Polyps of the Large Intestine

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Chapter 22

Polyps of the Large Intestine

Jason L. Hornick

Robert D. Odze

Introduction

Flexible sigmoidoscopy and colonoscopy frequently reveal polypoid lesions that are either sampled or removed endoscopically. Broadly speaking, the term polyp refers to any localized projection above the surrounding colonic mucosa. The vast majority of colorectal polyps may be categorized as inflammatory, hamartomatous, or epithelial. In addition, polyps may develop from mesenchymal proliferations, benign or malignant hematolymphoid tissue, metastatic tumors, and a wide variety of non-neoplastic substances, such as air. The relative proportions of these various types of polyps depend on the type of population undergoing endoscopy (e.g., age, associated risk factors such as inflammatory bowel disease [IBD] or polyposis syndrome) and the method of investigation (e.g., sigmoidoscopy versus total colonoscopy), but hyperplastic and adenomatous polyps are by far the most common types. In one study of 1050 colonic polyps, 82% were adenomatous, 12% were hyperplastic, 3% were inflammatory, and only 1.5% were mesenchymal polyps such as lipomas and leiomyomas.1

Inflammatory Polyps

Inflammatory polyps are defined as intraluminal projections of mucosa that are formed of a non-neoplastic mixture of stromal and epithelial components and inflammatory cells. These include inflammatory “pseudopolyps,” which may or may not be related to IBD; prolapse-type inflammatory polyps and their many variants; and inflammatory myoglandular polyps.

Inflammatory Pseudopolyp

Inflammatory pseudopolyps represent areas of inflamed and regenerating mucosa that project above the level of the surrounding mucosa, which is frequently ulcerated. They generally develop as a response to either localized or diffuse inflammatory diseases (e.g., Crohn’s disease, ulcerative colitis), but they also occur in association with other disorders, such as ischemic colitis,2 neonatal necrotizing enterocolitis,3 and infectious colitis,4 and they commonly form at the edges of intestinal ulcers and mucosal anastomoses. The pathogenesis is related to full-thickness ulceration of the mucosa, followed by inflammation and regenerative hyperplasia of the intervening nonulcerated epithelium. In rare cases, the patient may have no apparent underlying inflammatory disorder.

Pathologic Features

Grossly, inflammatory pseudopolyps may be sessile or pedunculated. They are almost always smaller than 2 cm, but so-called giant inflammatory polyps may grow to large sizes and cause obstruction.5,6 Filiform polyposis refers to the presence of numerous dense, filamentous polyps that can project several centimeters above the surrounding mucosa (Fig. 22.1).7 This form of polyposis is usually associated with IBD or, rarely, juvenile polyposis.

Histologically, some polyps, particularly those adjacent to ulcers or anastomotic sites, are formed entirely, or almost entirely, by inflamed granulation tissue. However, most inflammatory pseudopolyps are composed of a mixture of inflamed lamina propria and distorted colonic epithelium; surface erosions may or may not be present (Fig. 22.2). Colonic crypts are often dilated, branched, and hyperplastic, and neutrophilic cryptitis and crypt abscesses may be prominent. In the later stages of development, inflammatory polyps may consist of many finger-like projections of normal or near-normal mucosa surrounding a core of submucosal tissue.

Three potential pitfalls can occur in the histologic evaluation of inflammatory pseudopolyps. First, dysplasia may rarely develop in these lesions, particularly in those associated with IBD. Much more commonly, regenerating epithelium can be extreme, particularly in inflamed or eroded areas, simulating a neoplastic process. Careful attention to surface maturation, which is usually observed in regenerating epithelium and almost never in dysplasia, can help in making this distinction in difficult cases. Second, bizarrely shaped, enlarged, or multinucleated stromal cells that can mimic sarcoma (termed “pseudosarcoma”) may develop in inflammatory pseudopolyps.8 These cells may be spindled or epithelioid, and they often aggregate at the surface of the polyp, underneath areas of ulceration and granulation tissue (Fig. 22.3).

Finally, in many instances, the histologic appearance of inflammatory pseudopolyps may be indistinguishable from that of juvenile polyps. Distinction between these two types of lesions is based largely on clinical information, such as the age of the patient (almost all such polyps in young children are juvenile polyps), the presence or absence of a clinical history of a hamartomatous polyposis syndrome (juvenile polyposis, Cowden disease, and Bannayan-Riley-Ruvalcaba syndrome [BRRS] can all have juvenile-type polyps),9 and the presence or absence of an underlying inflammatory disorder.

Natural History and Treatment

Inflammatory pseudopolyps tend to persist even after healing of the surrounding mucosa has taken place. They are frequently found in quiescent ulcerative colitis. These polyps have no increased tendency for neoplastic transformation. Treatment is usually directed at the underlying inflammatory condition. Rarely, surgical excision is indicated when large or numerous polyps cause symptoms due to bleeding or obstruction.5

Prolapse-Type Inflammatory Polyp

Mucosal prolapse syndrome was proposed by du Boulay and colleagues in 1983 as a unifying term for the clinicopathologic abnormalities underlying solitary rectal ulcer syndrome and related entities.10 However, prolapse-type inflammatory polyps more commonly develop as a result of localized protuberances of mucosa unrelated to the solitary rectal ulcer syndrome. The pathogenesis in all instances is related to traction, distortion, and twisting of mucosa caused by peristalsis-induced trauma; this leads to torsion of blood vessels and tissue damage, localized ischemia, and repair in the form of lamina propria fibrosis. Depending on the anatomic location of the injury and the underlying cause, these polyps may be referred to as inflammatory cloacogenic polyps of the anal transitional zone, inflammatory cap polyps, colitis cystica polyposa, or diverticular disease–associated polyps. All demonstrate some overlapping histologic abnormalities that are usually the result of mucosal prolapse.11 Inflammatory cap polyps, colitis cystica profunda, and diverticular disease–associated polyps are described in detail in later sections.

Additionally, solitary or multiple polyps that demonstrate common histopathologic features of mucosal prolapse have been variably called polypoid prolapsing mucosal folds11 or prolapse-induced inflammatory polyps.12 The classic histologic features of prolapse-induced inflammatory polyps include (1) a variable degree of fibromuscular hyperplasia of the lamina propria; (2) thickening, splaying, and vertical extension of the muscularis mucosae into the lamina propria; (3) crypt abnormalities (e.g., elongation, hyperplasia, architectural distortion, serration); and (4) a variable degree of inflammation, ulceration, and reactive epithelial change (Fig. 22.4).11,12

Inflammatory Cap Polyp (and Cap Polyposis)

Inflammatory cap polyps were first described in abstract form in 1985 by Williams and co-workers.13 These rare lesions usually occur in the setting of cap polyposis, in which dozens of these types of polyps develop. There is no sex predilection, and they occur over a wide age range.14 Clinically, patients with cap polyposis often are seen with diarrhea, mucoid stools, gastrointestinal (GI) bleeding, and/or tenesmus. Occasionally, these symptoms are accompanied by severe hypoproteinemia. A direct loss of protein from cap polyps was confirmed in one 54-year-old woman by scintigraphy with the aid of technetium 99m–labeled diethylenetriaminepentaacetic acid (DTPA) complexed to human serum albumin.15

Endoscopically, most cap polyps are small, sessile or semipedunculated lesions that range in size from a few millimeters to 2 cm. The most common location is the rectum or rectosigmoid; less commonly, the descending colon is involved.16–19 Rarely, cap polyps may involve the entire colon and even the stomach.14,20 Multiple polyps are typically located at the crests of mucosal folds, separated by normal or edematous mucosa.

Histologically, cap polyps are non-neoplastic lesions composed of elongated, dilated, or tortuous hyperplastic colonic crypts with abundant inflammation in the lamina propria and a characteristic “cap” of inflamed and ulcerated granulation tissue (Fig. 22.5). Goblet cells of cap polyps have been shown by immunohistochemistry to express nonsulfated mucins.21 The intervening lamina propria typically contains increased acute and chronic inflammatory cells. The endoscopic “cap” is composed of an inflammatory exudate. Some polyps contain splayed smooth muscle fibers or fibrosis suggestive of a mucosal prolapse etiology.14,17

Many patients with multiple polyps require surgical resection for resolution of their symptoms,16,18,19 although some patients improve spontaneously14 or with therapy to eradicate Helicobacter pylori infection.20 Infliximab may also be effective therapy for cap polypsis.22 Isolated polyps are treated by simple polypectomy.

Colitis Cystica Profunda/Polyposa

Clinical Features

Colitis cystica profunda is a rare benign condition characterized by cystic dilatation and misplacement of mature crypts through the muscularis mucosae into the submucosa or deeper layers of the bowel wall. The term colitis cystica polyposa was first used by Virchow in 1863 to describe a case in which multiple polypoid lesions were produced by submucosal cysts.23 The term colitis cystica profunda subsequently came into use in 195724; most affected patients have both submucosal cysts and associated polypoid lesions. Similar lesions are found in the stomach (gastritis cystica profunda), where they are most frequently occur after Billroth II gastrectomy,25 and in the small bowel (enteritis cystica profunda), where they are often associated with Peutz-Jeghers syndrome (PJS).26

Rarely, colitis cystica profunda occurs as an isolated lesion (or lesions) in a patient with an otherwise apparently normal colon.27,28 However, most cases are associated with some form of colonic abnormality—most commonly, the solitary rectal ulcer syndrome,23,29,30 in which the lesions are located in the rectosigmoid. Distal lesions (sometimes called proctitis cystica profunda) have also been reported in paraplegics,31 in patients with self-inflicted rectal trauma,32 and in patients with postirradiation colonic strictures.33,34 Less commonly, a diffuse form of colitis cystica profunda occurs in patients with IBD (including ulcerative colitis, Crohn’s disease,35 and unclassified forms36) or infectious dysentery.23

The pathogenesis of colitis cystica profunda is believed to be related to prolapse and subsequent torsion and trauma of the mucosa and submucosa that leads to vascular compromise and ischemia.23 In solitary rectal ulcer syndrome (see Chapter 17), mucosal prolapse results in ischemia and ulceration by virtue of traction exerted on blood vessels.23 However, in colitis cystica profunda associated with infectious or idiopathic IBD, the pathologic changes probably occur as a result of misplacement and entrapment of regenerating glands in the submucosa during the process of reepithelialization and healing of ulcers.

Guest and Reznick23 reviewed the clinical features of 144 cases of colitis cystica profunda. Patients ranged in age from 4 to 76 years (median, 30 years). Males and females were approximately equally affected. The most common presenting symptoms were blood in the stool (68%), mucoid stools (43%), diarrhea (27%), tenesmus (13%), and abdominal discomfort (12%).23 Rarely, patients may be seen with obstruction.27

Pathologic Features

Grossly, colitis cystica profunda can be a focal, segmental, or diffuse lesion. Focal and segmental lesions can mimic invasive adenocarcinoma. Transrectal ultrasonography and other imaging modalities may aid in making the distinction by demonstrating multiple cysts limited to the submucosa and lack of lymph node involvement in the colitis cystica profunda lesion.37

Histologically, the condition is characterized by the presence of multiple cystically dilated, mucin-filled crypts in the submucosa and occasionally in the muscularis propria or serosa. The stroma surrounding misplaced crypts usually consists of lamina propria; this is helpful in distinguishing it from adenocarcinoma, which typically has a desmoplastic stroma. Furthermore, misplaced glands in colitis cystica profunda often grow in a lobular configuration without jagged borders or the unusual, irregularly shaped glandular profiles characteristic of adenocarcinoma. Misplaced crypts typically show either normal or reactive-appearing colonic epithelium. A mild degree of mucin depletion, pseudostratification, and increased mitotic activity may be observed as well. However, loss of nuclear polarity, an increased nucleus-to-cytoplasm (N : C) ratio, and atypical mitoses should alert one to the possibility of adenocarcinoma. Lamina propria surrounding misplaced glands and lack of dysplastic-appearing epithelium are key features that help distinguish colitis cystica profunda from invasive adenocarcinoma (Table 22.1; Fig. 22.6).

In many patients with rectal prolapse, treatment of the defecation disorder itself (e.g., education to avoid straining at defecation, a high-fiber diet, bulk laxatives) leads to remission of colitis cystica profunda.29 Some patients require surgical resection because of obstruction,27 confusion with carcinoma, severe symptoms, or coexist­ent IBD.36

Diverticular Disease–Associated Polyp

Polyps that occur in association with diverticulosis are of two types: inverted diverticula and polypoid prolapsing mucosal folds. Polyps of the former type have been described in patients with inverted Meckel diverticula of the ileum (wherein they may cause intussusception),38 isolated inverted colonic diverticula, or inverted sigmoid diverticula in the setting of sigmoid diverticulosis.39,40 Inverted colonic diverticula usually range from 0.2 to 2 cm. They may be sessile or pedunculated but characteristically have the same color as the surrounding mucosa.40 These polyps tend to vanish with gentle pressure from the biopsy forceps or from air insufflation at endoscopy.40 Bowel perforation may occur as a result of endoscopic polypectomy in cases in which the inverted diverticulum mimics an adenoma.40

Polypoid prolapsing mucosal folds are the more common form of diverticular disease–associated polyps. Grossly, these appear as bright red, polypoid, or slightly elevated patches of mucosa in patients with sigmoid diverticulosis.41 Swollen mucosal folds seen between diverticular ostia may reveal an apical brown discoloration. More advanced lesions characteristically show small, brownish, polypoid protrusions of the mucosal folds. Polyps normally range from 0.5 to 3 cm.

Histologically, early lesions show vascular congestion, hemorrhage, and hemosiderin deposition. More advanced lesions reveal edema, capillary thrombi, lamina propria fibrosis, and crypt architectural changes such as dilatation and branching. The most advanced, “leaflike” polyps show changes typically seen in mucosal prolapse, such as smooth muscle ingrowth into the lamina propria, crypt hyperplasia, mucin depletion, and serrated hyperplastic changes of the epithelium. Epithelial hyperplasia may be marked and should not be mistaken for an adenoma.42 Rarely, one may see pseudosarcomatous changes of the stroma, characterized by enlarged and hyperchromatic myofibroblasts that should not be mistaken for sarcoma.42

Redundant mucosal folds occur in a large majority (90% to 100%) of patients with advanced sigmoid diverticulosis, although only a minority develop grossly polypoid lesions or frank prolapse-like histologic alterations of the mucosa (Fig. 22.7).43,44 Thickening of the taenia coli, which leads to shortening of the sigmoid, is believed to be the initiating pathogenetic event in the development of these lesions.

Patients with diverticular disease–associated polyps may develop chronic low-grade blood loss.45 Treatment is similar to that for diverticulosis in general and in many instances has been shown to result in regression of polyps.45

Inflammatory Myoglandular Polyp

Inflammatory myoglandular polyps were described by Nakamura and associates in 1992.46 They are rare, often underrecognized lesions. Among the 32 cases reported by Nakamura’s group, most polyps were solitary and located in the sigmoid colon (18 cases); the remainder were distributed among the transverse colon (8 cases), descending colon (3 cases), and rectum (3 cases). An inflammatory myoglandular polyp of the terminal ileum has also been reported.47 The most common symptom is occult or overt rectal bleeding.46 Affected patients are predominantly male, with a wide age range (15 to 78 years).46 The pathogenesis of these lesions is controversial. Chronic trauma and mucosal prolapse have been proposed as etiologic possibilities. However, some authors believe that these polyps represent a type of hamartoma.

Grossly, inflammatory myoglandular polyps range from 0.4 to 2.5 cm.46 Most are pedunculated and spherical and contain a smooth surface, either with or without surface erosion.48 The cut surface typically contains scattered mucin-filled cysts set within a dark brown stroma.46 Histologically, these polyps are composed of a treelike network of radially arranged smooth muscle, similar to Peutz-Jeghers polyps. Hyperplastic and cystically dilated crypts are typical (Fig. 22.8). At the periphery or surface of the polyp, one often finds luminal fibrinoinflammatory exudate and granulation tissue. The surface epithelium may appear regenerative, with a serrated or hyperplastic appearance, and may show mucin depletion. Frequently, hemosiderin deposition is noted within the lamina propria, reflecting areas of mucosal erosion and hemorrhage.46

The main features distinguishing juvenile polyps from inflammatory myoglandular polyps are the younger mean age of patients with juvenile polyps and the presence of only a trace amount of smooth muscle within the lamina propria of juvenile polyps. In contrast to inflammatory myoglandular polyps, Peutz-Jeghers polyps do not typically reveal surface erosions or a granulation tissue reaction. However, in some isolated cases, distinction between these entities may not be possible solely on histologic grounds.

Hamartomatous Polyps

Hamartomas are defined as overgrowths of cells and tissues native to the anatomic location in which they occur. In the GI tract, hamartomas typically incorporate both stromal and epithelial components. Hamartomas are most often solitary but may occur as part of a hamartomatous polyposis syndrome such as juvenile polyposis syndrome (JPS), PJS, Cowden syndrome, or the BRRS. Because of genotypic and phenotypic overlap between Cowden disease and BRRS, these two conditions likely represent variations of the same entity (known as PTEN hamartoma tumor syndrome).49–52 Cronkhite-Canada syndrome, another form of GI polyposis, is believed to have an inflammatory rather than a genetic basis, but it is discussed in this section because of its histologic resemblance to JPS.

In aggregate, the hamartomatous polyposis syndromes account for less than 1% of the annual incidence of colorectal carcinoma in the United States and Canada.52 Isolated sporadic juvenile polyps and (less commonly) Peutz-Jeghers polyps also occur, but these have essentially no malignant potential.

Juvenile Polyps and Juvenile Polyposis

Clinical Features

Juvenile polyps occur in four distinct settings: sporadic or isolated juvenile polyps of the colon, infantile JPS, juvenile polyposis coli, and generalized JPS (involving the stomach, small bowel, and colon) (Table 22.2).53 Sporadic or isolated juvenile polyps are the most common type of colon polyp among patients in the first decade of life, occurring in 2% of the pediatric population,9 but they are not uncommonly detected in adults as well. One study reported a mean age at occurrence of 5.9 years.54 Children usually are seen with either painless rectal bleeding or prolapse of the polyp through the rectum.54 Adults, if they are symptomatic at all, often are seen with rectal bleeding.

First described in 1964 by McColl and co-workers,55 JPS is the most common GI hamartomatous polyposis syndrome. Separation of isolated juvenile polyps in childhood from JPS is important because of their divergent clinical behaviors and neoplastic risks (discussed later).53 Criteria for JPS are controversial and are rapidly evolving with the advent of newer molecular diagnostic techniques. At this point, the diagnosis should be suggested in any patient who has (1) any number of polyps in probands with a family history of JPS, (2) polyposis involving the entire GI tract, or (3) three or more colonic juvenile polyps. (This last figure has ranged from 3 to 10 polyps according to various diagnostic algorithms.53,56) Hamartomas do not occur outside the GI tract, but congenital birth defects are reported in 15% of JPS patients; these include malrotation of the gut and cardiac and genitourinary defects.53

In 1998, linkage analysis in a large Iowa kindred demonstrated that a gene for familial JPS maps to chromosome 18q21.1, a region containing both the DCC and the SMAD4 (DPC4, MADH4) tumor suppressor genes.57 Germline truncating mutations in SMAD4 were shown to be responsible for a subset of JPS patients.58 In 2001, germline mutations in the gene encoding bone morphogenic protein receptor 1A, BMPR1A, were also reported in JPS families lacking SMAD4 mutations.59 SMAD4 mutations account for 15% to 20% of patients with JPS, and BMPR1A mutations are found in 20% to 25% of JPS patients,53,60,61 suggesting that there is additional (as yet undefined) genetic heterogeneity in JPS. ENG mutations have now been reported in a small number of patients with JPS.62 Patients harboring SMAD4 mutations have a higher risk of generalized JPS,53 including massive gastric polyposis.63 Although JPS is transmitted in an autosomal dominant fashion, 25% of newly diagnosed patients have no family history and likely represent de novo mutations.49

JPS of infancy is a rare disorder with a poor prognosis that typically manifests in the first 2 years of life as generalized polyposis complicated by GI bleeding, diarrhea, rectal prolapse, and/or protein-losing enteropathy.53 Unlike conventional JPS, no family history is found in JPS of infancy. In 2006, Delnatte and colleagues reported that four patients with JPS of infancy were heterozygous for a de novo germline deletion of chromosome 10q, including the PTEN and BMPR1A genes, providing the first evidence of a genetic basis for this disorder.64

Pathologic Features

Isolated juvenile polyps are most common in the rectosigmoid colon (54%). However, 37% of patients have polyps proximal to the splenic flexure.54 In juvenile polyposis coli (polyps limited to the colon), polyps are most common in the rectosigmoid region and typically number as high as 200 (Fig. 22.9). The classic form of juvenile polyp (Fig. 22.10), found most frequently in isolated cases, is unilobulated and has a smooth, round surface contour. Histologically, these polyps are characterized by numerous cystic and dilated, often tortuous, crypts, some filled with neutrophils and inspissated mucin (which reflects the older term, mucous retention polyp). The intervening lamina propria is edematous and expanded by lymphocytes and plasma cells and occasional neutrophils and eosinophils. A few strands of muscle fibers may be present as well. In ulcerated cases, the epithelium may be markedly regenerative in appearance, simulating dysplasia. In patients with JPS, both classic (typical) and nonclassic (atypical) polyps are usually found. Nonclassic polyps (Fig. 22.11) are often larger, multilobulated, and villiform, frequently giving the gross appearance of several polyps attached to a single stalk. Histologically, compared with typical cases, they contain less abundant lamina propria and greater epithelial overgrowth, with many elongated, tortuous, and irregularly shaped crypts.65 The clonal origin of both the epithelium and the fibroblasts in juvenile polyps from SMAD4 mutation carriers has been shown by fluorescence in situ hybridization.66

Patients with JPS may have a combination of other types of polyps as well. Ganglioneuromatous proliferation of mature ganglion cells and nerve bundles may occur in the mucosa and the submucosa of polyps.67 Many patients also have separate adenomas or polyps with combined features of a juvenile polyp and an adenoma/dysplasia.68,69 In fact, true dysplasia (Fig. 22.12) has been detected in as much as 30% of polyps of JPS patients,65,70 but it is almost never observed in patients with isolated juvenile polyps. Gupta and associates reported dysplasia in only 1 of 331 juvenile polyps from 184 nonpolyposis patients.54

Natural History and Treatment

Patients with sporadic juvenile polyps have no increased risk for malignancy.71,72 Furthermore, they are not predisposed to the development of new juvenile polyps, and they do not require any particular type of follow-up.71 In contrast, estimates of the risk of GI carcinoma in JPS have varied widely. In one large kindred, the risk of upper and/or lower GI cancer in affected patients was 55%.73 In 1995, Desai and colleagues, in a reevaluation of data from the St. Mark’s Polyposis Registry, projected that the incidence of colorectal carcinoma through age 60 years was 68% (see Table 22.2).74 Surveillance recommendations should take into account the risks of both lower and upper tract cancer, including gastric cancer. Upper and lower endoscopy (including visualization of the entire colon) is usually recommended by age 15 years and should be repeated annually. Endoscopic polypectomies and histologic examination of all removed polyps should be performed until the patient is free of polyps, at which point the surveillance interval may be lengthened to 3 years. Consideration should be given to prophylactic gastrectomy or colectomy if diffuse polyposis cannot be controlled by endoscopic polypectomy or if there is a family history of GI carcinoma or dysplasia.75

Peutz-Jeghers Syndrome

Clinical Features

PJS is an autosomal dominant syndrome that is characterized by mucocutaneous pigmentation; distinctive hamartomatous polyps of the small intestine, colon, and stomach; and an increased risk for both intestinal and extraintestinal malignancies (see Chapters 20 and 21

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