FAP


Familial Adenomatous Polyposis (FAP)
APC-associated Adenomatous Polyposis

(based on Dutch Guideline 2017)

Diagnostic Criteria:

  • Detection of a mutation in the APC-gene
  • On clinical grounds, two types

– Classical FAP: >100 adenomatous polyps in the colon and rectum
– Attenuated FAP (AFAP): less adenomatous polyps in the colon and rectum (around   10-100); diagnosed at a later age; NB sometimes there are patients with FAP and AFAP in one family

Inheritance:

  • Autosomal dominant; penetrance almost 100%

Prevalence:

  • 1% of all colorectal cancers (CRC)

Clinical features:

  • Classical FAP: adenomatous polyposis occurs between 10 to 30 years of age; in 70-80% of the patients, the polyps are localized in the left-side of the colon and rectum; if prophylactic colectomy is not performed, CRC is diagnosed at an average age of 35 to 45 years.
  • AFAP: the cumulative risk of CRC is about 70% by 80-years of age. The mean age of adenoma diagnosis is 44 years and 56 years for CRC diagnosis.

Other findings:

  • Stomach: especially fundic gland polyps (25-60%), sometimes adenomas (antrum)
  • Duodenum: adenomatous polyps (35-90%), duodenal cancer (5-10%)
  • Desmoid tumors (15%)
  • Osteomas (75-90%), Congenital hypertrophy of retinal pigment epithelium (CHRPE) (60-90%), epidermoid cysts (50%), thyroid cancer (especially in young females; risk unknown), hepatoblastoma (in children, <1%), brain tumor (<1%), rarely tumor of pancreas, bile ducts and adrenal glands

Genetic basis:

  • APC-gene; 15-25% of FAP patients have de novo mutations (parents are not affected); 25% have somatic mosaicism (APC mutation present in only part of the body cells)
  • In AFAP the APC mutation is often found at the 3’or the 5′ end of the gene.

Indication for referral to a clinical geneticist for counseling and DNA diagnostics:
New patients with one of the following criteria:

  • Cumulative ≥10 adenomas with or without CRC in patients <60 years
  • Cumulative> 20 adenomas with or without CRC in patients <70 years
  • Family members of APC-mutation carriers

DNA diagnostics:

  • Mutation analysis of patients
  • Detection of APC-mutation in about 80% of patients with classical FAP
  • If mutation is known: pre-symptomatic DNA-diagnostics of the first-degree relatives from 10-12 years of age in FAP and from 18 years of age in AFAP

Periodic examination:
For mutation carriers and the first-degree relatives of the mutation carriers:

  • Sigmoidoscopy: 1×/ per 2 years starting from 10-12 year
  • Gastroduodenoscopy: 1x / 5 years from 25-30 years, frequency, depending on findings (Spigelman score) (see table 1 and 2)

For AFAP:

  • Colonoscopy 1x / 2 years from 18 years
  • Gastroduodenoscopy: 1x / 5 years from 25-30 years, frequency depending on findings (Spigelman score) (see table 1 and 2)

Table 1: Classification of the severity of duodenal polyposis in FAP according to Spigelman criteria

Criteria 1 point 2 points 3 points
Number of polyps 1-4 5-20 >20
Max. largest polyp 1-4 mm 5-10 mm >10 mm
Histology tubular tubulovillous Villous
Dysplasia Low-grade High-grade

Spigelman classification on the basis of the total points:

  • 1-4 points: stage I
  • 5-6 points: stage II
  • 7-8 points: stage III
  • 9-12 points: stage IV

Table 2: Surveillance intervals for follow-up of the duodenum of FAP patients

Spigelman stage Interval
I (or 0: no polyps) 5 years
II 3 years
III 1 year
IV 6 months

 

Surgical treatment:
Treatment and follow-up care of polyposis patients should be conducted in a specialized center.

Colorectal polyposis:
Colectomy with ileorectal anastomosis (IRA) or proctocolectomy with ileal pouch anal anastomosis (IPAA):
Time of operation depends on number, size and degree of dysplasia of polyps; In classical FAP usually between 15 and 25 years.
Colectomy (preferably laparoscopic) is indicated in all patients in which number and size of adenomas make adequate surveillance impossible.
Type of operation depends on number of adenomas in the rectum, age and the patient’s desire for children, presence of a metastatic rectal carcinoma, anal function, and patient preference.
More than 20 adenomas in the rectum, large polyps (> 5mm), fusion of polyps (carpeting), and high-grade dysplasia are a good indication for an lPAA.
The cumulative risk of rectal carcinoma after an IRA is 24% after 30 years of follow-up.
In general, IPAA is the appropriate treatment in classical FAP. In attenuated FAP, an IRA is recommended.
Rectum / pouch follow-up: 1x per 6- 12 months after IRA and IPAA due to the risk of developing new adenomas or carcinoma
The risk of polyps and carcinoma in the ileum in patients with a terminal ileostoma is low; Therefore, surveillance is not recommended (with the exception of patients with a continent ileostoma)

Duodenal polyposis:
Treatment of duodenal polyposis (endoscopic or surgical) should be considered in patients with Spigelman stage IV, a high grade dysplastic adenoma or a growing papillary adenoma.
Surgical treatment of duodenal polyposis consists of pancreaticoduodenectomy (Whipple procedure) or a pancreas-sparing duodenectomy; Following these operations, regular follow-up is required (frequency dependent on the findings, see Table 2).
Chemoprevention using COX-2 inhibitors in severe duodenal polyposis may be considered.

Literature:

  1.  www.oncoline.nl
  2. Vasen HF, Moslein G, Alonso A et al. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 2008; 57: 704-713
  3. Burt RW, Leppert MF, Slattery ML et al. Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis. Gastroenterology 2004; 127: 444-451
  4. Latchford AR, Neale KF, Spigelman AD et al. Features of duodenal cancer in patients with familial adenomatous polyposis. Clin Gastroenterol Hepatol 2009; 7: 659-663
  5. Koskenvuo L, Renkonen-Sinisalo L, Järvinen HJ et al. Risk of cancer and secondary proctectomy after colectomy and ileorectal anastomosis in familial adenomatous polyposis. Int J Colorectal Dis 2014; 29: 225-30
  6. Van Heumen BW, Nieuwenhuis MH, van Goor H et al. Surgical management for advanced duodenal adenomatosis and duodenal cancer in Dutch patients with familial adenomatous polyposis: a nationwide retrospective cohort study. Surgery 2012; 151: 681-90
  7. Steinhagen E, Guillem JG, Chang G et al. The prevalence of thyroid cancer and benign thyroid disease in patients with familial adenomatous polyposis may be higher than previously recognized. Clin Colorectal Cancer 2012; 11: 304-8
  8. Nieuwenhuis MH, Mathus-Vliegen EM, Baeten CG et al. Evaluation of management of desmoid tumours associated with familial adenomatous polyposis in Dutch patients. Br J Cancer 2011; 104: 37-42