Management of colorectal polyps
Authors: A. J. Markowitz, S. J. Winawer
Journal: CA A Cancer Journal for Clinicians (1997)

A colorectal polyp is defined as a visible protrusion above the surface of the surrounding normal large bowel mucosa. Polyps may be detected endoscopically by sigmoidoscopy or colonoscopy, or radiographically by barium enema. Colorectal polyps are classified histologically as either neoplastic (adenomatous polyps) or non-neoplastic (Table). Although all adenomatous polyps have malignant potential, the majority are benign when detected. In contrast, hyper-plastic, mucosal, inflammatory, and hamartomatous polyps are non-neoplastic and thus have no malignant potential. Lastly, submucosal polyps include lymphoid polyps, lipomas, and other less common histologic types. Appropriate management of colorectal polyps requires an understanding of the typical clinical presentation, anatomic distribution, and associated clinical findings of these variable histologic types. Furthermore, although most colorectal polyps occur sporadically, some may be associated with a hereditary syndrome, such as familial adenomatous polyposis (FAP), juvenile polyposis, Peutz-Jeghers, or hereditary nonpolyposis colorectal cancer (HNPCC). Adenomatous and hyperplastic polyps are the most commonly detected colorectal polyps and are the most likely to be found during screening sigmoidoscopy. In this article we review the epidemiology, diagnosis, initial management, and follow-up surveillance of each polyp type. We discuss the indications for biopsy and removal of polyps found at sigmodoscopy and colonoscopy and the need for further evaluation and follow-up. Additionally, we cover the diagnostic criteria, clinical manifestations, malignant potential, and recommendations for polyp management and surveillance in the associated hereditary syndromes. Adenomatous polyps, or adenomas, are attached to the bowel wall by a stalk (pedunculated) or by a broad, flat base (sessile) (Fig. 1). The clinical significance of identifying an adenoma is that it has malignant potential and may develop into a cancer.1 It is generally accepted that all colorectal cancers originate from a precursor adenoma. The National Polyp study has demonstrated that colonoscopic removal of adenomatous polyps significantly reduces the risk of developing colorectal cancer (Fig. 2).2 Colorectal adenomas are common in the general population. Autopsy studies from various regions of the world have reported prevalence rates ranging from 22 to 61 percent.6-11 Recent colonoscopy studies from the United States — including several screening studies of asymptomatic, average-risk individuals with no personal or family history of polyps or cancer —have demonstrated rates ranging from 25 to 41 percent.12-16 (A) Pedunculated polyp. (B) Small sessile polyp. Worldwide, the prevalence rate of adenomatous polyps shows geographic variation and correlates with the regional incidence rates of colorectal cancer.17, 18 Migration studies show that the prevalence rate of adenomas increases when people move from a low-risk country to one with a Westernized society.19 This suggests that environmental factors may exert some influence on the development of adenomas. Adenomatous polyps occur more frequently in men than in women.6, 10 Older patients have an increased risk of having an adenoma. Autopsy studies have reported adenoma rates of 17 percent in people younger than 50 years, 35 percent in those aged 50 to 59 years, 56 percent in those aged 60 to 69 years, and 63 percent in those aged 70 years or older.10 Screening colonoscopy studies in average-risk patients have demonstrated similar results, with rates ranging from 21 to 28 percent in those aged 50 to 59 years, 41 to 45 percent in those aged 60 to 69 years, and 53 to 58 percent in those aged 70 years or older.14, 15 Although adenomas vary greatly in size, most are small, measuring less than 1.0 cm in diameter. In the National Polyp Study, of the 3,371 colonoscopically removed adenomas, 38 percent were only 0.5 cm or less, 36 percent were 0.6 to 1.0 cm, and 26 percent were larger than 1.0 cm.20 In those found to have adenomatous polyps at colonoscopy, about 60 percent have a single adenoma and 40 percent have multiple adenomas.12 Increased age is associated with an increased rate of multiple adenomas.10 Adenomatous polyps exhibit the same predominantly left-sided colonic distribution that is found with colorectal cancers. Several clinical studies have reported that more than 60 percent of colonoscopically removed adenomas are located distal to the splenic flexure.20-22 Some autopsy studies of patients who had died of other causes, however, have shown that coincidentally found adenomas are more common in the proximal colon.8, 10 Cumulative incidence of colorectal cancer in the National Polyp Study cohort. The observed incidence is compared with the expected incidence based on data from the three reference groups: the Mayo Clinic cohort (United States), the St. Mark's cohort (United Kingdom), and the Surveillance, Epidemiology, and End Results (SEER) Program (United States).2-5 (Reprinted by permission of The New England Journal of Medicine, Winawer SJ, Zauber AG, Ho MN, et al, volume 329, page 1979, 1993. Copyright 1993. Massachusetts Medical Society. All rights reserved.) Adenomatous polyps are classified histologically as tubular, tubulovillous, or villous. Tubular adenomas are most common. The St. Mark's Hospital data and National Polyp Study data have shown that 75 to 87 percent of adenomas are tubular, 8 to 15 percent are tubulovillous, and 5 to 10 percent are villous.1, 20 In tubular adenomas, the adenomatous epithelium proliferates and forms straight or branched tubules that are separated by normal lamina propria (Fig. 3A). Grossly, tubular adenomas are more commonly pedunculated and have a smooth, lobulated surface. In villous adenomas, the epithelial proliferation results in adjacent elongated crypts that give an overall appearance of thin, villus-like projections of normal lamina propria surrounded by adenomatous epithelium, extending out perpendicularly from the muscularis mucosa (Fig. 3B). Classification as a villous adenoma requires that more than 75 percent of the polyp show villous architecture. Grossly, villous adenomas are more typically sessile and have a "shaggy" surface. Tubulovillous adenomas show a mixture of both tubular and villous architecture, demonstrating between 25 and 75 percent of villous features. (A) Tubular adenoma. (B) Villous adenoma. (Reproduced with permission from O'Brien MJ.101) The size of an adenoma correlates with its underlying histology. The St. Mark's Hospital data showed that of their tubular adenomas, 76 percent were smaller than 1.0 cm, 20 percent were between 1.0 and 2.0 cm, and 4 percent were larger than 2.0 cm; of their tubulovillous adenomas, 25 percent were smaller than 1.0 cm, 47 percent were between 1.0 and 2.0 cm, and 28 percent were larger than 2.0 cm; and of their villous adenomas, 14 percent were smaller than 1.0 cm, 26 percent were between 1.0 and 2.0 cm, and 60 percent were larger than 2.0 cm.1 Thus, larger adenomas are more likely to demonstrate villous features. Because adenomatous epithelium is by definition neoplastic, every adenoma exhibits some degree of dysplasia. Dysplasia is classified histologically as mild, moderate, or severe (high grade). The grade of dysplasia is determined by the degree of cytologic epithelial atypia and glandular architectural distortion. Carcinoma in situ and intramucosal carcinoma are terms used for adenomas with severe dysplasia contained within their mucosa and refer to dysplastic cells either being limited to the mucosal glands or extending out into the lamina propria, respectively. Because the severely dysplastic cells have not yet invaded through the muscularis mucosae, these adenomas pose no risk of lymph node metastases. Therefore, it is preferable to avoid using the terms carcinoma in situ and intramucosal carcinoma because they often produce unwarranted anxiety for both patient and physician and may lead to excessive surveillance and even unnecessary surgical resection. The National Polyp Study demonstrated that about 86 percent of adenomas show mild, 8 percent moderate, and 6 percent high-grade (severe or carcinoma in situ) dysplasia.20 Larger polyp size, greater villous architecture, and increased patient age are all associated with a higher risk of high-grade dysplasia in adenomas (Fig. 4).20 The concept of the adenoma-to-carcinoma sequence is well accepted and describes a stepwise progression from normal colorectal epithelium to adenoma to carcinoma, in association with an accumulation of multiple genetic alterations within the epithelial cells. Many lines of evidence support this concept. Prevalence rates of adenomas correlate with colorectal cancer incidence rates in different worldwide geographic regions, and prevalence rates increase after migration to a high-risk area for colorectal cancer.19 The risk of adenoma and the risk of cancer both increase with patient age.10, 14, 15 Cancer risk increases with increased adenoma size.1 In clinical studies, adenomas and cancers show a predominantly left-sided anatomic distribution.20-22 Synchronous adenomas are common in patients with cancer, and residual adenomatous tissue may often be found in the cancer.23 In familial adenomatous polyposis, colorectal cancer occurs several years after the development of hundreds to thousands of adenomas. Lastly, the National Polyp Study demonstrated that colorectal cancer incidence is decreased after colonoscopic removal of adenomas.2 National Polyp Study: frequency of high-grade dysplasia in adenomas by size. (Reproduced with permission from O'Brien MJ et al.20) At the molecular level, several well characterized genetic changes have been associated with the progression of normal colonic epithelium to invasive cancer. The earliest alteration appears to be a mutation in the adenomatous polyposis coli (APC) gene on chromosome 5q, which inactivates the gene and leads to epithelial cell proliferation and the development of an early adenoma. Additional major genetic alterations include oncogene activation, as a result of a mutation in the Ki-ras gene, and loss of tumor suppressor genes, caused by deletion of the deleted in colorectal cancer (DCC) gene on chromosome 18q and mutation of the p53 gene on chromosome 17p. Although the actual time course of the adenoma-to-carcinoma sequence is not certain, it appears to be a slow process occurring over many years. Data from both the National Polyp Study24 and the St. Mark's Hospital study,1 which described the long-term observation of un-resected colorectal adenomas, support an average time course of at least 5 to 10 years for progression from an adenoma to a carcinoma. An exception, however, may be seen in the hereditary nonpolyposis colorectal cancer syndrome. A report from the Netherlands showed an unexpectedly high incidence of advanced colorectal cancers detected within 3.5 years after a negative screening examination (colonoscopy or barium enema) in a large number of HNPCC patients participating in a national screening program.25 These findings suggest that HNPCC patients may have a shorter time interval to develop colorectal cancer and thus an accelerated adenoma-to-carcinoma sequence. Dietary factors such as high fat and low fiber have been associated with an increased risk of both colorectal adenomas26 and cancer.27, 28 Some evidence exists that modification of certain dietary factors may have an effect on the adenoma-to-carcinoma sequence. A study of calcium supplementation in patients with a family history of colorectal cancer showed a decrease in colonic epithelial cell proliferation.29 Modification of dietary fat intake has been reported to alter epithelial cell proliferation in humans.30 These results suggest that these and other dietary components found in fruits, vegetables, and other food sources may be able regulate colon cancer carcinogenesis at a relatively early stage in the adenomato-carcinoma sequence. An inherited predisposition to common, sporadic colorectal adenomas and cancer appears to exist.31 An individual's risk of having a colorectal adenoma is increased if he or she has a first-degree relative who had colorectal cancer.32 The National Polyp Study demonstrated that an individual's risk of developing colorectal cancer is increased if he or she has a sibling or a child who had an adenomatous polyp, particularly if the adenoma was diagnosed before 60 years of age.33 An individual's risk of colorectal cancer is also significantly increased if he or she has a first-degree relative who had colorectal cancer, particularly if the cancer was diagnosed before 55 years of age, and this risk is even greater if two first-degree relatives were affected with cancer.34 One can speculate that environmental factors such as dietary substances and toxic carcinogens may perhaps interact with underlying genetic factors in patients with an inherited predisposition to allow initiation of, and progression along, the adenoma-to-carcinoma sequence. Given that the prevalence of adenomatous polyps far exceeds that of colorectal cancer, it is clear that only a small proportion of adenomas go on to develop into cancer. Although it is not yet possible to determine which adenomas will progress, certain pathologic features of adenomas have been found to correlate with the risk of finding cancer in those polyps. Increased polyp size, villous histology, and severe dysplasia are all associated with an increased risk of malignancy in an adenoma. The St. Mark's Hospital study demonstrated that (1) 1.3 percent of adenomas smaller than 1 cm, 9.5 percent between 1 and 2 cm, and 46 percent larger than 2 cm were malignant; (2) 4.8 percent of tubular, 22.5 percent of tubulovillous, and 40.7 percent of villous adenomas were malignant; and (3) 5.7 percent of mild, 18 percent of moderate, and 34.5 percent of adenomas with severe dysplasia were malignant.1 A patient's future risk of colorectal cancer may also be associated with characteristic features of his or her adenomas. A pre-colonoscopy long-term follow-up study from St. Mark's Hospital of a large cohort of patients who had sigmoidoscopy and removal of rectosigmoid adenomas, but did not have colonoscopy, showed that distal villous, tubulovillous, or large (1 cm or more) adenomas increased their risk for the subsequent development of colon cancer, and that this risk was even greater for those who had multiple polyps.4 Presumably, this increased risk was caused by additional adenomatous polyps located more proximally in the colon that were not removed. Although colorectal adenomatous polyps may account for small amounts of stool blood loss, they are predominantly asymptomatic. Because of their high prevalence in our general population, however, adenomas are often found during screening examinations for colorectal cancer in asymptomatic individuals and during evaluations of symptomatic patients with gastrointestinal complaints. Adenomas may be detected either endoscopically (by sigmoidoscopy or colonoscopy) or radiographically (by barium enema). Patients with colorectal polyps detected radiographically are referred for colonoscopic polypectomy. If a small (less than 1 cm) polyp is found at sigmoidoscopy, it undergoes biopsy and further management is based on its underlying pathology. If a large (1 cm or more) polyp is detected, a biopsy is generally not necessary and the patient may be directly referred for colonoscopic polypectomy. If a polyp detected at sigmoidoscopy is found to be an adenoma after the biopsy, colonoscopy is recommended. At colonoscopy, the adenoma found during sigmoidoscopy is removed and the more proximal colon is examined for potential synchronous adenomas and other neoplastic lesions. Several colonoscopy studies support the increased risk of finding a proximal synchronous lesion in patients with a distal adenoma. In a recent prospective study of asymptomatic individuals at average risk for colorectal cancer, 31 percent of those who were found to have a benign distal adenoma at screening flexible sigmoidoscopy had proximal synchronous neoplasms, including eight percent with advanced adenomas (larger than 1 cm, villous, moderate to severe dysplasia) and invasive cancers.35 A second study of screening colonoscopy in asymptomatic average-risk men showed that 42 percent of those with distal adenomas found during the initial evaluation of their distal 60 cm of colon, before the examination was completed to the cecum, had proximal synchronous adenomas.14 Some investigators, however, question the need for colonoscopy in patients found to have a small (less than 1 cm) adenoma at sigmoidoscopy. In a study of asymptomatic and symptomatic patients who had colonoscopy after adenomas were found at sigmoidoscopy, the occurrence of a proximal advanced (larger than 1 cm, villous, or severe dysplasia) synchronous adenoma in those who had only one or more small (1 cm or less) tubular adenomas at sigmoidoscopy was less than one percent.36 Another study found that asymptomatic patients whose worst index lesion was a single small (less than 1 cm) tubular adenoma and who had no first-degree relatives with colorectal cancer had only a three percent prevalence rate of a proximal advanced synchronous adenoma or invasive cancer at colonoscopy, which was no greater than that expected in the general population.37 In comparison, a recent prospective study of asymptomatic, average-risk individuals showed a seven percent prevalence of synchronous proximal advanced adenomas and invasive cancers in those whose index lesion at screening flexible sigmoidoscopy was a small (1 cm or smaller) adenoma, including two proximal adenomas with severe dysplasia and two early (stage I) invasive cancers in four patients whose index adenoma was only 0.5 cm or less.35 In the St. Mark's Hospital's long-term follow-up study of patients who had removal of rectosigmoid adenomas without colonoscopic follow-up, patients who were initially found to have one or more small (less than 1 cm) tubular adenomas with only mild to moderate dysplasia had a low risk for subsequent development of colorectal cancer that was no greater than that in the general population.4 Thus, the need for colonoscopy and further follow-up surveillance in patients found to have a small distal tubular adenoma at sigmoidoscopy is controversial. Currently we recommend colonoscopy initially and post-polypectomy surveillance in these individuals. Longer surveillance intervals (perhaps every five years) may be reasonable in this group of patients. We consider colonoscopy to be superior to barium enema for the follow-up management of colorectal polyps. Although barium enema is less costly and has a low risk, colonoscopy offers a more sensitive examination and provides the opportunity for colonoscopic polypectomy in addition to diagnostic biopsies of suspicious mass lesions. At colonoscopy all polyps are completely removed. However, there are circumstances such as serious co-morbid medical conditions or a significantly reduced life expectancy that would preclude the removal of coincidentally found colorectal polyps detected during a diagnostic colonoscopy performed for evaluation of gastrointestinal symptoms in such patients. When a polyp is detected at colonoscopy, a polypectomy is performed and all tissue is retrieved and sent for pathologic evaluation. The most commonly used techniques for colonoscopic polypectomy include snare polypectomy, polyp fulguration using the hot biopsy forceps, and excisional biopsy without fulguration. Snare polypectomy is typically performed on pedunculated polyps and involves the placement of a wire snare around the polyp and subsequent application of electrocautery to transect the stalk. The excised polyp is then retrieved and sent to pathology. Small sessile polyps in the distal colon are commonly removed with the hot biopsy forceps. With this technique, the polyp is gently pulled upwards from the bowel wall and thermal energy is then delivered to fulgurate the lesion. The polyp tissue left inside the hot biopsy forceps is insulated from thermal damage and is sent for pathologic examination. Small sessile polyps may also be removed by excisional biopsy without fulguration. This is especially useful for small polyps in the proximal colon where biopsy fulguration has been associated with a higher frequency of post-polypectomy bleeding. Large sessile polyps with a broad base present more of a challenge to the endoscopist. In certain situations these large polyps may be removed with several applications of the snare cautery. Currently a new technique known as saline-assisted polypectomy may also be used for large sessile polyps. With this method, saline is first injected below the mucosa to lift the polyp up and off of the colonic wall before snare polypectomy. The saline injection provides a protective cushion that decreases the potential risk of post-polypectomy perforation. Large sessile polyps that cannot be removed safely or completely by endoscopy may be referred for surgical resection. Colonoscopic polypectomy is a safe technique with an acceptably low complication rate. Post-polypectomy perforation or major bleeding occurs in approximately 0.1 to 0.2 percent of cases. Follow-up colonoscopy is usually recommended after removal of one or more adenomatous polyps to decrease the patient's risk of developing colorectal cancer. The National Polyp Study38 recently demonstrated that surveillance colonoscopy can be safely deferred for three years after the complete colonoscopic removal of all colorectal adenomas. In that study 1,418 patients were randomly assigned after colonoscopic clearance of all adenomas to follow-up surveillance colonoscopy either at one and three years or at three years only. There was no difference (3.3 percent in both groups) in those found to have adenomas with advanced pathology (larger than 1 cm, severe dysplasia, or invasive cancer). After complete colonoscopic resection of an adenoma containing severe or high-grade dysplasia (carcinoma in situ) a three-year surveillance interval is recommended. Since pathologic studies of adenomatous polyps have shown that the lymphatic channels do not penetrate above the level of the muscularis mucosa,39 polyps with severely dysplastic cells limited to the mucosa are not at risk for lymph node metastases. Follow-up of patients after colonoscopic resection of these polyps has revealed no adverse outcome.40 In individual cases of patients who have had colonoscopic polypectomy of adenomas, earlier follow-up may be recommended after an incomplete polypectomy, removal of a very large sessile polyp, excision of multiple adenomas, or a suboptimal examination resulting from poor bowel preparation. A malignant colorectal polyp is an adenoma that contains invasive cancer, defined as malignant cells that have invaded down through the muscularis mucosa into the submucosa. Prior studies have reported that approximately five percent of endoscopically resected adenomas are malignant;41 however, recent data from the National Polyp Study have found this figure to be only two percent (Zauber, A: The National Polyp Study data, personal communication). Malignant polyps may be pedunculated or sessile. Although their gross appearance is generally not distinguishable from that of other benign polyps, colonoscopic findings that may suggest malignancy include irregularity of the polyp surface, ulceration, firmness when pushed with the biopsy forceps, a broad or deformed stalk, or excessive friability. In contrast to an adenoma with high-grade dysplasia, cancer cells in a malignant polyp are no longer limited to the mucosa; therefore, they do have the potential to metastasize. For this reason, after colonoscopic removal of a malignant polyp one must consider the need for surgical referral. This decision includes consideration of the risks of possibly leaving behind residual malignant disease at the polypectomy site and of lymph node metastases versus the surgical risks of laparotomy and bowel resection. Several important risk factors are used to guide the decision for surgical resection after colonoscopic removal of a malignant polyp. Favorable criteria include a well or moderately well differentiated adenocarcinoma, no venous or lymphatic invasion, a polyp resection margin that is clear of malignant cells, and colonoscopic assessment of a complete resection. Unfavorable criteria include a poorly differentiated adenocarcinoma, venous or lymphatic invasion (or both), malignant cells close to the resection margin, and colonoscopic assessment of an incomplete or questionably complete resection. The most common unfavorable finding is detection of cancer cells at or close to the margin of resection.42 A review of colonoscopically resected malignant polyps from the Cleveland Clinic by Cranley and colleagues, combined with their review of the literature, showed that the risk of residual cancer or lymph node metastases in polyps with favorable criteria was 0.3 percent for pedunculated polyps and 1.5 percent for sessile polyps.42 The mortality of elective colorectal surgery is approximately one to two percent; however, operative risk may be lower for young patients and higher for the elderly with significant comorbid medical conditions. After colonoscopic removal of a pedunculated malignant polyp with favorable risk criteria, because the risk of surgery is greater than that of having residual cancer or lymph node metastases, surgical resection is generally not indicated. In the case of a young otherwise healthy individual, however, surgery may be considered because operative risk is minimal and the patient may not accept even the most remote chance of residual disease or lymphatic spread. In contrast, after colonoscopic removal of a pedunculated malignant polyp demonstrating unfavorable risk criteria, patients are considered for surgical resection, unless they are poor surgical candidates. Controversy exists in the management of the sessile malignant polyp. In contrast to the pedunculated polyp, in which the submucosa extends out into the polyp stalk and head, in the sessile polyp the invasive cancer cells, by definition, invade into the submucosa of the colonic wall. Some physicians recommend surgery for all sessile malignant polyps, even if they demonstrate favorable risk characteristics, because they believe that the sessile morphology in and of itself increases the patient's risk of having residual disease.43, 44 Others believe that there is not enough evidence to support sessile morphology as an absolute indication for surgical resection in all cases. One group's review of the literature concluded that malignant polyps with favorable risk factors, whether pedunculated or sessile, did not differ in their risk of residual disease or lymph node metastases, and therefore suggested that small sessile polyps with favorable risk characteristics that did not have extensive malignant invasion and did not require piecemeal resection do not require surgical resection.45 Our approach to the management of the sessile malignant polyp with favorable risk criteria is that colonoscopic polypectomy alone is adequate treatment for most patients; however, the decision must be individualized for each patient. For the sessile malignant polyp with unfavorable risk characteristics our approach is the same as that for the pedunculated malignant polyp. At colonoscopy, when a polyp is found that is suggestive of malignancy, the endoscopist first assesses whether or not it is endoscopically resectable. Pedunculated and small sessile polyps may be completely resected, whereas very large sessile lesions undergo biopsy. When a polyp is removed, all tissue is retrieved and sent for pathologic evaluation. Polyp location is always carefully documented because if the polyp is found to be malignant and shows unfavorable risk characteristics, surgical resection may be necessary. At colonoscopy, India ink may be injected into the bowel wall at the polypectomy site to create a permanent localization marker for possible subsequent surgical resection. After colonoscopic removal of a malignant polyp with favorable risk criteria, a follow-up colonoscopy is generally performed in about three to six months to assess the polypectomy site for completeness of removal, particularly if the polyp was sessile. If residual cancer is found, the individual is referred for surgical resection, provided that the patient is a good surgical candidate. If there is no residual cancer, a one-year follow-up colonoscopy may be performed; if this examination has negative findings, it may be repeated again in three years. Additional clinical follow-up with radiographic imaging and other tests may be appropriate in select patients. Hyperplastic polyps account for the majority of non-neoplastic colorectal polyps. They are entirely benign and have no malignant potential. Autopsy and screening colonoscopy studies report prevalence rates of 20 to 34 percent.7, 9, 15, 16 Hyper-plastic polyps, predominantly located in the distal colon and rectum, are commonly found at sigmoidoscopy. A report of screening flexible sigmoidoscopy in 400 patients showed a prevalence rate of 30 percent. 46 Hyperplastic polyps generally appear as small (0.5 cm or less), sessile, flat or convex lesions that are relatively pale or the same color as the surrounding normal colorectal mucosa. Although most hyperplastic polyps are small, not every small polyp is hyperplastic. In a study of 1,048 colonoscopically removed small (0.1 to 0.6 cm) polyps only 20 percent were hyperplastic, compared with 61 percent neoplastic adenomas.47 Histologically, hyperplastic polyps demonstrate a characteristic extensive papillary infolding of their epithelial cells that results in elongated crypts and, at low power, a distin