Figure 67-14. Submucosal lipomas. A: Lipoma seen at colonoscopy. Submucosal fatty tissue causes the mucosa to protrude into the

lumen; such protrusion appears as a polyp. Overlying mucosa is smooth. B: Lipomatous infiltration of ileocecal valve seen at

colonoscopy. C: Colectomy specimen showing a large submucosal lipoma cut in cross section.

Figure 67-15. Lymphomatous polyposis of the colon. A: Colonoscopic view of B-cell lymphoma presenting as multiple colonic

polyps. B: Histology of lymphoma is one of the polyps.

Colitis cystica profunda is a rare condition in which the intestinal wall is thickened by submucosal

mucus-filled cysts of various sizes and an accumulation of fibroblasts in the lamina propria. It can

present as an ulcerating or mass lesion in the rectosigmoid in association with the solitary rectal ulcer

syndrome. Although the pathogenesis of this condition is unknown, it may result from the downward

displacement of colonic glands during trauma or chronic inflammation followed by healing. The

appearance of aberrant submucosal glandular epithelium and acellular mucous lakes must be

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distinguished from a colloid or mucinous carcinoma, because this lesion has no malignant potential.

Carcinoid tumors of the rectum appear as isolated, small, yellow-gray submucosal nodules. These are

often incidental findings during sigmoidoscopy. Most are smaller than 1 cm, have little malignant

potential, and are amenable to local excision. Lesions larger than 2 cm are more likely to be malignant

but seldom give rise to metastases. These lesions should be treated aggressively with complete excision.

Rectal carcinoid tumors are usually asymptomatic but may present with hematochezia. They are not

associated with the carcinoid syndrome. Carcinoid tumors in the proximal colon may be locally invasive

or metastasize to the liver, liberating vasoactive peptides into the systemic circulation and producing

the carcinoid syndrome.

Other lesions that can present as submucosal polyps include metastatic tumors, such as malignant

melanoma, and benign lesions, such as leiomyomas, fibromas, lymphangiomas, hemangiomas, and

endometriosis.

GASTROINTESTINAL POLYPOSIS SYNDROMES

Gastrointestinal polyposis indicates the presence of a systemic process that promotes the development

of multiple polyps throughout the gastrointestinal tract. In some instances, the polyps are located

predominantly in the colon; however, in others, polyps may be found in the stomach, small intestine,

colon, and rectum. The classification of the polyposis syndromes has traditionally been based on the

histologic characteristics of the polyps, but gradually an awareness of the genetic basis for the most

important of these syndromes has permitted more precise diagnosis and rational approaches to

treatment.

Familial Adenomatous Polyposis

4 FAP is an autosomal dominant, genetic disease characterized by the development of multiple

adenomatous polyps throughout the colon and rectum (Fig. 67-16). The polyps first appear in

adolescence, with the median age of onset being about 16 years. The number of polyps in each patient

is variable, and they increase in number and size with advancing age. The genetic basis for this disease

is an inactivating germline mutation in the APC gene. In part, the age of onset, number of polyps, and

age at which cancer develops are determined by the location of the mutation in the APC gene (Fig. 67-

17). Some mutations (located in the middle of the gene) predispose to a very large number of adenomas

(>5,000), and other mutations in the first three exons to a smaller number (<100). Additional factors

not related to the mutation on the APC gene, some genetic and some environmental, also modify the

clinical characteristics of the disease.56

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Figure 67-16. Familial adenomatous polyposis (FAP). A: Gross specimen of a resected colon from a patient with FAP. B: Sessile

and pedunculated adenomatous polyps in the colon of a patient with FAP. C: Close-up view of a profuse type of FAP, in which the

mucosa is carpeted with innumerable polyps. D: Photomicrograph demonstrating profuse FAP with both sessile and pedunculated

adenomatous polyps.

Figure 67-17. This scheme of the APC (adenomatous polyposis coli) gene illustrates the genotype–phenotype correlations. Most

mutations of APC result in premature stop codons; therefore, the site of the mutation usually indicates the relative length of the

mutant protein product. Mutations at the 5′ end of the gene produce “attenuated” FAP, a milder form of the disease. The retinal

lesions (congenital hypertrophy of retinal pigmented epithelium [CHRPE]) occur when the mutations are between exons 9 and 15.

The portion of the APC gene that binds to other cytoskeletal elements in the cell is represented at the 3′ end of the 15th exon.

Mutations in a hot spot immediately downstream from the β-catenin–binding site (between codons 1250 and 1464) result in a

more virulent, profuse form of familial adenomatous polyposis. This site is also the location of most of the acquired mutations in

sporadic colorectal neoplasms.

Gastrointestinal Features

Polyps in the stomach and small intestine develop in about 90% of patients with FAP. The gastric polyps

consist of fundic gland polyps, which are not premalignant lesions. These may appear to be dysplastic,

but in the Western world (North America and Europe), gastric cancer is rare. Gastric cancer is a

considerable diagnostic problem in FAP in Japan and Korea, however.

Small-intestinal neoplasia is not rare in FAP and principally occurs in the periampullary region of the

duodenum. Duodenal adenomatous polyps, which typically appear later than the colonic lesions, may be

multiple but tend not to carpet the proximal small intestine. The ampulla of Vater is a particular target

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for neoplastic development. With time, carcinoma develops in 5% to 10% of these patients, so that

duodenal surveillance is required. Spigelman has developed a classification system that can be used to

determine optimal surveillance for duodenal neoplasia, which is based on the number, size, and

histologic features of the duodenal polyps (Table 67-4). Adenomas and carcinomas occur in the jejunum

and ileum, but these are rare, and routine screening of the small intestine is not recommended. Polyps

in the terminal ileum may represent lymphoid aggregates rather than adenomas and should be biopsied

for diagnostic purposes.

Classically, it has been stated that the natural history of FAP is for cancer to develop at a median age

in the mid-40s. As mentioned, the development of cancer is variable and is based in part on the location

of the germline mutation in the APC gene. Colon cancer is rather unusual before 30 years of age, and

cancer may not develop in patients with the attenuated form of FAP until they are in their 50s or 60s.

Cancer occurring in the teenage years has been reported as a result of a patient who had both FAP and

Lynch syndrome. Thus, the treatment of these patients relies increasingly on a genetic characterization

of the disease.

Extraintestinal Features

Traditionally, patients with manifestations of FAP together with extraintestinal manifestations were

considered to have Gardner syndrome. It is now appreciated that families with FAP all have

extraintestinal manifestations and that no distinction can be made between families with Gardner

syndrome and those with FAP. FAP is characterized by osteomas of the mandible, skull, and long bones

and a variety of other benign soft tissue tumors, such as fibromas, lipomas (Fig. 67-18), and sebaceous

cysts, which should not be confused with the sebaceous adenomas and carcinomas seen in the Muir–

Torre syndrome variant of Lynch syndrome. Osteomas are commonly found in the skull and may be

multiple. Some of these lesions have been reported to regress and later reappear. Osteomas may also be

found in the mandible, and radiographs of the mouth may reveal impacted or supernumerary teeth.

Congenital hypertrophy of the retinal pigmented epithelium (CHRPE) is present in some families with

FAP, depending on the location of the mutation in the APC gene. CHRPE lesions may be seen in 5% of

the general population but are small and usually single. Multiple, bilateral, and large CHRPE lesions

strongly suggest FAP. It will require a slit-lamp examination and knowledgeable ophthalmologist to

make this diagnosis with confidence, as these are not readily seen in an office ophthalmoscopic

examination.

Table 67-4 Spigelman Classification for Management of Duodenal Adenomas in

Individuals with FAP

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