Cowden disease, also termed Cowden syndrome and multiple hamartoma syndrome, is an autosomal dominant condition with variable expression that can be associated with a mutation in the PTEN gene on arm 10q, as reported by Liaw et al.[1] Originally described in 1963 by Lloyd and Dennis, Cowden disease (multiple hamartoma syndrome) was named after the family in which it was first reported.[2] A broader category, PTEN (phosphatase and tensin homolog) hamartoma tumor syndrome includes Cowden disease (multiple hamartoma syndrome), Bannayan-Riley-Ruvulcaba syndrome (BRRS), Proteus syndrome, and Proteus-like syndrome, which all have PTEN mutations.
Cowden disease (multiple hamartoma syndrome) causes hamartomatous neoplasms of the skin and mucosa, GI tract, bones, CNS, eyes, and genitourinary tract. Skin is involved in 90-100% of cases, and the thyroid is involved in 66% of cases.
Mucocutaneous features of Cowden disease (multiple hamartoma syndrome) include trichilemmomas, oral mucosal papillomatosis, acral keratoses, and palmoplantar keratoses. Cowden disease (multiple hamartoma syndrome) is associated with the development of several types of malignancy, which is why recognition of individuals with the syndrome is important. In particular, a marked increase is seen in the incidence of breast carcinoma in women and of thyroid carcinoma in both men and women. Reports also exist of several other types of malignancies, such as colon cancer and renal cell carcinoma, in patients with Cowden disease (multiple hamartoma syndrome).
Traditionally, Cowden disease (multiple hamartoma syndrome) is caused by a mutation in the PTEN tumor suppressor gene (also termed MMAC1 or TEP1) on band 10q23.3. The protein product of the gene is a phosphatase that negatively controls the phosphoinositide 3-kinase–signaling pathway for regulating cell growth and survival by dephosphorylating the 3 position of phosphoinositide.
The original reports of families studied at tertiary referral centers found PTEN mutations in 80% of patients clinically diagnosed with Cowden disease.[1] However, newer prospective reports of unrelated individuals identified PTEN mutations in approximately 25% of individuals studied.[3] The relationship between Cowden disease and PTEN mutations is under investigation. Deep sequencing techniques have identified PTEN mosaicism not detected by traditional techniques.[4] Another study discovered germline mutations downstream in the phosphoinositide 3-kinase–signaling pathway.[5] Additional mutations related to the Cowden disease phenotype have been reported.[6, 7]
The PTEN protein is believed to promote cell death. A mutation that causes loss of the protein's function may result in overproliferation of cells, resulting in hamartomatous growths. Part of this overproliferation may be due to some interaction between the PTEN tumor suppressor gene and a more widely known tumor suppressor gene, TP53.PTEN mutations have been found to occur most frequently in association with endometrial cancer, glioblastomas, and prostate cancer.[8]
Identical mutations in PTEN have been described in Bannayan-Ruvulcaba-Riley syndrome (BRRS). Alternate names for BRRS include Bannayan-Zonana syndrome, Riley-Smith syndrome, and Ruvulcaba-Myhre-Smith syndrome.[9] Patients with BRRS have a much lower predisposition to cancer, which suggests that a mutation in the PTEN gene is not the only factor responsible for the clinical features of the disease.
A percentage of patients with Proteuslike syndromes, adult Lhermitte-Duclos disease (LDD), and autismlike disorders associated with macrocephaly have also demonstrated PTEN mutations.
Cowden disease (multiple hamartoma syndrome) is associated with a mutation in the tumor suppressor gene PTEN (also termed MMAC1 or TEP1) on band 10q23. PTEN is a lipid phosphatase that removes phosphate groups from signaling molecules. This activity normally restricts growth and survival signals, allowing for normal cell death. When PTEN is mutated, some cells are allowed to proliferate, sometimes (as in cancer) uncontrollably.
Cowden disease (multiple hamartoma syndrome) is inherited as an autosomal dominant condition. The percent of cases resulting from new mutations is unknown.
Other mutations have been identified in patients with Cowden disease phenotype include PIK3CA, AKT1, BMPR1A (bone morphogenetic proteins) gene, and KLLN.[5, 6, 7]
An infant with Proteus syndrome born to a mother with Cowden syndrome also correlates these 2 diseases with the PTEN mutation.[10]
Internationally, more than 300 cases have been published, including separate studies of several generations of affected family members, as reported by Tok Celebri et al.[11] The prevalence of Cowden disease (multiple hamartoma syndrome) is estimated to be approximately 1 case per 200,000 population; however, it is likely more prevalent because many features of Cowden disease (multiple hamartoma syndrome) are found in the general population and the diagnosis may be overlooked, which leads to underdiagnosis. Penetrance is thought to be nearly complete; it approaches 90% by age 20 years.[12]
Sex
Males and females inherit the mutated gene in equal number; it is autosomal dominant. Cutaneous manifestations of Cowden disease (multiple hamartoma syndrome) are similar in both sexes. However, the incidence of malignancies varies depending on the sex. For example, males are more likely to develop thyroid cancer, while females are at greater risk for breast cancer.
Age
Although the mutant gene is inherited, the onset of clinical manifestations of Cowden disease (multiple hamartoma syndrome) varies in age, ranging from birth to age 46 years.
Morbidity and mortality from Cowden disease (multiple hamartoma syndrome) primarily is associated with increased frequency of malignant tumors. Benign tumors that develop in Cowden disease (multiple hamartoma syndrome) patients also can cause significant morbidity. At least 40% of Cowden disease (multiple hamartoma syndrome) patients have a minimum of one malignant primary tumor, although with long-term follow-up care, this number may be higher. Yen et al have reported patients with more than 1 malignancy.[13] Many of the cancers are curable if detected early. Close follow-up care of these patients is necessary.
Counsel patients regarding the increased risk for malignancy, especially thyroid cancer and breast cancer in women, and the need for close follow up and cancer screening with their physicians. Instruct patients about the early signs of the most common cancers for which they are at risk.
Most patients present to the physician because of cutaneous manifestations. Individuals suspected of having Cowden disease (multiple hamartoma syndrome) should be questioned carefully about other family members with malignancies, especially concerning the breast and thyroid. A more detailed family history, including other cutaneous and mucosal lesions and cancers, as well as the developmental and neurologic abnormalities, may be helpful. A full review of systems also is warranted.
A baseline full physical examination with yearly follow-up examinations to help detect early changes resulting from malignancies is an essential component of Cowden disease (multiple hamartoma syndrome) patients' management. The physical signs that may be present with Cowden disease (multiple hamartoma syndrome) are discussed below.
Mucocutaneous surfaces
In 90-100% of patients, 1 of 4 types of mucocutaneous lesions is present.
Cutaneous facial papules are present. Most patients exhibit either flesh-colored, flat-topped lichenoid, or elongated verrucoid papules. The lesions may have a central keratin-plugged center and a diameter ranging from 1-5 mm. Typically, large numbers of lesions are present and have a predisposition for the periorificial region. Most of these lesions are trichilemmomas. Note the image below.
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Multiple trichilemmomas in patient with Cowden disease.
Oral lesions are common. Papules are 1-3 mm with a smooth surface and a whitish appearance and are present in the gingival, labial, and palatal surfaces of the mouth in more than 80% of patients. Lesions often coalesce into confluent sheets, which are described as having a cobblestone appearance. Histologically, they are benign fibromas. Thickening or furrowing of the tongue (scrotal tongue) also may be present. Note the image of oral lesions below.
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Multiple benign oral fibromas.
Acral keratoses are flesh-colored or slightly pigmented smooth or verrucoid papules on the dorsal hands and feet, and they occur in more than 60% of patients. The lesions must be differentiated from verruca plana and acrokeratosis verruciformis.
Palmoplantar keratoses are noted. Approximately 40% of Cowden disease (multiple hamartoma syndrome) patients have translucent punctate keratoses on the palms or soles. These need to be distinguished from benign keratoses and arsenic-induced keratoses.
Other cutaneous lesions may occur. Less frequently noted lesions include lipomas, neuromas, and hemangiomas and sclerotic fibromas. A report in 2006 documents multiple mucosal neuromas as the presenting sign of Cowden syndrome, adding this syndrome to the differential diagnosis list for multiple mucosal neuromas.[14] Multiple sclerotic fibromas are also documented by Requena et al as a cutaneous marker for Cowden disease (multiple hamartoma syndrome).[15]
An estimated lifetime risk for melanoma in patients with germline PTEN mutations has also been estimated at 6%.[16]
Head, nose, eyes, and throat
Findings may include macrocephaly (in as many as 80% of patients), adenoid facies, eye findings (in as many as 13% of patients, including angioid streaks, myopia), small jaw, and a high-arched palate.
Thyroid lesions
Abnormalities of the thyroid are present in approximately 60% of patients. Manifestations include goiter, benign adenomas, thyroglossal duct cysts, and follicular adenocarcinomas. Patients should be followed carefully for the development of thyroid carcinoma.[17]
Breast disease
Carcinoma of the breast occurs in 20-36% of female patients and is one of the most serious consequences of Cowden disease (multiple hamartoma syndrome). Carcinoma of the breast also has been reported in 2 men with Cowden disease (multiple hamartoma syndrome).[18] Fibrocystic disease and fibroadenomas are present in approximately 75% of patients.
GI tract
GI abnormalities are present in as many as 72% of patients. Polyps can occur in the esophagus, stomach, small or large intestine, or anus and are most common in the colon. Although Chen et al reported a few cases of adenocarcinoma of the colon in Cowden disease (multiple hamartoma syndrome) patients, the malignant potential of polyps is low.[19] Esophageal and gingival glycogen acanthosis has been documented in several patients with Cowden disease (multiple hamartoma syndrome).[20]
Genitourinary tract
The most common genitourinary tract manifestations are ovarian cysts and leiomyomas. The most serious genitourinary tract manifestation is endometrial cancer. One case of endometrial cancer has been reported in an adolescent.[21]
Teratomas, adenocarcinomas of the urethra and cervix, transitional carcinomas, renal cell carcinomas, and benign urethral polyps have been reported. In 2006, Woodhouse and Ferguson reported multiple bilateral hyperechoic testicular lesions in a small series of 8 male patients with documented PTEN mutations. Further testing indicated no effect on spermatogenesis or testicular function. Biopsies revealed lipomatosis in all but the youngest patient.[22]
Skeletal abnormalities
These include bone cysts, thoracic kyphosis, and kyphoscoliosis, as well as 1 case of osteosarcoma reported by Yen et al.[13]
CNS abnormalities
Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum) currently is considered to be part of Cowden disease (multiple hamartoma syndrome) and is caused by hamartomatous growths of the cerebellum. Patients have macrocephaly, slowly progressive cerebellar ataxia (which usually appears in adulthood), and signs of increased intracranial pressure.[23] Cases of Lhermitte-Duclos disease occurring without any other evidence of Cowden disease (multiple hamartoma syndrome) have been reported.
Seven reports in the literature describe meningiomas in patients with Cowden disease (multiple hamartoma syndrome).[24]
Diagnostic criteria
The Journal of the National Cancer Institute published updated diagnostic criteria based on a systematic review of Cowden disease and the PTEN hamartoma tumor syndrome.[25] The criteria published by the National Comprehensive Cancer Network in 2016 are described below.
Major criteria are as follows:
Breast cancer
Endometrial cancer (epithelial)
Thyroid cancer (follicular)
GI hamartomas (including ganglioneuromas, but excluding hyperplastic polyps; ≥3)
Lhermitte-Duclos disease (adult)
Macrocephaly (≥97th percentile: 58 cm for females, 60 cm for males)
Macular pigmentation of the glans penis
Multiple mucocutaneous lesions (any of the following): (1) Multiple trichilemmomas (≥3, at least one biopsy proven), (2) acral keratoses (≥3 palmoplantar keratotic pits and/or acral hyperkeratotic papules), (3) mucocutaneous neuromas (≥3), (4) oral papillomas (particularly on tongue and gingiva), multiple (≥3), OR (5) OR biopsy proven OR dermatologist diagnosed
Minor criteria are as follows:
Autism spectrum disorder
Colon cancer
Esophageal glycogenic acanthosis (≥3)
Lipomas (≥3)
Intellectual disability (ie, IQ ≤75)
Renal cell carcinoma
Testicular lipomatosis
Thyroid cancer (papillary or follicular variant of papillary)
Operational diagnosis in an individual (either of the following):
Three or more major criteria, but one must include macrocephaly, Lhermitte-Duclos disease, or GI hamartomas
Two major and three minor criteria
Operational diagnosis in a family where one individual meets revised PTEN hamartoma tumor syndrome clinical diagnostic criteria or has a PTEN mutation (any of the following):
Any two major criteria with or without minor criteria or
Cowden disease (multiple hamartoma syndrome) is associated with increased risk of breast and thyroid malignancies. Other cancers have been reported in Cowden disease (multiple hamartoma syndrome), although the magnitude of the risk for those malignancies is not known. The following cancers have been reported:
Breast cancer in 25-50% of female patients and in 2 cases in male patients
Thyroid cancer in up to 35% of patients, follicular cancer more common than papillary[16]
Colon cancer
Uterus (endometrial) cancer, 5-10%
Transitional cell carcinoma of the bladder (1 case)
Because a large number of hamartomas and malignancies have been reported in patients with Cowden disease (multiple hamartoma syndrome), monitoring patients closely using appropriate laboratory procedures is essential. Perform the following laboratory studies at baseline and as indicated clinically in subsequent years:
CBC count: Anemia can be a sign of malignancy (usually from GI blood loss), and an abnormal WBC count may indicate a lymphoproliferative disorder.
Thyroid function tests: A high risk of thyroid disease (including goiter, Hashimoto thyroiditis, adenomas, and carcinomas) exists in patients with Cowden disease (multiple hamartoma syndrome); therefore, routine monitoring is appropriate.
Urinalysis: Check for proteinuria or hematuria that may indicate kidney or bladder neoplasia.
Chemistry panels: These should include a calcium level to screen for parathyroid disease and liver function tests to detect possible hepatocellular carcinoma.
Skin biopsy: Perform skin biopsy for the pathologic diagnosis of potential trichilemmomas or sclerotic fibromas.
Initiate annual or biannual screening mammograms early in women, and perform them regularly to screen for breast cancer. See Medical Care for considerations regarding prophylactic mastectomy. Mammograms in men may be considered, especially if clinically indicated, but men’s risk for breast cancer may not be increased over the general male population.
Thyroid ultrasound is recommended at the time of diagnosis and annually thereafter.[27]
Chest radiography may be performed.
Consider MRI of the brain if CNS symptoms are present to exclude Lhermitte-Duclos disease (dysplastic gangliocytoma of cerebellum). Based on a report by Lok et al, obtaining baseline head MRI findings from all patients diagnosed with Cowden disease (multiple hamartoma syndrome) may be reasonable because 35% of the Cowden disease (multiple hamartoma syndrome) patients studied had significant findings when one was obtained.[24] Significant CNS symptoms (including headache or other focal neurologic signs) also may indicate the need for a follow-up head MRI in Cowden syndrome patients. A study of Lhermitte-Duclos disease patients using positron emission tomography suggested that these patients should be followed regularly in case of progression of these lesions.[28]
Perform barium swallow and enema to exclude hamartomas of the GI tract. Alternatively, upper and lower GI endoscopy may be used. Routine occult blood tests should also be performed, although the real increased risk of colon cancer is yet to be determined. Polyps in Cowden syndrome patients may be nonadenomatous, but these hamartomatous polyps have been documented to progress to colonic adenocarcinoma.[29]
Perform intravenous pyelography if indicated clinically or if urinalysis shows an abnormality. Additionally, ultrasonography of the testes can also be considered. Seven of 8 patients with Cowden syndrome were shown to have testicular lipomatosis.[22]
A multitude of methodologies are available to detect PTEN deletions in patients suspected to have Cowden disease (multiple hamartoma syndrome). Multiple ligation-dependent probe amplification (MLPA) is currently preferred. Other methods include Southern blotting, monochromosomal hybrid analysis, real-time polymerase chain reaction, and semiquantitative multiplex polymerase chain reaction.[12]
In practice, no set guidelines are available to determine when a patient is a candidate for PTEN mutation testing. In 2009, Pilarski recommended genetic testing in the following circumstances[30] :
Patients meeting or coming close to meeting the International Cowden Syndrome Consortium diagnostic criteria
All patients with adult Lhermitte-Duclos disease or multiple trichilemmomas
Patients with macrocephaly with other Cowden disease (multiple hamartoma syndrome) findings
PTEN mutation analysis is not indicated in patients with breast and thyroid cancer with no other manifestations of Cowden disease (multiple hamartoma syndrome) or in women with double primary cancers such as breast cancer and endometrial cancer with no other signs of Cowden disease (multiple hamartoma syndrome).[19]
Perform fine-needle aspiration or surgical biopsy on thyroid nodules found on physical examination or thyroid imaging studies.
Consider upper and lower GI endoscopy as a screening procedure or to obtain a biopsy specimen of lesions found on the barium study. Esophageal glycogenosis is very suggestive of Cowden disease (multiple hamartoma syndrome).
Submit skin biopsy specimens to a dermatopathologist for pathologic diagnosis of potential trichilemmomas or sclerotic fibromas.
Trichilemmomas are lobular proliferations of squamoid cells, often with a distinctive clear (glycogenated) appearance that resembles the outer root sheath of the hair follicle. Peripheral palisading of the lobules is apparent. Lobules often are bound by a thickened eosinophilic basement membrane. A small risk of trichilemmal carcinoma exists, as reported by O'Hare et al in 1 case.[31]
Sclerotic fibromas or storiform collagenomas are dermal tumors with coarse hyalinized collagen, often arranged in curved, nearly parallel strands with intervening parallel spaces, giving an overall storiform or whorled appearance. Breast fibroadenomas are the hyalinization of fibrous nodules that takes place at a young age.
See Guidelines for National Comprehensive Cancer Network 2018 management recommendations.
Systemic treatments (ie, acitretin) may be used to control some of the cutaneous manifestations of the disease; however, recurrence of lesions is typical after treatment is discontinued.[32]
Surgical care of facial papules may include the following:
Chemical peels
Laser resurfacing
Surgery and/or shave excisions only if symptomatic or malignancy is suspected because surgical removal may be complicated by recurrence or keloid formation
Consult the following specialists as determined necessary by laboratory test results and physical examination findings:
Ophthalmologist - For myopia, cataracts, and angioid streaks
Endocrinologist - If thyroid studies are abnormal
Gynecologist - For at least annual endometrial biopsy at age 30-35 years or at 5 years younger than the youngest age of a person in the family with a diagnosis of endometrial cancer
Neurologist and neurosurgeon - If initial MRI shows cerebellar enlargement or other abnormalities or if patient has a new onset of focal CNS symptoms
GI or general surgeon - If barium swallow and/or enema shows significant lesions (A consultation may also be obtained if the diagnosis has not yet been established in a suspected case.)
General surgeon - For mammogram abnormalities or consideration of prophylactic bilateral mastectomy, which some physicians recommend (Walton, et al[33] ) due to the 1 in 3 risk of women developing breast cancer
Radiologist - Annual mammography at age 30-35 years or at 5-10 years younger than the youngest age of a person in the family with a diagnosis of breast cancer
Annual or biannual follow-up visits are recommended, including history and physical examinations, as well as indicated laboratory or radiologic studies. Several physicians (if not a multidisciplinary team) should provide follow-up care.
Because Cowden disease (multiple hamartoma syndrome) is a familial cancer syndrome, all patients diagnosed with it should consider a consultation with a genetics counselor for more information (ie, should family members be informed and screened).
The National Comprehensive Cancer Network 2018 management guidelines for Cowden disease (multiple hamartoma syndrome) are described below.
For women, guidelines are as follows:
Breast awareness starting at age 18 years
Clinical breast examinations every 6-12 months starting at age 25 years or 5-10 years prior to earliest breast cancer diagnosis in family (whichever comes first)
Breast screening: (1) Annual mammography and breast MRI screening starting at age 30-35 years or 5-10 years prior to earliest breast cancer diagnosis in family (whichever comes first); (2) Age older than 75 years, management should be considered on an individual basis; (3) For women with a PTEN mutation who are treated for breast cancer, screening of remaining breast tissue with annual mammography and breast MRI should continue
For endometrial cancer screening, encourage patient education and prompt response to symptoms (ie, abnormal bleeding); consider annual random endometrial biopsies and/or ultrasound beginning at age 30-35 years
Discuss option of hysterectomy upon completion of childbearing
Discuss option of risk-reducing mastectomy
Address psychosocial, social, and quality-of-life aspects of undergoing risk-reducing mastectomy and/or hysterectomy
For men and women, guidelines are as follows:
Annual history and physical examinations starting at age 18 years or 5 years before the youngest age of diagnosis of a component cancer in the family (whichever comes first), with particular attention to the thyroid examination
Annual thyroid ultrasound starting at time of Cowden syndrome diagnosis, including in childhood or 5 years before the youngest age of diagnosis of a component cancer in the family (whichever comes first)
Colonoscopy, starting at age 35 years, unless symptomatic or if close relative with colon cancer before age 40 years, then start 5-10 years before the earliest known cancer in the family; colonoscopy should be performed every 5 years, or more frequently if patient is symptomatic or polyps found
Consider renal ultrasound starting at age 40 years, then every 1-2 years
Dermatologic management may be indicated for some patients
Consider psychomotor assessment in children at diagnosis and brain MRI if there are symptoms
Education regarding the signs and symptoms of cancer
For risk to relatives, guidelines are as follows:
Advise about possible inherited cancer risk to relatives, and give options for risk assessment and management
Recommend genetic counseling and consideration of genetic testing for at-risk relatives
Systemic therapy with retinoids may temporarily control some of the cutaneous lesions of Cowden disease (multiple hamartoma syndrome). Topical treatment usually is unsatisfactory.
Rapamycin has shown great promise in both regression of cutaneous lesions and prevention of the development of manifestations of Cowden disease (multiple hamartoma syndrome) in a mouse model with a PTEN deletion. In the mouse model, rapamycin inhibited a key downstream target, mammalian target of rapamycin (mTOR), which caused rapid regression of Cowden disease (multiple hamartoma syndrome)–like lesions.[34] At this time, however, use of rapamycin, should be limited to clinical trials. A clinical trial is currently underway that is studying the effects of rapamycin on syndromes with PTEN mutations.
Clinical Context:
Acitretin is a retinoic acid analog similar to etretinate and isotretinoin. Acitretin is the main metabolite of etretinate and has demonstrated clinical effects close to those seen with etretinate. Its mechanism of action is suspected to be through its ability to cause increased differentiation of cells.
Katherine H Fiala, MD, Clinical Associate Professor, Department of Dermatology, Baylor Scott and White Health, Texas A&M University College of Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Keemberly Kim, Texas A&M Health Science Center College of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Disclosure: Nothing to disclose.
Lester F Libow, MD, Dermatopathologist, South Texas Dermatopathology Laboratory
Disclosure: Nothing to disclose.
Chief Editor
William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine
Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.
Additional Contributors
Christopher Grant Staples, MD, Chief Resident, Department of Dermatology, Texas A&M University Health Science Center, Scott & White
Disclosure: Nothing to disclose.
Craig A Elmets, MD, Professor and Chair, Department of Dermatology, Director, Chemoprevention Program Director, Comprehensive Cancer Center, UAB Skin Diseases Research Center, University of Alabama at Birmingham School of Medicine
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: University of Alabama at Birmingham; University of Alabama Health Services Foundation<br/>Serve(d) as a speaker or a member of a speakers bureau for: Ferndale Laboratories<br/>Received research grant from: NIH, Veterans Administration, California Grape Assn<br/>Received consulting fee from Astellas for review panel membership; Received salary from Massachusetts Medical Society for employment; Received salary from UpToDate for employment. for: Astellas.
Acknowledgements
Christopher Grant Staples, MD Resident Physician, Scott and White Dermatology
Disclosure: Nothing to disclose.
Charles Miller, MD Chief, Department of Dermatology, Kaiser Permanente
Charles Miller is a member of the following medical societies: American Academy of Dermatology.
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