APC-Associated Adenomatous Polyposis

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 APC mutation 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 mutation:
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 mutations in codons 1250-1464.
AFAP correlates with mutations at the 5′ end and distal to the 3′ end of the APC gene, as well as in exon 9.
Mutations 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%

Overview of the Chapters on This Page:

APC-Associated Adenomatous Polyposis – Definition (This Section)

APC-Associated Adenomatous Polyposis – Diagnosis

Clinical Presentation

Special Features of Treatment

Recommendations for Early Detection in Your Patients

Further Information (e.g., Links to Support Groups)

APC-Associated Adenomatous Polyposis – Definition (This Section)

APC-Associated Adenomatous Polyposis – Diagnosis

Clinical Presentation

Special Features of Treatment

Recommendations for Early Detection in Your Patients

Further Information (e.g., Links to Support Groups)

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 mutation
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 an APC mutation 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 germline mutation 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 germline mutation 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 germline mutation 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 PolyposisWhat's Next?

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

Flexible sigmoidoscopy or colonoscopy from 10-15 years, annually until surgery
Esophagogastroduodenoscopy from 20-30 years (recommendations vary); every 6 months to every 4 years (depending on the number, size, histology, and dysplasia of the polyps)

Thyroid Carcinoma

Initiate thyroid cancer screening with ultrasound for all patients with Familial Adenomatous Polyposis (FAP) starting at age 16 and repeating ultrasound screenings every 2 years
Physical exams are not preferred for screening papillary thyroid carcinoma (PTC) due to their lower sensitivity
The risk of benign thyroid nodules in patients with FAP is estimated to be between 9% and 44%. Thus, fine-needle aspiration biopsy should be considered before surgical intervention
Consult with a pediatric endocrinologist experienced in evaluating thyroid nodules and tumor predisposition syndromes

Hepatoblastoma

In Europe, routine abdominal sonography and serum alpha-fetoprotein (AFP) testing are not recommended due to the only slightly increased risk of hepatoblastoma
In the USA and Canada, early detection of hepatoblastoma is recommended from birth to age 7, with screenings conducted every 4 to 6 months
Patients with familial adenomatous polyposis (FAP) should undergo screening for hepatoblastoma
The recommended screening for FAP patients includes abdominal ultrasounds and serum AFP testing every 3 months, starting from the time of FAP diagnosis until they reach 7 years of age

Desmoid Tumors

Palpatory examination of the abdomen annually
MRI/CT of the abdomen and pelvis 1 to 3 years after colectomy if there is a positive family history of desmoid tumors within the first three years after colectomy, then every 5-10 years

Medulloblastoma

Clinical neurological examination from childhood annually
Annual neurologic examinations should be conducted carefully. Parents should be educated about the signs and symptoms of brain tumors, such as severe or worsening headaches, headaches accompanied by vomiting, and focal neurologic symptoms. A low threshold for rapid evaluation with neuroimaging is essential.

Recommendations for Early Detection of AFAP

Colorectal Carcinoma and Other Intestinal Carcinomas

Colonoscopy from 15-19 years; every 3 years until adenomas appear, then annually
Esophagogastroduodenoscopy from 20-30 years of age (recommendations vary); every 6 months to every 4 years (depending on the number, size, histology, and dysplasia of the polyps)

Thyroid Carcinoma

Palpatory examination and sonography of the thyroid gland from 15-19 years; annually

Medulloblastoma

Clinical neurological examination from childhood; annually

Recommendations for Early Detection of GAPPS

Screening with upper endoscopy is recommended to begin at age 15. Prophylactic gastrectomy should be considered between the ages of 30 and 35, especially if there are fundic gland polyps, dysplasia, or a family history of cancer. It is important to note that GAPPS does not indicate a high risk for colorectal cancer; however, a baseline colonoscopy should be performed once at age 15.