Pancreatic Cancer
Epidemiology and Risk Factors
Guenter J. Krejs
Medical University of Graz, Austria
Pancreatic Cancer
• 80% ductal pancreatic carcinoma
• 10% from exocrine tissue:acinar cell carcinomacystadenocarcinomagiant-cell carcinomaintraductal papillar mucinous
neoplasm
• 10% neuroendocrine tumors
Pancreatic Cancer
Average incidence:
10 per 100 000 pop. per year
Cases per year:
USA: 35 000
Germany 8 000
Austria 1 200
Average age at diagnosis 63 years
Cancer of the pancreas in males, age-standardized incidence rate per 100 000 population for the year 2002
Pancreatic Cancer
Incidence and mortality are practically identical
250 000 deaths per year worldwide
Ranks 8th in a worldwide listing of cancer mortality
Pancreatic Cancer
RISK FACTORS:
Smoking
High-fat diet, obesity, diabetes
Chronic pancreatitis
Hereditary pancreatitis
Primary sclerosing cholangitis
Vincent van Gogh
Smoking and Cancer
Rel. Risk
Lung 22
Lip, oral cavity, pharynx 27
Larynx 10
Esophagus 8
Bladder, kidney 3
Pancreas 2
Stomach 2
Leukemia 2
Pancreatic Cancer and Smoking
• Dose relationship with number of cigarettes smoked
• N-nitroso compounds may trigger hyperplastic and proliferative changes in pancreatic ducts
• Pancreatic cancer occurs in smokers 10 years earlier than in non-smokers
• 25% of pancreatic cancers attributable to smoking
• Risk returns to that of non-smokers 15 years after smoking cessation
NET and Smoking
Neuroendocrine tumors Risk increase with smoking
Gastroenteropancreatic
(GEP NET) 30%
Thoracic 50%
A. Colar et al, ENET 2008
Pancreatic Cancer
Diet
Increased Risk Protective
High intake of meat Fresh fruits
and fat and vegetables
National Institutes of Health - AARP
• 302 060 persons followed for 5 years (1995-2000)
• 654 pancreatic cancers
Am J Epidemiol 2008; 176:586-597
Am J Epidemiol 2008; 176:590
Coffee and cancer of the pancreas
B MacMahon, S Yen, D Trichopoulos, K Warren, and G Nardi
We questioned 369 patients with histologically proved cancer of the pancreas and 644 control patients about their use of tobacco, alcohol, tea, and coffee. There was a weak positive association between pancreatic cancer and cigarette smoking, but we found no association with use of cigars, pipe tobacco, alcoholic beverages, or tea. A strong association between coffee consumption and pancreatic cancer was evident in both sexes. The association was not affected by controlling for cigarette use. For the sexes combined, there was a significant dose-response relation (P approximately 0.001); after adjustment for cigarette smoking, the relative risk associated with drinking up to two cups of coffee per day was 1.8 (95% confidence limits, 1.0 to 3.0), and that with three or more cups per day was 2.7 (1.6 to 4.7). This association should be evaluated with other data; if it reflects a causal relation between coffee drinking and pancreatic cancer, coffee use might account for a substantial proportion of the cases of this disease in the United States. NEJM March 12, 1981 Vol. 304:630-633
Other risk factors for pancreatic cancer identified in various case-
control studies
• Diabetes mellitus
• Heavy alcohol consumption?
New onset diabetes mellitus above the age of 50 years:
1% will develop pancreatic cancer within the next 3 years
ERCP
Pancreatic Cancer
Chronic PancreatitisNEJM 1993, 328:1430
• 56 cancers in 2015 patients
• Expected number: 2
• 20fold increase
• After 20 years of chronic pancreatitis:risk of cancer 4%
Chronic Pancreatitis Avanitakis M, Endoscopy 2004;36:535 K-ras (proto-oncogene located on chromosome
12p12)
Gene mutation in chain of events leading to ductal adenocarcinoma
___________________________________
Pancreatic duct brushings:
K-ras mutation found in 57 of 146 patients (38%)
Follow-up (3.5 yrs) in 112 pts: Ca in 4 of 44 with mutation, in 0 of 68 without mutation
Kindred followed at the Mayo Clinic
Hereditary PancreatitisPathophysiology
Mutated cationic trypsinogen
When activated to trypsin, cannot be inactivated by trypsin-like serine proteases that slice proteins at arginine and lysine residues
Hereditary Pancreatitis
Cancer risk 50 - 70fold increased.
At age 70, cumulative risk of 40%
25% of patients with Zollinger-Ellison syndrome have MEN-IRisk also increased in von Hippel-Lindau disease
Family History of Pancreatic Cancer
Familial Pancreatic Cancer (FPC)
Pair of first-degree relatives with pancreatic cancer
Germline mutations identified:
CDKN2A, BRCA2, PALB2, STK11 and PRSS1
9040 persons with pancreatic cancer in 1718 kindreds enrolled in National Familial Pancreas Tumor Registry
FPC kindred members 6.8x risk
SPC* kindred members 2.4x risk
*Sporadic pancreatic cancer
Brune KA, J. Natl. Cancer Inst 2010; 102, 119-126
FPC:
Young onset kindred member (< 50 yrs)Risk 9.3 x
No young onset kindred memberRisk 6.3x
(No such difference in SPC kindreds)
Brune KA, J. Natl. Cancer Inst 2010; 102, 119-126
Cancer of the Bile Ducts J. Hep 2002;36:321
Risk Factor
Primary sclerosing cholangitis (PSC)
609 patients with PSC, 6-year follow-up: 13% developed cholangiocarcinoma annual risk 1.5%
PSC:
14fold increased risk of pancreatic cancer
Armory in Graz