What Is Cowden Syndrome? Its Relationship with PTEN Mutation, Symptoms and Treatment

What is Cowden syndrome (CS)?

Cowden syndrome (CS), with a PTEN gene mutation as its cause, is part of a group of hereditary disorders called PTEN hamartoma tumor syndrome. Multiple hamartoma syndrome is another name for it. Hamartomas are benign (noncancerous) and show tumor-like growth. Bannayan-Riley-Ruvalcaba syndrome (BRR; diagnosed in children), Proteus syndrome and Proteus-like syndromes are other clinical syndromes that are part of PTEN hamartoma tumor syndrome.

Cowden syndrome carries a high risk of both benign and cancerous tumors in organs such as the breast, thyroid, endometrium, colorectum, kidney and skin. Other distinctive features of Cowden syndrome include skin changes such as trichilemmomas and papillomatous papules, and macrocephaly (a larger-than-normal head size).

How is CS diagnosed?

The diagnostic criteria for CS are complex and are frequently updated as genetics specialists obtain new information. CS can sometimes be difficult to diagnose. For this reason, teams of hereditary cancer risk specialists, including oncologists, genetics specialists, genetic counselors and nurses certified in hereditary cancer, worked together to establish diagnostic categories called major and minor criteria, outlined in National Comprehensive Cancer Network (NCCN) guidelines.

Below are the current major (main) and minor (secondary) criteria, as well as the genetic testing criteria for CS.

Major criteria:

• Breast cancer
• Endometrial cancer
• Follicular thyroid cancer
• Multiple gastrointestinal hamartomas or ganglioneuromas
• Macrocephaly
• Macular pigmentation of the glans penis (that is, a colorless area on the penis)
• Mucocutaneous lesions
• One biopsy-proven trichilemmoma
• Multiple palmoplantar keratoses (abnormal thickening on the hands and feet)
• Multifocal or widespread oral mucosal papillomatosis
• Multiple cutaneous facial papules, usually verrucous, meaning wart-like projections

Minor criteria:

• Colon cancer
• Esophageal glycogenic acanthosis (a type of esophageal disease)
• Autism spectrum disorder
• Intellectual disability
• Papillary or follicular variant of papillary thyroid cancer
• Thyroid lesions such as adenoma, nodule or goiter
• Renal cell carcinoma
• Vascular anomalies
• Lipomas (benign soft-tissue tumors)
• A single gastrointestinal hamartoma or ganglioneuroma
• Testicular lipomatosis

Various skin lesions from different patients with Cowden syndrome can be seen below.

What are the testing criteria for PTEN mutation in Cowden syndrome?

People with a history of any of the following should have PTEN mutation genetic testing performed:

• A family with a known PTEN gene mutation
• Meeting the clinical diagnostic criteria for CS above
• Bannayan-Riley-Ruvalcaba syndrome (BRR)
• Adult Lhermitte-Duclos disease (cerebellar tumors)
• Autism spectrum disorder and macrocephaly
• A diagnosis of trichilemmoma with two or more biopsies
• Two or more of the major criteria above (one must be macrocephaly)

For CS to be suspected, a person must have one of the following:

• 3 major criteria without macrocephaly
• 1 major and 3 minor criteria
• 4 minor criteria
• A relative diagnosed with CS or BRR

Research to better understand CS is ongoing. Approximately 80% of people diagnosed with CS have a mutation in the PTEN gene. A blood test can determine whether a person has a mutation in the PTEN gene. If a person has a mutation in the PTEN gene, CS is diagnosed.

How is CS passed to subsequent generations?

Normally, each cell has 2 copies of a gene, one inherited from the mother and one from the father. Cowden syndrome shows autosomal dominant inheritance, and a mutation in just one copy of a gene is sufficient for it to occur. This means that a parent with the gene mutation can pass a copy of either their normal gene or their mutated gene to their child. Therefore, a child with a parent who has the mutation has a 50% chance of inheriting it. The brother, sister or parent of a person with the mutation also has a 50% chance of having the same mutation. However, if the parents test negative for the mutation (no mutation is found in the test results), the risk to siblings is substantially reduced, although their risk may still be higher than average.

Some options are available for people who carry a hereditary cancer syndrome and want to have children. Preimplantation genetic diagnosis (PGT) is a medical procedure performed with in vitro fertilization (IVF) that can enable people to have children without passing on a specific gene mutation. The woman's eggs are removed and fertilized in a laboratory. When the embryos reach a certain size (approximately 8 cells), 1 cell is removed and tested for the hereditary condition in question. The parents can then choose to transfer embryos without the mutation into the woman's uterus. PGT has been used for more than twenty years to prevent various hereditary cancer predisposition syndromes. However, it is a complex procedure requiring consideration of financial, physical and emotional factors before starting PGT.

How common is CS?

CS is thought to be rare, although it is underdiagnosed. CS is estimated to affect approximately 1 in every 200,000 people.

As hereditary cancer testing expands to include multigene panels, the classic definition of syndromes such as CS may change. Some individuals may have a mutation in the PTEN gene but meet none of the CS criteria listed above. It is not known whether these people have the same risks of developing cancer.

What are the estimated cancer risks associated with CS?

• The greatest cancer risk for a woman with CS is breast cancer. A woman with CS is estimated to have a lifetime breast cancer risk in the range of 50% to 85%. Breast cancer may develop earlier in women with CS than in the general population. There is also a slightly increased risk of a second breast cancer in the other breast, and of breast cancer in men with CS, but the specific risk is not known.
• The risk of thyroid cancer in men and women with CS is estimated to be in the range of 30% to 40%. Thyroid cancer in CS is most commonly follicular but may also be papillary.
• The risk of developing kidney cancer is in the range of 30% to 35% and is one of the highest cancer risks for people with a PTEN gene mutation.
• The risk of endometrial cancer in women with CS is between 25% and 30%.
• The risk of colorectal cancer is in the range of 5% to 10%, and it generally occurs at a younger age than in the general population.
• The risk of melanoma is 6%. It is important to use sunscreen before age 20 to reduce this risk. Melanoma is influenced by many factors, such as skin, eye and hair color, sun exposure and, in some cases, inherited gene mutations.
• Other types of cancer have also been seen in people with CS, including liver, ovarian, bladder, skin (basal cell, squamous cell or Merkel cell), brain cancer, liposarcoma and non-small cell lung cancer. It is not yet known whether these cancer risks are increased in people with CS.

What are the screening options for CS?

Since every person is different, you can discuss the following screening options with your doctor:

At diagnosis:

For people with CS of any age: annual thyroid ultrasound screening and an annual skin examination.

From age 30:

Women with CS: annual mammography, annual breast MRI (according to the 2015 NCCN guideline), annual endometrial biopsy or transvaginal ultrasound (or 5 years before the age of the first uterine cancer in the family).

From age 40:

All adults with CS: colonoscopy every 2 years and kidney ultrasound screening or MRI every 2 years.

Preventive surgery:

Women with CS: Removal of the breasts for protection before cancer develops, in an operation called prophylactic mastectomy, may be considered. In addition, the uterus may be removed for protection in a procedure called prophylactic hysterectomy.

Surveillance (close medical monitoring) may begin 5 to 10 years before the age of the youngest person in the family diagnosed with a particular cancer (for example, if someone in your family was diagnosed at 40, your monitoring should begin at 30 or 35), but no later than the ages stated above. The frequency of planned colonoscopies may increase depending on how many polyps are found.

Screening options may change over time as new technologies are developed and more is learned about CS. You can discuss appropriate screening tests with your healthcare team.

Questions to ask the healthcare team

If you are concerned about your cancer risk, you can talk to your healthcare team. It may be helpful to bring someone to your appointments to take notes. You can ask your healthcare team the following questions:

• What is my risk of developing cancer?
• Where can I go for a hereditary cancer risk assessment?
• What can I do to reduce my cancer risk?
• What are my options for cancer screening and prevention?

If you are concerned about your family history and think your family may have CS, you can ask the following questions:

• Does my family history increase my cancer risk?
• Could my family have CS?
• Would you refer me to a genetic counselor for a cancer risk assessment?
• Should I see a genetic counselor?