Jack: Hi everyone, and welcome to today's lecture
on epidemiology of esophageal cancer.
In this lecture, we will begin
by reviewing the anatomy and function of the esophagus,
describing the global burden of esophageal cancer,
with a particular focus on the esophageal cancer belt.
We'll also describe squamous cell carcinoma
and adenocarcinoma of the esophagus.
And describe risk factors for esophageal cancer,
progression of Barrett's esophagus,
and prevention of esophageal cancer, so let's jump in.
So to talk about the anatomy of the esophagus,
it's important to note that the esophagus
is a muscular tube that transports saliva,
food, and liquids from the mouth to the stomach.
In the human adult, the esophagus
is about 20 centimeters, or eight inches long,
and it's lined by stratified squamous epithelium.
The upper esophageal sphincter,
which is located just below the pharynx,
allows passage of food and liquids during swallowing.
The lower esophageal sphincter, located
at the junction of the lower esophagus with the stomach,
regulates the passage of food and liquids into the stomach.
Just before entering the stomach,
the esophagus passes through the diaphragm.
This figure shows the incidence
of esophageal cancer across both sexes.
So approximately 5% of all cancer deaths
are due to esophageal cancer, making it
the sixth leading cause of death from cancer.
The incidence of esophageal cancer
shows marked international variability.
We see that some countries have much higher rates
of esophageal cancer incidence than others.
For example, the annual incidence
in North America and Western Europe ranges
from 3 to 5 cases per 100,000.
While the annual incidence is more
than 100 per 100,000 in Iran, and some parts of China.
In the US approximately 15,000 new cases
of esophageal cancer are diagnosed annually,
and 14,000 people die from the disease.
Approximately 50% of cases presented
with incurable advanced disease,
and the five-year survival rate
of patients with resectable esophageal cancer
is low, ranging from 20 to 30%.
When we look at the mortality of...
mortality rates for esophageal cancer
we see that they largely follow incidence rates
in different parts of the world.
In 2020 in the US the age standardized incidence
of esophageal cancer was 6.3 per 100,000
with esophageal cancer occurring
about three times higher in men than in women.
The age standardized mortality of esophageal cancer in 2020
in the US was 5.6 deaths per 100,000 people,
or 8.3 deaths per 100,000 men, and 3.2 per 100,000 women.
The esophageal cancer belt extends from northeast China
to parts of the Middle East, or southwest Asia.
The cumulative lifetime risk of esophageal cancer
in certain Chinese provinces,
and Northern Iran approaches 25%.
Cancer of the esophagus was a common condition
in the centuries past in both China and Iran,
suggesting the longstanding presence of major risk factors.
These risk factors may include drinking super hot tea,
or other beverages, exposure to alpha toxins
and other mycotoxins, exposure to excess nitrous ambience,
exposure to certain minerals like arsenic,
HPV and other viruses, nutritional deficiencies,
especially vitamins A, B, C, and E,
and tobacco, and alcohol use.
When we look at esophageal cancer epidemiology
it's important to compare the differences
between squamous cell carcinoma and adenocarcinoma.
So squamous cell carcinomas develop
in the middle and upper third of the esophagus
while adenocarcinomas arise in the lower esophagus
near the gastroesophageal junction.
And these risk factors differ by histology.
And we can see, you know, some of those major risk factors
in this chart here, as well as differences in age
when these different carcinomas occur.
So when we think about the pathogenesis of esophageal cancer
it's important to know that there has been
a marked increase in the incidence of adenocarcinomas
of the lower esophagus near the gastroesophageal junction,
particularly among men of the US, UK,
and other high income countries in recent decades.
Adenocarcinomas of the lower esophagus arise
by a sequence of metaplastic and dysplastic changes
in the esophageal epithelium known as Barrett's esophagus.
Such changes arise due to chronic gastroesophageal reflux
of acidic stomach fluid into the normally basic environment
of the lower esophagus.
Barrett's esophagus is a pre-malignant lesion
that must be aggressively treated to halt
its progression to invasive esophageal cancer,
a condition that is life-threatening.
And effective screening strategies have been proposed
for high-risk populations using endoscopy
with mucosal iodine staining, and biopsy
to identify severe dysplastic lesions and carcinomas
in situ that are curable by... or by radical mucosectomy
and adenocarcinomas of the lower esophagus
are now more common than squamous cell carcinomas in the US.
So the progression to squamous cell carcinoma occurs
when high high-grade dysplastic lesions transform
to carcinoma in situ and eventually to invasive cancer.
There's two major metrics that are used
when looking at the staging of esophageal dysplasia,
or squamous cell carcinoma, that would would be
whether the cancer has invaded contiguous tissues
and that's denoted with a T,
and whether the cancer has invaded lymph nodes,
and that's denoted with an N.
Key risk factors for squamous cell carcinoma
are tobacco, alcohol, betel quid, mycotic infection,
steaming hot beverages, and nutritional deficits.
Other risk factors for esophageal cancer
differ according to histologic subtype,
and anatomic location in the esophagus as we've noted.
We see that among the environmental risk factors
for both histologic types, chronic alcoholism
and cigarette smoking contribute most heavily
to the development of esophageal cancer.
And esophageal cancer is 25 times more common
among heavy drinkers than among controls.
Similarly, habitual smokers of cigarettes have
a six to sevenfold increased frequency of esophageal cancer
after adjustment for alcohol consumption.
So when we discussed adenocarcinoma before
we mentioned Barrett's esophagus.
And Barrett's esophagus is the term describing
a sequence of metaplastic and dysplastic changes
in the esophageal epithelium, so cellular changes arise due
to that chronic gastroesophageal reflux
of acidic stomach fluid into the lower esophagus,
as we mentioned before.
Barrett's esophagus is the pre-malignant lesion
of this lower esophageal area,
or a gastrointestinal junction.
Barrett's esophagus is likely related
to chronic GERD and obesity.
We also see that the COX-2 inflammatory pathway plays a role
in the progression to a malignant neoplasm,
and that Barrett's esophagus patients have
a 30 to 125 increase in relative risk of adenocarcinoma.
Unfortunately, there's no known effective screening tool
for Barrett's esophagus.
So as I just mentioned, COX-2,
or the cyclooxygenase enzyme plays a role
in the development of cancer from Barrett's esophagus.
So this COX-2 gene becomes markedly over expressed
throughout the progression of Barrett's esophagus
to esophageal cancer.
When we're discussing esophageal adenocarcinomas
and Barrett's esophagus, we see
that there have been associations
between increases in these carcinomas
in developed nations like the US and Great Britain.
And these increases have occurred
at the same time as increasing obesity
and gastroesophageal reflex disease or GERD,
and reduced rates of gastric infection
by helicobacter pylorus, so this seesaw diagram here,
really depicts the ways that people can be protected,
or communities can be protected
from esophageal adenocarcinoma, and the risk factors,
and how for any individual, they're going to have
some combination of these risk factors
and protective factors that's going to determine
their overall risk for developing esophageal adenocarcinoma.
So even though H. pylori infections
of the gastric mucosa heighten
the risk of developing stomach cancer.
This microbe appears to protect against the development
of Barrett's esophagus in esophageal adenocarcinoma.
H, pylori also produces ammonia,
which neutralizes gastric acid.
So when this gastric acid is coming
into the lower esophagus, it's possible
that it's being neutralized by the ammonia produced
by H. Pylori which then is not causing
as much cellular damage and inflammation
as it might be otherwise.
When we look at genetic risk factors for esophageal cancer
we see that there are various conditions, or syndromes,
as well as tumor suppressor genes that play a role
in one's risk for esophageal cancer.
So for example, achalasia, which is due to a dysfunction
of the gastrointestinal sphincter, interrupts
the passage of food from the esophagus into the stomach
and increases the risk of esophageal cancer by 15 fold.
The Plummer-Vinson syndrome consists of iron deficiency,
anemia coupled with muscle atrophy, dysphagia,
and the formation of esophageal rings,
or webs in the upper esophagus.
The syndrome is associated with the development
of squamous cell carcinomas proximal
to the upper esophageal webs.
Genetic polymorphisms of certain tumor suppressor genes
that modulate cell division may also contribute
to the genesis of esophageal cancer.
Scientists found genetic polymorphisms in cyclin D1
and P53 that increased the risk of esophageal cancer
by sixfold and threefold respectively.
So, as I just mentioned, there's increases
in the risk for esophageal cancer,
specifically Barrett's esophagus and adenocarcinoma
when we look at individuals
with certain genetic polymorphisms, like cyclin D1 and P53.
Finally, the prevention of esophageal cancer
can occur on many different fronts.
So to begin with, it's important to avoid exposure
to alcohol, tobacco, boiling hot beverages,
and other caustic substances
that can cause inflammation in the esophagus.
In low and middle income countries, avoiding intake
of multigrains and other foods or beverages fermented
from multigrain can decrease one's risk of esophageal cancer
And international efforts are now being directed
to the obesity pandemic in order to reduce
the burden of GERD and other obesity related diseases.
Multiple epidemiologic studies have examined
the potential role of aspirin,
and other non-steroidal anti-inflammatory drugs,
or NSAIDs, in the prevention of esophageal cancer.
In a recent meta-analysis of these studies that took place
in 2003 it was determined that regular use
of NSAIDs was associated with a 40% reduction
in the risk of esophageal cancer.
NSAIDs are known to reduce inflammation
by inhibiting the cyclooxygenase enzymes, COX-1
and COX-2 that are responsible
for aspects of the inflammatory cascade.
In high-risk populations, endoscopic screening
for Barrett's esophagus, or other dysplastic changes
in the esophageal mucosa, coupled with ablative treatment
have proven effective in preventing
the development of esophageal cancer.
Treatments found effective, include administration
of proton pump inhibitors,
and ablation by radiofrequency energy.
Patients with Barrett's esophagus
or other pre-malignant lesions should
thus seek immediate treatment
to prevent progression to esophageal cancer.
And over the counter chemo preventive medications
include proton pump inhibitors,
antacids, and histamine 2 receptor antagonists.
Finally, and just to circle back to this point, aspirin
and other NSAIDs reduce the risk through COX-2 inhibition
and thus, can prove to be important tools
in lowering one's risk for esophageal cancer.