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10 mg daily in the prevention of duodenal ulcer relapse. Aliment Pharmacol Ther 1994;8:541–548. 15. Kuipers EJ, Uyterlinde AM, Pena AS, Hazenberg HJA, Bloemena E, Lindeman J, Klinkenberg-Knol EC, Meuwissen SGM. Increase of Helicobacter pylori –associated corpus gastric during acid suppressive therapy: implications for long-term safety. Am J Gastroenterol 1995;90:1401–1406. 16. Kuipers EJ, Lee A, Klinkenberg-Knol, Meuwissen SGM. Review article: the development of atrophic gastritis— Helicobacter pylori and the effects of acid suppressive therapy. Aliment Pharmacol Ther 1995;9:331–340.

17. McCarthy DM. Sucralfate. N Engl J Med 1991;325:1017–1025. 18. Hogan DL, Ainsworth MA, Isenberg JI. Review article: gastroduodenal bicarbonate secretion. Aliment Pharmacol Ther 1994; 8:475–488. Address requests for reprints to: Roy E. Pounder, M.A., M.D., D.Sc.(Med), F.R.C.P., University Department of Medicine, Royal Free Hospital School of Medicine, Rowland Hill Street, London NW3 2PF, England. Fax: (44) 171-435-5803. 䉷 1996 by the American Gastroenterological Association 0016-5085/96/$3.00

Serrated Adenomatous Polyposis: A New Syndrome? See article on page 748.

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here are abundant clinical, morphological, epidemiological, and molecular data to support the role of adenomatous polyps as the precursors of most large bowel carcinomas.1 – 3 Histologically, adenomatous polyps are characterized by varying degrees of epithelial dysplasia, seen as disruption of the colonic architecture and cytology.3 Hyperplastic polyps exhibit a ‘‘saw toothed’’ or serrated microscopic appearance but no dysplasia.3 Dysplastic (adenomatous) polyps are known to progress to malignancy, whereas nondysplastic (hyperplastic) polyps rarely, if ever, undergo such a progression.3 Mixed hyperplastic/adenomatous polyps are very unusual and represent an entity recently referred to as serrated adenomas.4 These polyps show some features of dysplasia but also a serrated appearance similar to that seen in hyperplastic polyps. Hundreds to thousands of adenomatous polyps occur in the rare but well-described condition of familial adenomatous polyposis.5 Individuals with familial adenomatous polyposis have a very high risk of colon cancer. Cases with large numbers of hyperplastic polyps also have been observed, and this condition has been called hyperplastic polyposis. This extremely rare syndrome was first described by Williams et al. at the St. Marks Hospital in London.6 They reported 7 cases that grossly appeared to represent familial adenomatous polyposis, but histological examination of the polyps showed hyperplastic rather than adenomatous histology. A family history of colon cancer or polyposis was not apparent, and colon cancer risk was thought to be low. One or a few synchronous adenomatous polyps were found in several of the patients, however. There have been subsequent reports of hyper/ 5e0a$$0012

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plastic polyposis, some together with colon cancer, but the clinical characteristics, the natural history, and the cancer risk of the condition remain poorly defined. In this issue of GASTROENTEROLOGY, Torlakovic and Snover describe 6 patients with multiple serrated adenomatous polyps, all of whom were originally diagnosed as having hyperplastic polyposis.7 Four of the patients also had colon cancer. The authors suggest that some of the individuals previously reported as having multiple hyperplastic polyps could instead have had multiple serrated adenomatous polyps. This condition might, in fact, represent a new syndrome the authors call ‘‘serrated adenomatous polyposis.’’ Furthermore, the association sometimes found between hyperplastic polyposis and adenomas or cancers might be explained by cases of serrated adenomatous polyposis incorrectly categorized as hyperplastic polyposis. The main analysis of the study by Torlakovic and Snover is a morphological comparison of the polyps in their patients with adenomas, serrated adenomas, and hyperplastic polyps. They found histological similarities between the multiple polyps in their 6 cases and 3 solitary serrated adenomas selected as controls. Expression of p53 and reactivity with Lewisa and Lewisb antigens were also examined but were of little help in distinguishing hyperplastic, adenomatous, and serrated adenomatous polyps. Their histological characterization of the polyps in question as serrated adenomas was convincing, although it would have been even more convincing had the histological examinations been blinded, scored, and the scores quantitatively reported with statistical comparisons. A potentially helpful feature in distinguishing serrated adenomatous polyposis from hyperplastic polyposis may be polyp size. In all but 1 of the patients in WBS-Gastro

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the Torlakovic and Snover study, the smallest polyp diameter was 0.5 cm. The upper end of polyp sizes ranged from 1.5 to 4.5 cm. These sizes are remarkably different from sporadic hyperplastic polyps, which usually range from 0.1 to 0.5 cm in diameter and only rarely grow larger than 1.0 cm. 6 In the original report on hyperplastic polyposis by Williams et al., 4 of the 7 cases exhibited polyps 0.1 – 0.8 cm in diameter, sizes more characteristic of typical hyperplastic polyps. 6 The remaining 3 cases, however, might possibly have had serrated adenomatous polyposis because the polyp sizes in those cases ranged from 0.2 to 1.7 cm in diameter. The endoscopic appearance of polyps might also help to distinguish hyperplastic and serrated adenomatous polyposis. We have recently become aware of 2 cases that perhaps represent the serrated adenomatous polyposis described by Torlakovic and Snover. Endoscopic photographs sent by outside physicians showed multiple colonic polyps that were usually large, 1.0 – 3.0 cm in diameter, and sessile. The polyps exhibited a dark erythematous surface. Because of this gross polyp appearance, endoscopists expected a diagnosis of multiple villous adenomas. But the reported pathological interpretation was ‘‘hyperplastic polyps.’’ It would seem that the pathology should now be reviewed in light of the current report of serrated adenomatous polyposis. These 2 cases are very different from several we follow that seem to represent more classical hyperplastic polyposis. The colonoscopic appearance in these cases is that of 50 – 100, pale, sessile, polyps 0.1 – 0.4 cm in size, and the pathology is that of typical hyperplastic polyps. Further study is necessary to confirm whether the endoscopic appearance and size of polyps can be used as indicators of serrated adenomatous polyposis. The study by Torlakovic and Snover is most noteworthy because it suggests that some of the cases previously diagnosed as hyperplastic polyposis may instead comprise a new syndrome, that of serrated adenomatous polyposis. But verification of this possible new syndrome as well as the precise characterization of both hyperplastic and serrated adenomatous polyposis awaits further family, genetic, and endoscopic studies. Systematic endoscopic studies are needed in family members of affected patients to consider inheritance. Both hyperplastic and serrated adenomatous polyposis might arise from inherited mutations. The large numbers of colonic polyps and young age of onset in both disorders favor this hypothesis. The lack of a / 5e0a$$0012

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family history of colon cancer in previous reports does not exclude inheritance because the cancer risk may be only moderately increased. The presence of polyposis by endoscopic examination may be a more useful criterion. An examination of the frequency of mutations in the APC and K-ras genes in serrated adenomatous polyps may also be of interest. A recent molecular study found APC mutations in the large majority of small dysplastic (adenomatous) polyps but in none of the small nondysplastic (hyperplastic) polyps. 8 Mutations of K-ras, on the other hand, were present in both types of polyps. The authors concluded that dysplasia was closely associated with mutations of the APC gene but independent of K-ras mutations. Examination for the presence of mutations in these two genes is thus of particular importance in understanding the nature of the polyps in serrated adenomatous polyposis and in serrated adenomas in general. It would also be of interest to examine for mutations in the mismatch repair genes, now shown to be pathogenic for hereditary nonpolyposis colon cancer. It is expected that this report will stimulate the systematic endoscopic study of hyperplastic polyposis cases so that possible cases of serrated adenomatous polyposis can be separated and precisely defined. A consistent endoscopic description of these two entities should emerge with details of the spectrum of polyp size, number, distribution, and appearance. The natural history, cancer risk, and possible inheritance of both disorders (and both types of polyps) also need to be clarified as well as the possible occurrence of adenomatous polyps in cases of typical hyperplastic polyposis. Appropriate clinical management strategies can then be developed. RANDALL W. BURT WADE S. SAMOWITZ

Departments of Medicine and Pathology University of Utah College of Medicine Salt Lake City, Utah

References 1. Winawer SJ, Zauber AG, Ho MN, O’Brien MJ, Gottlieb LS, Sternberg SS, Waye JD, Schapiro M, Bond JH, Panish JF, et al. Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med 1993;329:1977–1981. 2. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759–767. 3. Morson BC. Major problems in pathology. Volume 10. The pathogenesis of colorectal cancer. Philadelphia: Saunders, 1978. 4. Longacre TA, Fenoglio-Preiser CM. Mixed hyperplastic adenomatous polyps/serrated adenomas: a distinct form of colorectal neoplasia. Am J Surg Pathol 1990;14:524–537. 5. Burt RW. Polyposis syndromes. In: Yamada T, ed. Textbook of

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gastroenterology. Volume 2. 2nd ed. Philadelphia: Lippincott, 1995:1944–1966. 6. Williams GT, Arthur JF, Bussey HJR, Borson BC. Metaplastic polyps and polyposis of the colorectum. Histopathology 1980;4:155– 170. 7. Torlakovic E, Snover DC. Serrated adenomatous polyposis in humans. Gastroenterology 1996;110:748–755. 8. Jen J, Powell SM, Papadopoulos N, Smith KJ, Hamilton SR, Vo-

gelstein B, Kinzler KW. Molecular determinants of dysplasia in colorectal cancer. Cancer Res 1994;54:5523–5526. Address requests for reprints to: Randall W. Burt, M.D., Division of Gastroenterology, Room 4R118, University of Utah Health Sciences Center, Salt Lake City, Utah 84132. Fax: (801) 581-7476. 䉷 1996 by the American Gastroenterological Association 0016-5085/96/$3.00

The Eosinophil in Gut Inflammation: Effector or Director? See article on page 768.

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potential role for eosinophils in inflammation of the gut is well recognized from the histopathology of eosinophilic gastroenteritis.1 Less appreciated is the presence of eosinophils in the infiltrates of ulcerative colitis,2,3 Crohn’s disease,4 and celiac sprue.5,6 Although a pathogenic role for eosinophils and proinflammatory proteins from their granules has not been established firmly in gastrointestinal disease, they have been implicated directly in the pathogenesis of inflammation at other sites. For example, correlations exist between the deposition of eosinophil granule proteins and tissue injury in the lungs of asthmatics7 and in the endocardium of patients with the idiopathic hypereosinophilia syndrome.8 The proinflammatory effects of eosinophil proteins are considered very important in the pathogenesis of bronchospasm9; eosinophil protein levels in the bronchial lavage fluid of asthmatics are correlated with the degree of bronchial hyperreactivity.10 Major basic protein, eosinophil cationic protein, and eosinophil peroxidase all injure and exfoliate respiratory epithelial cells,11 and eosinophil-derived neurotoxin causes a characteristic syndrome when injected intrathecally into rabbits.12 Major basic protein, which is toxic to mammalian tissues, including intestinal cells, in proportion to dose,13 activates complement,14 induces histamine release from basophils and mast cells,15 and stimulates superoxide anion and lysozyme release from neutrophils.16 Major basic protein also causes platelets to secrete 5-hydroxytryptamine and other bioactive substances in a dose-dependent fashion, affects coagulation by neutralizing heparin, inhibits Hageman factor, and impairs thrombomodulin.17 – 19 Eosinophilic gastroenteritis is a gastrointestinal disease in which eosinophils are most generally accepted as making a major contribution to tissue damage.1 The / 5e0a$$0012

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condition, which may be a composite of several etiologies and pathophysiologies, has been divided histopathologically into forms predominantly affecting the mucosa and/ or submucosa, muscular coat, or serosal surface. The clinical pictures, though poorly defined, appear to be somewhat distinct.1 The finding that tissue injury in these conditions correlated fairly well with the number of activated degranulated eosinophils20 is perhaps not remarkable but has received little comment. More surprising is the fact that the eosinophils’ role in the other inflammations of the gut has scarcely been examined. A very important, but not well-appreciated, fact is that the gut is quite special with regard to eosinophils. At all levels, the mucosa normally contains eosinophils.5 Indeed, the eosinophils’ constitutive presence in the gut is probably very important in host defense and the pathophysiology of disease because they release proinflammatory and damaging granule proteins. By contrast, healthy skin21 and respiratory mucosa (M. Kato, unpublished observations) contain no eosinophils! Skepticism regarding the eosinophils’ participation in gastrointestinal inflammation may relate to the fact that eosinophils are terminally differentiated, end-stage leukocytes. In addition, the discharge of potentially toxic, proinflammatory granule proteins may make the cells less readily identified by routine histology. Thus, eosinophils that have not been identified may already have participated in the inflammatory cascade! Moreover, their ability to transcribe and translate new proteins may be limited. In 1990, however, Wong et al. showed both transforming growth factor (TGF) a messenger RNA and protein in eosinophils infiltrating into oral cancer tissues,22 and since then the number of reports identifying cytokines produced by eosinophils has grown steadily. The current feeling is that eosinophils can probably transcribe and/or translate several cytokines and growth factors, including interleukin (IL) 1a, IL-3, IL-4, ILWBS-Gastro