Synonyms: Familial adenomatous polyposis (FAP), adenomatous polyposis coli (APC)
Etiology: Mutation in adenomatous polyposis coli (APC) gene, chromosome 5q21
Associations: Colonic tubular adenomas and carcinoma, cutaneous epidermoid cysts, fibromas, desmoids, osteomas
Histology: Epithelial cysts with pilomatrical differentiation, fibrous nodules
Evaluation: Ophthalmologic examination, panoramic dental radiographs, lower GI tract evaluation, possible APC gene mutation evaluation
Treatment: Prophylactic colectomy, periodic monitoring of upper GI tract and other organ systems for malignancy
Prognosis: Good, with early detection and intervention
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Gardner Syndrome
Gardner syndrome is a variant of familial adenomatous polyposis, an autosomal dominant disease characterized by multiple adenomatous polyps of the colon that inevi- tably transform into adenocarcinoma, usually by the fifth decade. Some cases are the result of spontaneous muta- tions. In 1951, Gardner described a familial adenomatous polyposis kindred with extracolonic manifestations, in - cluding bone tumors, and soft “cyst-like” surface tumors (1). Interestingly, the cutaneous lesions were not charac- terized in that report because one family member had expired shortly after having a cutaneous lesion removed, and others in the family were afraid they would meet the same fate if their lesions were removed.
Gardner syndrome (GS) was initially viewed as a dis- tinct variant of familial adenomatous polyposis (FAP).
However, it became clear that within a given kindred, there is highly variable expression of extracolonic mani- festations. Some patients express prominent extracolonic manifestations, and others express only gastrointestinal tract disease. The notion that GS and FAP are a single disease is supported by genetic studies that have localized germline mutations in FAP families to chromosome 5q21, within the adenomatous polyposis coli (APC) gene (2–4).
In a given kindred, the identical mutation may be associ- ated with pure colonic disease or colonic disease with prominent extracolonic manifestations, implicating other genetic or environmental factors in disease expression (4).
In one large kindred, there was a strong correlation of slow acetylators with extracolonic manifestations, but this has not been studied in other families (5). Somatic mutations in this same gene have been implicated as the cause of some cases of sporadic colon cancer (4).
The APC gene encodes a protein complex that functions as a tumor suppressor by its interactions with β-catenin.
β-catenin is a protein that is a component of the adherens junctions at the plasma membrane. β-catenin also has an unbound soluble form that can act as a transcription factor with T-cell factor in the nucleus. This complex induces the expression of genes such as c-MYC, cyclin D1, and matrix metalloproteinase 7, which are involved in cell proliferation, migration, and metastasis. APC protein inhibits this process by phosphorylating β-catenin in the cytoplasm, precipitating its degradation. In the nucleus, it blocks β-catenin-induced transcriptional activity and aids in its removal from the nucleus. Once in the cyto- plasm, β-catenin may be broken down or utilized at the adherens junctions (6). Thus, the effect of APC gene mutations is the cellular accumulation of β-catenin, with its resultant proliferative and tumorigenic effects. β- catenin stabilizing mutations have been implicated in some cases of colon cancer and cutaneous tumors with pilomatrical differentiation (7). β-catenin’s resistance to breakdown in these cases results in the same cellular accu- mulation of the protein as occurs in APC mutations.
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FAP patients will usually develop tubular adenomas of the colon in the second and third decade, and most will develop carcinomas by the fifth decade if not treated by prophylactic colectomy. FAP accounts for fewer than 1%
of cases of colon cancer, but implications of diagnosis and early treatment in affected kindreds are profound (8).
Expression of extracolonic manifestations may allow for early diagnosis of FAP, potentially resulting in life-saving intervention. Given the highly variable expression of FIGURE17.1. Epidermoid cyst with pilomatrical differentiation pretibial erythematous and violaceous cystic nodule.
the disease within individuals, it is important to have an awareness of the spectrum of its features.
Ocular manifestations are present in a high percentage of FAP patients. They consist of round or oval pigmented patches of the retina, referred to as congenital hypertrophy of the retinal pigmented epithelium (CHRPE). These are probably choristomas or hamartomas (9). CHRPE is found in up to 90% of FAP patients, and is bilateral in 78%. It should be noted that this fi nding is not specific.
Similar unilateral lesions are found in one-third of control patients, and bilateral lesions in 5% (10). Large or bilateral lesions are predictors of disease in the right clinical setting.
Evaluation for CHRPE is particularly useful because such lesions are likely congenital, whereas other manifestations of the disease may not develop until adulthood.
Cutaneous manifestations of FAP help to define Gardner syndrome. These include epidermoid cysts and fibromas (Figure 17.1). Cutaneous cysts are usually multiple, and most occur on the scalp and face. Many begin to develop before puberty. While some cysts have no distinctive fea- tures, a study of cysts from a large kindred of Gardner syndrome patients revealed foci of pilomatrical differen- tiation in 63% of lesions (Figure 17.2A and 17.2B). Pilo- matrical cells are those cells of the hair follicle that differentiate into the keratinizing cells that form the hair shaft. While the finding is of unknown specificity, such differentiation was not found in any of 100 randomly selected cysts (11). Multiple pilomatricomas may also be a cutaneous marker of Gardner syndrome (12). Nuchal- type fibroma is a deep-seated fibrous tumor, usually of the posterior neck, which may be associated with Gardner syndrome or, more commonly, diabetes mellitus. Tumors are composed of thick bundles of hypocellular collagen, which may entrap adipose tissue, and display traumatic
FIGURE17.2. (A and B) Dermal cyst with follicular infundibular (right on high power panel) and matrical (left on high power panel) differentiation.
A B
neuroma-like areas (Figure 17.3). A sparse population of CD34+ spindled cells is present (13,14). Similar lesions have been described at other anatomic sites in children with GS, as early as three months of age. In some, it represented the initial presentation of the disease.
Nuchal-type fibromas may recur as desmoid fibromatosis, a myofibroblastic proliferation also known to occur in GS patients (14). Some patients with Gardner syndrome have oral and cutaneous fibromas that do not display the typical features of nuchal-type fibroma. This observation sug- gests that Gardner’s fibroma and nuchal-type fibroma are not synonymous, and that GS should be regarded as being associated with a spectrum of benign fibrous lesions (15).
Desmoid fibromatosis, a benign-appearing myofibro- blastic proliferation that may display a locally invasive growth pattern, occurs in approximately 10% of individu- als with FAP (9). Abdominal cavity involvement, referred to as intra-abdominal fibromatosis, and abdominal wall involvement, are the most common sites of involvement.
Desmoids may be induced by pregnancy, oral contracep- tives, or surgical procedures. Microscopically, lesions have dense collagen with keloidal and myxoid change, vascular ectasia, and muscular hyperplasia of small arteries. Intra- abdominal fibromatosis occurs in the mesentery and in other peritoneal sites (Figure 17.4). Approximately 15% of those with intra-abdominal fibromatosis have Gardner syndrome, and most of that group have their disease induced by prior abdominal surgery, most commonly col-
ectomy. Some have coexistent abdominal wall involve- ment (16).
Other extracolonic manifestations of FAP are numer- ous. The association of brain tumors with FAP was origi- nally described as Turcot syndrome, but like Gardner syndrome, mutations within the APC gene will result in this phenotype. The noncutaneous extracolonic manifes- tations of FAP are summarized in Table 17.1. Of these, osteomatous jaw change is worthy of special mention, because it may have early onset and be fairly prevalent among those with APC mutations. This makes panoramic dental radiographs a worthwhile screening tool (17).
Cutaneous presentations of the Gardner syndrome variant of FAP usually consist of multiple cysts, or perhaps fibromas, nuchal-type or other, in childhood or early adulthood. Histopathologic evaluation of cysts is impor- tant because a finding of pilomatrical differentiation in such lesions should prompt a thorough evaluation for FAP.
Family history may reveal FAP, but the lack of a history does not exclude the disease, since 25% of cases may rep- resent spontaneous mutations. Evaluation in childhood should begin with ophthalmologic evaluation for pig- mented retinal lesions, and panoramic dental radiographs or computed tomography for osteomatous change or other dental abnormalities. Genetic testing for APC mutations may be undertaken, but the false negative rate is approxi- mately 20% (14). Direct visualization of colorectal mucosa should be a consideration in post-pubertal individuals depending upon the clinical setting.
FIGURE17.3. Nuchal-type fibroma:
dense collagen bundles admixed with adipose tissue.
Treatment of FAP consists of prophylactic colectomy since the incidence of carcinoma otherwise approaches 100% in the fifth decade. Polyps have been shown to regress with sulindac therapy, but they recur upon cessa- tion of treatment (18). Since treatment is unlikely to prevent carcinoma, this therapy probably does not have a place in the management of FAP patients. Even with total colectomy, periodic evaluation of the upper gastrointesti- nal tract is indicated because of a 10% –12% estimated lifetime risk of developing duodenal or ampullary carci- nomas (8). Thyroid screening has been advocated due to the occurrence of papillary carcinoma in some FAP patients (19). Onset of abdominal pain or gastrointestinal
tract bleeding should prompt consideration of upper gas- trointestinal tract tumors, obstructive pancreatitis due to periampullary tumors, or abdominal fibromatosis.
The Gardner syndrome variant of familial adenoma- tous polyposis is characterized by the presence of extra- colonic manifestations, particularly cutaneous cysts and fibromas. The development of these markers early in life may herald the development of colonic polyposis and subsequent carcinoma, allowing for early diagnosis and potentially life-saving intervention for the patient and other affected family members.
References
1. Gardner EJ. A genetic and clinical study of intestinal polyposis, a predisposing factor for carcinoma of the colon and rectum. Am J Hum Genet 1951; 3: 167–176.
2. Bodmer WF, Bailey CJ, Bodmer J, et al. Localisation of the gene for familial adenomatous polyposis on chromosome 5.
Nature 1987; 328: 614–616.
3. Leppert, M, Dobbs M, Scambler P, et al. The gene for familial polyposis coli maps to the long arm of chromosome 5. Science 1987; 238: 1411–1413.
4. Nishisho I, Nakamura Y, Miyoshi Y, et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991; 253: 665–669.
5. Scott RJ, Taeschner W, Heinimann K, et al. Association of extracolonic manifestations of familial adenomatous polyposis with acetylation phenotype in a large FAP kindred.
Eur J Hum Genet 1997; 5: 43–49.
FIGURE 17.4. Desmoid fibromato- sis: myofibroblastic spindle cell proliferation admixed with colla- gen and blood vessels.
Table 17.1. Noncutaneous Extracolonic Manifestations of FAP 1. Dento-maxillary—osteomas, diffuse osteomatous change,
odontomas, dentigerous cysts, impacted teeth, hypercementomas, supernumerary teeth, fused or long roots
2. Ocular—congenital hypertrophy of the retinal pigment epithelium (CHRPE)
3. Central nervous system tumors (Turcot syndrome)—cerebellar medulloblastoma (most common), glioblastoma,
craniopharyngioma
4. Gastrointestinal tract—duodenal and gastric polyps, periampullary adenoma and carcinoma (may cause obstructive pancreatitis), intra-abdominal fibromatosis
5. Bone—osteomas (facial or long bones)
6. Other malignancy—thyroid papillary carcinoma, hepatoblastoma, liposarcoma, osteosarcoma, testicular, renal
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10. Traboulsi EI, Krush AJ, Gardner EF, et al. Prevalence and importance of pigmented ocular fundus lesions in Gardner’s syndrome. N Engl J Med 1987; 316: 661–667.
11. Cooper PH, Fechner RE. Pilomatricoma-like changes in epidermal cysts of Gardner’s syndrome. J Am Acad Dermatol 1983; 8: 639–644.
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16. Burke AP, Sobin LH, Shekitka KM, Federspiel BH, Helwig EB. Intra-abdominal fibromatosis: A pathologic analysis of 130 tumors with comparison of clinical subgroups. Am J Surg Pathol 1990; 14: 335–341.
17. Utsunomiya J, Nakamura T. The occult osteomatous changes in the mandible in patients with familial polyposis coli. Br J Surg 1975; 62: 45–51.
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