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