HEREDITARY PANCREATITIS AND THE RISK OF PANCREATIC-CANCER

Background: Hereditary pancreatitis is an autosomal-dominant disease, with a variable expression and an estimated penetrance of 80%. The gen e for this disease has recently been mapped to chromosome 7q35, and th e defect is believed to be caused by a mutation in the cationic trypsi nogen gene. Acute attacks of abdominal pain begin early in life and th e disease often progresses to chronic pancreatitis. Although the risk of pancreatic cancer is thought to be increased in more common types o f chronic pancreatitis, the frequency of pancreatic cancer in the inhe rited type of pancreatitis is uncertain. Purpose: The aim of this stud y was to assess the frequency of pancreatic cancer and other tumors in patients with hereditary form of pancreatitis. Methods: To determine the natural history of hereditary pancreatitis, we invited all members of the American Pancreatic Association and the International Associat ion of Pancreatology to participate in a longitudinal study of this ra re form of pancreatitis. The initial criteria for patient eligibility were as follows: early age (less than or equal to 30 years) at onset o f symptoms, positive family history, and absence of other causes. From April 1995 through February 1996, 37 physicians from 10 countries con tributed medical records of 246 (125 males and 121 females) patients t hought to have hereditary pancreatitis as the most likely diagnosis. T his group included 218 patients where the diagnosis appeared to be hig hly probable and 28 additional patients where the diagnosis of heredit ary pancreatitis was less certain: 25 patients who had relatively late onset of disease and a positive family history and three patients wit h onset of disease before age 30 years but with an uncertain family hi story. We reviewed all causes of death and compared the observed to th e expected frequency of cancer in this historical cohort of patients w ith hereditary pancreatitis. The strength of the association between p ancreatitis and pancreatic cancer was estimated by the standardized in cidence ratio (SIR), which is the ratio of observed pancreatic cancer cases in the cohort to the expected pancreatic cancers in the backgrou nd population, adjusted for age, sex, and country. Results: The mean a ge (+/- standard deviation [SD]) at onset of symptoms of pancreatitis was 13.9 +/- 12.2 years. Compared with an expected number of 0.150, ei ght pancreatic adenocarcinomas developed (mean age +/- SD at diagnosis of pancreatic cancer: 56.9 +/- 11.2 years) during 8531 person-years o f follow-up, yielding an SIR of 53 (95% confidence interval [CI] = 23- 105). The frequency of other tumors was not increased: SIR = 0.7 (95% CI = 0.3-1.6). Eight of 20 reported deaths in the cohort were from pan creatic cancer. Thirty members of the cohort have already been tested for the defective hereditary pancreatitis gene: all 30 carry a mutated copy of the trypsinogen gene. The transmission pattern of hereditary pancreatitis was known for 168 of 238 patients without pancreatic canc er and six of eight with pancreatic cancer. Ninety-nine of the 238 pat ients without pancreatic cancer and six of the patients with pancreati c cancer inherited the disease through the paternal side of the family . The estimated cumulative risk of pancreatic cancer to age 70 years i n patients with hereditary pancreatitis approaches 40%. For patients w ith a paternal inheritance pattern, the cumulative risk of pancreatic cancer is approximately 75%. Conclusions: Patients with hereditary pan creatitis have a high risk of pancreatic cancer several decades after the initial onset of pancreatitis. A paternal inheritance pattern incr eases the probability of developing pancreatic cancer.