What is PTEN hamartoma tumor syndrome (PHTS)?

PTEN hamartoma tumor syndrome (PHTS) is disease due to a mutation (an inheritable and harmful change) in the PTEN gene. “Hamartoma” is a general term for a benign, or non-cancerous, tumor-like growth. PHTS includes patients with Cowden syndrome and Bannayan Ruvalcaba-Riley syndrome (BRRS).

Cowden syndrome and BRRS were first thought to be completely separate. But because they are caused by mutations in the same gene, patients with these syndromes face similar health risks. Patients with PHTS can develop characteristics associated with both Cowden syndrome and BRRS over their lifetime.

PTEN is a gene that makes a working protein with important roles in controlling cell growth and division. When a mutation stops PTEN from making this protein, uncontrolled cell growth can occur.

What is PHTS/Cowden syndrome?

This uncontrolled cell growth becomes obvious in patients with Cowden syndrome. These patients may develop both benign and malignant tumors, which commonly affect the breasts, uterus, thyroid, gastrointestinal tract, skin, and tongue and gums.

Other common findings in Cowden syndrome are a large head size (macrocephaly) and a variety of small benign skin tags. Cowden syndrome occurs in an estimated 1 out of every 250,000 people. The diagnosis of Cowden syndrome is made when a patient meets specific criteria (signs) of the disease.

People with Cowden syndrome are at greater risk than the general population for various cancers (see risks section below).

What is PHTS/Bannayan-Riley-Ruvalcaba syndrome (BRRS)?

In contrast to Cowden syndrome, BRRS tends to appear in childhood. This syndrome is suspected in people with:

• Fatty tumors (lipomas) on the skin
• Developmental delays, a large head size (macrocephaly)
• Certain type of polyps in the gastrointestinal tract
• Vascular malformations such as birthmarks
• Freckling on the penis

Little is known about the cancer risks of BRRS.

What are the cancer risks associated with PHTS/Cowden syndrome?

People with PHTS/Cowden syndrome require lifelong cancer screening and medical care by a healthcare team knowledgeable about PHTS/Cowden syndrome. This team may include endocrinologists, gastroenterologists, surgeons, gynecologists, breast health specialists, primary care physicians, geneticists, genetic counselors, hematologists and oncologists. The risks of various cancers for patients with PHTS/Cowden syndrome are shown below.

Cancer Type: Breast

• General population risk: 12%
• Lifetime risk with PHTS: ~85% (average age of diagnosis in 40s)
• Lifetime risk with Cowden syndrome, negative PTEN testing: 25-50%

Cancer Type: Thyroid

• General population risk: 1%
• Lifetime risk with PHTS: 35% (average age of diagnosis in 30s/40s)
• Lifetime risk with Cowden syndrome, negative PTEN testing: ~10%

Cancer Type: Endometrial (uterine)

• General population risk: 2.6%
• Lifetime risk with PHTS: 28% (average age of diagnosis in 40s/50s)
• Lifetime risk with Cowden syndrome, negative PTEN testing: Thought to be increased, but exact risk unknown

Cancer Type: Renal cell (kidney)

• General population risk: 1.6%
• Lifetime risk with PHTS: 34% (average age of diagnosis in 50s)
• Lifetime risk with Cowden syndrome, negative PTEN testing: Possibly increased, exact risk unknown

Cancer Type: Colon

• General population risk: 5%
• Lifetime risk with PHTS: 9% (average age of diagnosis in 40s)
• Lifetime risk with Cowden syndrome, negative PTEN testing: Possibly increased, exact risk unknown

Cancer Type: Melanoma

• General population risk: 2%
• Lifetime risk with PHTS: 6% (average age of diagnosis in 40s)
• Lifetime risk with Cowden syndrome, negative PTEN testing: Possibly increased, exact risk unknown

What are the signs of PHTS/Cowden syndrome?

Signs of PHTS/Cowden syndrome can include:

• Breast: Women with PHTS/Cowden syndrome can develop benign growths of many different types in their breasts. Common findings include fibrocystic changes, fibroadenomas, papillomas and atypical ductal hyperplasia.
• Uterus: Women with PHTS/Cowden syndrome can also develop benign fibroid tumors of the uterus.
• Thyroid: Men and women with PHTS/Cowden syndrome can also develop benign thyroid growths such as a multinodular goiter and/or Hashimito’s thyroiditis, an autoimmune thyroid condition.
• Intestinal: About 90 percent of patients with PHTS/Cowden syndrome will develop gastrointestinal polyps, ranging from one per patient to innumerable. Polyps can occur in both the colorectum and the upper gastrointestinal tract. Every microscopic type of polyp has been reported to occur in patients with PHTS/Cowden syndrome, but the most common types are hamartomatous and hyperplastic polyps, which both have low potential to become cancer. However recent studies show patients with Cowden syndrome have a significantly increased risk of colorectal cancer and need a regular screening colonoscopy.
• Skin: The characteristic skin findings of patients with PHTS/Cowden syndrome are papillomatous papules (benign, skin-colored, raised bumps), trichilemmomas (benign tumors coming from the outer cells of the hair follicle, most frequently on the head), and lipomas (benign fatty growths). Many patients develop papillomas on their gums and/or tongue, giving them a “cobblestone” appearance. Men with PHTS/Cowden syndrome can develop freckles on their penis. Many people with PHTS/Cowden syndrome also have acral and plantar keratoses (dark flat spots on their hands and feet) and some have hemangiomas or vascular malformations. The skin findings are often present by the time patients are in their late 20s.
• Head and brain: People with PHTS/Cowden syndrome also tend to have a large head size (macrocephaly) and a head shape that is especially long (dolichocephaly). Patients are also at increased risk to develop Lhermitte-Duclos disease, a benign tumor of the cerebellum (the part of the brain that controls coordination of movement). Autism and developmental delay have also been observed at increased frequency in people with PHTS/Cowden syndrome.

How is PHTS/Cowden syndrome inherited?

Everyone has two copies of the PTEN gene. People with PHTS have a mutation in one copy of their PTEN gene pair. The copy of the gene with the mutation can be passed on to future generations. The chance that a child of someone with PHTS would inherit the copy of the gene with the mutation is 50 percent. The chance that he or she would not inherit the mutation is also 50 percent.

People diagnosed with PHTS/Cowden syndrome should tell their family members about their diagnosis and encourage them to undergo genetic counseling. For patients with Cowden syndrome who do not have a PTEN gene mutation, family members may need evaluation by a medical geneticist to determine if they also meet the clinical criteria for a diagnosis of Cowden syndrome.

This includes an evaluation of their personal history, exploration of the family history, and genetic testing if a PTEN gene mutation has previously been identified in the family. Recommendations to keep the patient and his or her family healthy and to prevent cancer will also be provided.

How is PHTS/Cowden syndrome diagnosed?

PHTS is diagnosed when a mutation is found in the PTEN gene. The International Cowden Consortium has developed criteria (guidelines) to establish a diagnosis of Cowden syndrome. Additionally, both the National Comprehensive Cancer Network and Cleveland Clinic have established genetic testing guidelines for PHTS/Cowden syndrome. These are updated frequently based on new research.

A PHTS/Cowden syndrome evaluation should be considered for people with adult-onset Lhermitte-Duclos disease, macrocephaly plus autism/developmental delay, numerous and mixed types of gastrointestinal polyps or a combination of PHTS/Cowden syndrome features, such as thyroid and uterine cancers or breast and kidney cancers.

If a patient is found to meet clinical or testing criteria, testing of the PTEN gene may be offered. Genetic testing is done through a blood sample. Once a mutation is identified in a patient, family members can be tested for that mutation in order to determine who else in the family has PHTS.

How is PHTS/Cowden syndrome treated?

Currently, there is no cure for PHTS/Cowden syndrome. Patients undergo lifelong surveillance to monitor for benign and cancerous growths to help detect any problems at the earliest, most treatable point in time.

It’s recommended that people with PHTS/Cowden syndrome have:

• Specialized breast cancer screening. This should include breast self-examination every month beginning at age 18, breast examination by a doctor or nurse every 6 months beginning at age 25, and mammography/breast MRI once a year beginning at age 30-35 or 5-10 years earlier than the youngest breast cancer diagnosis in the family. There are men with PHTS/Cowden syndrome who have developed breast cancer. Although the risk is much lower than that for women, we would recommend that the men perform monthly breast self-examination. Some women at increased risk for breast cancer consider prophylactic mastectomy (removal of the breasts to prevent cancer).
• Thyroid cancer screening. For persons with PTEN mutations we recommend a baseline thyroid ultrasound at the age of diagnosis with at least yearly follow-up thereafter by an endocrine specialist.
• Imaging of the kidneys every 1-2 years starting at age 40.
• A baseline colonoscopy (examination of the colon and rectum with flexible lighted tube) should be done at age 35 years, or 5-10 years younger than the earliest colorectal cancer diagnosis in the family, with follow-up dependent on the number and type of polyps found. A variety of different types of hamartomatous polyps are commonly seen in the upper gastrointestinal tract and colorectum in persons with PTEN mutations. Baseline upper endoscopy may be recommended to help establish or confirm the diagnosis of Cowden syndrome. Ongoing upper endoscopic exam of the stomach and upper small bowel is based upon the findings on the baseline exam.
• Dermatologic management if needed.
• Women who are PTEN positive should also see a gynecologic oncologist to discuss what kind of screening for endometrial cancer should be performed. Consideration can be given to annual random endometrial biopsies.

PLEASE NOTE: There are no studies that prove that cancer screening is effective for individuals with PHTS/Cowden syndrome. The recommendations are based on the opinion of experts in the field of cancer genetics and PHTS/Cowden syndrome. As with most cancer screening, these recommendations will hopefully help to detect cancers at an earlier stage when they are more treatable, but they cannot prevent the cancer from occurring.