Pancreatic Cancer: Epidemiology, Genetics, and Approaches to Screening
Pancreatic Cancer: Epidemiology, Genetics, and Approaches to Screening
cancer is typically diagnosed at an advanced stage. Surgery is the only
potentially curative option, but fewer than 20% of patients are candidates for
curative resection at presentation. After resection, the 5-year survival rate is
35% to 40% for patients with small, node-negative tumors, but 12% to 15%
overall. Among patients with unresectable disease, the 5-year survival rate is
generally below 5%, even with optimal therapy.
Screening for early or preinvasive cancer in the pancreas has
remained an elusive goal. Extensive epidemiologic studies have allowed us to
better understand who is at risk for the disease. Advances in molecular genetics
over the past 15 years have contributed substantially to characterizing the
genetics of pancreatic cancer. These data provide opportunities to identify
high-risk individuals with greater fidelity and design more sophisticated
diagnostic and therapeutic approaches, with the hope of making earlier diagnoses
and providing more effective treatment (Table 1).
In the United States, pancreatic cancer accounts for only 2% of
all cancer diagnoses, with an incidence of just over 30,000 cases per year.
It is responsible for up to 5% of cancer deaths, making it the fourth leading
cause of cancer-related mortality among US men and women. The yearly
incidence and mortality are roughly equivalent. From 1930 to 1970, incidence
increased approximately twofold, to 10 cases per 100,000 men and 7.2 cases per
100,000 women, but has since stabilized and decreased modestly. This
favorable trend has been observed primarily among white men, whereas rates among
white women and black men and women have risen slightly.
As with cancer in general, the incidence and mortality rates are
slightly higher among African-Americans, with poorer survival for each
diagnostic stage. Black American men have the highest rate of pancreatic
cancer in the world, whereas the rate in African men is somewhat low.
In 1990, approximately 171,500 cases of pancreatic cancers were
diagnosed worldwide, accounting for approximately 168,000 deaths. Although it
ranks 13th among malignancies in incidence, it is the 9th most common cause of
cancer-related death, with a 98% mortality ratio. Other gastrointestinal cancers
occur in about a 2:1 male-to-female ratio, but for pancreatic cancer, the ratio
is nearly equally divided between the sexes.
Autopsy studies have consistently demonstrated that pancreatic
cancers compose a significant proportionas high as 25% to 40% in most studiesof
carcinomas of unknown primary.[5-7] Unknown primaries account for about 2% of
all cancer diagnoses, of which there are 8 million worldwide. The
annual incidence of carcinomas of unknown primary may, therefore, be close to
200,000, and an additional 50,000 to 80,000 pancreatic cancers may be
unaccounted for in compiled epidemiologic data.
Whereas several gastrointestinal cancers, including gastric,
hepatocellular, esophageal, and colorectal, show striking geographic variation,
that of pancreatic cancer is more modest but still noteworthy. The incidence
is highest in developed nationsnamely the United States, Canada, Scandinavia,
Western Europe, and Australiaand less common in developing areas, such as
Africa, South America, Mexico, the Caribbean, the Middle East, and Asia. A
geographic variation that correlated positively with latitude worldwide has been
noted. Within developed countries, the male-to-female disparity is more
pronounced, with incidence rates ranging between 6 and 10 cases per 100,000 for
men, and 4 to 6.5 cases for women.
• Age and GenderAge is an extremely important
determinant of risk. Pancreatic cancer rarely occurs before the age of 50 years,
and is seen most frequently in the 7th and 8th decades, regardless of etiology
(sporadic, familial, or smoking-related).
In the United States, males have a relative risk of 1.3 compared
with females. A family history of pancreatic cancer significantly increases an
individual’s risk for the disease, particularly in the setting of a familial
• EnvironmentEnvironmental factors also appear to
play a significant role. Tobacco smoking has been the most consistently
demonstrated risk factor and is implicated as a cause in roughly 30% of all
cases.[11-13] The relative risk depends on the number of cigarettes smoked and
ranges from 1.5 in light smokers to 10 for two-pack-per-day smokers. Rivenson et
al induced pancreatic carcinomas in rats by injecting them with various
nitrosamines (tobacco-specific chemical carcinogens), which are probably
culpable in humans, as well. Risk decreases with time following smoking
• RaceIncidence among African-Americans is about 30%
higher than among white Americans; therefore, race has been implicated as a risk
factor. This trend, however, may reflect disparities in wealth, education, and
access to health care rather than an inherent tendency toward pancreatic
cancer, as incidence among black Africans is low.
• DiabetesVarious comorbidities have been purported
to pose an increased risk of pancreatic cancer, with pancreatic diseases being
implicated in particular. A clear association with type 2 diabetes has been
recognized for decades; however, the cause-and-effect relationship has not
been fully elucidated. Among studies that have examined whether rates of
pancreatic cancer are higher in patients with long-standing vs recent-onset
diabetes, some have demonstrated a long-term risk[18,19] and others, a
short-term risk, with recent data supporting both theories.[21,22]
Long-standing diabetics who develop pancreatic cancer frequently experience an
exacerbation of their disease in the period preceding their diagnosis.
Diabetes does not just result from a destructive mechanical
effect of pancreatic cancer, as illustrated by the fact that although most
cancers occur in the head (70%) or body (20%) of the pancreas, most of the
insulin-producing beta cells are found in the tail. A physiologic basis for the
insulin-resistant state was suggested by Permert et al, who demonstrated
abnormalities in islet hormone levels in response to fasting and hyperglycemic
states in diabetics with pancreatic and nonpancreatic cancers, as well as in
healthy controls. Interestingly, in this study, responses of C-peptide and
islet amyloid polypeptide to glucagon normalized after subtotal pancreatectomy
for pancreatic cancer.
• PancreatitisChronic pancreatitis is also
associated with pancreatic cancer, but again, whether one is a consequence of
the other or if both result from a common cause has not been determined.
Additionally, overlapping signs and symptoms as well as common risk factors may
confound the diagnosis. Some studies have observed an 18- to 28-fold increase in
incidence compared to controls among patients with pancreatitis,[24,25] while
others have revealed more moderate associations.[26,27] A clear risk has been
established in the case of hereditary pancreatitis, resulting from mutations in
the trypsinogen gene, an autosomal dominant trait.
• SurgerySurgical procedures including partial
gastrectomy and cholecystectomy have been evaluated as risk factors. Several
studies have shown a two- to sevenfold increased risk, which manifests 1 or 2
decades following surgery, usually as peptic ulcer disease.[28-30] Theories to
explain this connection include hypergastrinemia, elevated levels of
cholecystokinin, and decreased gastric digestion of carcinogens. Other studies
have not demonstrated such a clear risk and suggest that smoking may be a
• DietSeveral large human studies have demonstrated
positive associations with meat consumption and carbohydrate intake and a
protective effect for dietary fiber and consumption of fruits and
vegetables.[32-34] Coffee drinking is no longer considered a risk factor; in
fact, recent studies suggest that it may be protective.
• OccupationOccupational risks, usually involving
exposure to industrial chemicals, have also been identified as minor
contributors to the development of pancreatic cancer. An elevated risk has been
identified among coke plant workers, chemists, and construction
workers. Exposure to pesticides and ionizing radiation has also been
• Height and WeightTwo US cohort studies identified
obesity and height as independent risk factors. Individuals with a body mass
index of at least 30 kg/m² had a relative risk of 1.7 compared to those
with a body mass index less than 23 kg/m². Height was associated with a relative
risk of 1.81 for the highest vs lowest categories.