Histologic Features

Adenomatous polyps are tumors of benign neoplastic epithelium that can either be pedunculated (i.e., attached by a stalk) or sessile (i.e., attached by a broad base with little or no stalk). The neoplastic nature of adenomas is apparent by histologic examination of their glandular architecture. Tubular adenomas are the most common subgroup and are characterized by a complex network of branching adenomatous glands (Fig. 122-1A). In villous adenomas, the adenomatous glands extend straight down from the surface to the center of the polyp, thereby creating long, finger-like projections (see Fig. 122-1B). Tubulovillous (villoglandular) adenomas manifest a combination of these two histologic types.

Figure 122-1. Comparison of tubular and villous histology. A, Tubular adenomas consist of branched, crowded glands arranged in a complex cerebriform pattern. B, Villous adenomas consist of glands that are long, finger-like fronds typically projecting from the polyp stroma to the surface without much branching.

(Courtesy of Noam Harpaz, MD, PhD, New York.)

A polyp is assigned a histologic type on the basis of its predominant glandular pattern, and in practice, pure villous adenomas are quite rare. According to the World Health Organization, adenomas are classified as tubular if at least 80% of the glands are of the branching, tubule type and as villous if at least 80% of the glands are villiform.¹ Of all adenomatous polyps, tubular adenomas account for 80% to 86%, tubulovillous for 8% to 16%, and villous adenomas for 3% to 16%.^2,3 Tubular adenomas usually are small and exhibit mild dysplasia, whereas villous architecture is more often encountered in large adenomas and tends to be associated with more severe degrees of dysplasia (Table 122-2).

By definition, all colorectal adenomas are dysplastic. Adenomatous epithelium is characterized by abnormal cellular differentiation and renewal, resulting in hypercellularity of colonic crypts with cells that possess variable amounts of mucin and that are hyperchromatic, with elongated nuclei arranged in a picket-fence pattern. These cytologic alterations confer an increased basophilic appearance to the adenomatous epithelium on conventional hematoxylin-eosin staining. Although the predominant cell type is an immature goblet cell or columnar cell, adenomas can contain other cell types, such as neuroendocrine cells, Paneth cells, squamous morules, and, rarely, melanocytes. On cross section, the inner contour of an adenomatous gland lumen usually is smooth, in contrast to the serrated appearance of a hyperplastic gland lumen (see later).

The dysplasia exhibited by all adenomas can be graded subjectively on the basis of certain cytologic and architectural features into three categories: mild, moderate, and severe. Some polyps contain the entire spectrum from mild to severe dysplasia, but in all cases, the adenoma is classified according to its most dysplastic focus. In cells that exhibit mild dysplasia, the nuclei in the cell maintain their basal polarity but are hyperchromatic, slightly enlarged, and elongated, yet uniform in size, without prominent nucleoli (Fig. 122-2A). There often is loss of goblet cell mucin. Architecturally, the glands manifest branching and budding and become more crowded. With moderate dysplasia, nuclei become stratified and pleomorphic, with prominent nucleoli, along with further loss of goblet cell mucin and increased glandular crowding. Severe dysplasia (see Fig. 122-2B) is characterized by further stratification and pleomorphism of nuclei, more numerous and prominent nucleoli, increased nucleus-to-cytoplasm ratios, and extreme glandular crowding.

Figure 122-2. Comparison of low-grade dysplasia (LGD) and high-grade dysplasia (HGD). A, LGD is characterized by branching crypts lined by cells with long, thin nuclei that begin to stratify, resulting in an increased nucleus-to-cytoplasm ratio and a loss of normal goblet cells. These changes occupy the entire crypt, including the surface epithelium. B, Adenoma with HGD and intramucosal carcinoma. This photomicrograph shows a section of adenoma with crypts demonstrating HGD (right, arrowheads). There is nuclear pleomorphism and abnormal cellular polarity resulting in a cribriform appearance (i.e., glands within glands). A focus of intramucosal carcinoma is seen in the center (arrows), characterized by cells with pleomorphic nuclei and poor gland formation that are located in the lamina propria.

(Courtesy Noam Harpaz, MD, PhD, New York.)

With further cell proliferation within the crypt, cells pile up, lose polarity, and create glands within glands, giving a disorderly cribriform appearance termed carcinoma in situ (see Fig. 122-2B). Most pathologists group severe dysplasia and carcinoma in situ, considering them both high-grade dysplasia²; one reason for this grouping is to avoid using the term carcinoma for these lesions because they often can be managed endoscopically rather than surgically (see later). Indeed, it is now common practice to categorize dysplasia in colorectal adenomas into only two grades: low-grade dysplasia, which includes mild and moderate dysplasia, and high-grade dysplasia, which comprises severe dysplasia and carcinoma in situ.

Carcinoma in situ is characterized by intracryptal cell proliferation that leaves intact the basement membrane surrounding the gland. If a focus of neoplastic cells grows beyond the basement membrane and into the lamina propria of the mucosa, the lesion is termed intramucosal carcinoma (see Fig. 122-2B). Both carcinoma in situ and intramucosal carcinoma are noninvasive lesions without metastatic potential, because lymphatics are not present in the colonic mucosa above the level of the muscularis mucosae.⁴ Because clinical confusion often arises on encountering these two entities, it has been suggested that both carcinoma in situ and intramucosal carcinoma be reported as “noninvasive carcinoma” to avoid unnecessarily aggressive management. Only when a focus of neoplastic cells has spread through the muscularis mucosae is the lesion considered invasive carcinoma (Fig. 122-3). An adenoma that contains a focus of invasive carcinoma commonly is referred to as a malignant polyp (see later).

Figure 122-3. Histopathology of a malignant polyp. This pedunculated adenoma demonstrates tubulovillous histology on the surface. The entire stalk of the polyp (center, arrows) contains numerous malignant glands representing well-differentiated adenocarcinoma. Unlike the adenomatous glands on the surface, many of the invasive glands demonstrate sharply angulated edges.

(Courtesy of Noam Harpaz, MD, PhD, New York.)

Of all adenomatous polyps, mild dysplasia is found in 70% to 86% moderate dysplasia in 18% to 20%, severe dysplasia (carcinoma in situ) in 5% to 10%, and invasive carcinoma in 5% to 7%.^3,5,6 Higher grades of dysplasia are more common in adenomas of larger size and greater villous content,² and adenomas with severe dysplasia are more likely to contain foci of invasive cancer.

Adenoma Size

Adenomas are categorized into three size groups: less than 1 cm, 1 to 2 cm, and greater than 2 cm.⁵ Overall, most adenomas are smaller than 1 cm, but the size distribution of adenomas can vary greatly among studies, depending on study design, age of the study population, and location of the adenomas within the colon. Thus, in autopsy series, which describe a presumably asymptomatic population dying of other causes, only 13% to 16% of adenomas are larger than 1 cm,^7–9 whereas surgical and colonoscopic series that include symptomatic or higher-risk patients report a higher prevalence (26% to 40%) of adenomas larger than 1 cm.^2,3,5 In countries where the prevalence of colon cancer is high, adenomas tend to be larger than in low-prevalence countries.^10,11 Adenoma size increases as a function of age,^8,12,13 even in low-prevalence countries,¹⁰ and larger adenomas are more common in distal colonic segments.^2,5,8

Diminutive Polyps

Diminutive polyps measure 5 mm or less in diameter and are commonly encountered during endoscopy. An earlier concept that these lesions were almost always non-neoplastic has been revised based on several flexible sigmoidoscopic and colonoscopic studies in which 30% to 50% of diminutive polyps were found to be adenomatous^14–18; despite the frequency of adenomatous change, however, they represent little if any threat of cancer. Earlier studies found that less than 1% of diminutive polyps were villous or contained a focus of severe dysplasia and that they almost never harbored invasive carcinoma.^14–16,18 In an analysis of 4381 diminutive polyps, 4.4% contained severe dysplasia or villous components, although still only 0.1% had invasive carcinoma.¹⁹ Moreover, in a retrospective study of predominantly asymptomatic people with diminutive adenomas found on flexible sigmoidoscopy, full colonoscopy identified a synchronous proximal adenoma in only 33% of subjects, and most of the proximal lesions were smaller than 5 mm.²⁰ Likewise, prospective colonoscopic studies confirm only a 24% to 34% prevalence of proximal adenomas in asymptomatic patients with distal diminutive polyps (of all histologic types)^21,22; the likelihood of finding proximal adenomas is greater when the distal polyp is larger than 5 mm.²¹ Diminutive adenomas manifest little, if any, appreciable growth over time.^23,24 A population-based study that involved fulgurating small polyps (even those up to 1 cm) without obtaining initial histologic identification reported that the subsequent risk for colorectal cancer and overall survival was no worse than in the general population.²⁵

Thus, taken together, these observations indicate that diminutive polyps, even when they prove to be adenomas, have little biologic or clinical significance. Nonetheless, the fact that these tiny polyps often are missed by computed tomographic (CT) colonography (or virtual colonoscopy; see later) has provided some fuel to the debate over the safety of leaving these lesions undetected. An important exception to the rule of the innocuous nature of diminutive adenomas is in the setting of hereditary nonpolyposis colorectal cancer (HNPCC), in which even small adenomas can display advanced pathologic features such as villous histology or high-grade dysplasia (see later).

Malignant Potential of Adenomatous Polyps

The three principal features that correlate with malignant potential for an adenomatous polyp are size, histologic type, and degree of dysplasia (Table 122-3). Although higher rates of malignant transformation are found when the source of the pathologic material is mainly from surgical polypectomies⁵ rather than colonoscopic polypectomies,⁶ the malignant potential is correlated directly with larger adenoma size, more villous histology, and higher degrees of dysplasia. These three histopathologic criteria usually are interdependent, so it is difficult to assign a primary premalignant role to any one of them. For example, although only 1.3% of all adenomas smaller than 1 cm harbor a cancer (see Table 122-3), if these small lesions have a predominant villous component or contain a focus of severe dysplasia, the cancer rate rises to 10% or 27%, respectively (Table 122-4). A small (<1 cm), tubular, mildly dysplastic adenoma is highly unlikely to harbor a focus of invasive cancer. Nonetheless, although this type of lesion is innocuous in itself, once removed, it often is considered a marker of a person who is at (low) risk for developing a recurrent adenoma (discussed later). Because adenomas that are larger than 1 cm, have villous architecture, or manifest high-grade dysplasia or carcinoma represent a more biologically hazardous group, the term adenoma with advanced pathology (AAP) often is applied to adenomas that display any of these features.

Other Adenoma Variants

Histogenesis

Adenomatous polyps are thought to arise from a failure in a step, or steps, of the normal process of cell proliferation and cell death (apoptosis). The initial aberration appears to arise in a single colonic crypt in which the proliferative compartment, instead of being confined to the crypt base, is expanded throughout the entire crypt. This disturbance results in a unicryptal adenoma. The DNA-synthesizing cells at the surface are not sloughed into the lumen, as normally occurs, and they accumulate in a downward infolding manner, interposing themselves between normal preexisting crypts. New adenomatous glands then are created either by further infolding or by branching. Thus, the unicryptal adenoma is believed to arise from a monoclonal expansion of an abnormal cell, and as the adenoma enlarges, the adenomatous cell population becomes polyclonal. Evidence for this concept comes from studying intestinal tissues from an extremely rare patient with FAP who was an XO/XY mosaic.⁴⁴ Analysis of Y chromosome expression in the intestinal mucosa of this patient revealed that normal crypts of the small and large intestine and even unicryptal adenomas were monoclonal (either XO or XY), whereas at least 76% of very small microadenomas were polyclonal. Whether the same situation also applies to sporadic adenoma development is not clear at present.

Adenoma-Carcinoma Hypothesis

It is generally accepted that most, if not all, colon cancers originate within previously benign adenomas. Rarely, colon cancers develop de novo in apparently flat, nonadenomatous epithelium although, as noted earlier, even these lesions might conceivably arise from preexisting flat adenomas, or serrated polyps. Evidence in support of the adenoma-carcinoma sequence comes from epidemiologic, clinical, pathologic, and molecular studies.

Pathways of Colon Carcinogenesis

It is useful to consider the process of colon carcinogenesis in two general stages: the formation of the adenoma, termed tumor initiation, and the progression of the adenoma to carcinoma, termed tumor progression (Fig. 122-4). It is believed that most, if not all, adenomas arise from an initial loss of APC gene function, and for that to happen, epithelial cells must lose the function of both APC alleles (two hits). In patients with FAP, one APC allele is inherited in a mutated form (germline mutation) from the affected parent. Adenomas arise when the second, normal copy of the APC gene from the unaffected parent either is lost or mutated (somatic mutation). Because persons with FAP are born with the first hit, they develop polyps at a much younger age and in much greater number than does the general population; thus, FAP can be considered a condition of accelerated tumor initiation. Despite this abnormal initiation rate, once adenomas form in patients with FAP, it is believed that each adenoma tends to display a normal progression to carcinoma. Thus, the inevitable progression to cancer in FAP is more a consequence of the numerous polyps than of any increased premalignant potential of the individual adenoma. In the general population, sporadic adenomas arise as a consequence of two acquired somatic mutations of the APC gene. Because two acquired hits are statistically less likely than one acquired hit, sporadic adenomas tend to occur later in life and to be fewer than the polyps in patients with FAP.

Figure 122-4. Pathways of colon carcinogenesis. Adenomas develop as a consequence of factors involved in initiating tumors, and they progress to carcinomas because of factors that act as tumor promoters. A simplified theory comparing the two hereditary colon cancer syndromes suggests that the adenoma-initiation phase is accelerated in patients with familial adenomatous polyposis (FAP), accounting for numerous polyps. In contrast, the adenoma progression phase is accelerated in hereditary nonpolyposis colorectal cancer (HNPCC) patients, accounting for the often rapid progression of adenomas to carcinoma. APC, adenomatous polyposis coli; DCC, deleted in colon cancer.

Another major molecular pathway for colon carcinogenesis involves mutations in DNA MMR genes (see Chapter 123); this is the predominant pathway in patients with HNPCC. Mutations in these enzymes result in a characteristic molecular phenotype termed microsatellite instability (MSI), a phenomenon that is observable in colon cancer cells from approximately 85% of HNPCC colon cancers but in only 15% of sporadic colon cancers. Although its name implies a lack of polyps, HNPCC colon cancers do arise from preexisting adenomas. It is believed that the numbers of adenomas that occur in patients with HNPCC are similar to those in the general population but that HNPCC is marked by an accelerated tumor progression stage, so the few adenomas that do arise often manifest advanced pathology (villous features, high-grade dysplasia) even at small sizes.⁵³ Indeed, adenomas in patients with HNPCC often manifest MSI⁵⁴ even in their earliest stages of formation. Because these adenomas tend to progress more rapidly to carcinoma,^55,56 surveillance intervals for colonoscopy following removal of adenomas in HNPCC patients should be shortened (see later; see also Chapter 123).

Prevalence

The prevalence of adenomatous polyps is affected by four major factors: the inherent risk for colon cancer in the population, age, sex, and family history of colorectal cancer. The frequency of colon adenomas varies widely among populations, but it tends to be higher in populations at greater risk for colon cancer (Table 122-5).¹⁰ One illustrative example is to compare the very high adenoma prevalence in Japanese living in Hawaii (a very high risk area for colon cancer) with the much lower adenoma prevalence in Japanese who still reside in Japan, an area of much lower risk. Even within Japan itself, adenoma prevalence correlates quite well with colon cancer prevalence in different prefectures of the country. Data from autopsy series provide an approximation of adenoma prevalence. In populations at low risk for colon cancer, adenoma prevalence rates are lower than 12% (see Table 122-5), whereas in most intermediate- and high-risk populations, adenomas are found in 30% to 40% of the population, and rates as high as 50% to 60% have been observed.^7,57 One half to two thirds of people older than 65 years in high-risk areas can harbor colonic adenomas.^7,57

The true prevalence rate of adenomatous polyps within an asymptomatic population is only now being elucidated because, until recently, colonoscopy was not performed on healthy persons in the absence of gastrointestinal symptoms. Approximately 27% to 32% of asymptomatic average-risk persons older than 50 years undergoing screening colonoscopy will have an adenoma, and 6% to 10% will have an AAP (Table 122-6).^58–61 By comparison, colonoscopic screening of asymptomatic persons between 40 and 49 years of age revealed prevalence rates of only 8.7% for tubular adenomas and 3.5% for AAP or cancer.⁶² Colonoscopic series indicate that men have a 1.5 relative risk of adenomas compared with age-matched women,^62,63 thus confirming earlier observations in autopsy series.^8,11 Men also have slightly higher rates of advanced adenomas than do women, with a relative risk of approximately 1.5.⁶⁴ A large database study found a higher rate of polyps larger than 9 mm in African Americans undergoing screening colonoscopy compared with age-matched whites.⁶⁵

The prevalence of adenomas is higher in older people, particularly those older than 60 years. In fact, age is the single most important independent determinant of adenoma prevalence^{7,11,12,57,62,63,66,67} in high-risk and low-risk regions of the world (see Table 122-5). Not only is advancing age associated with a higher prevalence rate of adenomas, but it also correlates with a greater likelihood for multiple polyps, adenomas with more severe degrees of dysplasia, and, in some studies, larger adenomas.

Adenoma prevalence also is higher in persons with a family history of colorectal cancer and adenomas,^67,68 particularly if more than one relative is affected with colorectal neoplasia and if the affected relative is young.

Incidence

Estimating the incidence of new adenomas requires examining the colon at more than one point in time. Two types of endoscopic studies lend themselves to this analysis: surveillance studies following polypectomy (or following cancer resection) and interval examinations in persons who initially had a negative examination. Of course, for both types of studies, the small but measurable miss rate of adenomas can influence the rate of apparent incident adenomas (see “Detection,” later). For the purposes of this discussion, adenomas found in persons after polypectomy are considered recurrences (see “Postpolypectomy Management”), whereas those found in persons after an initial negative colonoscopy are considered incident adenomas.

The incidence of new adenomas varies from 24% to 41%.⁶³ In one study, patients underwent colonoscopy twice on the same day to clear the colon of all potentially missed adenomas, and 38% were found to have new adenomas at colonoscopy two years later.⁶⁹ Three-year follow-up sigmoidoscopy after an initial negative examination in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial found a 3.1% incidence of all adenomas and 0.8% incidence of advanced adenomas or cancer.⁷⁰ A large surveillance study looked at findings on follow-up colonoscopy performed within 5.5 years of the index colonoscopy. Patients who had one or two tubular adenomas less than 10 mm were no more likely to have advanced neoplasia than patients with negative baseline colonoscopies. In average-risk, asymptomatic persons with no adenomas at baseline colonoscopy, repeat colonoscopy within five years detects an adenoma in approximately 16% to 27%^71,72 and an AAP in approximately 1% to 2.4%.^71–73

Anatomic Distribution

The distribution of adenomatous polyps within the colon differs, depending on the method of investigation (Table 122-7). In autopsy series in which the normal distribution is approximated in presumably asymptomatic subjects, adenomas are distributed uniformly throughout the colorectum; this even distribution has been confirmed in colonoscopic investigations of asymptomatic subjects.^23,57 Large adenomas in autopsy series have a distal predominance, in the region where most colon cancers arise, thereby supporting the adenoma-carcinoma hypothesis. Likewise, adenomas detected in surgical and colonoscopic studies of symptomatic people also display a left-sided predominance, indicating that distal adenomas are more likely to come to clinical attention. In older persons, particularly those older than 60 years, distribution of adenomas demonstrates a shift toward more proximal colonic locations. This phenomenon, which is based on autopsy^11,12 and on colonoscopic studies of symptomatic⁷⁴ and asymptomatic^{22,58,59,66,75} subjects, has importance for choosing appropriate colon cancer screening approaches (see Chapter 123). Some data suggest that African Americans have a greater proportion of proximal adenomas compared with whites, especially in persons older than 60 years.⁶⁵