Colonic Polyps and Neoplastic Disease

Polyps are most common in the colon but may occur in the esophagus, stomach, or small intestine. Those without stalks are referred to as sessile. As sessile polyps enlarge, proliferation of cells adjacent to the polyp and the effects of traction on the luminal protrusion may combine to create a stalk. Polyps with stalks are termed pedunculated. In general, intestinal polyps can be classified as nonneoplastic or neoplastic. The most common neoplastic polyp is the adenoma, which has the potential to progress to cancer. Nonneoplastic colonic polyps can be further classified as inflammatory, hamartomatous, or hyperplastic.

Inflammatory Polyps

The solitary rectal ulcer syndrome is associated with a purely inflammatory polyp. Patients present with the clinical triad of rectal bleeding, mucus discharge, and an inflammatory lesion of the anterior rectal wall. The underlying cause is impaired relaxation of the anorectal sphincter, creating a sharp angle at the anterior rectal shelf. This leads to recurrent abrasion and ulceration of the overlying rectal mucosa. Chronic cycles of injury and healing produce a polypoid mass composed of inflamed and reactive mucosal tissue.

Hamartomatous Polyps

Hamartomatous polyps occur sporadically and as components of various genetically determined or acquired syndromes. Hamartomas are disorganized, tumorlike growths composed of mature cell types normally present at the site at which the polyp develops. Hamartomatous polyposis syndromes are rare, but they are important to recognize because of associated intestinal and extraintestinal manifestations and the need to screen family members.

Juvenile Polyps

Juvenile polyps are the most common type of hamartomatous polyp. They may be sporadic or syndromic. Sporadic juvenile polyps are usually solitary, but the number varies from 3 to as many as 100 in individuals with the autosomal dominant syndrome of juvenile polyposis. In adults, the sporadic form is sometimes also referred to as an inflammatory polyp, particularly when dense inflammatory infiltrates are present. The vast majority of juvenile polyps occur in children younger than 5 years of age. Juvenile polyps characteristically are located in the rectum and most manifest with rectal bleeding. In some cases, prolapse occurs and the polyp protrudes through the anal sphincter. Dysplasia occurs in a small proportion of (mostly syndrome-associated) juvenile polyps, and the juvenile polyposis syndrome is associated with an increased risk for development of adenocarcinoma within the colon and at other sites. Colectomy may be required to limit the hemorrhage associated with polyp ulceration in juvenile polyposis.

Morphology

Individual sporadic and syndromic juvenile polyps often are indistinguishable. They typically are pedunculated, smooth-surfaced, reddish lesions that are less than 3 cm in diameter and display characteristic cystic spaces on cut sections. Microscopic examination shows the spaces to be dilated glands filled with mucin and inflammatory debris. Some data suggest that mucosal hyperplasia is the initiating event in polyp development, and this mechanism is consistent with the discovery that mutations in pathways that regulate cellular growth, such as transforming growth factor-β (TGF-β) signaling, are associated with autosomal dominant juvenile polyposis.

Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome is a rare autosomal dominant disorder defined by the presence of multiple gastrointestinal hamartomatous polyps and mucocutaneous hyperpigmentation that carries an increased risk for development of several malignancies, including cancers of the colon, pancreas, breast, lung, ovaries, uterus, and testes, as well as other unusual neoplasms. Germ line loss-of-function mutations in the LKB1/STK11 gene are present in approximately half of the patients with the familial form of Peutz-Jeghers syndrome, as well as a subset of patients with the sporadic form. LKB1/STK11 encodes a tumor suppressive protein kinase that regulates cellular metabolism, yet another example of links between alterned metabolism, abnormal cell growth, and cancer risk. Intestinal polyps are most common in the small intestine, although they may also occur in the stomach and colon and, rarely, in the bladder and lungs. On gross evaluation, the polyps are large and pedunculated with a lobulated contour. Histologic examination demonstrates a characteristic arborizing network of connective tissue, smooth muscle, lamina propria, and glands lined by normal-appearing intestinal epithelium.

Hyperplastic Polyps

Colonic hyperplastic polyps are common epithelial proliferations that typically are discovered in the sixth and seventh decades of life. The pathogenesis of hyperplastic polyps is incompletely understood, but formation of these lesions is thought to result from decreased epithelial cell turnover and delayed shedding of surface epithelial cells, leading to a "pileup" of goblet cells. Although these lesions have no malignant potential, they must be distinguished from sessile serrated adenomas, histologically similar lesions that have malignant potential.

Morphology

Hyperplastic polyps are most commonly found in the left colon and typically are less than 5 mm in diameter.They are smooth, nodular protrusions of the mucosa, often on the crests of mucosal folds. They may occur singly but more frequently are multiple, particularly in the sigmoid colon and rectum. Histologically, hyperplastic polyps are composed of mature goblet and absorptive cells. The delayed shedding of these cells leads to crowding that creates the serrated surface architecture, the morphologic hallmark of these lesions.

Adenomas

The most common and clinically important neoplastic polyps are colonic adenomas, benign polyps that give rise to a majority of colorectal adenocarcinomas. Most adenomas, however, do not progress to adenocarcinoma.

Colorectal adenomas are characterized by the presence of epithelial dysplasia. These growths range from small, often pedunculated polyps to large sessile lesions. There is no gender predilection, and they are present in nearly 50% of adults living in the Western world beginning at age 50. Because these polyps are precursors to colorectal cancer, current recommendations are that all adults in the United States undergo screening colonoscopy starting at 50 years of age. Because individuals with a family history are at risk for developing colon cancer earlier in life, they are typically screened at least 10 years before the youngest age at which a relative was diagnosed. While adenomas are less common in Asia, their frequency has risen (in parallel with an increasing incidence of colorectal adenocarcinoma) as Western diets and lifestyles become more common.

Morphology

Typical adenomas range from 0.3 to 10 cm in diameter and can be pedunculated or sessile, with the surface of both types having a texture resembling velvet or a raspberry, due to the abnormal epithelial growth pattern. Histologically,the cytologic hallmark of epithelial dysplasia is nuclear hyperchromasia, elongation, and stratification. These changes are most easily appreciated at the surface of the adenoma, because the epithelium fails to mature as cells migrate out of the crypt. Pedunculated adenomas have slender fibromuscular stalks containing prominent blood vessels derived from the submucosa. The stalk usually is covered by nonneoplastic epithelium, but dysplastic epithelium is sometimes present.

Adenomas can be classified as tubular, tubulovillous, or villous on the basis of their architecture. These categories, however, have little clinical significance in isolation. Tubular adenomas tend to be small, pedunculated polyps composed of small, rounded, or tubular glands. By contrast, villous adenomas, which often are larger and sessile, are covered by slender villi. Tubulovillous adenomas have a mixture of tubular and villous elements. Although foci of invasion are more frequent in villous adenomas than in tubular adenomas, villous architecture alone does not increase cancer risk when polyp size is considered.

The histologic features of sessile serrated adenomas, which are also referred to as sessile serrated polyps, overlap with those of hyperplastic polyps and lack typical cytologic features of dysplasia. Nevertheless, sessile serrated adenomas, which are most common in the right colon, have a malignant potential similar to that of conventional adenomas. The most useful histologic feature that distinguishes sessile serrated adenomas from hyperplastic polyps is the presence of serrated architecture throughout the full length of the glands, including the crypt base, associated with crypt dilation and lateral growth, in the former. By contrast, serrated architecture typically is confined to the surface of hyperplastic polyps.

Although most colorectal adenomas behave in a benign fashion, a small proportion harbor invasive cancer at the time of detection. Size is the most important characteristic that correlates with risk for malignancy. For example, while cancer is extremely rare in adenomas less than 1 cm in diameter, some studies suggest that nearly 40% of lesions larger than 4 cm in diameter contain foci of invasive cancer. In addition to size, high-grade dysplasia is a risk factor for cancer in an individual polyp (but not other polyps in the same patient).

Familial Syndromes

Several syndromes associated with colonic polyps and increased rates of colon cancer have been described. The genetic basis of these disorders has been established and has greatly enhanced the current understanding of sporadic colon cancer (Table 15.7).

Familial Adenomatous Polyps

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder marked by the appearance of numerous colorectal adenomas by the teenage years. It is caused by mutations of the adenomatous polyposis coli gene (APC). A count of at least 100 polyps is necessary for a diagnosis of classic FAP, and as many as several thousand may be present (Fig. 15.35). Except for their remarkable numbers, these growths are morphologically indistinguishable from sporadic adenomas. Colorectal adenocarcinoma develops in 100% of patients with untreated FAP, often before 30 years of age. As a result, prophylactic colectomy is standard therapy for individuals carrying APC mutations. However, patients remain at risk for extraintestinal manifestations, including neoplasia at other sites. Specific APC mutations are also associated with the development of other manifestations of FAP and explain variants such as Gardner syndrome and Turcot syndrome. In addition to intestinal polyps, clinical features of Gardner syndrome, a variant of FAP, may include osteomas of the mandible, skull, and long bones; epidermal cysts; desmoid and thyroid tumors; and dental abnormalities, including unerupted and supernumerary teeth. Turcot syndrome is rarer and is characterized by intestinal adenomas and tumors of the central nervous system. Two-thirds of patients with Turcot syndrome have APC gene mutations and develop medulloblastomas. The remaining one-third have mutations in one of several genes involved in DNA repair and develop glioblastomas. Some patients with hundreds of adenomas lack APC mutations but instead have mutations of the base excision repair gene MUTYH (also called MUTYH polyposis). The role of these genes in tumor development is discussed later.

Hereditary Nonpolyposis Colorectal Cancer

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, originally was described as familial clustering of cancers at several sites including the colorectum, endometrium, stomach, ovary, ureters, brain, small bowel, hepatobiliary tract, and skin. Colon cancers in patients with HNPCC tend to occur at younger ages than do sporadic colon cancers and often are located in the right colon (Table 15.7). Adenomas are present in HNPCC, but excessive numbers (i.e., polyposis) is not. In many cases, sessile serrated adenomas are associated with HNPCC, and mucin production may be a prominent in the subsequent adenocarcinomas.

Just as identification of APC mutations in FAP has provided molecular insights into the pathogenesis of a majority of sporadic colon cancers, dissection of the defects in HNPCC has shed light on the mechanisms responsible for most of the remaining sporadic cases. HNPCC is caused by inherited germ line mutations in genes that encode proteins responsible for the detection, excision, and repair of errors that occur during DNA replication. At least five such mismatch repair genes have been recognized, but a majority of HNPCC cases involve either MSH2 or MLH1. Patients with HNPCC inherit one mutated DNA repair gene and one normal allele. When the second copy is lost through mutation or epigenetic silencing, defects in mismatch repair lead to the accumulation of mutations at rates up to 1000 times higher than normal, mostly in regions containing short repeating DNA sequences referred to as microsatellite DNA. The human genome contains approximately 50,000 to 100,000 microsatellites, which are prone to undergo expansion during DNA replication and represent the most frequent sites of mutations in HNPCC. The consequences of mismatch repair defects and the resulting microsatellite instability are discussed next in the context of colonic adenocarcinoma.

SUMMARY

COLONIC POLYPS, ADENOMAS, AND ADENOCARCINOMAS

• Intestinal polyps can be classified as nonneoplastic or neoplastic. The nonneoplastic polyps can be further defined as inflammatory, hamartomatous, or hyperplastic.

• Inflammatory polyps form as a result of chronic cycles of injury and healing.

• Hamartomatous polyps occur sporadically or as a part of genetic diseases. In the latter case, they often are associated with increased risk for malignancy.

• Hyperplastic polyps are benign epithelial proliferations most commonly found in the left colon and rectum. They are not reactive in origin, in contrast with gastric hyperplastic polyps; have no malignant potential; and must be distinguished from sessile serrated adenomas or polyps.

• Benign epithelial neoplastic polyps of the colon are termed adenomas.The hallmark feature of these lesions, which are the precursors of colonic adenocarcinomas, is cytologic dysplasia.

• In contrast with traditional adenomas,sessile serrated adenomas, or polyps, lack cytologic dysplasia and share some morphologic features with hyperplastic polyps.

• Familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) are the most common forms of familial colon cancer. FAP is caused by APC mutations, and patients typically have over 100 adenomas and develop colon cancer before 30 years of age.

• HNPCC is caused by mutations in DNA mismatch repair genes. Patients with HNPCC have far fewer polyps and develop cancer at an older age than that typical for patients with FAP but at a younger age than in patients with sporadic colon cancer.