different signature pattern of somatic mutations.6

Figure 67-1. Proposed sequence of molecular genetic events in the evolution of colon cancer. Carcinomas arise from an

accumulation of events whose sequence has been defined for two of the carcinogenesis pathways. As illustrated here, tumors

progress through the adenoma-to-carcinoma sequence along pathways marked by chromosomal instability (CIN) or microsatellite

instability (MSI). At least one more pathway, characterized by promoter methylation of tumor-suppressor genes, serrated polyps,

and cancers with variable degrees of microsatellite instability, is incompletely understood, and not shown here. ACF, aberrant

crypt focus; TGF, transforming growth factor. (After Grady WM. Genomic instability and colon cancer. Cancer Metastasis Rev

2004;23:11; Grady WM, Carethers JM. Genomic and epigenetic instabilility in colorectal cancer progression. Gastroenterology

2008;135:1079–1099.)

The major form of hypermutation occurs when the DNA mismatch repair (MMR) system is

inactivated. Germline mutations in the DNA MMR genes MSH2, MLH1, MSH6, and PMS2 cause Lynch

syndrome, which historically was called HNPCC.7 In the hereditary CRC syndromes, germline mutations

inactivate one copy of the gene, and the other allele is inactivated by a “somatic” genetic event that

occurs locally in an individual colonic epithelial cell. Loss of DNA MMR results in a diffuse mutational

signature in the tumor called microsatellite instability, or MSI. This defect leads to the mutational

inactivation of several key genes important for maintaining normal cellular behavior. The transforming

growth factor-β receptor II (TGF-βRII) gene, for example, is mutated in 85% of MSI colorectal cancers.

This inactivates the receptor, renders the cell unresponsive to TGF-β, and permits it to escape normal

growth regulation. The MSI multistep carcinogenesis pathway to tumor development is seen in about

15% of all colorectal cancers,8 and progression from adenoma to carcinoma occurs in a shorter time

period than occurs in the chromosomal instability pathway seen in most colorectal cancers, which is

thought to require 10 to 20 years. MSI colorectal neoplasms appear to account for two clinical

observations. First, the MSI pathway may account for the occurrence of cancers 1 or 2 years after a

negative colonoscopy (“interval cancers”). Second, it may account for the relatively small number of

adenomatous polyps found with MSI, since they may evolve into cancer in a shorter timeframe than

usually occurs.

Histopathology and Malignant Potential

Adenomatous polyps are characterized according to their physical features, size, glandular structure, and

degree of dysplasia, which all have important implications for clinical management. Polyps may be

sessile, with a broad-based attachment to the colonic wall, or pedunculated, attached to the colonic wall

by way of a fibrovascular stalk (Fig. 67-2). Whether a polyp is sessile or pedunculated previously

determines whether the endoscopist can remove the polyp completely by snare polypectomy. Newer

endoscopic techniques such as endomucosal resection (EMR) and endomucosal dissection (ESD) have

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now allowed for resection of most sessile polyps. Diminutive polyps that measure 5 mm or less in

diameter are not likely to contain high-grade dysplasia or invasive carcinoma. Malignant potential

increases with polyp size in all histologic groups of adenoma.

Adenomas are classified histologically according to their glandular structure. Aberrant (dysplastic)

crypts and microadenomas may be the earliest lesions detected in the flat mucosa of patients at risk.

These enlarge and progress to macroscopic adenomatous polyps. Tubular adenomas are characterized by

a complex network of branching adenomatous glands, whereas villous adenomas contain fronds or folds

of mucosa that have overgrown their underlying stroma and project toward the colonic lumen (Fig. 67-

3). Often, both histologic types coexist in a mixed tubulovillous adenoma.

All conventional adenomas, by definition, consist of dysplastic mucosa. The term dysplasia refers to

abnormalities in crypt architecture (such as irregular branching or crowded “back-to-back” glands) and

cytologic detail (enlarged, pleomorphic, and hyperchromatic nuclei with multiple mitoses and

pseudostratification; Fig. 67-4). Dysplasia may be mild, moderate, or severe, depending on the degree

to which these characteristics are present. Severe, or high-grade, dysplasia represents carcinoma in situ

when the basement membrane has not been invaded. Extension into the lamina propria denotes

intramucosal carcinoma. Invasion into the muscularis mucosae defines invasive carcinoma and the

malignant polyp. The degree of dysplasia usually correlates with polyp size and the extent of villous

architecture. Occasionally, nonmalignant adenomatous mucosa can be displaced below the muscularis

mucosae, probably due to trauma associated with colonic motility. This must be distinguished from

malignant invasion and is termed pseudoinvasion.

Figure 67-2. Mucosal polyps of the colon may be sessile, protruding directly from the colonic wall, or pedunculated, extending

from the mucosa through a fibrovascular stalk. A: Large sessile polyp seen at colonoscopy. The polyp has a broad-based attachment

to the mucosa. B: Pedunculated polyp seen at colonoscopy. The polyp is attached to the mucosa through a distinct stalk. C: Lowpower photomicrograph of a pedunculated polyp (a tubular adenoma) cut in cross section to demonstrate its fibrovascular stalk

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(S).

It is now recognized that some serrated polyps (characterized by a “saw-tooth” pattern of colonic

crypts) may be precursors to carcinoma.9 HPs are typically small (diminutive polyps <5 mm) and are

usually located in the distal colon and rectum. These are the most common type of serrated polyps (30%

to 40% of all polyps and 80% to 90% of serrated polyps), and do not appear to have direct malignant

potential. SSAs are distinct from conventional adenomas with respect to histology and molecular

biology, and are typically nondysplastic. SSAs are characterized by distorted crypt bases and crypt

dilation (Fig. 67-5) and by migration of the proliferative zone to the side of the crypt. SSAs are

associated with BRAF mutations and CIMP, which can lead to epigenetic silencing of MMR genes such as

MLH1, resulting in MSI. SSAs are typically right-sided, often flat (Fig. 67-5A), and may be covered by a

so-called “mucous cap” (Fig. 67-5B). TSAs are the least common form of serrated lesion. They have

villiform features and are typically protuberant or pedunculated left-sided lesions which contain areas of

dysplasia. TSAs commonly have KRAS mutations and may give rise to microsatellite stable cancers.

Serrated polyposis syndrome is a syndrome characterized by multiple serrated polyps (Fig. 67-5D).9–11

These polyps are most often SSAs, but HPs and TSAs may also occur in this setting. The exact genetic

defect and actual risk of malignancy associated with this syndrome are unknown.

Even though nearly all adenocarcinomas of the colon and rectum arise in adenomatous polyps, not all

polyps evolve into carcinoma; in fact, most do not. The malignant potential of adenomatous polyps is

related to polyp size and the histologic characteristics. Large polyps and those with predominantly

villous architecture are more likely to contain coincident carcinoma (Fig. 67-6). These features are

interdependent, however, because large polyps are more likely to be villous and dysplastic. Adenomas

that measure 0.5 cm or less are most often tubular adenomas and rarely contain severe dysplasia or

carcinoma (<0.5% in autopsy series). Likewise, only 1% to 2% of adenomatous polyps smaller than 1

cm contain carcinoma, but autopsy studies suggest that as many as 40% of adenomas greater than 2 cm

contain cancer. Data derived from the examination of colonoscopic polypectomy specimens indicate

similar trends but suggest a lower incidence of cancer-containing polyps.

Figure 67-3. Histology of adenomatous polyps. A: Tubular adenomas are characterized by a complex network of branching

adenomatous glands (see also C). B: Villous adenomas consist of glands that extend straight down from the surface to the base as

fingerlike projections; this pattern may be suggested by the gross appearance of these polyps. C: Tubulovillous adenoma.

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Figure 67-4. Moderate dysplasia. Dysplastic mucosa is characterized by crowded, irregular glands and cells with enlarged,

hyperchromatic nuclei of varied size and shape that do not line up uniformly on the basement membrane (pseudopalisading).

Adenomas are composed of dysplastic mucosa in which the degree of atypia may vary. These changes precede the development of

invasive carcinoma.

Epidemiology

Prevalence

The descriptive epidemiology of adenomatous polyps of the colon and rectum parallels that of colorectal

carcinoma with relation to geographic distribution, age, prevalence, and genetic susceptibility. Like

colorectal cancer, adenomas are common in Western countries such as the United States, but their

prevalence traditionally has been low in parts of Asia (notably India), South America, and sub-Saharan

Africa. Epidemiologic patterns for both adenomas and carcinomas are shifting with the acquisition of a

“Western” lifestyle in many areas, particularly in Korea, Japan, and parts of Southeast Asia. Estimates of

adenoma prevalence in the United States vary depending on the mode of data collection. Data from

older studies were collected from autopsies and sometimes grouped all polyps together, whereas more

recent studies have examined adenoma prevalence in the context of endoscopic screening. Studies using

colonoscopy previously suggested an adenoma prevalence in patients without symptoms who are older

than 50 years that ranges between 20% and 40%. More recent data from colonoscopies, where quality

measures such as optimized cleansing preparations and withdrawal times have been employed, suggest

adenoma detection rates (ADRs) which may exceed 50%.12 Based on autopsy studies, one-half to twothirds of people older than 65 years have colonic adenomas. Adenoma prevalence increases with age in

all populations. Age-associated prevalence rates suggest that adenomas precede carcinomas in a given

population by at least 5 to 10 years; it may be much longer, as polyps do not produce symptoms and,

unlike cancers, dating the onset can only be estimated. Advancing age also correlates with multiplicity

of polyps, polyp size, and higher degrees of dysplasia. In addition, 30% to 50% of patients with one

adenoma have a synchronous adenoma elsewhere in the colon.13

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Figure 67-5. Sessile serrated adenomas are often flat lesions located in the right colon (A). They may be obscured by “mucous

caps” (B). Histologically they are characterized by a serrated surface epithelium, distorted crypt bases (C) and crypt dilation.

Serrated polyposis syndrome presents with multiple serrated polyps (D).

Heredity

2 Heredity plays a role not only in FAP and Lynch syndrome but also in the development of sporadic

adenomas. Sporadic (nonsyndromic) adenomatous polyps and colon cancers represent more than 95% of

colorectal neoplasms. Clinical studies, including case-control and prospective analyses, indicate a two- to

threefold increased risk for colon cancer among first-degree relatives of patients with a history of

colonic adenoma or carcinoma. The relative risk increases when there are more affected relatives and

when adenomas and carcinomas occur in young relatives. The impact of family history becomes

prognostically insignificant in patients whose polyps are discovered after age 60. In most families, it is

not possible to separate the impact of commonly shared genes from the impact of shared environmental

exposures.

Anatomic Distribution

Autopsy series and colonoscopic examination of patients who do not have symptoms previously

suggested that although adenomas are uniformly distributed throughout the colon, the distribution of

clinically important larger adenomas is more similar to that of carcinomas, with a left-sided

predominance. There appears to have been a “migration” over the past few decades, toward right-sided

lesions in Western countries; 75% to 90% of SSAs are right sided, as are about 90% of sporadic CRCs

with MSI.

Natural History

3 Adenomas are common in people older than 50 years, and although most carcinomas arise in

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adenomatous polyps, relatively few adenomas progress to carcinoma. Little precise information is

available on what proportion of adenomas evolves to carcinomas. In Norway, an example of a high-risk

Western population, it has been estimated that colorectal adenomas are present in 29% of the

population older than 35 years. The conversion rate from adenoma to carcinoma in this group (based on

cancer incidence from multiple tumor registries) has been calculated to be 0.25% per year. In other

words, the risk that a colorectal cancer will develop in a polyp-bearing person within 10 years is 2.5%.

The annual conversion rates to invasive cancer for people with adenomas larger than 1 cm, villous

components, and severe dysplasia have been estimated to be 3%, 17%, and 37%, respectively, based on

these inferences. Data from a national colonoscopy database in Germany suggested that the annual

transition rates from advanced adenoma (adenomas ≥1 cm, tubulovillous or villous adenomas,

adenomas with high-grade dysplasia) to cancer is comparable among women and men, but strongly

increases with age.14 Projected annual transition rates from advanced adenoma to cancer increased from

2.6% in age group 55 to 59 years to 5.1% in age group 80 and older among men, for example. These

estimated rates in older age groups are in line with previous estimates derived from small case series

but are considerably lower for younger age groups.

Figure 67-6. The relation of adenoma size and histology to malignant potential based on an analysis of 7,000 endoscopically

removed polyps. The incidence of polyp-associated carcinoma determined from examination of polypectomy specimens is lower

than that derived from early autopsy studies. (Data derived from Shinya H, Wolff WI. Morphology, anatomic distribution, and

cancer potential of colonic polyps. Ann Surg 1979;1990:675.)

Both longitudinal follow-up of a small number of people with unresected adenomas and studies of age

distribution provide indirect evidence that the evolution from adenoma to carcinoma takes at least 5 to

10 years. Age prevalence data from the National Polyp Study (NPS), for example, suggest that it may

take as long as 5 to 10 years for normal-appearing mucosa to develop into a macroscopically visible

adenomatous polyp, and an additional 3 to 5 years for invasive carcinoma to develop, in most instances.

Case-control studies also support that the development of adenomas in the colon and the evolution to

carcinoma occur slowly. Several studies, including the NPS, have estimated that the significant

protective effect of screening endoscopy may last at least 10 years.15 The risk and rate of progression of

SSAs is not as well documented. It has been postulated that the evolution of SSAs to invasive carcinoma

may take place in a shorter period of time than the conventional adenoma to carcinoma sequence, but

this remains to be firmly established.

Associated Disease States

A number of clinical situations have been associated with a greater than average risk for adenoma

development, but the evidence in most cases is tenuous. Although adenomas and carcinomas develop

frequently in patients who have undergone urinary diversion by way of ureterosigmoidoscopy, this is

largely of historical interest. Nonetheless, patients who have undergone this procedure require periodic

colonoscopic surveillance for adenoma and carcinoma development. An increased prevalence of colonic

adenomas and carcinomas has been reported in patients with acromegaly, and patients with elevated

gastrin levels have been reported to be at increased risk for colorectal neoplasia. Alleged associations

between colorectal adenomas and a history of prior cholecystectomy, atherosclerosis, acrochordons

(skin tags), and HPs remain unproven.

Clinical Features

Adenomatous polyps of the colon and rectum are highly prevalent in Western societies, but most

patients with colonic adenomas do not have symptoms directly referable to these lesions. Overt

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