Section 6 -

Small Intestinal Metaplasia and Dysplasia Robert D. Odze, M.D. Jonathan Glickman, M.D., Ph.D. Mark Redston, M.D.

1. Metaplasia 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 [1]. In many (if not most) cases of duodenal ulcer and duodenitis in the proximal duodenum, H. pylori infection of the stomach is also present [2]. However, other etiologies, such as Crohn's disease or NSAID-related injury, may also give rise to duodenal ulcers. In mucous cell metaplasia, the villous epithelium, which is normally comprised of absorptive and goblet cells, is replaced by gastric-type mucous cells. In contrast to the acid mucin-positive goblet cells of the normal intestinal epithelium, these cells contain neutral mucin and, therefore, stain positively with PAS and negatively with Alcian Blue. Biopsies of chronic duodenitis also show villous shortening and Brunner's gland hyperplasia, and a variable amount of chronic active inflammation. Overall, these changes can easily be distinguished from gastric heterotopia, the latter of which contains architecturally intact gastric oxyntic-type mucosa (chief cells and parietal cells) in addition to surface mucous cells [3]. H. pylori organisms may colonize metaplastic epithelium and can cause further mucosal damage [4] Pyloric metaplasia, a condition in which small intestinal crypts are replaced by gastric type mucous glands, is present in up to 22% of biopsies with chronic ileitis, often secondary to Crohn's disease [5], but it can occur secondary to drug-induced (e.g. NSAID) injury as well. It is usually an incidental finding which helps confirm the presence of chronic mucosal injury, but may occasionally form an endoscopically visible nodule. Some investigators have hypothesized that these glands represent an "ulcer-associated cell lineage" that secrete a variety of growth regulatory peptides that help in the mucosal healing process [6, 7]. Some of these peptides include TGF alpha, EGFR, TFF-1 as well as other "trefoil" peptides. 2. Dysplasia A. Dysplasia in Crohn's Disease Crohn's disease (CD) may involve any portion of the gastrointestinal tract, but affects the ileum in approximately 80% of individuals. Approximately 5% of CD patients will develop cancer over their lifetime, usually after at least 15 years of disease [8, 9]. Although patients with CD have a 20-100 fold greater relative risk of small intestinal adenocarcinoma compared to the general population, the absolute risk of malignancy in this location is actually quite low [10]. Approximately 70% of CD-associated carcinomas occur in the colon and rectum [11, 12, 13]. It is widely believed that carcinoma in CD evolves through progressive stages of dysplasia, similar to ulcerative colitis (UC). However, relatively few studies have examined CD-associated dysplasia of the small intestine. Low or high-grade dysplasia is present adjacent to adenocarcinoma in up to 80% of cases [11], and is morphologically similar to that seen in the colon of patients with CD or UC. Thus, the classification and morphologic criteria of CD-associated dysplasia are similar to ulcerative colitis-associated colonic dysplasia (see section on colitis). B. Dysplasia in Sporadic and Polyposis-Associated Adenomas Adenomas are far less common in the small intestine compared to the colon. They account for less than 1% of all intestinal adenomas [14]. The majority of adenomas arise in the ampullary and/or periampullary region, and may be pedunculated or sessile, single or multiple. Small intestinal adenomas closely resemble colonic adenomas morphologically. Most contain low grade dysplastic epithelium and commonly contain abundant Paneth cells. In fact, in diagnostically difficult cases, the presence of Paneth cells in the upper crypt and surface villi may help differentiate true adenomatous epithelium from reactive epithelium, where Paneth cells are limited to the crypt bases. Approximately 45-60% of small intestinal adenomas contain adenocarcinoma [15, 16, 17]. Similar to the colon, larger adenomas (>1-2 cm), or those with a villous architecture, more frequently contain carcinoma. Adenomatous epithelium is present in the duodenum in up to 92% of patients with familial adenomatous polyposis, and is usually located in the ampullary or periampullary region. These patients have a 4% lifetime risk of developing carcinoma in this location, which is 100 times greater than that of the general population. In fact, periampullary adenomas represent a major cause of morbidity and mortality in FAP patients who have had a total colectomy. In one follow-up study, approximately 15% of ampullary adenomas progressed to carcinoma over a mean interval of 3.5 years [17]. C. Dysplasia in Peutz-Jeghers Syndrome Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant inherited cancer syndrome characterized by the presence of hamartomatous polyps and mucocutaneous melanin pigmentation [18, 19]. Polyps associated with PJS may occur anywhere in the GI tract, from the stomach to the colon, but most occur in the jejunum and ileum, where they are multiple in number. The histologic appearance of PJS polyps is distinctive. They show a central core of branching smooth muscle bundles that supports nondysplastic intestinal mucosa. These polyps may show epithelial misplacement into the polyp stalk in up to 10% of cases. This feature may cause confusion with invasive well-differentiated adenocarcinoma [20]. Patients with PJS have up to 80% lifetime risk of developing cancer. Approximately 75% of malignancies originate in the GI tract [21, 22, 23]. Gastrointestinal carcinomas often arise in polyps, with low and high grade dysplasia, but can also develop in non-polypoid areas of mucosa as well [34]. The precise risk of dysplasia, or malignant degeneration, in PJS polyps is controversial, since several large retrospective series failed to show any appreciable risk of dysplasia or carcinoma in these lesions [18, 21]. References Fitzgibbons PL, Dooley CP, Cohen H, Appelman MD. Prevalence of gastric metaplasia, inflammation, and Campylobacter pylori in the duodenum of members of a normal population. Am J Clin Pathol. 1988; 90:711-4. Wyatt JI. Histopathology of gastroduodenal inflammation: the impact of H. pylori. Histopathology 1995; 26:1-15. Mann NS, Mann SK, Rachut E. Heterotopic gastric tissue in the duodenal bulb. J Clin Gastroenterol. 2000; 30:303-6. Frierson HF, Caldwell SH, Marshell BJ. 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