Surgical Pathology and Current Molecular Aspects of Dysplasia in the GI Tract
Robert D. Odze, M.D.
Jonathan Glickman, M.D., Ph.D.
Mark Redston, M.D.
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Barrett's esophagus (BE) is defined as columnar metaplasia of esophageal squamous epithelium, of any length, that can be recognized at endoscopy, and is confirmed to have intestinal metaplasia (goblet cells) by mucosal biopsy analysis of the tubular esophagus.
Esophageal squamous cell carcinoma, similar to its counterparts in the skin or cervix, is believed to develop through a progression of premalignant, or dysplastic precursor lesions.
It has become clear in recent years that non-dysplastic columnar-lined esophageal mucosa may harbor genetic alterations. Acquired genetic alterations lead to clonal expansion, and these abnormal cells may occupy large regions of esophageal mucosa. In addition to abnormal DNA content and p53 mutations, a number of chromosomal deletions (loss of heterozygosity) have also been found.
The only molecular alteration that has been significantly studied in premalignant squamous lesions of the esophagus is p53. This gene is mutated in a high proportion of squamous cell carcinomas, particularly in regions of high endemic risk. In such cases, p53 immunohistochemical staining reveals nuclear positivity (consistent with mutation) in dysplasia, and in focal areas of non-dysplastic squamous epithelium.
The nomenclature and classification of gastritis and gastric dysplasia has undergone considerable evolution over the past decades, rendering some past literature confusing. However, certain themes have persisted despite changing terminology, and the concept that many gastric adenocarcinomas arise through a sequence of epithelial metaplasia and dysplasia is now well established.
Mucous cell metaplasia and pylori or "pseudopyloric" metaplasia are the two most common forms of metaplastic reaction in the small intestine. Mucous cell metaplasia of the intestinal villous epithelium commonly occurs in association with chronic peptic duodenitis, and is most pronounced in the bulb and first portion of the duodenum.
Although there are a significant number of studies regarding molecular alterations in gastric cancer, studies investigating the progression from premalignant precursors are more limited .
Several studies suggest that given a similar duration and extent of disease, the risk of neoplasia is similar in Crohn's disease (CD) and ulcerative colitis (UC). In CD, there is also an increased risk of dysplasia and adenocarcinoma in excluded segments of bowel, and in the small intestine.
The molecular genetic basis of colorectal adenoma-to-carcinoma progression has served as the prototypical model of human neoplastic genetic progression, and the molecular biologic alterations in general have been extensively studied. While colitis-associated neoplasms account for only a small portion of the overall burden of colorectal cancers, the molecular biologic alterations in this pathway have been well studied.
There are two categories of human cancer genes: oncogenes and tumor supressor genes. Some investigators also include a third category: genome-maintenance genes. Cancer genes may possess activity in more than one of these categories. Cancer genes can be further sub-classified based on their normal cellular functions.