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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