General
Multiple Hamartoma Syndrome (also known as Cowden Disease and Cowden Syndrome) is part of a group of conditions known as the PTEN Hamartoma Tumour Syndromes (PHTS),
which includes Cowden Syndrome,
Bannayan-Riley-Ruvalcaba Syndrome,
Proteus Syndrome and Proteus-like syndrome.
These conditions are linked to mutations of the PTEN tumour suppressor gene and a mutation is identified in 85% of patients with Cowden Syndrome [1].
Cowden Syndrome is the only one of the group with a definite increased risk of malignancy [2] with one study showing an 89% lifetime risk of cancer [3].
As the name suggests,
hamartomas and other benign neoplasms are associated and can involve many different parts of the body.
It has a prevalence of approximately 1 in 200,000 and is more common in females [4].
It is autosomal dominant with approximately 40-60% inherited and the remainder due to new mutations [2].
The syndrome can present in a variety of ways making the diagnosis difficult,
relying on clinical suspicion and satisfying certain criteria,
which are set out in various guidelines [4,
5].
Skin and Subcutaneous
Cutaneous lesions are a major feature and are seen in 99% of patients by the age of 30 [1].
These include trichilemmomas (arising from hair follicles),
acral keratoses (wart-like lesions on the hands and feet) and papillomatous papules involving the hands,
feet,
face and mouth [2,
4,
5].
Subcutaneous lesions such as lipomas and vascular malformations are also associated [5].
Neurological
Lhermitte-Duclos disease describes a dysplastic cerebellar gangliocytoma and the lifetime risk of developing this is 32% in patients with Cowden Syndrome [3].
It normally presents between the ages of 20 and 40 [6] and is considered pathognomonic of Cowden Syndrome in adults [7].
Although this is not malignant it can cause a variety of symptoms such as ataxia,
headache and seizures due to mass effect and raised intracranial pressure.
The classic imaging appearance is a low T1,
high T2 lesion which does not enhance arising from a cerebellar hemisphere with a “tiger-stripe” appearance due to enlargement of the cerebellar folia [6,
8].
They are treated with excision but can reoccur after surgery [7].
Macrocephaly and dolicocephaly are also associated with Cowden Syndrome.
Thyroid
Thyroid disease is thought to affect between 50% and 70% of patients with Cowden Syndrome [9].
In this group of patients thyroid cancer is normally follicular or papillary,
with those patients positive for the PTEN mutation having a much higher risk of follicular thyroid cancer than those without [10].
Estimates of lifetime risk vary between 10% [2,
4] and 20% [3] chance of developing thyroid cancer compared to 1% in the general population.
Medullary thyroid cancer is not thought to be associated [1].
Benign thyroid abnormalities such as multinodular goitre,
thyroiditis and adenomas are also common [9]
Breast
The most common malignancy associated with Cowden Syndrome is breast cancer and the lifetime risk for females is approximately 25-50% compared to 12-13% in the general population [2,
4],
although some studies has shown higher risks of 85% [11] and 81% [3].
It tends to present at a younger age with an average of 38-46 years [12].
Patients are also at increased risk of developing benign breast lesions such as breast hamartomas,
fibroadenomas and fibrocystic change [5].
There is also an increased risk of male breast cancer.
GI
Multiple gastrointestinal polyps are common in this group of patients and can occur at any point in the gastrointestinal tract [13].
They are identified in up to 95% of patients with Cowden Syndrome having colonoscopy [5].
Several types of polyp such as hamartomas,
lipomas,
ganglioneuromas,
fibrous polyps,
leiomyomas,
hyperplastic,
inflammatory and adenomatous polyps,
may be seen [4,
14].
Patients with Cowden Syndrome are at increased risk of colorectal cancer [11] and screening can be difficult in the context of multiple polyps as these are not always benign [14].
Other
Women are at increased risk of developing endometrial cancer with a 5-10% lifetime risk compared to 2-4% for the general population [4].
Cowden Syndrome is also associated with an increased risk of melanoma,
and renal cancer [11,
15].
Other features include fibroids,
fibromas,
testicular lipomatosis and testicular lipomas [4,
5].
Surveillance
Because of the increased risk of malignancy,
regular surveillance is vital in order to pick up any signs of cancer as soon as possible.
For breast cancer,
guidelines from the US National Comprehensive Cancer Network from 2009 suggest monthly self-examination from age 18,
6 monthly clinical examination from age 25 and annual mammography/MRI from age 30-35.
If there is a family history of breast cancer the clinical and imaging surveillance is suggested to begin 5-10 years before the age at which the earliest known breast cancer was diagnosed in the family [4].
For the thyroid,
annual clinical examination and ultrasound is recommended from the age of 18,
or 5 years before the earliest known thyroid cancer in the family [1,
4].
Other suggestions include annual endometrial blind biopsy from age 35-40 or 5 years before the earliest known diagnosis of endometrial cancer in the family and yearly ultrasound after the menopause [1,
12] as well as renal US/MRI and colonoscopy every other year [11].
Prophylactic mastectomy and hysterectomy are other options to reduce the risk of developing cancer,
both of which require careful discussion with the patient [11].