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Familial adenomatous polyposis (FAP)

Familial adenomatous polyposis is a rare autosomal dominant disease caused by a defect in the apc gene on chromosome # 5q21-22, and characterised by at least 100 colorectal adenomas and extracolonic manifestations. More than one thousand pathogenic mutations have been identified, and the family specific mutation is identified in more than 80% of the families.

Almost all affected untreated patients will die from colorectal adenocarcinoma at the age of 40-50 years. The incidence rate is 1.9 x 10-6 or 1:7000 live births, about 10 new cases annually in Denmark. In 1999 the prevalence rate was 4.65 x 10-5. In 1990-1998 FAP only constituted 0.07% of all Danish patients with colorectal cancer.

MYH-polyposis (MuTYH-associated polyposis) share most features with FAP, but the syndrome is autosomal recessive and the number of colorectal adenomas is smaller. At present there are five families with MYH-polyposis in Denmark.

Patients with classical FAP have from 100 to more than 5000 colorectal adenomas and all patients have rectal adenomas. The adenomas most often appear at the age of 10-20 years, and rarely above the age of 40 years.

Patients with attenuated FAP (AFAP) have less than 100 colorectal adenomas, often most pronounced in the right colon. Compared with classical FAP the adenomas develop at a higher age, the risk of colorectal cancer is smaller and cancer develops at a higher age. AFAP may occur in single members of a polyposis family, or in all members.

Furthermore, FAP includes a variety of extracolonic manifestations:

Fundic gland polyposis is found in most FAP patients and diagnosed endoscopically as multiple few mm dome-shaped polyps in the gastric fundus and corpus. Biopsy demonstrates cystic dilatation of fundic glands without any epithelial dysplasia. The condition is not neoplastic and surveillance thus unnecessary.

Duodenal adenomatosis is seen in the second and upper third part of the duodenum in more than 90% of FAP patients. Gastroduodenoscopy shows multiple sessile white longitudinal polyps on the mucosal folds, varying from few mm to several cm. Histology demonstrates adenomas, most often of the tubular type.

At endoscopy a few patients have no visible polyps, but random biopsies may reveal microadenomas. Duodenal adenomatosis is classified according to the Spigelman Classification i 4 stages according to the number and size of polyps, the histological type and degree of dysplasia.

Duodenal adenomatosis worsen by increasing age, and the lifetime risk of developing Spigelman stage IV is 35 %, and in this stage the lifetime risk of developing carcinoma is 33%. Duodenal adenomatosis is more rarely seen in AFAP compared with FAP.

Small bowel adenomas may occur in the ileum, but carcinoma is very rare.

Desmoids occur in 10% as fibromatous tumours in fasciae, muscles or aponeuroses. They may develop in scars after laparotomy, the small bowel mesentery, in the retroperitoneum in the extremities. They may become very large and cause obstruction of the small bowel or the ureters, but despite a tendency to local invasive growth they are benign and never metastasize.

Polyposis patients may develop benign epidermoid cysts, osteomas and dental anomalies. Papillary thyroid carcinoma is seen in 1% of female polyposis patients. The prognosis is good, and therefore prophylactic thyroid examination is not recommended. Hepatoblastoma occurs in rare cases in infancy.

At the diagnosis of FAP colorectal cancer has developed in 67% of probands (diagnosed due to symptoms), but only in 3% of call-up cases (screen-detected).

The proportion of call-up cases increased from 19% in 1900-1975 (before establishment of the Danish Polyposis Register) to 58% in 1976-2001. The frequency of colorectal cancer at diagnosis of FAP decreased from 60% before 1976 to 27% in 1976-2001, and the colectomy rate increased from 52% before 1976 to 93% in 1976-2001.

The cumulative 10-year survival rate in all polyposis patients increased from 23% before the register was established to 75% i 1976-2001, and the cumulative 10-year survival rate after colectomy in call-up patients was 95% after 1975.