If one looks at the global distribution of cancers, one finds that cancers of the lower gastrointestinal tract, such as colorectal cancer, predominate in the countries of the West, while cancers of the upper GI tract, gastric and esophageal cancer, are most prevalent in the rest of the world. Thus, esophageal cancer is the seventh most common cancer worldwide. But what is important to appreciate is that these are primarily cancers that originate from the flat squamous epithelium that lines the esophagus, serving as a protective covering against external exposures in what is ingested. These become squamous cell carcinomas (SCC) of the esophagus and occur most commonly in the setting of heavy tobacco and alcohol use, certainly in the U.S., though other factors may play a role globally, such as poor nutrition or the consumption of very hot beverages.

There are about 25,000 esophageal cancers annually in the U.S., but the incidence of squamous cell carcinomas has been declining dramatically as the prevalence of cigarette smoking has declined. Despite this significant decrease in SCC, the overall incidence of esophageal cancer has remained relatively constant as there has been a simultaneous dramatic rise in esophageal adenocarcinomas (EAC), cancers originating in the glandular cells in the esophagus. EACs occur solely in the distal third of the esophagus (the region of the esophagus closest to the stomach) and resemble cancers of the gastric cardia (the proximal stomach or portion of the stomach closest to the esophagus) in many respects.

EACs occur mainly in North America and the European Union and are rare in the developing world, where SCC predominates. It appears to be a disease of the upper social classes. It is significantly more common among Whites than Blacks and in those of upper socioeconomic status. It is five to six times more common in males than females.

EAC was virtually unknown prior to 1950 and has been among the most rapidly rising cancers since then. Interestingly, cancers of the gastric cardia have also been rising at a similarly rapid pace; whether the reasons are similar or not is uncertain.

To some degree, it is not easy to distinguish EAC from cancers of the gastric cardia—their anatomic sites overlap and their histology and appearance is similar under a microscope to a pathologist. Thus, given this ambiguity, a third entity has arisen—adenocarcinoma of the gastroesophageal junction (GEJ), which includes cancers which obviously are uncertain as to their exact subsite origin. The one way to be certain of EAC origin is if the biopsies reveal the presence of so-called Barrett’s esophagus, a form of benign tissue which is the precursor lesion for most or all cases of EAC. But it may not always be observed, in which case there remains uncertainty among the three diagnoses. We will discuss Barrett’s esophagus in more detail in next week’s article.

The exact diagnosis among these three entities may not be that critical under most circumstances. In reality, the treatment of all three types of cancer is similar. Similar approaches are used in terms of surgery, and the combined chemotherapy and radiotherapy regimens, with minor variations, for the three subsites for localized cases. For metastatic or recurrent disease, similar if not identical drug regimens are also used. The main interest and reason for distinguishing the three diagnoses is for nosological purposes.

So why did esophageal adenocarcinoma or EAC arise and increase in the U.S. and the West over the past five or more decades? In truth, it is not entirely clear. Both smoking and alcohol are risk factors for esophageal adenocarcinomas as they are for squamous cell carcinomas, but not to the same degree. What seems to be a more important risk factor is a condition known as GERD (gastroesophageal reflux disease), a condition in which gastric acid apparently washes back up into the esophagus from the stomach and causes heartburn symptoms. Many people have heartburn symptoms on occasion which can be treated acutely with antacids and will usually then resolve. But if these reflux symptoms persist and become chronic over years, they can cause esophagitis and under these circumstances, this condition is associated with a seven- to eight-fold increased risk of EAC. If these symptoms are severe, the associated risk of EAC can be as high as 40-fold.

That leads us to the question of why has GERD increased in the U.S.? Obesity is associated with GERD and is also associated with EAC; many experts attribute the dramatic rise in EAC to the rise in obesity in the U.S. and the EU over the last few decades. Undoubtedly other factors are at play in this as well, but these two phenomena—obesity and GERD—are definitely playing highly significant roles in the rise of EAC. Next week, we will discuss how this affects Barrett’s esophagus and possible interventions.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York. Email: [email protected].

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.