Figure 67-10. Diagram representation of cancer-containing polyps. Pedunculated adenoma is described on the left and a sessile

adenoma on the right. In carcinoma in situ, malignant cells are confined to the mucosa. These lesions are adequately treated by

endoscopic polypectomy. Polypectomy is adequate treatment for invasive carcinoma only if the margin is sufficient (2 mm), the

carcinoma is not poorly differentiated, and no evidence of venous or lymphatic invasion is found. (After Haggitt RC, Glotzbach RE,

Soffen EE, et al. Prognostic factors in colorectal carcinomas arising in adenomas: implications for lesions removed by endoscopic

polypectomy. Gastroenterology 1985;89:328.)

Primary Prevention of Adenoma Recurrence

Primary prevention relates to the ability of identifying genetic, environmental, and biologic factors that

cause cancer, and to mitigate their outcomes. Laboratory, clinical, and epidemiologic evidence suggests

that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, is associated

with a substantially decreased risk for the development of colorectal cancer. Four published trials have

demonstrated a reduction in adenoma recurrence in chemoprevention trials involving aspirin.50,51 Given

the biologic plausibility, preclinical in vitro and animal data, and data on adenoma regression in

patients with FAP, three large randomized trials, which studied over 6,000 patients in total, were

undertaken to examine the effect of cyclooxygenase-2 (COX-2)–selective inhibitors on new adenoma

formation in individuals with a history of sporadic adenomas. All of these trials demonstrated a highly

significant reduction in new adenoma formation in those taking a COX-2–selective inhibitor (celecoxib

or rofecoxib) compared to placebo over 3 years. In the Adenoma Prevention with Celecoxib (APC)

trial,52 the use of celecoxib was associated with a dose-dependent 33% to 45% reduction in the

development of new adenomas by 3 years, with a 57% to 66% reduction in the number of patients

developing advanced adenomas. Unfortunately, adverse thrombotic cardiovascular events were

associated with COX-2 inhibition in two of these trials. Recent data suggest that increased

cardiovascular risk may be associated with most NSAIDs, and not just COX-2 inhibitors.

Other agents currently undergoing study for chemoprevention of colorectal neoplasia include the

ornithine decarboxylase inhibitor difluoromethylornithine (DFMO), the bile acid ursodiol, the 3-

hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors such as pravastatin and

lovastatin, epidermal growth factor receptor (EGFR) inhibitors, and matrix metalloproteinase (MMP)

inhibitors. The combination of DFMO and the NSAID sulindac were studied in a randomized placebocontrolled trial to assess their efficacy in preventing sporadic adenoma recurrence in 375 subjects. The

use of this regimen was associated with a 70% reduction in new adenomas at 3 years compared to

placebo.53 Larger studies are underway to confirm this result and to fully assess toxicity of this

combination. A population-based case-control study of individuals with colorectal cancer and matched

controls demonstrated a 47% relative reduction of colorectal cancer associated with statin use, but

further investigation is needed to assess the overall benefits of this group of agents.

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Figure 67-11. Invasive carcinoma in the stalk of an adenomatous polyp. A: Low-power view. Malignant glands can be seen

invading fibrovascular stalk. B: High-power magnification of malignant glands in stalk. Nuclei are large, hyperpigmented, and

crowded.

Supplemental calcium reduces proliferative activity in the mucosa of experimental animals and

patients at high risk for the development of colorectal cancer. A large body of observational and

laboratory studies suggests a role for dietary calcium supplementation in chemoprevention. A

prospective, double-blind, placebo-controlled trial showed that supplemental calcium (3,000 mg of

calcium carbonate per day, equivalent to 1,200 mg of elemental calcium) reduced the incidence and

number of recurrent adenomas in subjects with a recent history of such lesions. The protective effect of

calcium supplementation on the risk of colorectal adenoma recurrence extended up to 5 years after

cessation of active treatment, even in the absence of continued supplementation.54 Analysis of serum

vitamin D status in subjects suggested that calcium supplementation and vitamin D status appear to act

together to reduce the risk of adenoma recurrence. A prospective trial designed to assess the individual

effects of calcium and vitamin D and the combination on adenoma recurrence, however, failed to

demonstrate an effect of any of these agents.

“Essential” fatty acids are required for biologic processes, but cannot be synthesized by humans and

must therefore be obtained from dietary sources. The main polyunsaturated fatty acids (PUFAs)

docosahexaenoic acid (DHA, 22:6∆4,7,10,13,16,19) and eicosapentaenoic acid (EPA, 20:5∆5,8,11,14,17) are

considered “essential” and are obtained predominantly from cold water oily fish such as mackerel and

salmon. A randomized trial in subjects with FAP demonstrated that an enteric-coated formulation of

EPA has chemopreventive efficacy in reducing rectal polyp burden to a degree similar to that previously

observed with selective COX-2 inhibitors.55 The role for N-3 PUFAs in “sporadic” colorectal adenoma

prevention is currently being evaluated.

Trials of supplemental dietary fiber, as well as antioxidant vitamins such as β-carotene and vitamins C

and E, have not convincingly demonstrated any effect on adenoma recurrence.

OTHER MUCOSAL SUBMUCOSAL POLYPS

Hyperplastic Polyps

HPs are small, usually sessile lesions most frequently encountered in the distal colon and rectum (Fig.

67-12A). Although grossly indistinguishable from small adenomas, they carry no significant potential for

malignant degeneration particularly when located in the distal colon or rectum. However, HPs must be

distinguished from SSAs, which carry significant malignant potential. Macroscopically, HPs are almost

always less than 1 cm in size, and most are in the distal colon. In fact, when HPs are found proximal to

the rectosigmoid region, one must consider the possibility that this is actually an SSA. Microscopically,

HPs are characterized by a saw-toothed epithelial pattern representing micropapillary luminal infoldings

of columnar absorptive cells and mature, frequently hyperdistended goblet cells (Fig. 67-12B).

Elongation and subsequent infolding of the epithelium may be caused by an expanded, but otherwise

normally located, replication zone in the crypt. The cytologic atypia characteristic of adenomatous

polyps is not seen in these lesions.

HPs are common age-related lesions found in about one-third of the population older than 50 years.

Although they often coexist with adenomas in polyp-bearing patients, no convincing evidence has been

found that HPs per se are harbingers of adenoma development. Because HPs are asymptomatic and carry

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no malignant potential, no specific treatment is required for these lesions. If an HP is the only lesion

detected on index-flexible sigmoidoscopy or colonoscopy, no further evaluation is indicated.

Sessile Serrated Adenomas

SSAs or SSPs – the terms are essentially interchangeable – are distinct from conventional adenomas with

respect to histology and molecular biology, and are typically nondysplastic in appearance (Fig. 67-5),

but may contain areas of dysplasia or intramucosal carcinoma. They are characterized by the serrated

appearance of the surface epithelium (common to all serrated lesions), distorted crypt bases and crypt

dilation, and by migration of the proliferative zone to the side of the crypt. SSAs represent 3% to 22%

of serrated lesions and 75% to 90% of SSAs are right-sided.9 They are often flat (>90%), and may be

covered by a so-called “mucous cap.” These features often make endoscopic detection difficult,

emphasizing the importance of high-quality endoscopy including an excellent bowel preparation and

adequate withdrawal times to yield high polyp detection rates. These polyps are thought to be the

precursors of sporadic (non-Lynch syndrome) colorectal cancers with MSI, which are overwhelmingly

found in the proximal colon.

Figure 67-12. Hyperplastic polyps. A: Several diminutive hyperplastic polyps seen in the rectum during flexible sigmoidoscopy. B:

Photomicrograph of a hyperplastic polyp, characterized by elongated glands with papillary infoldings that have a typical serrated

epithelial pattern.

Figure 67-13. Inflammatory polyps. A: Severe mucosal inflammation with infiltrates and granulation tissue shown here

microscopically can appear clinically with a polypoid configuration. B: Resolution of inflammation can leave exuberant polyps

covered by normal epithelium, which are called pseudopolyps, a misnomer. These are truly polyps, but are not neoplastic.

Juvenile Polyps

Juvenile polyps can occur sporadically or as part of a juvenile polyposis syndrome (JPS). These mucosal

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polyps consist of dilated cystic mucus-filled glands and abundant lamina propria with an inflammatory

infiltrate. Seventy-five percent of these occur in children younger than 10 years of age, often appearing

as single pedunculated cherry-red polyps with a smooth surface and contour. The exact prevalence of

such lesions has not been determined, but they are thought to be acquired lesions detectable in about

2% of children. Juvenile polyps often present with hematochezia because they are highly vascularized

lesions. Rectal prolapse and auto-amputation may occur with distal lesions, whereas intussusception

may be precipitated by proximal juvenile polyps, particularly in the context of familial syndromes.

Individually, these polyps have no malignant potential, but symptomatic polyps should be removed to

prevent further complications. Juvenile polyposis, on the other hand, is associated with an increased

risk for the early development of cancer.

Inflammatory Polyps

Inflammatory mucosal polyps are common in the setting of idiopathic inflammatory bowel disease.

Marked inflammation and ulceration coexist with granulation tissue in a distorted mucosal architecture

that appears polypoid because of confluent areas of ulceration, leaving behind islands of intact

epithelium (Fig. 67-13A). Subsequent healing leads to the appearance of polypoid, nonneoplastic

excrescences covered by normal colonic epithelium, and are called “pseudopolyps,” in spite of the fact

that they are truly polypoid excrescences (Fig. 67-13B). They need not be removed and are important

largely because they make it difficult to recognize subtle, early neoplastic lesions in these high-risk

patients. Severe chronic inflammation of any kind, including a variety of infectious diseases

(tuberculosis, amebiasis, schistosomiasis, and amebic colitis), may result in inflammatory polyps that

resemble those found in idiopathic inflammatory bowel disease.

Submucosal Polyps

Submucosal masses can expand to push the colonic mucosa into the bowel lumen and thus appear as

polypoid lesions. Many submucosal lesions (e.g., lipomas, leiomyomas) are clinically asymptomatic and

must be differentiated from neoplastic lesions. Others are malignant lesions that require early detection,

such as lymphomas and metastatic tumors. Many submucosal lesions are not detected on endoscopic

mucosal biopsy because standard biopsy forceps do not reach beyond the mucosa. If a submucosal lesion

is suspected, multiple biopsy specimens of the same site sometimes provide tissue for diagnosis.

Lipomas are benign fatty tumors that occur throughout the gastrointestinal tract but are most

commonly found in the cecum near the ileocecal valve (Fig. 67-14). They appear endoscopically as soft,

smooth polyps that are pliable and deformable. The overlying mucosa is intact but may be light yellow

in appearance. These are benign lesions that have little clinical significance and are more commonly

seen in obese patients.

Isolated lymphoid nodules consisting of benign lymphoid tissue may appear as sessile smooth polyps of

various sizes, with a predilection for the distal colon and rectum. These are usually asymptomatic.

Diffuse nodular lymphoid hyperplasia also occurs in children as an incidental finding. The nodules must

be distinguished from primary or secondary lymphoma of the large intestine, which may present as

mucosal nodularity resembling the pseudopolyposis of inflammatory bowel disease or even a familial

polyposis syndrome (Fig. 67-15). Flow cytometry of the lymphocytes in the lesion will be helpful;

benign polyposis is polyclonal, whereas lymphomas are monoclonal and may overexpress cyclin D.

Pneumatosis cystoides intestinalis consists of multiple air-filled cysts within the submucosa. This may be

an incidental finding in patients with chronic obstructive pulmonary disease, scleroderma, or an

asymptomatic pneumoperitoneum secondary to recent surgery or instrumentation, in which air or

colonic gas diffuses into the cysts. These sometimes resolve with administration of oxygen. A far more

virulent form of pneumatosis is associated with fulminant mucosal inflammation, ischemia, or

necrotizing enterocolitis in children. These cysts are thought to result from mucosal invasion by gasproducing bacteria.

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