APC-Associated Adenomatous Polyposis – Definition
APC-associated adenomatous polyposis (OMIM #175100) includes familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP) and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). In FAP, hundreds to thousands of intestinal, mostly colorectally localized polyps usually occur from adolescence onwards, which can degenerate and lead to carcinomas if left untreated. In addition, the risk of developing further malignant and benign tumors is increased.
AFAP is a variant of FAP with significantly fewer polyps and later occurrence of carcinomas.
GAPPS is characterized by polyposis in the area of the gastric fundus and an increased risk of gastric carcinomas. The colon is only involved to a limited extent.
Synonyms:
–
Gene:
APC
Gene products:
APC
Function:
Part of the β-catenin degradation complex in the Wnt signaling pathway
Inheritance:
autosomal-dominant
Prevalence:
FAP: Incidence Ranges from 1 in 9,000 to 1 in 18,000 Live Births
Genotype-phenotype correlation:
- The most common pathogenic variant in the APC gene is found at codon 1309 and leads to many adenomas at a young age.
- The average age of onset correlates with the location of the pathogenic variant:
Codon 1309: 20 years,
Between codons 168 and 1580 (excluding 1309): 30 years,
5′ of codon 168 and 3′ of codon 1580: 52 years. - Many polyps have been found with pathogenic variants in codons 1250-1464.
- AFAP correlates with pathogenic variants at the 5′ end and distal to the 3′ end of the APC gene, as well as in exon 9.
- Pathogenic variants between codons 543 and 713, 1310, and 2011 increase the risk of developing desmoid tumors.
- APC promoter 1B mutations are associated with GAPPS.
Penetrance:
- in FAP for untreated colorectal cancer almost 100%
- in AFAP for colorectal cancer up to 80 years, about 70%
APC-Associated Adenomatous Polyposis – Diagnosis
APC-associated adenomatous polyposis is suspected if the following findings are present:
- Multiple colorectal adenomatous polyps (at least 10-20)
- Positive family history of multiple colorectal polyps and/or extracolonic manifestations as listed below
- Hepatoblastoma, especially with undetected CTNNB1 pathogenic variant
- Multifocal/bilateral congenital hypertrophy of the retinal pigment epithelium (CHRPE)
- Desmoid tumor
- Papillary thyroid carcinoma
- WNT-activated medulloblastoma (CTNNB1 wild type)
In addition, genetic testing for a pathogenic variant in APC should be considered for the following findings: early-onset colorectal carcinoma with few to no adenomatous polyps, dental abnormalities (e.g., supernumerary teeth), odontomas, osteomas, epidermoid cysts, duodenal adenomas and carcinomas, polyposis ventriculi, gastric, pancreatic, or small intestinal carcinoma.
Genetic Diagnostics
The diagnosis of “APC-associated adenomatous polyposis” is confirmed by detecting a heterozygous pathogenic germline variant of the APC gene by sequence or deletion/duplication analysis. Panel examinations, in which several genes are recorded, can also be helpful.
Diagnostic Criteria
The diagnosis of “Familial Adenomatous Polyposis (FAP)” is confirmed by genetic evidence of a heterozygous pathogenic germline variant of the APC gene and one of the following findings:
- At least 100 colorectal adenomatous polyps (in young patients or after colectomy, there may be fewer than 100 polyps)
- Multiple, but less than 100 adenomatous polyps and one relative with confirmed FAP
The diagnosis of “Attenuated Familial Adenomatous Polyposis (AFAP)” is considered confirmed if there is genetic evidence of a heterozygous pathogenic germline variant of the APC gene and:
- One relative with confirmed AFAP and/or
- Less than 100 colorectal adenomatous polyps or
- More than 100 colorectal adenomatous polyps at an advanced age (>40 years)
The diagnosis of “Gastric Carcinoma with Proximal Polyposis (GAPPS)” is considered confirmed in patients with the following findings:
- Gastric polyps are limited to the corpus and fundus
- More than 100 polyps in the proximal stomach or more than 30 polyps in a first-degree relative
- Predominantly polyps of the fundic glands; some have dysplastic regions (or a relative with dysplastic polyps of the fundic glands or gastric carcinoma)
- Picture of an autosomal dominant mode of inheritance
- No evidence for colorectal or duodenal polyposis
Differential Diagnoses
- MUTYH-associated polyposis
- Hereditary non-polyposis colorectal carcinoma, also known as Lynch syndrome
- MSH3-associated polyposis
- Peutz-Jeghers syndrome
- PTEN hamartoma tumor syndrome, also known as Cowden syndrome
- Juvenile polyposis syndrome
- Hereditary mixed polyposis syndrome
- Neurofibromatosis type 1
- NTHL1-associated polyposis
- Constitutional mismatch repair deficiency (CMMRD)
Clinical Presentation
Familial Adenomatous Polyposis
In FAP, the first adenomatous polyps usually appear in late childhood to adolescence. The number of polyps increases steadily over the years to hundreds or thousands, so by the age of 35, around 95% of FAP patients have polyps. These polyps have a tendency to degenerate, which almost always leads to colon cancer if left untreated. The average age is 39 years, but 7% of untreated FAP patients develop colon carcinoma by the age of 21.
In addition to colon carcinoma, the risk of developing other extracolonic malignancies is increased. Around 40% of FAP patients with colorectal carcinoma have another malignant tumor at the same time.
| Disease | Risk of disease |
|---|---|
| Small bowel carcinoma (duodenum or periampullary) | 4 – 12% |
| Small bowel carcinoma (distal to the duodenum) | rare |
| Adenocarcinoma of the pancreas | approx. 1% |
| Papillary thyroid carcinoma (cribriform-morular variant) | 1-12% |
| (WNT-activated) medulloblastoma (usually before the age of 3) | <1% |
| Hepatoblastoma | 1,6% |
| Bile duct carcinoma | low, but increased |
| Adenocarcinoma of the stomach | <1% |
Non-malignant extraintestinal manifestations also occur in the context of FAP:
| Disease | Risk of disease |
|---|---|
| Osteomas | 20% |
| Dental abnormalities, odontomas | 17% |
| Congenital hypertrophy of the retinal pigment epithelium (CHRPE) | 75% |
| Benign cutaneous lesions (e.g. epidermoid cysts, fibromas) | |
| Desmoid tumors (partly provoked by surgical interventions) | 10 – 30% |
| Space-occupying lesions in the area of the adrenal glands | 7 – 13% |
Attenuated Familial Adenomatous Polyposis
There are significantly fewer polyps in AFAP than in FAP (average of 30 polyps). There is also an increased risk of colorectal cancer in AFAP, although the average age of 50-55 years at diagnosis is higher than in FAP.
In addition to colorectal carcinoma, there is an increased risk of other gastrointestinal polyps and carcinomas and thyroid carcinomas in AFAP. Extraintestinal manifestations occur as in FAP, but CHRPE and desmoid cysts are rarer.
Gastric Carcinoma with Proximal Polyposis
This clinical picture, first described in 2012, involves polyposis of the gastric fundus glands, which can lead to stomach adenocarcinoma. The risk of developing gastric carcinomas in the corpus and fundus is increased compared to FAP and AFAP, but there is no increased risk of developing colon carcinomas.
Special Features of the Treatment
The treatment of colorectal adenomas or carcinomas essentially consists of colectomy. This is recommended in FAP as soon as adenomas appear, but it can be delayed depending on the size, histology, and number of adenomatous polyps. If a colorectal carcinoma is diagnosed, a colectomy is unavoidable.
A colectomy is also often necessary in AFAP. However, a colonoscopic polypectomy is sufficient in around a third of cases.
No standardized recommendations are yet available for GAPPS.
Diagnose APC-Associated Adenomatous Polyposis. Wie geht es weiter?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Diagnosis of "APC-Associated Adenomatous Polyposis" What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Recommendations for Early Detection in Your Patients
Prior guidelines have suggested delaying genetic testing for familial APC variants until closer to the age of the first colonoscopy; however, given an improved understanding of the early childhood tumor spectrum, the AACR guidelines 2024 continue to recommend testing in infancy or early childhood to initiate surveillance.
AACR 2024 Recommendations for Early Detection of FAP
Colorectal Carcinoma and Other Intestinal Carcinomas
- Yearly colonoscopy from age 10-15 years, later start may be considered in attenuated FAP
- Oesophagogastroduodenoscopy yearly from 20-25 years of age
Thyroid Carcinoma
- Thyroid ultrasound every 2 years from the age of 16, more often if nodules are found
Hepatoblastoma
- Abdominal ultrasound and AFP measurement every 3 months from birth to 7 years of age
Desmoid Tumors
- Palpatory examination of the abdomen annually
- Abdominal and pelvic MRI 1-3 years after colectomy every 5-10 years only in people at increased risk of desmoid tumours (positive family history, specific genotype: upstream codon 1400 and codon 543-714)
Medulloblastoma
- Clinical neurological examination from childhood yearly
- Explain the warning signs of increased intracranial pressure (severe or worsening headache, headache associated with vomiting and focal neurological symptoms, etc.).
Recommendations for Early Detection of GAPPS
- Regular gastroscopy from the age of 15
- Prophylactic gastrectomy may be considered from the age of 30-35, depending on the presence of fundal polyps, dysplasia and family history.
- Baseline colonoscopy at age 15 (or at diagnosis if later)
