Familial Adenomatous Polyposis
Diseases

Author: chiara grasso
Date: 31/03/2010

Description

DEFINITION

FAP is an autosomal dominant disease characterized by the development of hundreds to thousands of adenomas in the rectum and colon during the second decade of life. Almost all patients will develop colorectal cancer (CRC) if they are not identified and treated at an early stage. In other words, FAP is a colon cancer predisposition syndrome (with complete penetrancy), which is inherited in an autosomal dominant manner.
Attenuated FAP (AFAP) is a milder form that is characterized by fewer (from 10 to 100) adenomas, a later age of adenoma development (mean age of polyp diagnosis is 44 years) and cancer (mean age 56 years).
Other forms: Gardner’s syndrome ( a clinical variant of FAP where the extra-colonic features are
prominent), and Turcot syndrome (it is a case of FAP having a medulloblastoma brain tumor).
Familial adenomatous polyposis 2009

LINKS

DatabaseLink
WikipediaFAP
The Diseases DatabaseFAP
OMIMFAP

EPIDEMIOLOGY

CRC is a major cause of cancer associated morbidity and mortality worldwide; its incidence is notably different among different populations with the highest incidence seen in Western and industrialized countries. Worldwide, about 85% of CRCs are considered to be sporadic, while approximately 15% are familial with FAP considering for less than 1%. However, FAP is one of the best known and understood genetic diseases.
In 1955 in the UK, Reed and Neel calculated the incidence of FAP at birth to be 1:8’300; in 1975 in Sweden, Alm presented an incidence rate of 1:7’645. Finally in 2009 the European Medicines Agency (EMEA) estimated that FAP affected approximately 3-10/100,000 people in Europe (which corresponds to 11,300 - 37,600 individuals).
Classic FAP manifests equally in both sexes by the late teens and in the twenties age group.
Symptoms are uncommon in the child and adolescent until the adenomas are fairly large and numerous to cause rectal bleeding or anaemia. About half of FAP patients develop adenomas by 15 years of age and 95% by age 35 years.
Generally, colon cancer start to develop a decade after the appearance of the polyps so, if the colon is left intact, the majority of patients with FAP eventually develop CRC by the ages 40-50 years. However, although uncommon, CRC can develop in children or in older adults.
In AFAP cases, although these individuals have a number of polyps smaller than classic FAP, they still have an increased risk of cancer that, in general, occurs approximately 10-15 years later.
Familial adenomatous polyposis 2009

SYMPTOMS

DIAGNOSIS

HYSTOPATHOLOGY

FAP is characterized by the presence of hundreds to thousands of colorectal adenomas of different sizes. In the majority of patients polyps begin to develop during childhood, mostly in the distal colon (rectosigmoid) as small intramucosal nodules.
The colonic polyps are numerous and present as a carpet of polyps ranging from 1-2 mm to 1 cm or larger. In all cases, large numbers of adenomas carpet the colon, occurring initially in the left colon and then eventually spreading to involve the entire colon.
Colon, polyposis syndromes 2008

ENDOSCOPY (WCE) and ENTEROSCOPY

WCE is a promising noninvasive new method for the detection of small-intestinal polyps.
The advent of WCE in 2000 has changed noticeably the diagnosis and management of numerous diseases of the small intestine, including polyps associated with FAP.
WCE is able to detect even small polyps in the entire small intestine in subjects with FAP; this procedure is able to find jejunal and ileal polyps.
But it cannot be defined the true sensitivity of WCE for detection of small-bowel adenomas because the lack of visualization of the entire small-bowel mucosa by WCE leads to underestimation of polyp burden.
The advent of double or single balloon enteroscopy of the small bowel may have opened a new avenue to gain less invasive access, even to polyps located in the distal small bowel.
Double balloon enteroscopy appears to be equivalent to an intraoperative enteroscopy for observation of smallintestinal polyps in FAP.
Wireless capsule endoscopy in detecting small-intestinal polyps in familial adenomatous polyposis 2009

MAGNETIC RESONANCE

Magnetic resonance enteroclysis combines the advantages of cross-sectional resonance with those of
the volume challenge of conventional enteroclysis in the recognition and characterization of small-bowel-wallVabnormalities, including initial tumors. There are few promising reports about the role of magnetic resonance enteroclysis and CT enteroclysis in the diagnosis of small-bowel neoplasms.
Wireless capsule endoscopy in detecting small-intestinal polyps in familial adenomatous polyposis 2009

RADIOLOGY

images from conventional radiography

LABORATORY TESTS

The diagnosis of classic FAP is based on a detailed family cancer history and clinical suspictions. Whenever possible, the clinical diagnosis of FAP can be confirmed by sequence analysis of the APC gene through a test which is commercially available. Direct DNA sequencing is successful in finding a pathogenetic mutation in most, but not all, cases. Sometimes for the diagnosis a Southern blot may be necessary, to find large genomic rearrangements, such as genetic deletions, and MYH sequencing is often helpful in the cases in which there aren’t detectable APC alterations. Once a disease-causing mutation is known, affected family members or relatives at risk can be tested for the presence of this mutation after careful genetic counseling.
Today a good number of genetic tests are available to test for APC germline mutations. Among these are sequencing of the full APC gene, combination of conformation strand gel electrophoresis (CSGE) screening and protein truncation test (PTT), protein truncation test alone and finally linkage analysis. The most commonly used today is direct sequencing of the APC gene.
The mutation detection rate is 70%. Large insertions and deletions need other tests and add about the 5% of the cases. MUTYH mutations are responsible for a little group of the remaining cases.
When the family’s specific APC mutation is identified, genetic testing of all first degree relatives should be performed even when the parents’s test is negative. Parents of children at-risk should be informed that genetic testing is recommended just before puberty or preferably in middle adolescence, when the diagnosis begins to gain clinical importance in terms of cancer prevention or for surgical intervention.
The genetic alteration in AFAP is associated with APC mutations occurring most commonly at the 5’ or at the 3’ end of the gene proximal to codon 1517 or distal to codon 1900. Therefore, DNA sequencing is usually recommended.
Molecular Pathogenesis of Colorectal Cancer 2005

Differential diagnosis of FAP

There are other disorders causing multiple polyps. These include hamartomatous polyps, as those seen in Peutz-Jeghers syndrome (mainly in the small bowel but may occur anywhere along the gastrointestinal tract), familial juvenile polyps or hyperplastic polyposis and hereditary mixed polyposis syndromes. Multiple lymphoid aggregates can appear as early FAP, especially in children and young adults.
The diagnosis depends on the correct histological classification of the polyps. Dysplastic changes occurring in a non-adenomatous polyp can be erroneusly identified as a multiple adenoma syndrome compatible with FAP. Moreover, it’s difficult to differentiate between AFAP and Lynch syndrome (hereditary non polyposis colorectal cancer, HNPCC), because both may have a low polyp number, presenting mainly in the right colon.
Familial adenomatous polyposis 2009

PATHOGENESIS

FAP is usually caused by germline mutations of the tumor-suppressor gene adenomatous
polyposis coli (APC), which takes part in the Wnt pathway; somatic (or acquired) APC alterations are seen in most (85–90%) colorectal neoplasms. On the contrary, AFAP is mostly caused by specific APC mutations, not germline mutations.
Another gene resposible is MYH, or MUTYH (recessive, then it is necessary a biallelic inactivation); in this case, FAP is an autosomal recessive disorder, which clinically may appear as a sporadic disease. The MYH gene encodes a DNA glycosylase that is involved in the process of base excision repair and primarily targets repair of oxidative DNA damage.
Most of the patients with FAP develop benign adenomas, but some of these will progressively accumulate additional mutations, and inactivation of the p53 gene mediates the conversion of benign lesions to malignant ones (es. CRC).
Molecular Pathogenesis of Colorectal Cancer 2005

PATIENT RISK FACTORS

  • age
    Most people who have colorectal cancer are over age 50, however, it can occur at any age.
  • polyps
    Benign growths on the wall of the colon or rectum are common in people over age 50, and lead to colorectal cancer.
  • personal history
    People who have had colorectal cancer, as well as ovarian, uterine, or breast cancers, have a slightly increased risk for colorectal cancer.
  • family history
    People with a strong family history of colorectal cancer or adenomatous polyps in a first-degree relative (in a parent or sibling before the age of 50 or in two first-degree relatives of any age), have an increased risk for colorectal cancer.
  • ulcerative colitis / crohn's disease
    People who have ulcerative colitis, an inflamed lining of the colon, have an increased risk for colorectal cancer.
  • obesity
  • physical inactivity
  • high-fat and/or low-fiber diet
  • alcohol consumption
  • smoking
  • type 2 diabetes

Information About Colorectal Cancer

Hormonal risk factors

Probably oestrogens are risk factors to develop desmoid tumours with disproportionate frequency in patients with familial adenomatous polyposis. Usual first-line therapy is with sulindac with or without an anti-oestrogen.
Current ideas in desmoid tumours 2006

COMPLICATIONS

  • Extracolonic manifestations
    • FAP can also present with extraintestinal manifestations during the development of the disease, such as osteomas, dental abnormalities (unerupted teeth, congenital absence of one or more teeth, supernumerary teeth, dentigerous cysts, and odontomas), congenital hypertrophy of the retinal pigment epithelium (CHRPE) or retinal lesions, duodenal or ampullary polyps, desmoid tumors or extracolonic cancers (thyroid, liver, bile ducts, central nervous system). Some lesions (skull and mandible osteomas, dental abnormalities, fibromas on the scalp, shoulders, arms, and back) are indicative of the Gardner variant of FAP.
      In particular, desmoid tumors are usually benign, but can be lethal, and occur in 10–15% of FAP patients; these cases are more common in some families, and are the major nonmalignant cause of morbidity and mortality in FAP.
      In AFAP cases, the most prominent extracolonic findings are upper gastrointestinal polyps,
      duodenal and gastric adenomas and fundic gland polyps, as seen in FAP. Gastric and breast adenocarcinomas, as well as hepatoblastoma, have also been documented in AFAP.
      Familial adenomatous polyposis 2009

PROGNOSIS

The aim is a pre-symptomatic genetic diagnosis of APC mutation-carriers that can lead to improved clinical care and prevent mortality from cancer or other FAP complications and manifestations.
Moreover, individuals with FAP carry a 100% risk of colorectal cancer that is reduced almost absolutely when patients enter in a screening-treatment program.
Duodenal cancer and desmoids are the two main causes of mortality after total colectomy has removed the risk for CRC.
The colectomy and the conseguent change in bowel habits, frequently lead to dietary changes that can be unbalanced and lead to vitamin-mineral deficiencies. Notable is the possibility of vitamin B12 deficiency due to rapid intestinal transit, ileal resection and upper bacterial overgrowth. All these problems require a careful follow-up and supportive care.
Familial adenomatous polyposis 2009

THERAPY

Cancer prevention and maintaining good quality of life are the main objective in management of patients with clinical or genetic evidence of FAP. Large bowel endoscopy is the most important clinical examination; however, the disease is systemic with extracolonic manifestations and should be looked for by systematic re-examination.
Around ages 16-18 patients with FAP should be subjected by annual or less frequent colonoscopic examinations (depending on the polyp quantity at last colonoscopy) and all significant sized
adenomas should be removed. In addition, both forward–viewing and side-viewing upper tract endoscopies should be performed to find gastric but mainly duodenal and periampullary
adenomas, respectively.
Usually, by the late teens or early twenties, due to the increasing number of adenomas, prophylactic cancer-preventive colorectal surgery is recommend. Surgical options include subtotal colectomy with ileorectal anastomosis (IRA), total proctocolectomy with ileostomy, and proctocolectomy with or without mucosectomy and ileal pouch anal anastomosis (IPAA).
Given the substantial risk of rectal cancer developing after colectomy and ileorectal anastomosis, most experts advise total proctocolectomy for the typical FAP patient with multiple rectal adenomas. This surgery includes removal of the entire large bowel and striping of the remaining rectal mucosa down to the dentate line if there are multiple polyps or leaving a cuff of rectal mucosa. However, this operation requires careful biannual or annual examination and removal of
adenomas that can return. This surgery is called total proctocolectomy with ileoanal J-pouch and it is the surgical procedure of choice for most patients with classical FAP.
In cases with few rectal polyps, IRA can be a suitable alternative procedure, but with a satisfactory life-long rectal surveillance. Later conversion of an ileorectal anastomosis to a J-pouch can be performed, but may be difficult because of desmoid formation in the operated area.
Familial adenomatous polyposis 2009

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