Controversies in the current therapy of carcinoma of the esophagus.

Although esophageal carcinoma is a relatively uncommon malignancy, its prevalence is increasing by approximately 10% per year, which is faster than any other malignancy. This increase is largely secondary to the well-established association between gastroesophageal reflux disease, Barrett’s esophagus, and esophageal adenocarcinoma. In most Western countries, esophageal carcinoma has undergone a profound epidemiologic shift, from predominantly squamous cell carcinoma (SCC) seen in association with tobacco and alcohol abuse to adenocarcinoma associated with Barrett’s metaplasia seen almost exclusively in middle-aged Caucasian men with gastroesophageal reflux disease. The reasons for this change remain an enigma. Esophageal cancer is highly lethal. More than 90% of the estimated 12,300 patients who develop the disease in the United States in 2000 will die from it in a relatively short period of time. Over the last two decades surgeons have played a major role in improving the prognosis of patients with this deadly disease. Earlier detection combined with complete extirpation of disease and lower postoperative mortality have all contributed to improved survival. Major progress has been made in the understanding of the disease’s molecular biology, and improvements have occurred in staging, surgical techniques, and neoadjuvant therapy. These advances have resulted in clinically relevant changes in the management of patients with this difficult cancer. THE IMPACT OF AN IMPROVED UNDERSTANDING OF MOLECULAR BIOLOGY ON OPERATION FOR ESOPHAGEAL CARCINOMA Understanding of the molecular events underlying the metaplasia-dysplasia-carcinoma sequence in adenocarcinoma is slowly emerging. The specialized intestinal metaplasia found in Barrett’s esophagus can be characterized by a loss of differentiation, an increased proliferative rate, expression of growth factors, alteration in adhesion molecules, and abnormal apoptosis. Metaplastic Barrett’s mucosa retains pluripotent potential in its differentiation and demonstrates high proliferative indices along with expression of inducible nitric oxide synthetase and cyclooxygenase-2. Epigenetic alterations produce increased expression of epidermal growth factors and their receptors, causing genetic instability and dysplasia. Loss of regulatory genes such as p53 and cadherin/catenin complexes inhibits apoptosis. All of these changes have been associated with the histologic change from dysplasia to carcinoma manifested by tissue invasion. Chromosomal loss, DNA mutation, and gene silencing through DNA methylation have all been shown to occur in the metaplasia-dysplasia-carcinoma sequence. Meticulous prospective studies from the University of Washington have shown that the sequence of acquisition of these genetic changes and the evolution of clonal populations manifesting genetic errors occur in a complex, nonlinear fashion. Diploid cell progenitors containing genetic or epigenetic abnormalities in the p53 and p16 genes were shown to proliferate widely throughout large areas of Barrett’s mucosa. The subsequent premalignant progeny appear to undergo random mutation and loss of heterozygosity at various genetic loci, leading to neoplastic progression. For these reasons, conceptually, Barrett’s mucosa represents a mosaic of metaplastic clonal cell populations, many of which might have dysplastic and malignant potential. These molecular findings have great bearing on the treatment options of surveillance, mucosal ablation, or esophageal resection. Surveillance No competing interests declared.