What is APC-associated adenomatous polyposis?

APC-associated adenomatous polyposis includes three diseases caused by mutations – or genetic changes – in the APC gene, namely familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), and stomach cancer with proximal polyposis (gastric adenocarcinoma and proximal polyposis of the stomach, GAPPS).

Starting in adolescence, FAP usually leads to the development of hundreds to thousands of polyps (protrusions of mucous membrane) that are located in the gastrointestinal tract, most frequently in the large intestine. These polyps can progress and result in malignant diseases, such as colon cancer. In addition, there is an increased risk that other benign and malignant tumors will develop.

AFAP is a variant of FAP which is characterized by fewer polyps and a later onset of malignant disease.

GAPPS is characterized by a large number of gastric polyps and an increased risk of stomach cancer. It rarely affects the intestine.

How is APC-associated adenomatous polyposis diagnosed?

Clinical Diagnostics

APC-associated adenomatous polyposis is suspected in a person who exhibits at least one of the following:

  • Multiple polyps in the colon (at least 10-20)

  • Relatives with multiple polyps in the colon and/or manifestations outside of the gastrointestinal tract

  • Congenital hypertrophy of the retinal pigment epithelium, or CHRPE (pigment spots in the retina)

  • Desmoid tumor (a connective tissue tumor that often occurs post- surgery)

  • Papillary thyroid cancer

  • A specific form of medulloblastoma (a malignant brain tumor) (called a WNT-activated, CTNNB1 wildtype)

  • A specific form of hepatoblastoma (a malignant liver tumor) (called a hepatoblastoma without a CTNNB1 mutation)

In addition, genetic testing for an APC mutation should be considered with presentation of the following: early onset of colon cancer with few or no polyps, dental abnormalities (e.g. excess teeth), odontomas (benign tumors of the tooth-forming tissue), osteomas (benign bone tumors), epidermoid cysts (benign cysts arising from skin cells), benign or malignant tumors of the duodenum, multiple polyps in the stomach, or cancer of the stomach, pancreas, or small intestine.

Genetic Diagnostics

The diagnosis of “APC-associated adenomatous polyposis” is confirmed by the detection of a mutation – or genetic change – in the APC gene.

Diagnostic Criteria

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

  • At least 100 polyps in the large intestine (there may be fewer than 100 polyps in young patients or after the colon has been removed)

  • Multiple, but fewer than 100 polyps and a relative with confirmed FAP

The diagnosis of attenuated familial adenomatous polyposis (AFAP) is confirmed by the detection of a mutation in the APC gene and:

  • a relative with confirmed AFAP and/or

  • fewer than 100 polyps in the large intestine or

  • more than 100 polyps in the large intestine 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:

  • Gastric polyps limited to the corpus and fundus (body and fundus of the stomach)

  • More than 100 polyps in the upper stomach (corpus and fundus) or more than 30 polyps in a first-degree relative

  • Polyps primarily in the fundus of the stomach; a few patients exhibit regions with an altered tissue structure (or have a relative who has polyps of the stomach fundus with an altered tissue structure or has stomach cancer)

  • An autosomal-dominant pattern of inheritance

  • No indications of polyps in the large intestine or duodenum

What is the risk of cancer?

Familial Adenomatous Polyposis

With FAP, the first 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 developing polyps by the age of 35. These polyps have a tendency to progress and invariably lead to the development of colon cancer if left untreated. While the average age here is 39 years, 7% of untreated FAP patients have already developed colon cancer by the age of 21.

In addition to colon cancer, the risk of developing other malignant diseases is also higher. Around 40% of FAP patients with colon cancer develop another malignant tumor.

Disease Risk of Disease
Cancer of the small intestine 4-12%
Pancreatic cancer Approx. 1%
Papillary thyroid cancer 1-12%
Medulloblastoma <1%
Hepatoblastoma 1,6%
Biliary tract cancer minor, but increased
Stomach cancer <1%

Benign changes occur as part of FAP as well:

Manifestation Frequency of Occurrence with FAP
Osteomas (benign bone tumors) 20%
Dental abnormalities, benign tumors of the tooth-forming tissue 17%
Congenital hypertrophy of the retinal pigment epithelium (CHRPE) 75%
Benign skin lesions (e.g. epidermoid cysts, fibromas) Unknown
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, way fewer polyps occur than with FAP (30 polyps on average). While there is also an increased risk of colon cancer with AFAP, the average age at diagnosis is 50-55 and therefore much higher than with FAP.

In addition to colon cancer, AFAP also involves an increased risk of other gastrointestinal polyps/cancer and thyroid cancer. Diseases outside of the gastrointestinal tract occur as with FAP, although CHRPE and desmoid cysts are rarer.

Stomach Cancer with Proximal Polyposis

In this clinical picture, which was first described in 2012, numerous polyps that can lead to stomach cancer develop in the stomach fundus. The risk of stomach cancer is greater compared to FAP and AFAP, but there is no increased risk that colon cancer will develop.

What causes APC-associated adenomatous polyposis?

APC-associated adenomatous polyposis is caused by a mutation – or genetic change – in the APC gene. This gene encodes for the APC protein, which is responsible for breaking down another protein, β-catenin. β-catenin in turn regulates cell division and by extension cell proliferation.

Now if the APC gene is present in an altered form, β-catenin will no longer be broken down by the APC protein. The resulting massive amount of β-catenin therefore results in the unregulated proliferation of cells, which leads to the formation of polyps and tumors.

Most of the people affected inherited the genetic change from a parent. Around 75-80% of patients have a parent who also suffers from APC-associated adenomatous polyposis. It is inherited as an autosomal dominant disorder.

Is there a treatment?

The treatment of colon cancers or their preliminary stages mainly involves the surgical removal of the colon (colectomy). This is recommended for FAP as soon as adenomas (benign tumors that are regarded as a preliminary stage of cancer) occur; however, the procedure may be delayed depending on the size, histology, and number of adenomatous polyps present. If colon cancer is diagnosed, a colectomy is inevitable.

A colectomy is frequently necessary for AFAP as well. But approximately one third of cases only require removal the polyps by colonoscopy.

No general recommendations are available for GAPPS to date.

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

FAP

Colon Cancer and other Cancers of the GastrointestinalTract

  • A colonoscopy from 10-15 years of age; once a year until the surgery

  • A gastroscopy from 20-30 years of age (recommendations vary); every 6 months up to every 4 years (depending on the number, size, histology, and the nature of polyp tissue alterations)

Thyroid Cancer

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

Hepatoblastoma

  • Ultrasound of the abdomen and a blood test (AFP in the serum) from birth until 7 years of age; every 4-6 months

Desmoid Tumors

  • Examination of the abdomen; annually

  • MRI/CT of the abdomen and pelvis when desmoid tumors are in the family; within the first three years after the colectomy, then every 5-10 years

Medulloblastoma

  • Clinical neurological examination starting in childhood; annually

AFAP

Colon cancer and other cancers of the gastrointestinal tract

  • Colonoscopy from 15-19 years of age; every 3 years until adenomas occur, then annually

  • A gastroscopy from 20-30 years of age (recommendations vary); every 6 months up to every 4 years (depending on the number, size, histology, and the nature of polyp tissue alterations)

Thyroid Cancer

  • Palpatory examination and an ultrasound of the thyroid from 15-19 years of age; annually

Medulloblastoma

  • Clinical neurological examination starting in childhood; annually

GAPPS

It is as yet unknown whether surveillance examinations for the early detection of stomach cancer or precautionary removal of the stomach yield positive results.

Self-Care and Support

What should I pay special attention to?

You should see a doctor as soon as you develop symptoms affecting the gastrointestinal tract. They may involve blood or mucous in the stool, stool abnormalities such as diarrhea or constipation, flatulence, or pain. Even non-specific signs such as weight loss should be paid attention to and reported to a doctor so that he or she can check whether you have colon cancer.

You should also see a doctor right away if you notice any other newly occurring anomalies or symptoms, such as difficulty swallowing, skin lesions, abdominal pain, headaches, or dizziness.

Support Groups and Additional Information