PART 6 Pancreatic Disease
SECTION II Neoplastic
Pancreatic cancer: epidemiology
OVERVIEW
The pancreas is an organ located in the retroperitoneum, which
has both exocrine and endocrine functions. The exocrine
pancreas is composed of duct cells and acinar cells that produce
enzymes that break down carbohydrates, proteins, and lipids
promoting digestion. Greater than 90% of malignant pancreatic
neoplasms are presumed to arise from the exocrine component
(Cowgill et al, 2003; Li, 2003).
Pancreatic ductal adenocarcinoma (PDAC) is the most
common type of pancreatic cancer (PC), representing greater
than 90% of the exocrine pancreas cases (see Chapter 59). The
other 10% of exocrine tumors are mucinous tumors, mixed
adenosquamous tumors, or acinar cell tumors (Cowgill et al,
2003; Li, 2003). Endocrine neoplasms (islet cell tumors and
pancreatic neuroendocrine tumors) contribute approximately
5% of the total pancreatic cancer cases (Cowgill et al, 2003; Li,
2003).
PDAC is responsible for 2.8% of all new cancers and 6% of
all cancer deaths in the United States (Siegel et al, 2014). PC
is the fourth leading cause of cancer death in men, after lung,
prostate, and colorectal cancer, and as of 2014, it is also the
fourth leading cause of cancer death in women, following lung,
breast, and colorectal cancer (Siegel et al, 2014). More than
46,000 incident cases of PC are predicted annually in the
United States., with about 40,000 deaths. The diagnosis of
PDAC continues to confer an unfavorable prognosis, with an
increase in the death rate for PDAC cases of 0.4% between
2006 and 2010 (American Cancer Society [ACS], 2014).
PDAC is predicted to become the second leading cause of
cancer death by 2030 (ACS, 2014; Smith et al, 2009). This is
mainly due to greatly improved survival for the other leading
cancers and limited advances in the chemotherapeutic adjuvant
treatment of PDAC.
Traditionally, PDAC had been considered a predominantly
male cancer. Since 2000, the incidence rates in men and women
have been increasing at the about the same rate, 1.3% per year.
In 2009, the actual number of incident cases in women (21,420)
exceeded the number of new cases in men (21,050) (Jemal
et al, 2009). The 2014 Surveillance Epidemiology and End
Results (SEER) data indicate that the number of new cases and
incidence rates in men (23,530) and women (22,890) are nearly
equal (Siegel et al, 2014). Cigarette smoking is the leading
environmental cause of PDAC, accounting for 25% to 35% of
C. Malignant Tumors
CHAPTER 61
Theresa Pluth Yeo and Charles J. Yeo
cases (Lowenfels et al, 2004). The difference in cigarette
smoking rates in men and women narrowed in the mid-1980s.
The stabilization of incidence rates by gender may indicate that
the health consequences of smoking by women over the last 3
decades have gained parity. Currently, cigarette smoking in the
United States varies by race, with 21% of white men identifying
as smokers, compared with 19% of white women, 22% of
African-American men and 15% of African-American women,
17% of Hispanic men and 8% of Hispanic women, and 17%
of Asian men and 5% of Asian women (ACS, 2014).
In the United States, the peak incidence of PDAC occurs
in the seventh and eighth decades of life (Howlader et al,
2014). The U.S. population risk for pancreatic cancer is 14.0
per 100,000 for men and 10.7 per 100,000 for women. The
main risk factor for PDAC is advancing age. Between 2007 and
2011, the median age at diagnosis for cancer of the pancreas
was 71 years, and the median age at death was 73 years accord-
ing to SEER data (Howlader et al, 2014). More than 60% of
new PDAC cases occur between the ages 65 and 84 years. The
incidence of PDAC remains highest for black Americans, with
rates of 17.2 per 100,000 in men and 14.2 per 100,000 in
women. The lowest risk of pancreatic cancer is among Asian/
Pacific Islander men and women (10.7 and 8.9 per 100,000,
respectively).
Between 1950 and 1995, the worldwide incidence rates of
PDAC increased ninefold in men (1.4 to 12.5 per 100,000) and
women (0.8 to 6.8 per 100,000), but rates have leveled off since
1985 (Lin et al, 1998).The annual incidence rate worldwide for
all histologic types of pancreatic cancer is approximately 4.9
new cases per 100,000 persons, ranking 12th among all cancers
globally (Globocan, 2012a). In 2012, 337,872 new cases of
pancreatic cancer were reported worldwide, with 330,372
annual deaths (Globocan, 2012b).
RACE AND ETHNICITY
African Americans
African Americans have the highest death rates from cancer and
the shortest survival period of all racial groups (DeSantis et al,
2013). African-American males have higher incidence rates for
all cancers combined and also for the most common cancers
(prostate, lung, colorectal, and pancreas). Death rates, per
100,000 population, from PDAC are 15.5 for African-American
men and 12.6 for women, compared with 12.4 for white men
971
972 PART 6 PANCREATIC DISEASE Section II Neoplastic

and 9.3 for African American women. African Americans of uncovered. The etiology of PC is multifactorial and involves
lower socioeconomic status are more likely to be diagnosed with several common underlying pathways: insulin resistance,
advanced stage pancreatic cancer and are less likely to undergo inflammation, hemostasis, and infection (Maisonneuve et al,
surgery or to receive chemotherapy (Chang et al, 2005; Elou- 2015). Pancreatic carcinoma is also characterized by multiple
beidi et al, 2006; Silverman et al, 2002). Other known risk germline and somatic genetic mutations (Hruban et al, 1998).
factors for PDAC (obesity, diabetes, and pancreatitis) are more (This topic is covered extensively in Chapter 9B.) The majority
common in African Americans. of PCs (>80%) are due to sporadically occurring mutations. It
It has been reported that serum cotinine levels, the primary is estimated that less than 3% of pancreatic cancers are truly
metabolite of nicotine, are consistently higher in African Ameri- hereditary and due to inherited germline mutations and their
cans than in whites and Mexican Americans, even after adjust- respective syndromes (Wang et al, 2009).
ment for the number of cigarettes smoked per day, the number Personal risk factors for PC include tobacco exposure,
of smokers in the home, the number of hours of environmental including cigarette, cigar, and pipe smoking; ETS exposure,
tobacco smoke (ETS) exposure at work, the number of rooms also known as second-hand smoke or passive smoke exposure;
in the home, and the region of the country where the subject exposure to occupational and environmental carcinogens;
lived (Caraballo et al, 1998). This suggests that genetic differ- African-American race; Ashkenazi Jewish heritage; high-fat and
ences in cigarette product metabolism may influence rates of high-cholesterol diets; obesity; alcohol abuse; pancreatitis;
PDAC. diabetes; blood group subtype; and infectious agents (Table
61.1) (Everhardt et al, 1995; Gold et al, 1998; Maisonneuve
Ashkenazi Jews et al, 2014; Silverman et al, 1994; Wynder, 1975). Maison-
Pancreatic cancer occurs in excess in Jews, particularly Jews of neuve and Lowenfels recently (2015) completed an extensive
Ashkenazi heritage (Lynch et al, 1996). The age-standardized meta-analysis of 117 studies on putative causative factors for
rates for PDAC in Jews in Israel significantly exceed the rates PC and have calculated the population attributable risk for
for Israeli non-Jews (7.2 per 100,000 for all Jewish men and many of the known risk factors.
5.7 per 100,000 for Jewish women vs. 4.0 per 100,000 for
non-Jewish men and 2.9 per 100,000 for non-Jewish women).
Approximately 5% to 10% of this discrepancy is attributed to
the BRCA2 mutation, 6174delT, which is also associated with TABLE 61.1 Risk Factors Associated With Cancer of the
breast, gastric, ovarian, and bile duct cancers. The 6174delT Pancreas: Summary of Previous Reports
mutation is present in approximately 1% of Ashkenazi Jews
and in approximately 4% of all patients with PDAC (Ferrone Lifestyle and Environmental Dietary Factors
Factors High fat/cholesterol
et al, 2009; Struewing et al, 1995). The BRCA1 (185delAG, Overweight and obesity
Cigarette smoking (dose-
5382insC) founder mutation occurs less commonly than the response relationship) Nitrosamines in food
BRCA2 mutation. In a study of 187 Jewish patients with PC, a Environmental tobacco smoke Occupational Exposure to
BRCA1 founder mutation was identified in 1.3% of the patients exposure, particularly early Carcinogens
compared with the BRCA2 mutation, which was present in in life Asbestos, 2-naphthylamine,
Alcohol benzidine, gasoline
4.1% of the patients (Ferrone et al, 2009). Residential radon products, PAHs, dry-
Race/Ethnic Factors cleaning agents, DDT, radon
Asians African-American men and Selected High-Risk
Asian patients with PDAC have been reported to have less women Occupations
aggressive tumors than non-Asians (either black or white Native female Hawaiians Dry cleaning or chemical plant
Ashkenazi Jews work, sawmill work,
patients) and higher survival rates when assessed on a stage-
Inherited Predisposition electrical equipment
adjusted basis (Clegg et al, 2008). To determine whether Asians Hereditary pancreatitis manufacturing work, mining
develop a histologically different type of PDAC than Western Hereditary nonpolyposis and metal working
populations, Longnecker and colleagues (2000) conducted a colorectal cancer occupations
population-based study using three SEER geographic areas: Hereditary breast and ovarian Height
cancer RR, 1.81 (CI, 1.31 to 2.52)
Hawaii, San Francisco, and Seattle. They compared PC cases Familial atypical multiple mole when comparing tallest-
in Japanese, Chinese, Filipino, Hawaiian, black, and white melanoma syndrome and shortest-height
patients in these areas. The study revealed that Japanese patients Peutz-Jeghers syndrome categories for men and
had the highest fraction of localized tumors with the lowest Ataxia-telangiectasia women
grade, and that Chinese, Filipino, and Japanese women had Fanconi anemia Previous Surgery
Cystic fibrosis Cholecystectomy
longer survival times than did whites, although survival time Medical Conditions Gastrectomy
was significantly different for Japanese women only. The reason Chronic pancreatitis
for these differences is unknown, but race-related genetic and Cirrhosis
environmental exposure factors may be the cause of these Diabetes (or impaired fasting
survival discrepancies. blood glucose)
Helicobacter pylori infection
Periodontal disease
RISK FACTORS FOR PANCREATIC DUCTAL CI, Confidence interval; DDT, dichlorodiphenyl-trichloroethane; PAHs, polyaromatic hydrocarbons;
ADENOCARCINOMA AND PANCREATIC RR, relative risk.
CANCERS (SEE CHAPTER 9C) Not all listed factors have been definitively proven to cause pancreatic cancer.
Data from Ahlgren, 1996; Efthimiou et al, 2001; Ekbom et al, 1994; Garabrant et al, 1993; Gold
The risk factors for developing pancreatic cancer have been et al, 1998; Hruban et al, 1998; Kogevinas et al, 2000; Lowenfels et al, 1997; Lynch et al, 1996;
extensively studied, and new information continues to be Maisonneuve, 2015; Michaud et al, 2001; Silverman et al, 1998; and Yeo et al, 2009.

Familial Pancreatic Cancer and Inherited
Genetic Disorders
Family history of PDAC is a strong risk factor in 5% to 10%
of cases (Lowenfels et al, 2005). In the National Familial
Pancreas Tumor Registry at Johns Hopkins Hospital, pro-
spective studies of family members of pancreatic cancer kin-
dreds found a twofold increased risk of pancreatic cancer in
the first-degree relatives of persons with sporadic pancreatic
cancer and a ninefold increased risk in first-degree relatives
of those with familial pancreatic cancer (Klein et al, 2004;
Wang et al, 2009). Germline mutations of BRCA2 are found
in 6% to 19% of familial pancreatic cancer patients (Murphy
et al, 2002). When a more stringent definition of familial
pancreatic cancer is used, a 57-fold increased risk of PC was
reported in kindreds with three or more family members
affected with PC (Tersmette et al, 2001). This corresponds to
a notably high incidence rate of 301 cases per 100,000 per
year compared with the SEER age-adjusted rate for the entire
U.S. population of 8.8 cases per 100,000 per year. A recent
report identified a germline truncating mutation of the
PALB2 gene in 3% of familial pancreatic cancer patients
(Blackford et al, 2009; Jones et al, 2009). Despite these many
advances in the understanding of the mutations involved in
the pathogenesis of PC, no single “pancreatic cancer gene”
has been identified.
Two recent studies have documented an increased risk of
PC in persons with A, B, and AB blood types. (Amundadottir
et al, 2009; Petersen et al, 2010). This risk has been attributed
to an ABO single nucleotide polymorphism, rs505922. Overall,
56% of the population has a non-O blood group and the pro-
portion of PDAC due to non-O blood group is 13% to 19%
(Maisonneuve et al, 2015).
Six Genetic Syndromes Associated With Pancreatic
Ductal Adenocarcinoma
Six genetic familial syndromes and their respective predisposing
genes have been identified and linked to the development of
PC; these are described briefly later (Table 61.2). Although
individuals with these syndromes have an increased risk of
developing PC, collectively these syndromes account for less
TABLE 61.2 High-Risk Genetic Disorders Associated With
Familial Pancreatic Cancer
Gene/Chromosomal
Genetic Syndrome Mutation Region
Hereditary PRSS1 (7q35)
pancreatitis
Hereditary hMSH2, hMSH1,
nonpolyposis hPMS2, hMSH3,
colorectal cancer hPMS1, hMSH6/
(Lynch II variant) GTBP
Hereditary breast and BRCA2 (13q12-
ovarian cancer q13)
FAMMM syndrome p16 (9p21)
Peutz-Jeghers STK11/LKB1
syndrome (19p13)
Ataxia-telangiectasia ATM (11q22-23)
FAMMM, Familial atypical multiple mole melanoma; PDA, pancreatic ductal carcinoma.
C. Malignant Tumors Chapter 61 Pancreatic cancer: epidemiology 973
than 5% of the familial aggregation of PC. The mean age of
onset of familial PC is similar to that of nonfamilial cases: 65.8
years versus 65.2 years (Hruban et al, 1998). Familial cases
have also been noted to have a somewhat increased incidence
of secondary primary cancers (23.8%) when compared with
their nonfamilial counterparts (18.9%).
Hereditary Pancreatitis
Children and adolescents with hereditary pancreatitis (HP)
may develop severe pancreatitis at a young age, often in child-
hood or adolescence, with a resultant 50-fold to 80-fold
increased risk of PC developing over their lifetime. HP results
from germline or new somatic mutations in the PRSS1 cationic
trypsinogen gene (Lowenfels et al, 1997). Approximately 40%
of those with HP will develop PC when the additional risk
factor of cigarette smoking is added. The risk of cancer seems
to be limited to pancreatic cancers and not tumors in other
organs.
Hereditary Nonpolyposis Colorectal Cancer
Hereditary nonpolyposis colorectal cancer is an autosomal
dominant inherited disease that predisposes affected persons to
colorectal cancer and PC (Hruban et al, 2002). It is usually
caused by germline mutations in a number of DNA mismatch
repair genes. Of the inherited syndromes associated with an
increased risk of PDAC, hereditary nonpolyposis colorectal
cancer is the least strongly linked to pancreatic cancer.
Hereditary Breast and Ovarian Cancer
Patients with germline BRCA2 mutations have up to a 10-fold
increased risk (range, 3.5- to 10-fold) of PC, even in patients
without a strong family history of breast cancer. Goggins and
colleagues (1996) identified germline BRCA2 mutations in 7%
of sporadic (nonfamilial) PC patients screened, none of whom
had a family history of breast cancer or PC. BRCA1 mutation
carriers followed in a breast and ovarian cancer evaluation
center, had a threefold increased risk of PC, a twofold increased
risk for colon cancer, a fourfold increased risk for gastric cancer
and a 120-fold increased risk for fallopian tube cancer com-
pared with SEER population-based estimated risk (Brose et al,
2002).
Familial Atypical Multiple Mole and Melanoma Syndrome
Familial atypical multiple mole and melanoma (FAMMM)
syndrome is rare condition associated with p16 germline muta-
tions, a tumor suppressor gene that may be mutated or may
have its expression altered by posttranscriptional methylation.
Estimated Increased The syndrome predisposes affected individuals to melanomas,
Risk of PDA multiple nevi, atypical nevi, and PC (Lynch et al, 1990). Those
50-80 times with FAMMM have a 20- to 34-fold increased risk of PC over
their lifetime.
Undefined
Peutz-Jeghers Syndrome
Peutz-Jeghers syndrome is a rare autosomal dominant disease
associated with alterations in the STK11 gene, in which
3.5-10 times affected individuals develop hamartomatous polyps of the
gastrointestinal tract and lip freckles referred to as mucocutane-
20-34 times ous melanocytic macules (Hruban et al, 2002). Individuals with
75-132 times this syndrome have a roughly 100-fold increased risk of
developing PC (Giardiello et al, 2000), and they also appear
Undefined
to have a tendency to form intraductal papillary mucinous
neoplasms.
974 PART 6 PANCREATIC DISEASE Section II Neoplastic
Ataxia-Telangiectasia
Ataxia-telangiectasia is an autosomal recessive inherited disor-
der associated with ATM gene mutations, in which affected
persons present with cerebellar ataxia, conjunctival telangiecta-
sias, a hypofunctioning thymus gland, and oculomotor abnor-
malities. An association between ataxia-telangectasia and the
subsequent development of PC has been reported, but it is less
well established than with the other five familial syndromes
(Lynch et al, 1996).
Tobacco Exposure
Cigarette smoking has been definitively identified as a causative
agent in 25% to 35% of the cases of PDAC and is the most
consistently reported risk factor (Iodice et al, 2008; Jemal et al,
2009, Lowenfels et al, 2004). Smoking is associated with
increased risk of PC in at least 29 epidemiologic studies (Silver-
man et al, 1994), and smokers have a 70% increased risk of PC
compared with nonsmokers. Smoking habits in the 15 years
preceding the diagnosis of PC appear to be more relevant to
increased risk, whereas former smokers who have quit for more
than 13 years decrease their PC risk to that of lifetime non-
smokers (Howe et al, 1991). A meta-analysis of 83 epidemio-
logic studies found that the overall relative risk of PC in current
and former smokers was 1.74, a 74% increased risk of PC in
these groups (Iodice et al, 2008). A retrospective analysis
comparing smoking in cases of familial PC and sporadic PC
found that 57% and 60%, respectively, of patients reported
prolonged cigarette smoking, with an overall mean of 35 packs/
year history (Yeo et al, 2009).
Prospective and retrospective studies have found that the
risk of PC increases consistently with cigarette smoking but
inconsistently with cigar or pipe smoking (Wynder, 1975).
Cigar consumption has increased 233% between 2000 and
2011; regular cigar smokers have 4 to 10 times the risk of dying
from laryngeal, oral, or esophageal cancers (and likely PC) than
do nonsmokers (Centers for Disease Control and Prevention,
2013).
A dose-response relationship between PDAC and the
number of cigarettes consumed has been documented in
several investigations (Ahlgren, 1996; Howe et al, 1991). For
current smokers who also have a family history of pancreatic
cancer, the relative risk of PC has been reported to be as
high as 8.23 (Schenk, 2001). Lowenfels and colleagues (1997)
found that individuals with familial PC tend to smoke more
than those with sporadic PC. These observations raise the
possibility that smoking is interactive, perhaps multiplicatively,
with genetic mutations known to be present in persons with
familial PC. Postmortem examinations of the pancreatic ducts
of smokers have found widespread ductal hyperplasia, that
is, lesions termed pancreatic intraepithelial neoplasia, which are
considered to be premalignant lesions. Neugut and associates
(1995) found a relationship between cigarette smoking and the
development of PC as a second malignancy in patients with a
smoking-related first malignancy, such as lung, head and neck,
or bladder cancer. This relationship is likely due to overlap-
ping smoking-related genetic mutations among these different
malignancies.
Smoking is most common in the least educated; in 2012,
adults with a Bachelor’s degree were less likely to be current
smokers than those adults with less education. (National
Center for Health Statistics, 2012). Eighteen percent of adults
and 14% of high school students in the United States report
current smoking Centers for Disease Control and Prevention.
A 2003 study of adults aged 30 to 39 years that included
parental occupation, adult educational attainment, and
household income as indicators of socioeconomic status
(SES) found that those of lower SES were more likely to
start smoking and to become regular smokers and were less
likely to quit smoking than their higher SES counterparts
(Gilman et al, 2003).
The carcinogenic components of cigarette smoke are
usually cleared from the bloodstream and excreted into bile;
they reach the pancreas from the bile duct through biliary-
pancreatic reflux, or they may be carried into the pancreatic
parenchyma directly by the bloodstream. Cigarette smoke
contains more than 60 known carcinogens, including polycy-
clic aromatic hydrocarbons (PAHs), nitrosamines, benzo[a]
pyrene, β-napthylamine, methylfluoranthenes, and arylamines
(Hecht, 2003). These carcinogens may bind to DNA and form
adducts, which increase the risk of somatic mutations and
cancer if unrepaired. Nitrosamines are known to be organ
specific, causing pancreatic carcinomas in hamsters that are
histologically similar to the type found in humans (Wang et al,
2009). Little research has been conducted on the other car-
cinogens in cigarette smoke and their relationship to PC.
Another possible mechanism by which cigarette smoke leads
to PC is unrelated to the carcinogens in the smoke. Rather,
higher cholesterol (lipid) levels are measured in smokers than
in nonsmokers. The pathophysiologic mechanism of hypercho-
lesterolemia may be partially due to nicotinic stimulation of
circulating catecholamines, which increase serum cholesterol
levels. Elevated lipid levels may also be causative in the induc-
tion of PC (Wang et al, 2009).
Environmental Tobacco Smoke and Second-Hand Smoke
ETS is related to the development of PC, with a likely dose-
response relationship (Ahlgren, 1996; Villeneuve et al, 2004).
A mildly elevated odds ratio (OR, 1.2.1; confidence interval
[CI], 0.60 to 2.44) has been reported, suggesting a weak asso-
ciation between PDAC and ETS exposure in nonsmokers who
reported ETS exposure both as an adult and in childhood. The
effect was more pronounced in smokers who reported ETS
exposure. Findings from a 2009 retrospective case—only analy-
sis of familial and sporadic PDAC—indicate that nonsmokers
with PC who were exposed to ETS early in life (<21 years of
age) were diagnosed with PC at a significantly younger mean
age (64.0 years) when compared with nonsmoker, non–ETS-
exposed cases (66.5 years) (Yeo et al, 2009). Moreover, both
cigarette smoking and ETS exposure in nonsmokers younger
than 21 years are associated with a younger mean age of diag-
nosis in familial, sporadic, and Ashkenazi Jewish cases of PC.
In 2006, the U.S. Surgeon General determined that second-
hand smoke contains at least 69 human carcinogens for which
there is no safe exposure level (Office on Smoking and Health
[US], 2006). There are more than 45,000 annual deaths in the
United States from lung cancer and heart disease in persons
who have no personal smoking history but did report exposure
to second-hand smoke (Max et al, 2012).
Smokeless Tobacco
Smokeless tobacco includes dry snuff, chewing tobacco, snus
(moist smokeless tobacco), and dissolvable nicotine products.
Sales of these products are increasing at a faster rate than
 C. Malignant Tumors Chapter 61 Pancreatic cancer: epidemiology 975

TABLE 61.3 Occupations Associated With Excess Risk of Pancreatic Cancer

Reference Occupation Risk Estimate 95% CI

Falk et al, 1994 Chemical processor 1.22 OR NR

Chemical fertilizer 1.20 OR NR
Li et al, 1969 Chemist 10.2 MH NR
Lin et al, 1981; Falk et al, 1990 Auto mechanic (gasoline exposure) 5.1 RR if >10 years exposure NR
Service station worker 1.6 SMR NR
Machine repairer 2.45 OR NR
Lin & Kessler, 1981 Dry cleaner 2.1 RR NR
Edling et al, 1985 Leather tanner 3.1 MH (1.1-9.2)
Pickle et al, 1980 Oil refinery worker 2.11 OR (0.86-5.20)
Rockette et al, 1983 Aluminum mill worker 125.2 SMR NR
Norell et al, 1986 Floor polisher 1.3 SMR NR
Falk et al, 1990 Electrical assembler/installer/repairer 2.20 OR NR
Tolbert et al, 1992 Metalworker 2.0 SMR (0.9-3.8)
Eisen et al, 1992 Manufacturing plant worker 3.0 SMR (1.2-6.24)
Bardin et al, 1997 Assembly worker 3.0 SMR (1.0-7.5)
Rotimi et al, 1993 Foundry and engine plant workers 3.0 SMR (121-624)
Bu-Tian et al, 2001 Plant/system operator 6.1 OR (1.1-33.9)
Bu-Tian et al, 2001 Pharmacist, dietician, therapist 7.1 OR (1.8-27.5)
CI, Confidence interval; MH, Mantel-Haenszel estimate; NR, not reported; OR, odds ratio; RR, relative risk; SMR, standardized mortality ratio.

cigarettes. The use of smokeless tobacco is being promoted as

TABLE 61.4 Occupational Exposures Linked to Pancreatic
safer than cigarette smoking and as a method to quit
Cancer (PC)
smoking. There is no evidence that smokeless tobacco is an
effective method of smoking cessation. These products do, PC Risk
however, cause oral, esophageal, and pancreatic cancer, as Chemical Exposure Route Estimates
well as bone loss around teeth and nicotine addiction Methylene chloride Spray paints 1.61 OR
(Bofetta, 2008). (chlorinated Paint strippers 1.40 OR
hydrocarbons) Aerosol propellant 1.6 RR
High-Risk Occupations Metal degreasing agent
Paint/paint thinners
The evidence linking occupational exposures to PC is inconsis-
Varnish
tent, reflecting the difficulty of quantifying workplace exposure Solvents
to carcinogens and of differentiating these exposures from other Pesticides/ Corn wet-milling 1.4 OR
risk factors. A number of epidemiologic investigations have herbicides
suggested excess risk of PC in certain occupations. Definitively DDT Farming 4.8 RR
establishing certain occupations as high risk for the develop- DDD Flight attendants 4.3 RR
ment of PC is difficult because of the problems with self-
Ethylan 5.0 RR
reported exposures, lack of objective quantitative monitoring
Asbestos Industrial 3.0 OR
data, personal comorbidities, and the presence of other con-
Fertilizer Farming 1.2 OR
founding and modifying risk factors. The available studies are
summarized in Table 61.3. Cotton dust Farming 4.37 OR
Cement Construction work 1.28 OR
Occupational Exposures (manufacturing of cement)
Studies examining specific occupational exposures that increase Lead Various 1.28 OR
a worker’s risk of developing PC have been conducted both in Metalworking fluids Machinist 2.0 OR
the United States and in Europe, particularly in the Scandina- DDD, Dichlorodiphenyl-dichlorethane; DDT, dichlorodiphenyl-trichloroethane; OR, odds ratio; RR,
vian countries. Occupational exposures linked to PC are sum- relative risk.
marized in Table 61.4. Overall, the occupational etiologic Data from references cited in Table 61.3.
fraction for PC was estimated at 12% in a meta-analysis of 20
occupational studies conducted between 1969 and 1998 (Oja-
jarvi et al, 2000). A retrospective analysis of more than 22
occupational and environmental studies reporting on people Calvert and colleagues (1989) conducted a review supported
with PC found that exposure to asbestos, pesticides and herbi- by the National Institute for Occupational Safety and Health of
cides, residential radon, coal products, welding products, and five cohort studies reporting an association between the use of
radiation were the most commonly reported exposures (Yeo metalworking fluids (MWFs) used in industrial machining and
et al, 2009). grinding operations and the development of all types of cancer,
976 PART 6 PANCREATIC DISEASE Section II Neoplastic
including PDAC (Acquavella et al, 1993; Hoppin et al, 2000;
Porta et al, 1999; Rotimi et al, 1993; Tolbert et al, 1992). More
than 1 million workers are exposed to MWFs according to
National Institute for Occupational Safety and Health estimates
(Calvert et al, 1989). Substantial evidence was found for an
increased risk of cancer at several sites, including the pancreas,
larynx, rectum, skin, scrotum, and bladder. MWFs contain
a number of compounds suspected to be cancer initiators or
promoters, including long-chain aliphatics, PAHs, nitrosa-
mines, sulfur-containing compounds, formaldehyde-releasing
biocides, and heavy metals (Tolbert et al, 1992).
Diabetes
Diabetes and prediabetes are risk factors for PC and may also
be a consequence of PC (Liao, 2015). The majority of PDAC
patients (50% to 80%) have either subclinical impaired glucose
tolerance or type 2 diabetes at the time of diagnosis (Yalniz
et al, 2005). PC causes alteration of islet cell function—
specifically, the loss of β-cell mass from tumor growth—or a
result of disruptions in acinar–islet cell interactions. The chronic
hyperinsulinemia and hyperglycemia associated with type 2
diabetes has been proposed as the underlying mechanism of
PC. Experimental evidence suggests that insulin promotes
proliferation and reduces apoptosis in pancreatic cancer cells,
both directly and indirectly through increased bioavailability of
insulin-like growth factor (Butler et al, 2010; Han et al, 2011;
Li, 2012). Hyperglycmia can also enhance proliferation and the
invasion capability of pancreatic cancer cells. A 2015 meta-
analysis of nine prospective studies involving 2408 patients
examined the association between elevated blood glucose and
PC and found that every 0.56 mmol/L increase in fasting blood
glucose was associated with a 14% increase in the rate of PC
(Liao, 2015).
Meta-analyses performed in the 1990s on the relationship
between diabetes and the risk of PC found that the pooled rela-
tive risk (RR) of PDAC in people diagnosed with diabetes 5
years or more prior to the PC diagnosis was double the risk
(RR, 2.0; 95% CI, 1.3 to 2.2) of those without diabetes (Ever-
hardt et al, 1995). In a population-based case-control study of
484 PDAC cases and 2099 control subjects in three geographic
areas of the United States, those diagnosed with diabetes at
least 10 years prior to the development of PDAC had a
50% increased risk of PDAC compared with the control
group (Silverman et al, 1998). Insulin treatment did not
appear to alter the risk of development of PDAC (OR, 1.6 with
insulin and 1.5 without). Two other recent investigations found
a self-reported history of new onset diabetes prior to PC diag-
nosis in 26% and 31% of the study populations (Yeo et al,
2009, 2012).
During an 18-year follow-up study of 88,802 women in
the Nurses’ Health Study (NHS), 180 incident cases of PC
were reported (Michaud et al, 2001). A positive association
was observed between fructose intake and impaired glucose
metabolism and increased PC risk. The risk was most apparent
in women with an elevated body mass index (BMI) above
30 kg/m2 and low physical activity. A diet high in glycemic
load (defined as the glucose response to each unit of
carbohydrate-containing foods), may increase the risk of PC
in women with underlying insulin resistance as a result of
obesity. Chronically elevated plasma glucose levels and
increased PC risk were also observed by Gapstur and col-
leagues (2000), further suggesting that impaired glucose
tolerance, insulin resistance, and hyperinsulinemia are involved
in the etiology of PC.
Pancreatitis
Pancreatitis has been widely studied as a risk factor for PC.
The population-attributable fraction of pancreatitis to the
development of PC was 1.34% (i.e., a 34% excess risk) in
an analysis of 10 pooled studies (Duell et al, 2012). When
the pancreatitis occurred more than 3 years prior to the
diagnosis of PC, the association was stronger (OR, 4.0; CI,
2.5 to 6.0). Acute pancreatitis may be the initial clinical
presentation of PDAC, preceding the malignant diagnosis by
weeks or months (see Chapter 55). A 2014 Veterans Health
Administration retrospective study found that 10.7% of
veterans diagnosed with PC had a history of acute pancre-
atitis within 2 years of the cancer diagnosis (Munigala et al,
2014). The risk was greatest in the first year following the
episode of acute pancreatitis and further elevated in persons
70 years of age.
Chronic pancreatitis has been linked to the development of
PC (see Chapter 57). It is not clear whether chronic pancreati-
tis is a risk factor or if it represents an indolent presentation of
PC. The standardized incidence ratio of PDAC in individuals
with a diagnosis of chronic pancreatitis was 16.5 compared
with the 1.76 expected number of cases (Lowenfels et al,
1993). Because PC may mimic chronic pancreatitis, misdiag-
nosis is a possibility. A review of the records of patients with
acute, chronic, or unspecified pancreatitis was conducted on all
inpatient medical institutions in Sweden from 1965 to 1983. In
7956 patients with pancreatitis, 46 pancreatic cancers were
diagnosed compared with 21 expected cases, a standardized
incidence ratio of 2.2 (CI, 1.6 to 2.9) (Ekbom et al, 1994).
Although it seems reasonable to conclude that the cellular
destruction and glandular dysfunction caused by pancreatitis
may yield an environment favoring the initiation of tumor
growth, it remains problematic that some premalignant lesions
such as intraductal papillary mucinous neoplasms may be ini-
tially incorrectly diagnosed as chronic pancreatitis.
Hereditary pancreatitis is an autosomal inherited disease
that begins in childhood or adolescence. A PRSS1 (7q35)
mutation has been identified, and the cumulative risk of PC is
50% to 80% in these individuals. Cigarette smoking in combi-
nation with hereditary pancreatitis may lower the age at
diagnosis.
Cholecystectomy
A history of cholelithiasis and/or cholecystectomy may precede
the diagnosis of PC; however, the evidence suggesting that
cholecystectomy promotes its development is weak (Maison-
neuve et al, 2015). Individuals who underwent cholecystectomy
in the year preceding the diagnosis of PC had an exceedingly
high risk of developing PC (OR, 57.9) in one investigation
(Everhardt et al, 1995). This finding is most likely explained by
the misdiagnosis of gallbladder disease, either cholelithiasis or
cholecystitis, in the setting of cryptic PDAC, often prompting
gallbladder removal, with an undetected tumor being left in
place. However, when data subset analyses were performed in
patients with a history of cholecystectomy 20 years or more
prior to the diagnosis of PC, a 70% excess risk of PC was still
evident. In case-control and cohort studies, gastrectomy also
appears to be associated with a 50% increased risk of PC
(Bosetti et al, 2013; Gong et al, 2012).

Hormonal Factors
In recent years, a link between female reproductive factors and
PC has been hypothesized. A case-control study of 52 post-
menopausal women with PDAC and 233 matched control
subjects was conducted as a component of the Canadian
Enhanced Cancer Surveillance Project (Kreiger et al, 2001). A
questionnaire focused on reproductive history, cigarette
smoking, physical activity, diet, occupation, residential history,
and sociodemographic information was mailed to eligible
patients diagnosed with PDAC. Multiparity, defined as three or
more children, and the use of oral contraceptives were associ-
ated with a decreased risk of PDAC (OR, 0.22 and 0.36,
respectively). Older patient age at birth of the first child signifi-
cantly increased the risk of PDAC (OR, 4.05; CI, 1.50 to 10.92
for ages 25 to 29 years; for women 30 or older, OR, 3.78; CI,
1.02 to 14.06). No relationships were found between age of
menarche or menopause and PDAC. The inverse relationship
between parity and PDAC suggests that PDAC may be partially
an estrogen-dependent transformation, or that estrogen may act
in an inhibitory manner upon pancreatic carcinogenesis.
Lifestyle Factors and Height and Weight
Michaud and associates (2001) first reported on the relation-
ship between BMI, height, physical activity, and smoking
and the risk of PC in two large, prospective cohort studies:
the Health Professional Follow-up Study (HPFS) and the
NHS. Activity levels and body weight were ascertained pro-
spectively. A higher risk of PDAC was found among obese
men and women: 10% higher for overweight persons and
20% higher in obese persons compared with normal-weight
persons. A 5-unit increase in BMI corresponded to a 10%
excess risk of PC (Aune, 2012). The proportion of PC
attributable to obesity ranges from 3% to 16% (Maisonneuve
et al, 2015).
A direct association between above-average height and risk
of PC was also observed, such that an additional 2.54 cm of
height above average increased the risk of PC by 6% in the
HPFS and by 10% in the NHS. The association between height
and general cancer risk has been identified in other studies
(Giovannucci et al, 1995; Smith et al, 1998). Maisonneuve and
colleagues (2015) found no association between height and PC.
Height may serve as a proxy for calorie intake or exposure to
growth factors, such as insulin or insulin-like growth factor-1,
in childhood.
Michaud and colleagues (2001) also reported an inverse
relationship between moderate physical activity and PC.
Walking or hiking 1.5 hours or more per week in the overweight
cohort was associated with a 50% reduction in PC risk, but
physical activity had no effect on PC risk for participants who
were not overweight. Likewise, BMI had no effect on risk if the
participant was a moderate exerciser. However, individuals with
a BMI of at least 30 kg/m2 had an elevated risk of PC (RR,
1.72; CI, 1.19 to 2.52) compared with those with a BMI of less
than 23 kg/m2. The authors speculated that the PDAC risk
associated with obesity might be linked to glucose intolerance,
peripheral insulin resistance, and/or hyperinsulinism.
Diet
It is estimated that 30% to 50% of pancreatic cancers may be
attributable to dietary factors. Both butter consumption and
saturated fat intake were positively associated with PDAC
C. Malignant Tumors Chapter 61 Pancreatic cancer: epidemiology 977
(hazard ratio [HR], 1.40; CI, 0.87 to 2.25; and HR, 1.60; CI,
0.96 to 2.64, respectively) in the Finnish Cancer Registry
(Stolzenberg-Solomon et al, 2005). Fat entering the duodenum
stimulates cholecystokinin secretion, and it is possible that
chronic hypercholecystokininemia may be associated with an
increased susceptibility of the pancreas to carcinogens. Other
possible explanations include that the increased intake of satu-
rated fat may lead to insulin resistance and the development of
diabetes or that foods with a high soluble fat content may be
contaminated with carcinogenic organochloride compounds
from the environment.
Processed meats have been linked to the development of PC.
In a prospective study of more than 200,000 people, 482
individuals developed PC during 7 years of follow-up (Nöth-
lings et al, 2007). Those who had consumed the greatest
amount of processed meats had a 67% increased risk of PC.
Diets laden with pork and red meat intake were associated with
a 50% increase in PC risk, but poultry, fish, dairy products, and
egg consumption conferred no additional risk. Heterocyclic
amines and polycyclic aromatic hydrocarbons that form during
high-temperature cooking are known to be carcinogenic and
may be responsible for the increased risk of PC observed with
processed and barbecued meats. These compounds have also
been linked to the development of other cancers.
Several recent investigations have focused on the relation-
ship between glycemic load and glycemic index. Consumption of
fruit juices and soda has been evaluated in six studies to date
with conflicting results (Michaud et al, 2002; Mueller et al,
2010; Nöthlings et al, 2007; Silvera et al, 2005; Stolzenberg-
Solomon et al, 2005). Two studies found no relationship
between PDAC and glycemic load; carbohydrate intake; or
sugar, sucrose, or fructose intake (Johnson et al, 2005; Silvera
et al, 2005). Three studies reported mixed findings (Michaud
et al, 2002; Nöthlings et al, 2007; Stolzenberg-Solomon et al,
2005). In the Multiethnic Cohort Study, BMI modified the
effect of high sucrose intake and the occurrence of PDAC, with
elevated BMI increasing the risk and normal BMI decreasing
the risk (Nöthlings et al, 2007). A positive association with
PDAC was also observed with a high fructose intake, but no
association was observed with consumption of soft drinks (diet
or regular).
Mueller and colleagues (2010) conducted a retrospective
analysis of the Singapore Chinese Health Study, regarding soft
drink and fruit consumption and the risk of PDAC. Among
63,257 participants, 142 incident PDAC cases were identified,
generating an elevated HR for those consuming two to three
soft drinks per week. However, only 56.4% of the PDAC cases
were histologically confirmed, 5% were reported from death
certificate data, and 38.8% were identified by signs and symp-
toms possibly related to PDAC but not proven. The finding of
an elevated HR for PDA in those who drink two to three soft
drinks per week is suspect in this setting and requires further
evaluation.
Coffee and Alcohol Consumption
Cohort studies from the 1970s and 1980s indicating that heavy
coffee and alcohol consumption led to an excess risk of PDAC
were often confounded by excessive smoking among the heavy
coffee and alcohol drinkers (Michaud et al, 2001). Three sub-
sequent investigations have attempted to clarify this issue while
controlling for smoking (Ghadirian et al, 1991; Lagergren et al,
2002; Michaud et al, 2001). Ghadirian and colleagues (1991)
978 PART 6 PANCREATIC DISEASE Section II Neoplastic
conducted a case-control study of residents of greater Montreal,
obtaining all information through questionnaires administered
to either the patient or a proxy. The results indicated that those
who consumed alcohol were, in general, at lower risk for PDAC
(OR, 0.65; CI, 0.30 to 1.44). This was true for beer, white wine,
and hard liquor. The OR for red wine drinkers was elevated at
1.57, but it did not achieve statistical significance. Likewise,
coffee drinkers had a lower overall risk of developing PDAC
(OR, 0.55; CI, 0.19 to 1.62), regardless of whether they drank
caffeinated or decaffeinated coffee. The increased risk when
coffee was taken on an empty stomach or between breakfast
and lunch (OR, 1.30 and 1.15, respectively) was not statistically
significant.
Lagergren and colleagues (2002) hypothesized that because
heavy alcohol intake often causes chronic pancreatitis, which
may be a risk factor for PDAC, the ideal group to examine
would be those with a diagnosis of alcoholism, alcoholic chronic
pancreatitis, and alcoholic liver cirrhosis. Using the Swedish
National Board of Health and Welfare, data were collected on
178,688 patients over a 30-year period. A total of 305 incident
cases of PDA were identified in the group, representing a 40%
excess risk in observed compared with expected cases. Alcohol-
ics with chronic pancreatitis or cirrhosis had a twofold increased
risk of PDAC. A major limitation of the study was the lack of
information on smoking. The authors estimated that the
observed excess risk of PDAC in the alcoholic group “may be
almost totally attributable to the confounding effect of smoking”
(Lagergren et al, 2002).
Michaud and colleagues (2001) examined data on coffee
and alcohol consumption and other dietary factors obtained
at baseline in two large, national cohort studies. The HPFS,
initiated in 1986, includes 51,529 men aged 40 to 75 years
who responded to a mailed questionnaire; the NHS began in
1976 and includes 121,700 registered nurses. Follow-up
information was gathered via a mailed questionnaire from
both groups on age, marital status, weight, height, medical
history, medication use, smoking status, physical activity, and
intake of coffee and alcohol. The results regarding coffee and
alcohol are compelling: During 1,907,222 person-years of
follow-up, 288 incident cases of PDAC were diagnosed. Data
were analyzed separately for each of the cohorts and then
pooled to compute overall RR estimates. The results revealed
that neither coffee consumption nor alcohol consumption
conferred an excess risk of PDAC; a pooled RR of 0.62 was
reported (95% CI, 0.27 to 1.43) for more than three cups of
coffee per day versus no coffee, and a pooled RR of 1.00
(95% CI, 0.57 to 1.76) for more than 30 g alcohol per day
versus no alcohol were found.
Most recently, Brand and colleagues (2009) examined data
on 29,239 histologically confirmed cases of PC from 350 U.S.
hospitals between the years 1993 and 2003 by cigarette smoking
and alcohol consumption self-reported history. Current smokers
were diagnosed with PC at significantly younger ages (6.3 to
8.6 years) than nonsmoking counterparts. Among nonsmokers,
age at diagnosis of PC progressed linearly according to the
amount of alcohol consumed, from 6 years younger for minimal
drinkers to 8.7 years younger for self-reported heavy alcohol
consumers.
Infectious Agents
Helicobacter pylori has emerged as a moderate risk factor for
PDAC in analysis of seven studies (Risch, 2012). The global
prevalence of H. pylori infection ranges from 25% to 50% in
Westernized countries. It is thus estimated that 45 to 25% of
PC cases in these countries may be due to H. pylori (Maison-
neuve et al, 2015). Chronic infection with the hepatitis B virus
(HBV) increases the risk of PDAC (OR, 1.42) in blood group
A individuals. HBV can infect the pancreas as well as the liver.
Wang and colleagues (2012) reported a 40% to 60% excess risk
of PC in HBV-positive persons.
SUMMARY
PDAC is a complex biologic process, the etiology of which is
multifactorial, although certain risk factors are clear and ame-
nable to modification. Strategies to reduce PC risk include the
following:
• Avoiding the use or proximity to tobacco products,
specifically:
• Do not start smoking, or if you do smoke cigarettes or
cigars, quit
• Do not use smokeless tobacco products
• Avoid persons who are actively smoking
• Ask smokers to not smoke in the home
• Diet changes
• If overweight or obese, reduce weight through menu-
based and calorie restriction programs
• Consider surgical obesity intervention, if appropriate
• Increase daily intake of fruits and vegetables
• Reduce intake of simple carbohydrates and fats
• Avoid processed meats, limit red meat intake, and increase
fish and poultry portions
• Occupational and environmental protection
• For those engaged in high-risk occupations or environ-
mental exposure, regular use of the Occupational
Safety and Health Administration–recommended per-
sonal protective equipment
• Screening of high-risk individuals to detect precursor lesions
and early-stage tumors, including
• Older smokers with new-onset of diabetes
• Unintentional weight loss
• Suspicious pancreatic or biliary tree lesions that are
incidentally found and may be asymptomatic
A considerable amount of epidemiologic data point to PC
causes that are largely avoidable. Nearly two thirds of the major,
noninherited genetic risk factors are modifiable through
increased public awareness, screening of high-risk individuals
to detect advanced precursor lesions, and promotion of healthier
lifestyles. This knowledge offers an opportunity for prevention
and perhaps bending the curve on the predicted rise of PC.
References are available at expertconsult.com.