Definition

APC-associated adenomatous polyposis (OMIM #175100) includes familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), and gastric carcinoma with proximal polyposis (gastric adenocarcinoma and proximal polyposis of the stomach, GAPPS). With FAP, starting in adolescence, it is most often the case for hundreds to thousands of intestinal polyps to occur – usually located in the colorectal region – that can progress if left untreated and lead to carcinomas. In addition, there is an increased risk that other malignant and benign tumors will develop.

AFAP is a variant of FAP with much fewer polyps and a later onset of carcinomas.

GAPPS is characterized by polyposis in the gastric fundus region and an increased risk of gastric carcinoma. The colon is only marginally involved.

Key Data
Diagnosis
Differential Diagnoses
Clinical Presentation
Therapeutic Considerations
Surveillance Recommendations
Additional Information

Key Data

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Synonym
Gene	APC
Gene product	APC
Function	Part of the β-catenin degradation complex in the Wnt signaling pathway
Heredity	Autosomal dominant
Prevalence	FAP: Incidence of 1:9,000-1:18,000 live births
Genotype-phenotype correlation	The most frequent APC mutation occurs in codon 1309 and leads to a large number of adenomas at a young age. The average age of onset correlates with the location of the mutation:  Codon 1309: 20 years, between codon 168 and 1580 (except for 1309): 30 years, 5′ of codon 168 and 3′ of codon 1580: 52 years A disproportionately high number of polyps have been found with mutations in codons 1250-1464. AFAP correlates with mutations in the 5′ region and the 3′ distal end of the APC gene and in Exon 9. There is an increased risk of desmoid tumors developing when there are mutations between codons 543 and 713 and between codons 1310 and 2011. APC promoter 1B mutations are associated with GAPPS.
Penetrance	Nearly 100% with FAP for untreated colorectal carcinoma Around 70% with AFAP for colorectal carcinoma up to 80 years of age

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Diagnosis

Clinical Diagnostic Criteria

APC-associated adenomatous polyposis is suspected when the following findings apply:

Multiple colorectal adenomatous polyps (at least 10-20)
A concomitant family history of multiple colorectal polyps and/or extracolic manifestations such as those listed below
Hepatoblastoma, particularly when there is no evidence of a 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 when the following findings are present: early onset of colorectal carcinoma with few or no adenomatous polyps, dental anomalies (e.g. excess teeth), odontomas, osteomas, epidermoid cysts, duodenal adenomas and carcinomas, ventricular polyposis, or gastric, pancreatic, or small intestinal carcinoma.

Genetic Diagnostics

The diagnosis of “APC-associated adenomatous polyposis” is confirmed by the detection of a heterozygous germline mutation in the APC gene through sequence analysis or deletion/duplication analysis. It may be helpful to use panel examinations consisting of multiple genes.

Diagnostic Criteria

The diagnosis of “familial adenomatous polyposis (FAP)” is confirmed by the detection of a heterozygous germline mutation in the APC gene and one of the following:

At least 100 colorectal adenomatous polyps (there may be fewer than 100 polyps in young patients or after a colectomy)
Multiple, but fewer than 100 adenomatous polyps and a relative with confirmed FAP

The diagnosis of “attenuated familial adenomatous polyposis (AFAP)” is confirmed by the detection of a heterozygous germline mutation in the APC gene in conjunction with

a relative with confirmed AFAP and/or
fewer than 100 colorectal adenomatous polyps or
more than 100 colorectal adenomatous polyps at an advanced age (> 40 years)

The diagnosis of “gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)” is confirmed in patients presenting with the following findings:

Gastric polyps limited to the corpus and fundus
More than 100 polyps in the proximal stomach or more than 30 polyps in a first-degree relative
Mainly polyps of the fundic glands, a few of them exhibiting dysplastic regions (or a relative with dysplastic polyps of the fundic glands or gastric carcinoma)
Pattern of an autosomal-dominant mode of inheritance
No evidence of colorectal or duodenal polyposis

Differential Diagnoses

MUTYH-associated adenomatous polyposis
Hereditary non-polyposis colorectal carcinoma, also Lynch syndrome
MSH3-associated polyposis
Peutz-Jeghers syndrome
PTEN hamartoma tumor syndrome, also 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

With FAP, the first adenomatous polyps usually do not occur until late childhood or adolescence. Over the course of years, the number of polyps constantly increases, with around 95% of FAP patients exhibiting polyps at the age of 35. These polyps have a tendency to progress, almost always leading to the development of colon carcinoma if left untreated. While the average age here is 39 years, colon carcinoma already develops in 7% of untreated FAP patients by age 21.

In addition to colon carcinoma, the risk of developing other extracolic malignant diseases is also higher. Around 40% of FAP patients with colorectal carcinoma have another malignant tumor at the same time as well.

Disease	Risk of Disease
Small intestinal carcinoma (duodenal or periampullary)	4 – 12%
Small intestinal carcinoma (of the distal duodenum)	Rare
Pancreatic adenocarcinoma	Approx. 1%
Papillary thyroid carcinoma (cribriform-morular variant)	1-12%
(WNT-activated) medulloblastoma (usually before 3 years of age)	<1%
Hepatoblastoma	1,6%
Cholangiocarcinoma	Slight, but increased
Gastric adenocarcinoma	<1%

Non-malignant extraintestinal manifestations also occur as part 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 (in part provoked by surgical interventions)	10 – 30%
Space-occupying lesions in the area of the adrenal glands	7 – 13%

Attenuated Familial Adenomatous Polyposis

With AFAP, much fewer polyps occur than with FAP (30 polyps on average). While there is also an increased risk of colorectal carcinoma with AFAP, the average age is 50-55 at the time of diagnosis and therefore much higher than with FAP.

In addition to colorectal carcinoma, AFAP also involves an increased risk of other gastrointestinal polyps, carcinomas, and thyroid carcinomas. Extraintestinal manifestations occur as with FAP, although CHRPE and desmoid cysts are rarer.

Gastric Carcinoma with Proximal Polyposis

In this clinical picture, first described in 2012, polyposis of the gastric fundic glands occurs, which may lead to gastric adenocarcinoma. The risk of developing gastric carcinoma in the corpus and fundus regions is greater compared to FAP and AFAP, but there is no increased risk that colon carcinoma will develop.

Therapeutic Considerations

A colectomy is the basic therapy used for colorectal adenomas and carcinomas. This is recommended for FAP as soon as adenomas occur; however, it may be delayed depending on the size, histology, and number of adenomatous polyps. If colorectal carcinoma is diagnosed, a colectomy is inevitable.

A colectomy is frequently necessary for AFAP as well. However, a colonoscopic polypectomy is sufficient in around one third of all cases.

No general recommendations are available for GAPPS to date.

Surveillance Recommendations

Surveillance Recommendations for FAP

Colorectal Carcinoma and Other Intestinal Carcinomas

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

Thyroid Carcinoma

Palpatory examination, possibly with an ultrasound of the thyroid from 15-19 years of age; annually

Hepatoblastoma

Ultrasound of the abdomen and AFP in the serum from birth until 7 years of age; every 4-6 months

Desmoid Tumors

Palpatory examination of the abdomen; annually
MRI/CT of the abdomen and pelvis when a concomitant family history of Desmoid tumors exists; within the first three years after the colectomy, then every 5-10 years

Medulloblastoma

Clinical neurological examination starting in childhood; annually

Surveillance Recommendations for AFAP

Colorectal Carcinoma and Other Intestinal Carcinomas

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