Figure 67-18. Extraintestinal manifestations of familial adenomatous polyposis (FAP). A: Skull film demonstrating osteomas of the

calvarium (arrows). B: Photograph of the mandible demonstrating protuberant mandibular osteomas. C: Mandibular radiograph

demonstrating a large osteoma of the mandible. D: Chest radiograph demonstrating multiple fibromas (arrows) in a patient with

FAP.

Malignant tumors in the colon are considered to be nearly inevitable in FAP patients, and they may

occur occasionally in the duodenum or (less commonly) elsewhere in the gastrointestinal tract. Patients

with FAP are also at increased risk for brain tumors, thyroid tumors, adrenal tumors, and malignant

tumors of the hepatobiliary tree. Medulloblastomas are a rare complication of FAP, but the risk for this

tumor is increased 99-fold in FAP families.

Desmoid Tumors

Desmoid tumors are currently the major cause of mortality and morbidity in FAP (after colorectal

cancer) and develop in 10% to 15% of such patients, often as a complication of laparotomy, but

sometimes spontaneously. These are benign but aggressive tumors of mesenteric fibroblasts that can

encase and obstruct the gastrointestinal tract, arteries, veins, or ureters. They frequently occur in the

abdominal wall. In some instances, desmoid tumors can virtually fill the abdominal cavity, and can be

lethal. Desmoids are readily visualized on CT of the abdomen, and surgical management of these should

be avoided unless they are superficially located. These are more common in women and in those with a

positive family history of desmoid tumors.

Genetic Basis of FAP

FAP occurs when a germline mutation in the APC gene inactivates the function of the APC protein. In

most instances, the genetic lesion creates a premature stop codon in the APC gene, which in turn leads,

to nonsense-mediated decay of the mRNA or the translation of a truncated, nonfunctional APC protein.

Germline deletions of APC also cause FAP. The APC gene encodes a large protein (311 kd) that binds to

other intracellular proteins – most importantly, the catenins. The APC gene encodes 2,843 codons (one

for each amino acid) and is broken into 15 translated exons. The structure of the APC gene is unique in

that the 15th exon makes up about 75% of the coding sequence of the gene. Because it is unusually

large, this long, open reading frame is a large target for mutations. This genetic vulnerability probably

accounts for the fact that about 25% of mutations in the APC occur de novo, in which neither parent

carries the mutation, and there is no prior family history of FAP.

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The location of the germline mutation is of some clinical significance (Fig. 67-19). For example,

mutations that occur at the 5′ end of the gene, particularly in the first three exons, result in a clinically

mild or “attenuated” form of FAP, in which the number of polyps is smaller and the onset of disease

occurs about 10 years later, with cancer developing in the sixth or seventh decade. This occurs because

the APC gene has an internal ribosomal reentry site downstream of the mutation, which permits the cell

to bypass and ignore the premature stop codon. To complicate the situation, family members with the

same mutation may have variable manifestations of the disease. Indeed, some members who inherit this

mutation have few polyps and no cancer, yet can pass an increased risk for cancer to their progeny.

In contrast, mutations that occur in the “mutation cluster region” of the 15th exon, in a segment

between codons 1,250 and 1,464, are associated with a particularly virulent form of the disease, in

which the number of polyps is greater than 5,000 and the average age for the development of colorectal

cancer is significantly earlier (median age, 34 years). Also, mutations at the extreme 3′ end of the gene

may be associated with a milder phenotype, with fewer polyps and later onset of cancer. In families

who have FAP with CHRPE lesions, the mutations are usually in exons 9 through 15 and only rarely in

families whose mutations are in the first 8 exons. Thus, knowledge of the location of the germline

mutation can be useful in predicting the clinical manifestations and guide therapy.

Diagnosis

The clinical diagnosis of FAP is usually obvious clinically, but the availability of a genetic diagnosis has

changed the approach to this disease. Currently, optimal practice is to obtain a germline diagnosis in an

individual who is definitely affected, in order to characterize and counsel the family. A mutation in APC

can be found in most (90%) of these individuals using commercially available diagnostic laboratories.

This will assist in the early and definitive identification of family members who carry the diseasecausing mutation and will alleviate anxiety for those who do not. The risk to inherit the mutated gene

from an affected parent is 50%, and there is no gender preference. A genetic diagnosis is particularly

useful in the attenuated forms of FAP, where the diagnosis is not obvious, and this can help select those

family members who need additional surveillance and reassure those who do not. Family members who

have the APC mutation should begin endoscopic surveillance from their early teens at yearly intervals.57

About 25% of patients have FAP that is not present in either parent. This can represent the autosomal

recessive form of the disease (MutYH-associated polyposis; see later), misattribution of paternity, or

phenotypic variation in which a parent actually has a milder form of the disease.

Genetic testing is an essential part of the clinical management of the hereditary cancer, but it can be a

challenge. The genetic results are sometimes ambiguous and difficult for the physician to interpret.

Additionally, some patients mistake the germline test as a test for cancer. Issues of guilt and denial are

prominent in genetic disorders. It is strongly recommended that physicians enlist the involvement of

genetic counselors when performing genetic testing and counseling in such patients. The federal

“Genetic Information and Non-Discrimination Act” (GINA) protects asymptomatic patients carrying a

germline mutation for a serious disease from discrimination in the workplace or with health insurance.

Management

Surgery is the only reasonable management option in FAP, and the clinical decision involves the

selection and timing of the operation. The diagnosis of FAP is often made in adolescence, but the

development of cancer may not be anticipated for 20 to 30 years after the first polyp appears,

depending on the location of the mutation in the APC gene. When a child is found to have a germline

mutation in APC, sigmoidoscopy should begin in the early teenage years, particularly if the mutation is

in the “mutation cluster region” or the family’s phenotype is known to be associated with thousands of

polyps. Ideally, one would like a patient to reach adulthood prior to the colectomy, as the pelvis is

larger and the individual is better able to cope with the disease psychologically.

The safest surgical approach is a total proctocolectomy with an ileoanal J-pouch anastomosis. No

rectal mucosa should be left behind, since it is at risk for the development of neoplasia. Even with

careful endoscopic surveillance of the rectal segment, invasive carcinomas may develop.

The fact that small adenomatous polyps of the rectum can spontaneously regress visibly after a

subtotal colectomy and ileorectal anastomosis underscores the reversible nature of the benign adenoma.

Additionally, it has been found that adenomas can regress in FAP in response to treatment with

sulindac. Several reports have confirmed that even large numbers of polyps regress in patients on 150 to

200 mg of sulindac twice per day. Unfortunately, the polyps reappear when the drug is stopped, and

cancer may develop despite treatment with sulindac. Medical treatment is therefore not a safe or

reliable first-line treatment for FAP. Furthermore, such treatment may create the illusion of false

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assurance of preventing cancer. Sulindac is not effective in the management of upper gastrointestinal

tract neoplasia.

Management of Extracolonic Disease. In addition to the risks for colorectal neoplasia, patients with

FAP are at risk for the development of osteomas, lipomas, fibromas, and a variety of other lesions.

Although these mesenchymal tumors can degenerate into sarcomas, this is a sufficiently rare event that

prophylactic surveillance and surgery are not indicated. Likewise, CHRPE lesions do not require

treatment. Gastric carcinoma is distinctly uncommon in North American populations where the lifetime

risk for gastric cancer in FAP is 0.5%. The bigger problem is that the gastric polyps may look ominous

endoscopically and dysplastic pathologically, and one should be reluctant to perform a gastrectomy on a

person who has already had a colectomy. Caution is advised when following large gastric polyps in FAP.

The two major management issues after removal of the colon and rectum are periampullary neoplasia

and desmoid tumors. One or more adenomas are found in the duodenum in 90% of patients with FAP,

usually close to the ampulla of Vater. These lesions should be excised for biopsy and destroyed by

electrocautery, laser, or other ablative approaches. Subsequent examination of the upper

gastrointestinal tract is guided by the Spigelman criteria (Table 67-4). Complex neoplasms, including

adenomas with varying degrees of dysplasia, may require individualized management, including the use

of biliary stents while extensive ablative therapy of the periampullary region is performed. Surgical

approaches may be required for advanced neoplasms (i.e., carcinoma in situ or invasive carcinoma), but

therapeutic endoscopy remains the first option. Duodenotomy with local surgical excision is an option

for some of these lesions; occasionally, a Whipple procedure is required for invasive lesions in this

region, with low mortality, but considerable morbidity.58

Desmoid tumors are aggressive benign tumors of fibroblasts that can cause multiple clinical

complications; they are a significant cause of morbidity and mortality in FAP. They typically grow

slowly and can surround or compress vascular structures, nerves, or the abdominal viscera. They are

more common in women and may be hormonally responsive, so estrogen administration (oral

contraceptives or hormone replacement therapy) should be avoided in these patients. Surgical

management is generally avoided unless simple local excision of an abdominal wall lesion is possible,

and postoperative recurrences are common. Radiotherapy has been used to control the growth of some

of these but is generally reserved for superficial lesions. No medical approach to this disease has been

uniformly successful. A combination of sulindac plus tamoxifen may be tried for intra-abdominal tumors

and has been successful in some patients. Cytotoxic chemotherapy with doxorubicin was successful in a

patient whose tumor was refractory to other treatment. Anecdotally, some of these lesions may have ckit mutations and are responsive to imatinib (Gleevec).

Familial Adenomatous Polyposis Variants

5 A number of names, especially Gardner syndrome, have been attached to variations of FAP to

emphasize the presence of particular extracolonic findings. As mentioned, Gardner syndrome is the same

entity as FAP. A few families with prominent sebaceous cysts were historically said to have Oldfield

syndrome, and families with brain tumors were said to have Turcot syndrome. All these syndromes

represent the variable expression of germline mutations in the APC gene and are largely of historical

interest. The current mode of classifying FAP families is based on the APC gene mutation.

MutYH-Associated Polyposis or MAP

An autosomal recessive form of polyposis has been linked to inheritance of germline mutations in the

base excision repair gene MutYH, a DNA glycolase.59–61 MAP should be considered when multiple

adenomatous polyps occur in siblings or in a person who has no vertical family history of polyposis and

there is no detectable germline mutation in the APC gene. These patients have a relatively mild

(attenuated) form of adenomatous polyposis, typically develop 20 to 500 adenomas, and the polyposis

is frequently detected in patients 35 to 65 years old. These patients are at very high risk for colorectal

cancer, and the disease may present with cancer. The extraintestinal manifestations of FAP, such as

duodenal adenomas or CHRPE lesions, occasionally occur but are less common in MAP than FAP. The

pathogenesis of this disease is that the germline mutations in MutYH permit an excess number of

acquired mutations in the APC gene (and other genes) to occur in the colon; these mutations are

typically G:C → T:A transversions, which is a consequence of losing the DNA base excision repair

system. More than 1.3% of the Caucasian population carries a single copy of the MutYH alleles Y179C,

G396D, and E480X (previously designated Y165C, G382D, and E466X, respectively, but changed due to

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