renumbering of the coding sequence), and these carriers have a slight increase in colon cancer risk. The

Y179C variant has less enzymatic activity than G396D mutation; therefore, homozygotes with Y179C

have the most severe phenotype, followed by those with one Y179D and some other mutation, followed

by other mutations, which explain the phenotypic heterogeneity in this disease.62 Many reference

laboratories test for the three commonest MutYH mutations on DNA sent from patients with a diagnosis

of FAP if there is no detectable germline mutation (or deletion) in APC. This strategy is only rational

when dealing with European-based mutations. For non-European populations in which this diagnosis is

being considered, it is necessary to have the entire MutYH gene sequenced. MAP patients can sometimes

be managed with frequent colonoscopy when the phenotype is mild, but a colectomy or

proctocolectomy may be indicated depending upon the size and distribution of the adenomas, or in

patients who choose not to comply with regular colonoscopic surveillance.

Peutz–Jeghers Syndrome

Peutz–Jeghers syndrome is an autosomal dominant familial syndrome associated with multiple

gastrointestinal polyps and characteristic skin pigmentation. The gene responsible for this disease

encodes a serine/threonine kinase called LKB1 or STK11 (Table 67-5); carriers of the gene are highly

predisposed to a number of early-onset cancers.

Gastrointestinal Features. The gastrointestinal polyps in Peutz–Jeghers syndrome are nonneoplastic

hamartomas consisting of a supportive framework of smooth muscle tissue covered by somewhat

hyperplastic epithelium (Fig. 67-20). These are histologically distinct from juvenile polyps and show no

inflammatory cell infiltrate. Polyps may be found in the stomach, small intestine, or colon, and in each

instance they have a distinctive appearance. Peutz–Jeghers polyps can usually be identified as such by

the pathologist, and the characteristic cutaneous pigmentation makes this syndrome readily

recognizable.

Table 67-5 Genetic Alterations in Colonic Polyposis Syndromes

Skin Lesions. The cutaneous manifestations of Peutz–Jeghers syndrome may be found early in life and

consist of dark, macular lesions on the mouth (both on the skin and in the buccal mucosa), nose, lips,

hands, feet, genitalia, and anus. These lesions tend to become less obvious by the time of puberty.

Unlike ordinary freckles, the cutaneous lesions of Peutz–Jeghers syndrome are present from birth.

Moreover, ordinary freckles typically do not extend beyond the vermilion border of the lips, nor is the

buccal mucosa involved, as it is in Peutz–Jeghers syndrome.

Clinical Complications. The principal complication of Peutz–Jeghers syndrome is intestinal

obstruction, which may develop in infancy or childhood. This complication is most prominent in the

small intestine because of its narrower diameter. Gastrointestinal bleeding may also be seen in this

disease.

Cancer in the small intestine or colon can occur in Peutz–Jeghers syndrome; however, this is an

uncommon complication.63 It is thought that neoplasia may arise from foci of adenomatous epithelium

found in some Peutz–Jeghers polyps. The risk for cancer is such that prophylactic surgery is not

recommended.

Patients with Peutz–Jeghers syndrome are at increased risk for cancers within and outside the

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gastrointestinal tract. Cancer developed in about half of the patients in one large study at a median age

of about 50 years. At risk are the stomach, small intestine, colorectum, gonads, breasts, pancreas, and

biliary tree. Ovarian cysts and sex cord tumors are seen in 5% to 12% of female patients, and boys are

at risk for endocrinologically active Sertoli cell testicular tumors that may produce feminizing features

before puberty. No internal organ is individually at sufficiently high risk for cancer that a specific

screening regimen or prophylactic surgery is indicated. The clinician should be aware of these risks,

however, and should be particularly alert to gonadal tumors (which are otherwise rare) and breast

cancer (for which screening should start at an early age and bilateral disease should be suspected).

Management. The management of Peutz–Jeghers syndrome is limited to the removal of polyps;

endoscopic techniques should be used when possible. Surgery may be required for intussusception

caused by small-intestinal polyps. The risk for neoplastic development should be kept in mind, but these

patients are not candidates for prophylactic removal of any section of the gastrointestinal tract. As

mentioned earlier, gonadal neoplasms and breast cancer are potential complications that may require

surgery.

Figure 67-19. Peutz–Jeghers syndrome. A: Perioral hyperpigmentation. B: Hyperpigmented buccal mucosa. C: Gross specimen of a

Peutz–Jeghers polyp illustrating a large multilobular lesion. D: Low-power photomicrograph of a Peutz–Jeghers polyp of the colon

revealing smooth muscle stroma covered by nonneoplastic colonic epithelium. E: Photomicrograph of the Peutz–Jeghers polyp at

higher power indicates that the stroma contains arborizing bands of smooth muscle.

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Juvenile Polyposis

Juvenile polyps are pathologically characteristic lesions that can be solitary or part of a polyposis

syndrome. Juvenile polyps are most commonly solitary lesions found in the rectum during childhood.

The lesions may be large and are made up of an edematous, mildly inflamed lamina propria covered by

normal colonic epithelium (Fig. 67-17). If multiple polyps are found, a familial JPS should be suspected.

Three different syndromic presentations have been reported; it is not known, however, whether these

are truly distinctive syndromes. They may consist of JPS limited to the colon, JPS throughout the

gastrointestinal tract, and JPS limited to the stomach. The genetic basis of this syndrome is not

completely understood, but germline mutations in the SMAD4 (also called the MADH4 gene) and

BMPR1A genes each account for about 20% of JPS cases in which the genetic cause can be found.64,65

Both these genes are involved in the TGF-β signaling pathway. Also, there are rare cases of patients who

have both JPS and hereditary hemorrhagic telangiectasia; these patients typically have mutations in the

SMAD4 gene. Although alterations in the PTEN gene were reportedly linked to JPS, germline mutations

in this gene are only found in the rare Bannayan–Riley–Ruvalcaba variant, a childhood disorder

characterized by macrocephaly, intestinal hamartomatous polyps, and unique pigmented macules of the

penis.66 Other characteristics include ocular abnormalities, delayed motor development, lipid storage

myopathy, and Hashimoto disease. This disorder shares features with Cowden syndrome, which is also

caused by PTEN mutations.67

Figure 67-20. Photomicrograph of a juvenile polyp reveals an attenuated surface epithelium overlying an edematous lamina

propria with fluid- and mucus-filled cystic structures.

The manifestations of JPS can vary but are usually limited to bleeding, intussusception, obstruction,

and the passage of autoamputated lesions. In some children, a life-threatening protein-losing

enteropathy may develop that requires surgical resection of the affected segment of intestine. Patients

with familial juvenile polyposis are at increased risk for the development of colorectal cancer and

require careful surveillance.

Other Familial Polyposis Syndromes

A variety of other rare syndromes may give rise to multiple gastrointestinal polyps. Cowden syndrome

consists of multiple gastrointestinal hamartomas and may be complicated by multiple lesions of the face

that arise from follicular epithelium and are pathologically trichilemmomas.68 This disease is most often

linked to germline mutations in the PTEN gene. The diagnosis of Cowden syndrome should be

considered for patients with multiple trichilemmomas. Gastrointestinal polyps, which are usually

asymptomatic, may develop in these patients. The polyps may include hamartomas, HPs, and

ganglioneuromas of the colon. Glycogenic acanthosis of the esophagus may also occur and usually is

found incidentally as multiple, diminutive, flat polyps of the esophagus. These patients have an increase

in the estimated lifetime risks for the development of breast cancer (85%), thyroid cancer (35%),

endometrial cancer (28%), colorectal cancer (9%), kidney cancer (34%), and melanoma (6%).69 Cowden

syndrome patients should be in the care of someone knowledgeable with these risks. Germline

mutations of the PTEN gene can be identified in most families with Cowden syndrome.70

Other diseases, such as neurofibromatosis (von Recklinghausen syndrome) and the basal cell nevus

syndrome, may be associated with multiple gastrointestinal polyps; however, symptomatic

complications of these polyps are uncommon.

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NONFAMILIAL GASTROINTESTINAL POLYPOSIS SYNDROMES

Multiple gastrointestinal polyps are occasionally seen in nonfamilial syndromes. The Cronkhite–Canada

syndrome is an acquired, nonfamilial syndrome characterized by cutaneous lesions (Fig. 67-21), chronic

diarrhea, protein-losing enteropathy, and gastrointestinal polyps. The enteropathy may produce

progressive inanition and dehydration that can result in death. The diarrhea is attributable to diffuse

mucosal injury of the small intestine but may be complicated by bacterial overgrowth. Gastrointestinal

polyps are present in most patients and occur in the stomach, small intestine, colon, and rectum. These

polyps are pathologically similar to juvenile retention-type polyps. The lamina propria is edematous and

contains an inflammatory infiltrate. As has been reported in juvenile polyps, the lesions in this

syndrome may contain adenomatous epithelium, and occasionally carcinomas have complicated this

disease, but this is not a usual feature of the disease. A variety of medical and surgical measures have

been used as treatment, and primary attention should be drawn to the treatment of the diarrhea and

maintenance of the nutritional status. The cutaneous lesions consist of onycholysis, alopecia, and

hyperpigmentation. Multiple therapeutic approaches have been tried, including broad-spectrum

antibiotics, steroids, antihistamines, and extended bowel rest with parenteral nutritional support. Each

approach has had occasional success, but none is uniformly effective. The disease is more common in

Asia than in North America or Europe. Curiously, the cutaneous features may resolve despite persistence

of the gastrointestinal polyps.

Figure 67-21. Cronkhite–Canada syndrome. Onycholysis and hyperpigmentation are characteristic cutaneous manifestations of

Cronkhite–Canada syndrome, a nonfamilial, poorly understood, and acquired condition in which multiple juvenile, inflammatorytype gastrointestinal polyps and characteristic cutaneous features are found.

Other acquired lesions that may present with multiple gastrointestinal polyps include inflammatory

pseudopolyps in the setting of inflammatory bowel disease, lymphoma, pneumatosis cystoides

intestinalis, and multiple lipomas or HPs. None of these syndromes requires specific surgical treatment.

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