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(Drug information on 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(Drug information on 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.
A 70-year-old man with a history of localized prostate cancer treated with whole-pelvis radiation therapy with a boost to the prostate, in conjunction with androgen deprivation therapy 7 years prior, presented with lower back pain. A bone scan revealed an area of activity in the sacrum. What is the most likely diagnosis?
