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Adenocarcinoma of the Esophagus: Risk Factors and Prevention

Adenocarcinoma of the Esophagus: Risk Factors and Prevention

ABSTRACT: Esophageal cancer, with an estimated number of 12,300 new cases in the year 2000, is relatively uncommon in the United States but produces a high number of annual deaths, estimated at 12,100. Moreover, the incidence of the adenocarcinoma histologic type of esophageal cancer has been rising over the past two decades. Identification of risk factors could lead to primary prevention, as well as earlier diagnosis, treatment, and increased survival. Multiple risk factors are associated with the development of esophageal adenocarcinoma. These include Barrett’s esophagus, acid peptic disorders, motor disorders of the esophagus, other malignancies, medications, environmental exposures, diet, and nutrition. However, no one particular risk factor is responsible for the rising incidence of esophageal cancer. Several preventive strategies are under investigation using such agents as non-steroidal anti-inflammatory drugs (NSAIDs), selenium, alpha-difluoro-methylornithine (DFMO), and retinoids. As we gain more insight into the biology of this disease, other risk factors will hopefully be identified that will enable us to develop effective prevention strategies and, thus, reverse the current rising incidence of esophageal carcinoma. [ONCOLOGY 14(4);507-514, 2000]

Introduction

The estimated number of new cases of esophageal
cancer (adenocarcinoma and squamous cell carcinoma) in the United
States is 12,300, and, unfortunately, the estimated number of deaths
from this cancer is 12,100.[1] Of the 12,300 new cases, 9,300 occur
in males—a reflection of the fact that this disease is three
times more likely to occur in males than females.

The incidence of adenocarcinoma of the esophagus has risen
dramatically in the past two decades in the United States, Great
Britain, and Scandinavia.[2] In white males under 65 years of age,
the rate of adenocarcinoma has doubled, whereas in white males over
the age of 65 years, there has been a three- to fourfold increase in
age-adjusted incidence rates.[3] Although the overall incidence of
squamous cell carcinoma of the esophagus is declining, this
histologic type remains six times more likely to occur in
African-American males than in white males (Figure 1).[3,4]

These disturbing changes in esophageal cancer epidemiology have
driven researchers to study possible risk factors. Identification of
risk factors could lead to primary prevention, as well as earlier
diagnosis, treatment and increased survival.

Risk Factors

Various risk factors for the development of esophageal adenocarcinoma
have been identified (Table 1). These include Barrett’s
esophagus, acid peptic disorders, motor disorders of the esophagus,
other malignancies, medications, environmental exposures, diet, and nutrition.

Barrett’s Esophagus

Barrett’s esophagus is a disease that occurs when metaplastic
columnar epithelium replaces normal stratified squamous epithelium of
the distal esophagus.[5] The number of Americans with Barrett’s
esophagus is estimated to be 700,000, but the true prevalence is most
likely higher because of asymptomatic, undiagnosed disease.

Barrett’s esophagus is attributed primarily to chronic
gastroesophageal reflux disease (GERD).[6,7] The chronic acidic
environment damages the squamous epithelial lining, and,
subsequently, undifferentiated pluripotent stem cells (either already
present or newly migrated to the area) develop into columnar
epithelium. Other mechanisms, including tobacco-and alcohol-associated
damage to the esophageal epithelium, may also contribute to the
development of Barrett’s esophagus, but overall, GERD is
believed to be the most prominent etiologic factor.

Different grades of dysplastic tissue (low-, indefinite-, or
high-grade) can develop within Barrett’s esophagus. The
progression from dysplasia to adenocarcinoma occurs when neoplastic
cells break through the basement membrane. The risk of progression to
esophageal adenocarcinoma in patients with Barrett’s esophagus
is estimated to be 30- to 125-fold higher than that in the general
population.[8,9] However, no precise odds ratio has been defined.
Studies in the literature, however, report no difference in the
actuarial survival of patients with Barrett’s esophagus (age
greater than 55 years) compared to control populations.[8,10]

Calculating the cancer risk in patients with Barrett’s esophagus
is difficult for a number of reasons. Only 10% to 12% of patients
with symptomatic GERD who undergo endoscopy are found to have
Barrett’s esophagus,[9] and, as mentioned above, the estimated
number of people with asymptomatic Barrett’s esophagus is much
higher than the number with symptomatic disease.[11] Autopsy studies
examining for Barrett’s esophagus reveal a prev-alence rate of
376 cases per 100,000 population.

Thus, for every 1 patient diagnosed, approximately 20 cases go
undiagnosed.[12] Moreover, the number and quality of tissue biopsy
specimens obtained during upper endoscopy and the accuracy of
pathologic diagnosis are operator dependent and variable. Despite
these limitations, patients with Barrett’s esophagus are
recognized to have a higher risk for developing adenocarcinoma of the
esophagus than the general population.

Acid Peptic Disorders

Gastroesophageal reflux occurs when the lower esophageal sphincter
(LES) pressure is decreased and the gastrointestinal contents flow
back into the esophagus. The complex pathophysiology of GERD results
in damage to the esophageal epithelium and such clinical symptoms as
heartburn, chest pain, and dysphagia.

In addition to its role in the pathogenesis of Barrett’s
esophagus, GERD is an independent risk factor for the development of
adenocarcinoma. Lagergren et al found that recurrent symptoms of
reflux were associated with a 7.7-fold (95% confidence interval [CI],
5.3 to 11.4) increase in the risk of esophageal adenocarcinoma but no
increase in the risk of squamous cell carcinoma of the esophagus.[13]

Treatment of GERD involves conservative measures, such as sleeping
with the head of the bed elevated, weight reduction, and smoking
cessation, as well as medical therapy with histamine-2-receptor
antagonists (H2 -blockers), proton pump inhibitors, and pro-kinetic
agents. The objectives of non-medical and medical therapy are to
reduce gastric pressure and increase LES pressure. Whether or not
treatment of GERD decreases the risk of adenocarcinoma of the
esophagus has yet to be determined.

Complications of GERD—One complication of GERD is
esophagitis. The spectrum of esophagitis ranges from mild disease
with no visible endoscopic damage to severe disease, characterized by
erythema, bleeding, and inflammation, with granulocytes and
eosinophils infiltrating the epithelium. Esophagitis alone as a
consequence of GERD does not increase the risk of adenocarcinoma
unless there is replacement of the squamous epithelium with columnar
epithelium (Barrett’s esophagus).

A hiatal hernia develops when a portion of the stomach protrudes
through the diaphragm into the thoracic cavity. Hiatal hernia may
play a role in the pathogenesis of GERD but, by itself, is not a risk
factor for esophageal adenocarcinoma.

Gastric and/or duodenal ulcers also do not carry an increased risk of
esophageal adenocarcinoma.

Motor Disorders of the Esophagus

Achalasia is a motor disorder involving the smooth muscle of
the esophagus. The LES does not relax upon swallowing, and, as a
result, abnormal contractions replace normal peristalsis. The
esophagus progressively dilates as it fills up with food debris.

Long-standing achalasia has been associated with squamous cell
carcinoma of the esophagus. A population-based study conducted in
Sweden by Sandler et al demonstrated that patients with achalasia are
at increased risk of developing squamous cell cancer of the
esophagus.[14] Similar findings were reported by Loviscek et al from
Argentina based on their study of patients who had had achalasia and
marked food retention for more than 20 years.[15]

No studies have identified achalasia as a risk factor for esophageal adenocarcinoma.

Scleroderma (systemic sclerosis) is a disease that causes
fibrosis of the skin, gastrointestinal tract, and other vital organs.
Increased collagen deposits in the lower two-thirds of the esophagus
and thinned mucosa result in a dysfunctional LES, the development of
GERD, and, potentially, Barrett’s esophagus. Thus, the increased
risk of esophageal adenocarcinoma is secondary to the development of
Barrett’s esophagus.[16-18] Individuals with scleroderma and
symptomatic GERD should be evaluated with upper endoscopy to look for
the presence of early metaplastic or dysplastic changes.

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