Eugene P. DiMagno

BACKGROUND: The results of case-control studies and anecdotal reports suggest that pancreatitis may be a risk factor for pancreatic cancer, but there have been no studies of sufficient size and power to assess the magnitude of the relation between these two diseases. METHODS AND RESULTS: We undertook a multicenter historical cohort study of 2015 subjects with chronic pancreatitis who were recruited from clinical centers in six countries. A total of 56 cancers were identified among these patients during a mean (+/-SD) follow-up of 7.4 +/- 6.2 years. The expected number of cases of cancer calculated from country-specific incidence data and adjusted for age and sex was 2.13, yielding a standardized incidence ratio (the ratio of observed to expected cases) of 26.3 (95 percent confidence interval, 19.9 to 34.2). For subjects with a minimum of two or five years of follow-up, the respective standardized incidence ratios were 16.5 (95 percent confidence interval, 11.1 to 23.7) and 14.4 (95 percent confidence interval, 8.5 to 22.8). The cumulative risk of pancreatic cancer in subjects who were followed for at least 2 years increased steadily, and 10 and 20 years after the diagnosis of pancreatitis, it was 1.8 percent (95 percent confidence interval, 1.0 to 2.6 percent) and 4.0 percent (95 percent confidence interval, 2.0 to 5.9 percent), respectively. CONCLUSIONS: The risk of pancreatic cancer is significantly elevated in subjects with chronic pancreatitis and appears to be independent of sex, country, and type of pancreatitis.

BACKGROUND: Hereditary pancreatitis is an autosomal-dominant disease, with a variable expression and an estimated penetrance of 80%. The gene for this disease has recently been mapped to chromosome 7q35, and the defect is believed to be caused by a mutation in the cationic trypsinogen gene. Acute attacks of abdominal pain begin early in life and the disease often progresses to chronic pancreatitis. Although the risk of pancreatic cancer is thought to be increased in more common types of chronic pancreatitis, the frequency of pancreatic cancer in the inherited type of pancreatitis is uncertain. PURPOSE: The aim of this study 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 Association of Pancreatology to participate in a longitudinal study of this rare form of pancreatitis. The initial criteria for patient eligibility were as follows: early age (< or = 30 years) at onset of symptoms, positive family history, and absence of other causes. From April 1995 through February 1996, 37 physicians from 10 countries contributed medical records of 246 (125 males and 121 females) patients thought to have hereditary pancreatitis as the most likely diagnosis. This group included 218 patients where the diagnosis appeared to be highly probable and 28 additional patients where the diagnosis of hereditary pancreatitis was less certain: 25 patients who had relatively late onset of disease and a positive family history and three patients with onset of disease before age 30 years but with an uncertain family history. We reviewed all causes of death and compared the observed to the expected frequency of cancer in this historical cohort of patients with hereditary pancreatitis. The strength of the association between pancreatitis and pancreatic cancer was estimated by the standardized incidence ratio (SIR), which is the ratio of observed pancreatic cancer cases in the cohort to the expected pancreatic cancers in the background population, adjusted for age, sex, and country. RESULTS: The mean age (+/- standard deviation [SD]) at onset of symptoms of pancreatitis was 13.9 +/- 12.2 years. Compared with an expected number of 0.150, eight pancreatic adenocarcinomas developed (mean age +/- SD at diagnosis of pancreatic cancer: 56.9 +/- 11.2 years) during 8531 person-years of 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 pancreatic 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 cancer and six of eight with pancreatic cancer. Ninety-nine of the 238 patients without pancreatic cancer and six of the patients with pancreatic cancer inherited the disease through the paternal side of the family. The estimated cumulative risk of pancreatic cancer to age 70 years in patients with hereditary pancreatitis approaches 40%. For patients with a paternal inheritance pattern, the cumulative risk of pancreatic cancer is approximately 75%. CONCLUSIONS: Patients with hereditary pancreatitis have a high risk of pancreatic cancer several decades after the initial onset of pancreatitis. A paternal inheritance pattern increases the probability of developing pancreatic cancer.

To investigate the functioning reserve capacity of the exocrine pancreas, we studied the relations of steatorrhea and creatorrhea to lipase and trypsin outputs in 17 patients with chronic pancreatitis and 33 healthy subjects. A standard diet was given, and stools were collected for 48 hours. Total enzyme outputs in response to duodenal perfusion of essential amino acids (78 mM) and intravenously administered cholecystokinin-pancreozymin (0.25 U per kilogram per minute) were compared in patients and in healthy subjects. Steatorrhea was not observed until lipase output was 10 per cent or less of normal; similarly, creatorrhea occurred only when trypsin outputs were less than 10 per cent of normal. These relations demonstrate the large reserve capacity for enzyme secretion by the exocrine pancreas and explain the often late development of steatorrhea and creatorrhea in chronic pancreatitis. (N Engl J Med 288:813–815, 1973)