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Cowden Disease
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 manner and is part of a spectrum of disorders with mutations in the phosphatase and tensin homolog (PTEN) gene.[2] Cowden syndrome represents the most common phenotypical presentation of this spectrum and 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] An interprofessional approach to treatment is necessary, with cancer screening tests as a priority. Medications currently being studied show encouraging results.a
Etiology
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Etiology
Autosomal-dominant mutations in the tumor suppressor gene PTEN cause Cowden disease.[7] Other conditions, such as Bannayan-Riley-Ruvalcaba syndrome and segmental overgrowth lipomatosis arteriovenous malformation epidermal nevus (SOLAMEN) syndrome, also harbor mutations in the PTEN gene.[8][9]
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 indicate an incidence of about 1 in 200,000 people.[6][10][11]
Pathophysiology
The protein encoded by the PTEN gene plays a role in apoptosis and the cell cycle.[12] Specifically, the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is downregulated by the PTEN gene product, leading to decreased cellular proliferation and survival.[1] When heterozygosity for the PTEN gene is lost by a "second hit" mutation, the resulting phenotype is multiple hamartomas and neoplasms.[13] Most commonly, patients present with macrocephaly and mucocutaneous lesions, including oral papillomas, tricholemmomas, and acral keratoses.
Histopathology
Histopathological analysis of Cowden disease varies depending on the lesion biopsied. Tricholemmomas often have pale glycogenated cells attached to the epidermis and an associated hair follicle with peripheral palisading.[14] Squamous papillomatous changes or follicular infundibular hyperplasia can be seen in some non-specific facial papules.[15] Keratotic papules generally have hyperkeratosis, with possible 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 in Cowden disease, patients develop skin and mucous membrane findings.[17] More than 80% of patients develop skin involvement early, and lesions on the skin or mucous membranes are usually evident 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 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, including keratotic papules on the palmar and plantar areas, the dorsal aspects of the hands and feet, and the extensor aspects of the 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 are usually seen elsewhere on the head and neck. Soft-tissue tumors, such as lipomas or angiolipomas, can occur in characteristic locations, including the testicles and 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] 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 lives. 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 cerebellar tumor 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, occult blood stool test, imaging, or urinalysis can be very useful for identifying possible malignancies. The International Cowden Syndrome Consortium has established diagnostic criteria.[1]
Major Criteria
Patients must meet 2 major criteria to be diagnosed with Cowden disease (*1 of the 2 must be either Lhermitte-Duclos disease or macrocephaly):
- Lhermitte-Duclos disease*
- Thyroid carcinoma
- Macrocephaly*
- Breast cancer
Minor Criteria
Patients with 1 major and 3 of the following minor criteria or 4 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 primarily guided by 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 modalities, including surgical excision, 5-fluorouracil, mTOR inhibitors (currently under investigation), laser therapy, isotretinoin, or other destructive methods.[30][31] It is important to consult system-specific specialists, such as obstetricians/gynecologists, gastroenterologists, endocrinologists, dermatologists, neurologists, or radiologists, for screening, imaging, and tests.(B3)
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 clinically resemble 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
The prognosis is fair, and if cancers are recognized early, patients may live close to normal life spans.[1]
Deterrence and Patient Education
The PTEN Hamartoma 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 lives. 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. To improve patient outcomes, a screening program must be in place to detect malignancies at an early stage. The quality of life of most patients is poor because of the continuing hospital admissions and workup to rule out malignancy.
References
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