Continuing Education Activity

Cowden disease, also known as Cowden syndrome or multiple hamartoma syndrome, is an uncommon autosomal dominant genodermatosis and is a member of the spectrum of disorders involving mutations in the phosphatase and tensin homolog gene. Cowden syndrome represents the most common phenotype associated with this spectrum and it is classically is characterized by multiple benign hamartomas that can occur in any organ. Patients with Cowden syndrome characteristically develop mucocutaneous lesions and macrocephaly. The majority of patients with Cowden syndrome develop a malignant neoplasm of the thyroid, endometrium, or breast. This activity describes the pathophysiology, evaluation, and management of Cowden syndrome and highlights the role of the interprofessional team in the care of affected patients.

Objectives:

• Describe the pathophysiology of Cowden syndrome.
• Describe the presentation of a patient with Cowden syndrome.
• Describe the utility of routinely screening for malignancy in patients with Cowden syndrome.
• Explain the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by Cowden syndrome.

Introduction

Cowden disease, also known as Cowden syndrome or multiple hamartoma syndrome, is a genodermatosis originally described in 1963 by Lloyd and Dennis.[1] It is an uncommon condition that is inherited in an autosomal dominant fashion and is part of a spectrum of other disorders that have mutations in the phosphatase and tensin homolog gene (PTEN).[2] Cowden syndrome represents the most common phenotypical presentation of this spectrum and classically is characterized by multiple hamartomas that can occur in any organ. Characteristically, patients with Cowden syndrome develop mucocutaneous lesions and macrocephaly.[1][3] The majority of patients affected with the disease go on to develop a malignant neoplasm of the thyroid, endometrium, or breast.[4][5][6][5][4] An interprofessional approach to treatment is necessary, with cancer screening tests paramount. Medications currently being studied show encouraging results.

Etiology

Autosomally dominant inherited mutations in the tumor suppressor gene PTEN are responsible for Cowden disease.[7] Other conditions such as Bannayan-Riley-Ruvalcaba syndrome and segmental overgrowth lipomatosis arteriovenous malformation epidermal nevus (SOLAMEN) syndrome also share a mutation in the PTEN gene.[8][9][8]

Epidemiology

Some studies have shown a female predominance in Cowden syndrome, and most patients reported in the literature are of the white race. Some estimates show the incidence to be about 1 in 200,000 people. [6][10][11]

Pathophysiology

The protein encoded by the PTEN gene contributes to the control of apoptosis and the cell cycle.[12] Specifically, the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is down-regulated by the PTEN gene product, resulting in decreased cellular proliferation and survival.[1] When heterozygosity for the PTEN gene is lost by a "second hit" mutation, the resulting phenotype of multiple hamartomas and neoplasms is produced.[13] Most commonly, patients experience macrocephaly along with mucocutaneous lesions such as oral papillomas, tricholemmomas, and acral keratoses.

Histopathology

The histopathological analysis of Cowden disease varies based upon the particular lesion biopsied. Tricholemmomas often have pale glycogenated cells attached to the epidermis and an associated hair follicle with peripheral palisading.[14] Squamous papillomatous change or follicular infundibular hyperplasia can be seen in some non-specific papules on the face.[15] Keratotic papules generally have hyperkeratosis with possibly some verrucous changes. Whorls of fibrous tissue and collagen arranged in a lobular or nodular-type pattern can be seen in oral mucosal lesions. A characteristic hypocellular collagen pattern reminiscent of the Vincent van Gogh painting Starry Night can be seen in sclerotic fibromas.[16] Other histological findings associated with the respective lesion can be found in Cowden disease but are beyond the scope of this discussion.

History and Physical

Cowden syndrome is generally characterized by hamartomas that can involve any organ and have the potential for malignant transformation.[2] Early on in Cowden disease patients start to develop signs on their skin and mucous membranes.[17] More than 80% of patients will develop skin involvement early on, and usually, lesions on the skin or mucous membranes can be seen by the second to third decade of life.[18] Oral lesions are generally papillomatous or a cobblestone pattern and generally are the color of the surrounding mucosa. The tongue and lips are most commonly involved in mucosal lesions, but any part of the mouth can be involved.[19] Skin colored to yellow-brown, warty papules on the central face are characteristic features of tricholemmomas.[20] Well circumscribed dermal papules or nodules are a more specific finding in Cowden disease and represent sclerotic fibromas.[21] The histopathology of sclerotic fibromas is relatively specific as well including keratotic papules on the palmoplantar areas, dorsal aspect of hands and feet, as well as extensor aspects of extremities. The keratotic papules usually have a punctate central depression and have a clear or translucent appearance. Other papules in the central face with non-specific features can also be seen. Acrochordons and inverted follicular keratoses can usually be seen in other areas on the head and neck. Soft tissue tumors such as lipomas or angiolipomas can be seen in characteristic locations such as the testicles or other parts of the body.[22] Hamartomas composed of various types of tissue such as fibrous tissue, fat, or vasculature can also be seen in the soft tissue and are mostly located subcutaneously or intramuscularly. Vascular malformations can also occur in various locations.  

Multiple extra-mucocutaneous manifestations can also occur in Cowden disease. The skeletal system may form a high-arched palate, scoliosis, or macrocephaly. More than 85% of patients may have gastrointestinal involvement with hamartomatous polyps.[1] The risk of colon cancer in patients is slightly elevated.[5] Uterine leiomyomas and ovarian cysts can occur in females and may produce menstrual abnormalities along with a possible 20% to 30% increased risk of endometrial carcinoma.[23][24][25][23] Females with Cowden disease are also at a much higher risk of breast carcinoma, with about 85% of females with Cowden syndrome developing breast carcinoma at some time in their life. Interestingly, breast carcinoma has also been reported in men.[26] Benign fibrocystic disease and fibroadenomas are also commonly seen in females. Thyroid abnormalities such as goiter, thyroglossal duct cysts, and adenomas are also common. Thyroid carcinoma risk is also increased by up to 30%. A dysplastic gangliocytoma of the cerebellum, also called Lhermitte-Duclos disease, is a benign tumor of the cerebellum that is specific to Cowden disease.[27] Renal carcinoma may be present in up to 30% of patients.[28] Melanoma skin cancer is also increased in patients with Cowden disease and may occur in 5% of patients.[29]

Evaluation

Evaluation of patients with suspected Cowden disease consists of various tests. A skin biopsy can be very useful if skin lesions such as tricholemmomas or sclerotic fibromas are present. A complete blood count, thyroid function test, stool for occult blood, imaging, or urinalysis can be very useful for identifying possible malignancies. The International Cowden Syndrome Consortium has established diagnostic criteria.[1]

Major Criteria

Patients need to have two major criteria to be diagnosed with Cowden disease. (*One of the two must be either Lhermitte-Duclos disease or macrocephaly.)

• Lhermitte-Duclos disease*
• Thyroid carcinoma
• Macrocephaly*
• Breast cancer

Minor Criteria 

Patients with one major and three of the following minor criteria or four minor criteria may be diagnosed with Cowden disease.

• Genitourinary tumors or malformations
• Lipomas
• Fibromas
• Mental retardation
• Fibrocystic disease of the breast
• Gastrointestinal hamartomas,
• Other thyroid lesions such as goiter

Mucocutaneous lesions or palmoplantar keratosis can meet the criteria alone if 6 or more are present.

Treatment / Management

Management of patients with Cowden disease is interprofessional and mainly stems from patient-specific findings.[4] Genetic counseling is beneficial, especially since other family members may also be diagnosed with the disease. Cutaneous lesions may be treated with various things such as surgical excision, 5-fluorouracil, mTOR inhibitors (currently under investigation), laser, isotretinoin, or other destructive methods.[30][31] It is important to refer to system-specific specialists such as obstetricians/gynecologists, gastroenterologists, endocrinologists, dermatologists, neurologists, or radiologists for screening imaging and tests.

Differential Diagnosis

An autosomal dominant disease with mutations in the SDHB/C/D genes can present with similar findings as Cowden syndrome such as thyroid, breast, and renal cancers. Facial lesions such as fibrofolliculomas (Birt-Hogg-Dube syndrome) or angiofibromas (MEN 1 or tuberous sclerosis) may be clinically similar to tricholemmomas.[32] Oral lesions such as focal epithelial hyperplasia (seen in Heck disease), papillomas in Goltz syndrome, or mucosal neuromas in MEN 2B can present similarly to oral papillomas seen in Cowden syndrome. Bannayan-Riley-Ruvalcaba syndrome has very similar features to Cowden syndrome and is considered an overlapping PTEN disorder, but it does tend to have genital lentigines characteristically.[9]

Prognosis

Prognosis is fair, and if cancers are recognized early on in the process, then patients may live close to normal life spans.[1]

Deterrence and Patient Education

The PTEN Hararmatoma Tumor Syndrome Foundation is a recommended resource of support for patients and families. Patients should have regular screening and should be encouraged to avoid sun exposure.

Enhancing Healthcare Team Outcomes

Because of the diverse presentation and multiple organ involvement, Cowden syndrome is best managed by an interprofessional team including oncology nurses. 

Even though Cowden syndrome is associated with benign hamartomas, clinicians need to be aware that long term monitoring of these patients is mandatory because of the risk of malignancy. The risk of colon cancer in patients is slightly elevated] Uterine leiomyomas and ovarian cysts can occur in females and may produce menstrual abnormalities along with a possible 20% to 30% increased risk of endometrial carcinoma. Females with Cowden disease are also at a much higher risk of breast carcinoma, with about 85% of females with Cowden syndrome developing breast carcinoma at some time in their life. Thyroid abnormalities such as goiter, thyroglossal duct cysts, and adenomas are also common. Thyroid carcinoma risk is also increased by up to 30%. Melanoma skin cancer is also increased in patients with Cowden disease and may occur in 5% of patients. In order to improve patient outcomes, a screening program must be in place to ensure that the malignancies are detected at an early stage.

The quality of life of most patients is poor because of the continuing hospital admissions and work up to rule out malignancy.