In current practice in surgical pathology, colorectal polyps

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1 Colorectal Polyps With Extensive Absorptive Enterocyte Differentiation Histologically Distinct Variant of Hyperplastic Polyps Hidejiro Yokoo, MD; M. Irtaza Usman, Bsc(Hons); Susan Wheaton, MD; Patricia A. Kampmeier, MD Background. The histologic classification of colorectal polyps is well established. However, practicing pathologists may still occasionally encounter colorectal polyps that are difficult to classify. We studied 6 colorectal polyps that showed uncommon histologic features that have not been described in the English language literature. Materials and Methods. The polyps were studied using standard hematoxylin-eosin stain, mucin histochemistry, and electron microscopy. Results. The 6 polyps we studied showed extensive papillary and villous structures with alternating villi and In current practice in surgical pathology, colorectal polyps are classified into different groups according to well-established histologic criteria. 1 5 Their gross and microscopic features and the potential to transform into cancers have been well established. 1,6,7 Among these polyps, the most frequently encountered are hyperplastic polyps and adenomas. The distinction between these 2 types of polyps is important because of the malignant potential of the latter, whereas the former do not carry such potential. 1,5 7 Recently, another type of polyp, serrated adenoma, has been added to this classification scheme. 8 This adenoma histologically resembles the hyperplastic polyp, but the glandular cells possess the appearance of adenoma Foci of severe dysplasia and intramucosal carcinoma have Accepted for publication January 18, From the Departments of Pathology, Northwestern Memorial Hospital, Chicago, Ill (Dr Yokoo and Mr Usman); Mercy Hospital, Coon Rapids, Minn (Dr Wheaton); and Condell Medical Center, Libertyville, Ill (Dr Kampmeier). Reprints: Hidejiro Yokoo, MD, Department of Pathology, Northwestern Memorial Hospital, 303 E Chicago Ave, Chicago, IL crypts. The villi were lined by well-differentiated absorptive cells, whereas the crypts were lined by immature glandular cells, thus mimicking the histology of the small intestinal mucosa. Conclusions. These polyps appear to represent a variant of the hyperplastic polyp, in as much as cellular maturation (immature glandular cells differentiate into the mature surface absorptive cells) is the essential feature distinguishing hyperplastic polyps from adenomas. (Arch Pathol Lab Med. 1999;123: ) been found in some serrated adenomas, suggesting that the adenoma-carcinoma sequence does occur in serrated adenomas. 5,8,13 16 We have observed yet another histologically distinct variant of polyps, which is characterized by a complex polypoid papillary architecture lined by surface epithelial cells consisting entirely of absorptive enterocytes. When encountered by surgical pathologists, these uncommon polyps cause considerable difficulty in diagnosis because of a lack of description in the literature and can result in arbitrary diagnoses, such as tubular or serrated adenoma. This article describes the detailed histologic features of 6 polyps of this type. MATERIALS AND METHODS Six of the unusual polyps were studied. Case 1 was contributed by one of the authors (P.A.K.), and the remaining 5 polyps were collected from our surgical pathology files. Cases 3 and 4 were obtained from the same patient, who underwent polypectomy at 2 different times. All polyps were fixed in 10% buffered formalin and processed by the standard method. Sections were cut from paraffin blocks and stained with the hematoxylin-eosin method. Table 1. Case No. Age, y/sex Location/Size, cm Clinical and Pathological Data of Polyps % of Polyp With Absorptive Enterocyte Differentiation % of Polyp With Other Histologic Type Original Diagnosis 1 81/M Rectum/ Tubular Serrated adenoma 2 66/M Sigmoid/ Tubular Serrated adenoma 3 67/M Sigmoid/ Tubular adenoma 4 67/M Rectosigmoid/ Tubular adenoma 5 69/M Rectum/ Tubular, Tubular adenoma 20 serrated 6 75/M Rectum/ Tubular adenoma 404 Arch Pathol Lab Med Vol 123, May 1999 Colorectal Polyp With Enterocyte Differentiation Yokoo et al

2 Periodic acid Schiff stains, with or without diastase pretreatment, and Alcian blue stains at ph 2.5 were also performed on all specimens. Mucin histochemistry was also studied, using the method of Spicer and Meyer. 17 Electron microscopy was performed on all specimens, utilizing paraffinized formalin-fixed tissue. Figure 1. A prominent papillary architecture is seen in this polyp (case 2). The extensively branching papillary configuration is highly characteristic and was seen in all the polyps in our series (hematoxylineosin, original magnification 32). RESULTS The age of the patients ranged from 66 to 81 years, with a mean of 71 years (Table 1). The polyps ranged in size from 0.3 to 2.0 cm in maximum diameter. All the polyps showed extensive foci of branching papillary configurations (Figure 1). Some of the polyps contained areas of tall villous architecture resembling villous adenoma on lowpower magnification (Figure 2). However, unlike typical villous adenoma, these villous structures were studded with small crypts (Figure 3), which alternated with small flat villi along the lateral aspects of the tall villous structures (Figure 4). This architecture of alternating villi and crypts appears to be the basic growth pattern seen in all the polyps in our series. In general, the absorptive enterocytes lining the villi appear well differentiated. They are arranged in a single layer of cells with tall columnar eosinophilic cytoplasm and elongated benign-appearing nuclei (Figure 5). Along the luminal surface, these cells exhibited prominent brush borders resembling the absorptive enterocyte seen in normal small and large intestine. No mitotic figures were seen among these cells. Both periodic acid Schiff, with or without diastase pretreatment, and Alcian blue stains failed to stain these cells, except for the brush borders, which stained positively, suggesting that these cells possess tall microvilli. The presence of tall microvilli was supported by electron microscopic study of these cells. Interspersed among these absorptive cells were occasional goblet cells and interepithelial lymphocytes, which mimicked the normal histology of small intestinal villi (Figure 6). Mucin histochemistry studies showed these goblet cells predominantly stained positively for sialomucins, as do goblet cells in the small intestinal mucosa. Figure 2. Case 3. Tall villous structures (as shown) were present in some of the polyps. Architecturally, this area closely resembles the small intestinal mucosa on low-power magnification because of the presence of tall villi with alternating crypts (hematoxylin-eosin, original magnification 50). Arch Pathol Lab Med Vol 123, May 1999 Colorectal Polyp With Enterocyte Differentiation Yokoo et al 405

3 Table 2. Case No. Clinical Presentation 1 No GI complaints, positive hemoccult test Summary of Clinical Data Other Coexisting Colonic Polypoid Lesions Coexisting 3 polyps; tubulovillous adenoma of sigmoid, tubulovillous adenoma of rectum with severe dysplasia, tubulovillous adenoma of rectum Follow-up Information Patient not seen since polypectomy 5 Tubular adenoma removed from sigmoid colon 6 Constipation, positive hemoccult test * GI indicates gastrointestinal. Figure 3. Case 3. On higher magnification, the lateral aspect of a villous stalk is studded with small crypts (arrows) that alternate with small flat villous projections (arrowheads). This feature is not seen in either the colonic villous adenoma or the small intestinal villi (hematoxylin-eosin, original magnification 190). Alternating and contiguous with these villous structures were invaginating crypts lined by cuboidal glandular cells, which, unlike the surface absorptive cells, appeared immature (Figure 7). Taken together, the cytologic and architectural features of these polyps were more akin to the normal histology of small intestinal mucosa than colonic mucosa. 2 No GI complaints 2 years later no polyps seen on colonoscopy 3 No GI complaints, positive hemoccult test 1 year later another polyp removed (case 4) 4 Colonic polyp, removed 1 year previously (case 3) 5 years later 0.7-cm inflammatory polyp removed from transverse colon 4 years later no polyps seen on colonoscopy To be scheduled for colonoscopy The glandular cells interposed between the adjacent normal colonic mucosa and these polyps showed gradual transition in morphology from the normal to these polyps. Three of the 6 polyps were composed entirely of the type of histology described, whereas the remaining 3 polyps contained small foci of tubular or serrated adenomatous tissue at the periphery of the polyps (Figure 8). These minor components comprised from 5% to 30% of the entire polyp (Table 1). Morphologically, transitional changes were seen in the glandular cells between these polyps and other adenomatous or nonadenomatous elements, when present. Electron microscopic study of the absorptive enterocytes seen in these polyps showed the presence of numerous tall microvilli on the luminal surface. Mitochondria, free ribosomes, endoplasmic reticulum, and Golgi apparatus were present. Figure 9 is an electron micrograph of these cells, which closely mimic the absorptive enterocytes of normal small intestinal mucosa; the 2 cell types are shown together for comparison. The original pathologic diagnosis on each polyp is listed in Table 1. Two of the 6 polyps were diagnosed as serrated adenomas, whereas the remaining 4 polyps were diagnosed as tubular adenomas. The clinical presentations of these patients are summarized in Table 2. Some patients underwent colonoscopy based on a positive hemoccult test, whereas others underwent coloscopy as part of follow-up or part of routine physical examination. COMMENT Genetic alterations leading to invasive carcinoma in colorectal tumors have been the subject of active research in recent years. The participation of certain tumor suppressive genes, oncogenes, and DNA mismatch repair genes has been identified in familial adenomatous polyposis, hereditary nonpolyposis colorectal cancers, and other sporadic colorectal cancers. 18,19 In these studies, the histology of benign adenomas, adenomas with severe dysplasia, and invasive carcinomas has been correlated with sequential genetic alterations within the tumor cells. Thus, precise histologic identification of colorectal polyps is of clinical importance. Although the current histologic classification of colorectal polyps has been well established, 1 5 surgical pathologists may occasionally encounter difficulties in 406 Arch Pathol Lab Med Vol 123, May 1999 Colorectal Polyp With Enterocyte Differentiation Yokoo et al

4 Figure 4. Case 3. Another area on the lateral aspect of a villous structure showing alternating villi and crypts. Note that the crypts are lined by immature cells, whereas the small flat villi are lined by absorptive cells with brush borders (hematoxylin-eosin, original magnification 270). Figure 5. Case 3. The tip of a villus is lined by tall columnar absorptive cells with elongated nuclei and prominent brush borders (arrows), which are strikingly similar to the absorptive cells lining the small intestinal villi (hematoxylin-eosin, original magnification 172). classifying certain colorectal polyps. The recent addition of the serrated adenoma to this classification scheme has further improved our diagnostic accuracy, 8 but some polyps still defy precise histologic classification, such as the type described here. To our knowledge, the detailed microscopic description of the polyps presented here has not appeared previously in the English language literature. The histologic features distinguishing these polyps are mainly threefold. First, the architectural appearance of these polyps is papillary and has extensive branching, which is not usually seen in colorectal polyps (Figure 1). Second, some of the polyps showed tall villi-like structures that resembled villous adenoma. On close examination, however, these villous structures are extensively corrugated and studded with small crypts that alternate with small, flat, villouslike structures (Figure 4). In other areas, the polyps contained tall villi alternating with crypts, the appearance of which is strongly reminiscent of the mucosa of the small intestine (Figure 2). This pattern of alternating villi and crypts appears to represent the basic growth pattern seen in all 6 polyps presented here. Finally, the surface lining cells of the villi are composed almost exclusively of tall columnar cells with elongated nuclei and abundant eosinophilic cytoplasm with prominent brush borders, which are similar to the absorptive enterocytes seen in normal small and large intestine. Among these cells are interspersed lymphocytes and occasional goblet cells. Unlike the commonly encountered hyperplastic polyps, which are rich in goblet cells, these polyps contain far fewer goblet cells. Our study of mucin histochemistry showed that these goblet cells interposed between the absorptive cells predominantly stained for sialomucin and neutral mucin. Our histologic studies of the absorptive cells revealed that they are devoid of acidic and neutral mucins, except for the luminal surface, which stained positively, indicating the presence of prominent Arch Pathol Lab Med Vol 123, May 1999 Colorectal Polyp With Enterocyte Differentiation Yokoo et al 407

5 Figure 6. Another area of surface absorptive cells with interspersed interepithelial lymphocytes (arrows) and some goblet cells (arrowheads) (hematoxylin-eosin, original magnification 430). Figure 7. Case 2. Tall villi (arrow) with alternating crypts (arrowheads) in this polyp resemble the small intestinal mucosa. The crypts are lined by immature cells, whereas the villi are lined by absorptive cells (hematoxylin-eosin, original magnification 95). microvilli. This finding was supported by the electron microscopic study of these cells, which showed tightly packed tall microvilli on the luminal surface, similar to the absorptive enterocytes seen in small and large intestinal mucosa. Other ultrastructural features seen in these cells also resemble the absorptive enterocyte These findings suggest that the histology and histochemistry of these polyps closely mimic those of the normal small intestinal mucosa. 20,21,24 The cells lining the crypts in these polyps appeared to be immature. They were contiguous and had well-differentiated absorptive cells lining the villi, whereas cells between these 2 types of lining cells showed transitional morphology, suggesting that crypt cells differentiate into the absorptive cells lining the villi. The essential feature distinguishing hyperplastic polyps from adenomas is cellular differentiation. 4 Therefore, the cellular differentiation seen in these polyps suggests that the polyps described here represent a variant of the hyperplastic polyp. However, it is of interest to note that although 3 of our polyps were composed entirely of this type of histology, the remaining 3 polyps contained minor foci of tubular or serrated adenomatous tissue. These different elements were present at the periphery of the polyps with transitional morphology between these different elements. We believe that this finding is somewhat akin to that described in the mixed hyperplastic adenomatous polyp, in which adenomatous elements are seen within or adjacent to hyperplastic polyps. If this assumption is correct, these polyps, which are morphologically benign in appearance, may possess malignant potential if adenomatous elements are found within the polyps, as in the mixed hyperplastic adenomatous polyp. Finally, it should be pointed out that absorptive cell differentiation is normally seen in the colonic mucosa, as well as in the usual goblet cell rich hyperplastic polyps. 2,4,24, Arch Pathol Lab Med Vol 123, May 1999 Colorectal Polyp With Enterocyte Differentiation Yokoo et al

6 Figure 8. Case 1. A coexisting tubular adenoma is seen next to the one of the polyps (hematoxylin-eosin, original magnification 83). Figure 9. Electron micrograph of an absorptive cell seen in case 2 (A) is shown together with the ultrastructure of an absorptive enterocyte of normal small intestine (B). Ultrastructural similarity between these 2 cells, including the presence of tall microvilli (brush border), is evident (uranyl acetate and lead citrate, original magnification 1290). For instance, Franzin et al 25 wrote, metaplastic polyps [synonymous with hyperplastic polyps] usually show an excess of absorptive cells, thus, exhibiting a rather small intestinal pattern. Their illustration 9b shows a microscopic area of hyperplastic polyp with small intestinal features that are identical to ours. However, these investigators did not describe hyperplastic polyps with extensive absorptive cell differentiation, such as we have presented here. We believe these polyps possess sufficient morphologic features to justify separate recognition as a variant of hyperplastic polyp. If surgical pathologists are unaware of this variant, arbitrary diagnoses, such as villous adenoma, tubular adenoma, serrated adenoma, or even adenoma with severe dysplasia, are possible. References 1. Morson BC, Sobin LH. Histological Typing of Intestinal Tumours. Geneva, Switzerland: World Health Organization; International Histological Classification of Tumours; No Morson BC, Dawson IMP, eds. Morson & Dawson s Gastrointestinal Pathology. 3rd ed. Oxford, England: Blackwell Scientific Publications; Fenoglio-Preiser CM, ed. Gastrointestinal Pathology: An Atlas and Text. New York, NY: Raven Press; Fenoglio-Preiser CM, Pascal RR, Perzin K. Tumors of the Intestine. Bethesda, Md: Armed Forces Institute of Pathology; Atlas of Tumor Pathology; 2nd series, fascicle Fenoglio-Preiser CM, Hunter RV. Colorectal polyps: pathologic diagnosis and clinical significance. CA Cancer J Clin. 1985;35: Spjut H, Estrada RG. The significance of epithelial polyps of the large bowel. Pathol Annu. 1977;12(pt 1): Fenoglio CM, Pascal RR. Colorectal adenomas and cancer: pathologic relationships. Cancer. 1982;50(suppl): Longacre TA, Fenoglio-Preiser CM. Mixed hyperplastic adenomatous polyps/serrated adenomas: a distinct form of colorectal neoplasia. Am J Surg Pathol. 1990;14: Urbanski SJ, Kossakowska AE, Marcon N, Bruce WR. Mixed hyperplastic adenomatous polyps an underdiagnosed entity: report of a case of adenocarcinoma arising within a mixed hyperplastic adenomatous polyp. Am J Surg Pathol. 1984;8: Gebbers JO, Laissue JA. Mixed hyperplastic and neoplastic polyp of the colon: an immunohistological study. Virchows Arch A Pathol Anat Histopathol. 1986;410: Goldman H, Ming S, Hickock DF. Nature and significance of hyperplastic polyps of the human colon. Arch Pathol. 1970;89: Estrada RG, Spjut HJ. Hyperplastic polyps of the large bowel. Am J Surg Pathol. 1980;4: McCann BG. A case of metaplastic polyposis of the colon associated with focal adenomatous change and metachronous adenocarcinomas. Histopathology. 1988; Bengoechea O, Martinez-Penuela JM, Larrinaga B, Valerdi J, Borda F. Hyperplastic polyposis of the colorectum and adenocarcinoma in a 24-year-old man. Am J Surg Pathol. 1987;11: Cooper HS, Patchefsky AS, Marks G. Adenomatous and carcinomatous changes within hyperplastic colonic epithelium. Dis Colon Rectum. 1979;22: Franzin G, Novelli P. Adenocarcinoma occurring in a hyperplastic (metaplastic) polyp of the colon. Endoscopy. 1982;14: Arch Pathol Lab Med Vol 123, May 1999 Colorectal Polyp With Enterocyte Differentiation Yokoo et al 409

7 17. Spicer SS, Meyer DB. Histochemical differentiation of acid mucopolysaccharides by means of combined aldehyde fuchsin-alcian blue staining. Am J Clin Pathol. 1960;33: Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61: Chung DC, Rustgi AK. DNA mismatch repair and cancer. Gastroenterology. 1995;109: Segal GH, Petras RE. Small intestine. In: Sternberg SS, ed. Histology for Pathologists. New York, NY: Raven Press; 1992: Ham AW. Histology. 6th ed. Oxford, England: Blackwell Scientific; Kaye GI, Fenoglio CM, Pascal RR, Lane N. Comparative electron microscopic features of normal, hyperplastic, and adenomatous human colonic epithelium: variations in cellular structure relative to the process of epithelial differentiation. Gastroenterology. 1973;64: Fenoglio CM, Richart RM, Kaye GI. Comparative electron-microscopic features of normal, hyperplastic, and adenomatous human colonic epithelium, II: variations in surface architecture found by scanning electron microscopy. Gastroenterology. 1975;69: Filipe MI. Mucins in the human gastrointestinal epithelium: a review. Invest Cell Pathol. 1979;2: Franzin G, Zamboni G, Scarpa A, Dina R, Iannucci A, Novelli P. Hyperplastic (metaplastic) polyps of the colon: a histologic and histochemical study. Am J Surg Pathol. 1984;8: Arch Pathol Lab Med Vol 123, May 1999 Colorectal Polyp With Enterocyte Differentiation Yokoo et al