Onlyincreasing age was significantly related to the developmentof pancreatic cancer. A model that included terms for smokingstatus, drinking status, clinical center, sex, and age yieldedrisk ratios of 3.1 (95 percent confidence interval, 1.1 to 8.6)for subjects who were 40 to 59 years of age and 9.7 (95 percentconfidence interval, 2.7 to 35.1) for subjects who were 60 yearsof age or older, as compared with subjects who were less than40 years of age.
The cumulative incidence of pancreatic cancer in patients withchronic pancreatitis who were followed for a minimum of twoyears is shown in Figure 1. Because of the exclusion criteria,no subjects given a diagnosis of pancreatic cancer during thefirst two years of follow-up were included in the analysis.The cumulative proportion of subjects estimated to have pancreaticcancer 10 years after the diagnosis of pancreatitis was 1.8percent (95 percent confidence interval, 1.0 to 2.6 percent),and the cumulative proportion with pancreatic cancer 20 yearsafter the diagnosis of pancreatitis was estimated to be 4.0percent (95 percent confidence interval, 2.0 to 5.9 percent).Over a 20-year period, the cumulative risk of pancreatic cancerappeared to increase nearly linearly.
Figure 1. Cumulative Incidence of Pancreatic Cancer in 1552 Subjects with Chronic Pancreatitis with a Minimum of Two Years of Follow-up.
The vertical lines represent 95 percent confidence intervals. The numbers in parentheses are the numbers of subjects at risk. One additional case of cancer developed after 25 years of follow-up.
A total of 425 subjects (27 percent) who were followed for twoor more years died during follow-up, including 28 of the 29subjects with pancreatic cancer. One hundred thirty-seven subjectswere known to have died of nonpancreatic cancers.
Discussion
The results of this historical cohort study suggest that patientswith chronic pancreatitis have an increased risk of pancreaticcancer; the excess risk was observed in men and women, in alcoholicand nonalcoholic types of pancreatitis, and in all six countriesincluded in the study.
The study population may have been followed more closely thanthe general population, and this increased surveillance couldaccount for some of the large excess of pancreatic cancer thatwe observed. However, comparable results have been obtainedin countries with different surveillance systems. Moreover,even if the true background incidence of pancreatic cancer inthe various countries was twice as high as reported, the overallstandardized incidence ratios for subjects with a minimum oftwo years of follow-up would still be significant (standardizedincidence ratio, 8.2; 95 percent confidence interval, 5.5 to11.8).
Another important problem concerns the possibility of misdiagnosis.We recognize that pancreatic cancer can mimic chronic pancreatitisand that some subjects initially classified as having chronicpancreatitis could conceivably have had pancreatic cancer. Misdiagnosiscould explain why subjects in the initial cohort, which includedsome who had been followed for less than two years, had a higherrisk of pancreatic cancer than subjects who had been followedfor longer periods. However, pancreatic cancer is a rapidlyprogressive tumor with an overall five-year survival rate ofonly 3 percent23. Thus, with longer periods of observation,the probability of misdiagnosing pancreatic cancer as pancreatitiswould become less likely. Indeed, we noted that the overallrisk ratio appeared stable at two years, and changed only minimallythereafter. Another possible explanation for the higher risksobserved during the early period is that about 5 percent ofcases of alcoholic pancreatitis and over 50 percent of casesof idiopathic pancreatitis are initially painless17. Thus, thediagnosis of pancreatitis could be delayed until shortly afterthe onset of cancer-associated abdominal pain.
Classifying cases of pancreatitis as pancreatic cancer wouldlead to inflated risk ratios. This possibility is unlikely sincethe diagnosis was verified histologically in 24 of the 29 subjectssuspected to have cancer and in 14 of the 18 subjects followedfor five or more years. If the analysis is restricted to biopsy-provedcases with long follow-up periods, the results are still significant(standardized incidence ratio, 11.3; 95 percent confidence interval,6.2 to 18.9).
Finally, part of the excess incidence of pancreatic cancer couldbe caused by the selective loss to follow-up of patients atlow risk of pancreatic cancer. To determine the maximal effectof the loss of patients to follow-up, we reanalyzed our dataassuming that in each center all subjects with incomplete follow-updata were followed until the end of the study period and nonew cases of pancreatic cancer occurred despite the additionof these extra person-years. After this adjustment, the totalnumber of person-years for subjects with a minimum of two yearsof follow-up increased from 11,438 to 17,824 and the standardizedincidence ratio was 9.3 (95 percent confidence interval, 6.2to 13.3). Thus, even when we assumed that follow-up was completeand that no additional cancers occurred, the results remainedsignificant.
Diabetes, a suggested risk factor for pancreatic cancer,24,25,26was present in 728 subjects (47 percent). In these subjectswith chronic pancreatitis, however, diabetes was not an independentpredictor of pancreatic cancer in the Cox proportional-hazardsmodel.
Heavy consumption of alcohol, which was characteristic of mostof the subjects in this cohort, is a recognized cause of chronicpancreatitis, but alcohol has generally not been associatedwith pancreatic cancer1,2,27,28,29. In contrast, smoking maybe a risk factor for both pancreatic cancer8 and chronic pancreatitis30,31,32.The risk of pancreatic cancer has also been reported to be increasedin hereditary33 and tropical34 pancreatitis -- diseases notthought to be associated with either drinking or smoking. Itis of interest that there may be an excess incidence of pancreaticcancer among young subjects with cystic fibrosis -- anotherdisease characterized by marked pancreatic dysfunction35. Oneexplanation for all these observations is that chronic pancreatitis,whether induced by environmental, genetic, or other causes,is an intermediate stage between normal pancreatic functionand some cases of pancreatic cancer.
In all forms of pancreatitis there appears to be cellular dysfunction,glandular destruction, and presumably, increased cell turnover.Increased cell division has been suggested as a potential precursorof cancer in many organs36. The excess risk of pancreatic cancerthat we observed in this large group of subjects with varioustypes of pancreatitis is consistent with this hypothesis.
Supported by grants from the C.D. Smithers Foundation and SolvayPharmaceuticals, Inc.
Source Information
From the Departments of Surgery and Community and Preventive Medicine, New York Medical College, Valhalla (A.B.L.); the Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy (P.M.); the Service of Gastroenterology and Digestive Endoscopy, University of Verona, Verona, Italy (G.C.); the Gastroenterology Service, Department of Medicine, University Hospital, Zurich, Switzerland (R.W.A.); the Departments of Internal Medicine, University of Gottingen, Gottingen, Germany, and the Municipal Hospital of Luneburg, Luneburg, Germany (P.G.L.); the Department of Gastroenterology, Hvidovre Hospital, University of Copenhagen, Denmark (J.R.A.); the Gastrointestinal Research Unit and Section of Clinical Epidemiology, Mayo Clinic, Rochester, Minn. (E.P.D.); the Department of Surgery, Lund University, Lund, Sweden (A.A.-S.); and the Department of Surgery, Orebro Medical Center Hospital, Orebro, Sweden (L.D.). Presented as an abstract at the annual meeting of the American Pancreatic Association, November 5-6, 1992.In addition to the authors, the members of the International Pancreatitis Study Group included Vincenzo Di Francesco, M.D., Paolo Pederzoli, M.D., Annette Lohr-Happe, M.D., Einar Krag, M.D., L. Joseph Melton, III, M.D., Peter Boyle, Ph.D., C.S. Pitchumoni, M.D., M.P.H., and Pe Shein Wynn, M.D., M.P.H.
Address reprint requests to Dr. Lowenfels at the Department of Surgery, New York Medical College, Valhalla, NY 10595.
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