Jack: Hi, y'all.
In this lecture, we'll be discussing
the epidemiology of pancreatic cancer.
Our goals for this lecture are to review studies
of coffee and pancreatic cancer,
to review the anatomy and function of the pancreas,
to describe the global burden of pancreatic cancer,
review key studies of tobacco and alcohol,
describe the role of pancreatitis and pancreatic cancer,
review key studies of dietary fat,
describe how bile acids promote pancreatic cancer,
and finally to discuss prevention and control
of pancreatic cancer.
So to begin with, an article was published
on March 12th, 1981, showing a statistical link
between the drinking of coffee and cancer of the pancreas,
which is the fourth most common cause
of cancer death among Americans.
This discovery was unexpected
and the significance is not yet clear.
The report wrote that it reflects a causal relation
between coffee drinking and pancreatic cancer,
and that coffee use might account
for a substantial proportion
of the cases of pancreatic cancer in the US.
The report was published
in the "New England Journal of Medicine",
a prestigious medical journal.
Although the statistical association in the study
does not prove that coffee causes cancer,
one of the investigators in the study
stopped drinking coffee
because of the potential relationship
between coffee and pancreatic cancer.
The study was a case control study
and it looked at 360 cases
and 643 group matched hospital controls
who were treated by the same physicians
who treated the cases.
We see that of the cases, 20 consumed coffee,
or 20 did not consume coffee and 347 did consume coffee,
whereas in the control, it was 555 consumed coffee
and 88 did not consume coffee.
Many investigations after this one
failed to confirm the association
observed in the first 1981 study, so it's generally accepted
that there's no causal association
between coffee and cancer of the pancreas.
If we remember Hill's criteria of causality,
we know that causal relationships are only determined
by looking at the full balance of evidence
through multiple independent studies.
So to turn to the anatomy and function of the pancreas,
we see that the pancreas is a dual functioning gland
located deep in the abdomen just behind the stomach.
Numerous pancreatic ducts communicate
with the main's pancreatic duct
that merges with the common bile duct
to form the ampulla of Vater that empties into the duodenum,
which is the upper small intestine.
The pancreas is an endocrine and exocrine gland,
and specialized endocrine cells
called the islets of Langerhans are instrumental
in the secretion of insulin and glucagon
to maintain tight control of blood glucose.
There are other exocrine cells called acinar cells
that support powerful digestive enzymes
like trypsin, lipase, and amylase,
as well as alkaline fluid into the pancreatic ducts
that eventually drain into the main pancreatic duct
and the duodenum.
The digestive enzymes secreted by the pancreas
break down protein, fats, and carbohydrates.
So the incidence of pancreatic cancer
shows clear patterns of high incidence in the US,
in Argentina, in Australia,
and some parts of Central Asia and Western Europe.
Similarly, mortality rates
are similarly high in parts of Western Europe,
Russia, Argentina, the US, and South Africa.
Pancreatic cancer
accounts for about 2% of all cancers in the US
and it's uniformly fatal.
It's the fourth leading cause of cancer deaths.
The peak incidence is at age 60 to 65 years,
when it's an incidence of 60 per 100,000 people.
In 2020 in the US, the overall incidence was 4.9
per 100,000 people,
with an incidence of 5.7 per 100,000
and 4.1 per 100,000 women.
The mortality is 4.5 per 100,000 overall total population,
and 5.3 per 100,000 men and 3.8 per 100,000 women.
Key risk factors for pancreatic cancer
include alcohol abuse, biliary obstruction,
chronic pancreatitis,
diabetes, obesity,
a high fat diet, and chronic tobacco smoking.
As we can see from this figure,
the risk of pancreatic cancer greatly increases
with the number of cigarettes per day.
That is, individuals smoking 40,
or more than 40 cigarettes per day
have 4.5 times the chances of developing pancreatic cancer
than those who do not smoke cigarettes.
There's also acute and chronic pancreatitis
that can play a role in the causation of pancreatic cancer.
So acute pancreatitis
is defined as the inflammation, hemorrhage,
and necrosis of the pancreas, While chronic pancreatitis
is progressive relapsing acute pancreatitis.
Signs and symptoms of acute pancreatitis
include abdominal pain, hemorrhage,
fat necrosis, jaundice or yellowing of the skin,
ascites, and shock.
The treatment for acute pancreatitis is the pain control,
going to the emergency department of the hospital,
NPO, and surgery.
Chronic pancreatitis can be treated by changes in diet,
abstaining from alcohol, and cholecystectomy.
Alcohol is related to pancreatic cancer
in a dose-dependent fashion.
There is a two to threefold increased risk
of pancreatic cancer in heavy drinkers
who consume four or more drinks per day.
Alcohol is an independent risk factor for pancreatic cancer,
and chronic alcohol abuse causes pancreatitis,
which can then transform into invasive pancreatic cancer.
The progressive cascade of pathogenic events
in chronic alcoholic pancreatitis
involves chronic inflammation, cell necrosis
release of digestive enzymes,
cell autodigestion, formation of reactive oxygen species,
collagen deposition, fibrosis,
scarring of the pancreatic tissues,
and transformation to neoplasia.
Chronic pancreatitis refers to the persistent inflammation
of the pancreas irrespective of the cause.
It's a strong risk factor for the development
of pancreatic cancer,
and the risk increase,
the risk of pancreatic cancer associated with pancreatitis
is independent of gender,
country of origin, and type of pancreatitis.
The main cause of chronic pancreatitis
is chronic alcohol abuse.
More than 70% of adult patients with chronic pancreatitis
have a history of excessive alcohol intake.
The majority of patients report daily consumption
of at least 150 grams of alcohol for more than five years.
Type 2 diabetes is also a key risk factor
for pancreatic cancer.
The twin epidemics of obesity and diabetes mellitus type 2
have emerged in many populations throughout the world.
Both conditions are independently associated
with the development of pancreatic cancer,
and obesity is associated with the onset of diabetes.
Meta-analysis of epidemiologic studies
show a twofold elevation in the risk of pancreatic cancer
among individuals with a five year history
of type 2 diabetes.
Currently, however, there's no general consensus
as to a cause and effect relationship
between type 2 diabetes and pancreatic cancer.
One argument against such a relationship
is the fact that rates of pancreatic cancer
have remained constant or declined in many nations,
even though prevalence rates of obesity and type 2 diabetes
have increased dramatically.
Nevertheless, in subjects
with longstanding type two 2 diabetes,
the pancreas is chronically exposed to hyperinsulinemia,
and since cultures of pancreatic cancer cells
have been found to express insulin receptors,
it's possible that hyperinsulinemia could serve
as a promoter of pancreatic cancer.
A major problem with studies
of the association of pancreatic cancer and diabetes
is that since both conditions evolve
in the same organ over a period of many years,
it's difficult to determine the causal pathway.
There's also an association
between dietary fat and pancreatic cancer.
The US National Institutes
of Health American Association of Retired Persons,
or AARP, Diet and Health Study
was designed to provide definitive evidence
and dietary risk factors in the development
of a variety of chronic diseases,
including pancreatic cancer.
The investigation of the relationship between dietary fat
and pancreatic cancer was based upon a cohort of 308,736 men
and 216,737 women
aged 51 to 70 years of age
who completed a food frequency questionnaire
between 1995 and 1996.
The study found that pancreatic cancer risk
increased with high intake of total fat,
saturated fat, or monounsaturated fat.
The risk was highest for high intake of saturated fat
from animal food sources,
and results suggest that high intake
of dietary fat of animal origin increases the risk
of developing pancreatic cancer.
The possible pathogenesis behind this
is that diets with high fat content
stimulate or stimulate bios secretion
by the liver and biliary tract.
Bio acids have been found
to induce cyclooxygenase two or COX-2
and lead to inflammation in pancreatic cancer cell lines.
This inflammation can then lead
to carcinogenic mutagenesis.
So approximately 99% of pancreatic cancers
evolve from the ductal epithelium
and only 1% arise from acini.
Pancreatic carcinogenesis involves chronic inflammation
and promotion of cell division without normal apoptosis.
Germline mutations can also be a cause of pancreatic cancer.
Familial breast or ovarian cancer
is often caused by heritable mutation
in either of two tumor suppressor genes,
the BRCA1 or BRCA2 genes.
Females who inherit mutant alleles of one of these genes
are not only at high risk of developing breast cancer
and/or ovarian cancer, but they're also at increased risk
for the development of other tumors,
including pancreatic cancer.
The familial atypical mole and melanoma syndrome or FAMM
is a rare genetic disorder giving rise
to multiple dysplastic pigmented moles of the skin
that can progress to malignant melanoma.
There's also a risk of developing pancreatic cancer.
The Peutz-Jeghers syndrome is a rare
autosomal dominant disorder
characterized by the development
of benign hamartomatous polyps in the gastrointestinal tract
and hyperpigmented macules in the lips and oral mucosa.
This syndrome is caused
by a mutant tumor suppressor gene as well.
Finally, the Lynch syndrome is characterized
by high lifetime risk for the development of colon cancer.
The cause of the syndrome is an inherited mutation
in at least one set of genes that normally repair DNA.
The genetic disorder also carries an increase
in the risk of developing pancreatic cancer.
Somatic mutations involving base pair changes in DNA
occasionally occur in specific cells
of specific tissues of the human body.
The phenotypic effects of such mutations
persist in the lineage of the cell of origin.
Somatic mutations of K-RAS gene have been observed
in up to 90% of certain malignancies,
like colon cancer, lung cancer, and pancreatic cancer.
This gene communicates signals from outside the cell
to the nucleus, a process known as signal transduction.
Because this signal transduction stimulates cell division,
its dysregulation may result
in heightened cell proliferation
and malignant transformation.
Epigenetics are the study of changes
in the expression of genes
without any alteration in the base pair sequence of the DNA.
Is also related to the development of pancreatic cancer.
So in epigenetics,
different genes can be up or downregulated,
and COX-2 upregulation is common in pancreatic cancer cases.
This upregulation of COX-2
can lead to chronic pancreatitis and necroinflammation.
And as we've discussed, inflammation is closely related
to the causation of cancer.
Next, islet cell tumors are a form
related to pancreatic cancer,
and they arise from endocrine cells
in the islets of Langerhans.
Most are beta cell tumors,
since the beta cells elaborate insulin.
Insulinomas are clinically characterized
by attacks of hyperinsulinemia and hypoglycemia.
These tumors are a component
of the Zollinger-Ellison syndrome defined by the triage
of various ulcers, secretion of different enzymes,
and pancreatic islet cell tumors.
Most islet cell tumors are benign
and less than 10% are malignant carcinomas.
Finally, to turn to pancreatic cancer prevention,
unfortunately there are no preventive methods.
In order to reduce risk,
individuals can avoid tobacco and alcohol,
maintain a healthy weight through regular exercise,
eat a diet rich in fruits, vegetables, and whole grains,
and maintain blood glucose within normal limits.