AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Cowden disease (CD), also termed Cowden syndrome and multiple hamartoma syndrome, is an autosomal dominant condition with variable expression that results most commonly (80%) from a mutation in the PTEN gene on arm 10q, as reported by Liaw et al. A broader category, "PTEN (phosphatase and tensin homolog) hamartoma tumor syndrome," has been suggested as a name to combine multiple phenotypic presentations all due to PTEN genetic diseases. Rare cases of CD are due to a germline mutation in BMPR1A (bone morphogenetic proteins).

CD 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 CD include trichilemmomas, oral mucosal papillomatosis, acral keratoses, and palmoplantar keratoses. CD 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 occurring in patients with CD.

Pathophysiology

CD is caused by a mutation in the PTEN tumor suppressor gene (also termed MMAC1 or TEP1) on band 10q23. The protein product of the gene is a phosphatase that regulates the function of other proteins by removing phosphate groups from those molecules. The PTEN protein product negatively controls the phosphoinositide 3-kinase–signaling pathway for regulating cell growth and survival by dephosphorylating the 3 position of phosphoinositide. 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.

Identical mutations in PTEN have been described by Tok Celebri et al in Bannayan-Zonana syndrome, and patients with either syndrome share some clinical features. Patients with Bannayan-Zonana syndrome 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 small percentage of patients with Proteus and Proteus-like syndromes have also demonstrated PTEN mutations.

Frequency

International

Internationally, over 300 cases have been published, including separate studies of several generations of affected family members, as reported by Tok Celebri et al.

Mortality/Morbidity

Morbidity and mortality from CD primarily is associated with increased frequency of malignant tumors. Benign tumors that develop in CD patients also can cause significant morbidity.

Sex

Males and females inherit the mutated gene in equal numbers as it is autosomal dominant. Cutaneous manifestations are similar in both sexes. However, the incidence of malignancies varies depending on the sex, eg, 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 CD varies in age, ranging from birth to 46 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Most patients present to the physician because of cutaneous manifestations. Individuals suspected of having CD 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.

Physical

A baseline full physical examination with yearly follow-up examinations to help detect early changes resulting from malignancies is an essential component of CD patients' management. The following physical signs may be present with CD:

• Mucocutaneous surfaces: In 90-100% of patients, 1 of 4 types of mucocutaneous lesions is present.
• • Cutaneous facial papules: 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 that have a predisposition for the periorificial region. Most of these lesions are trichilemmomas.
  • Oral lesions: 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.
  • Acral keratoses: Flesh-colored or slightly pigmented smooth or verrucoid papules on the dorsal hands and feet occur in more than 60% of patients. The lesions must be differentiated from verruca plana and acrokeratosis verruciformis.
  • Palmoplantar keratoses: Approximately 40% of CD 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. 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 (Schaffer, 2006).
• Head, nose, eyes, and throat
• • 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
  • 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.
• Breast disease
• • Carcinoma of the breast occurs in 20-36% of female patients and is one of the most serious consequences of CD. It also has been reported by Fackenthal et al in 2 men.
  • 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 CD patients, the malignant potential of polyps is low. Esophageal glycogen acanthosis has been documented in several patients with CD.
• Genitourinary tract
• • The most common genitourinary tract manifestations are ovarian cysts and leiomyomas.
  • The most serious genitourinary tract manifestation is endometrial cancer.
  • Teratomas, adenocarcinomas of the urethra and cervix, transitional carcinomas, renal cell carcinomas, and benign urethral polyps have been reported.
• Skeletal abnormalities: These include bone cysts, thoracic kyphosis, and kyphoscoliosis as well as 1 case of osteosarcoma reported by Yen et al.
• CNS abnormalities: Lhermitte-Duclos disease currently is considered to be part of CD 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. Cases of Lhermitte-Duclos disease occurring without any other evidence of CD have been reported.
• Diagnostic criteria: The International Cowden Syndrome Consortium has proposed operational criteria for the diagnosis of CD. Unfortunately, their "pathognomonic" criteria (which include facial trichilemmomas, acral keratoses, papillomatous papules, and mucosal lesions) are not specific enough for use by dermatologists. The other and more useful criteria are the following:
• • Major criteria
    • Breast cancer
    • Thyroid carcinoma, especially follicular thyroid carcinoma
    • Macrocephaly (>97 percentile)
    • Lhermitte-Duclos disease
  • Minor criteria
    • Other thyroid lesions (eg, adenoma, multinodular goiter)
    • Mental retardation (intelligence quotient <75)
    • GI hamartomas
    • Fibrocystic disease of the breast
    • Lipomas
    • Fibromas
    • Genitourinary tumors (eg, uterine fibroids) or malformations
  • Operational diagnosis in an individual
    • Mucocutaneous lesions alone meet the criteria if (1) 6 or more facial papules are present, of which 3 or more must be trichilemmomas, (2) cutaneous facial papules and oral mucosal papillomatosus are present, (3) oral mucosal papillomatosus and acral keratoses are present, or (4) 6 or more palmoplantar keratoses are present.
    • Two major criteria are met, but one must include either macrocephaly or Lhermitte-Duclos disease
    • One major and 3 minor criteria are met.
    • Four minor criteria are met.
  • Operational diagnosis in a family in which one individual is diagnostic for CD
    • Any single major criterion with or without minor criteria is met.
    • Two minor criteria are met.

Causes

CD is caused by a mutation in the tumor suppressor gene PTEN (also termed MMAC1 or TEP1) on band 10q23. At least 80% of CD patients have a PTEN mutation. Sixty percent of Bannayan-Riley-Ruvalcaba syndrome patients have a similar mutation.

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. The disease is inherited as an autosomal dominant condition. The percent of cases resulting from new mutations is unknown. An infant with Proteus syndrome born to a mother with Cowden syndrome also correlates these 2 diseases with the PTEN mutation (Loffeld, 2006).

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Central facial lesions
Multiple trichilemmomas
Multiple trichoepitheliomas
Adenoma sebaceum (multiple angiofibromas)
Darier disease
Syringomas (usually located under eyes as opposed to perinasally)
Fibrofolliculomas (in Birt-Hogg-Dube syndrome)

Oral papillomas
Multiple benign fibromas
Multiple neuromas (Sipple syndrome, multiple endocrine neoplasia 2b, or multiple endocrine neoplasia 3)
Tuberous sclerosis
Darier disease
Heck disease
Lipoid proteinosis
Goltz syndrome
Florid oral papillomatosis

Palmoplantar keratosis
Arsenic keratoses
Keratosis palmaris et plantaris punctata
Darier disease

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Since a large number of hamartomas and malignancies have been reported in patients with CD, it is essential to monitor patients closely using appropriate laboratory procedures. Perform the following lab 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 CD; 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.

Imaging Studies

• Annual or biannual mammograms: Initiate screening mammograms early in women (possibly as soon as puberty is complete) and perform them regularly to screen for breast cancer. (see later section on consideration of prophylactic mastectomy). Mammograms in men may be considered, especially if clinically indicated, but their risk for breast cancer may not be increased over the general male population.
• Chest radiograph may be performed.
• Thyroid scans may be performed.
• Consider head MRI 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 CD may be reasonable because 35% of the CD patients studied by Lok et al had significant findings when one was obtained. Significant CNS symptoms (including significant 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 (Van Calenbergh, 2006).
• Perform barium swallow and enema to exclude hamartomas of the GI tract. Alternatively, upper and lower GI endoscopy may be employed. 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 (Bosserhoff, 2006).
• Perform intravenous pyelogram if indicated clinically or if urinalysis shows an abnormality.
• An ultrasound of the testes can also be considered. Seven of 8 patients with Cowden syndrome were shown to have testicular lipomatosis (Woodhouse, 2006).

Procedures

• 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 biopsy lesions found on the barium study. Esophageal glycogenosis is very suggestive of CD.
• Submit skin biopsy specimens to a dermatopathologist for pathologic diagnosis of potential trichilemmomas or sclerotic fibromas.

Histologic Findings

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 risk of trichilemmal carcinoma exists as reported by O'Hare et al in 1 case.

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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Perform annual history and physical examinations on CD patients, as well as appropriate laboratory tests and imaging studies to check for internal malignancies.

Systemic treatments (ie, acitretin) may be used to control some of the cutaneous manifestations of the disease; however, the recurrence of lesions is typical after treatment is discontinued.

Surgical Care

• Surgical care of facial papules
• • Chemical peels
  • Laser resurfacing
  • Surgery and/or shave excisions

Consultations

• Consult specialists as determined necessary by laboratory tests and physical examination.
• • Ophthalmologist - For myopia, cataracts, and angioid streaks

    Endocrinologist - If thyroid studies are abnormal

  • Gynecologist - For at least annual endometrial biopsy at age 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) due to the 1 in 3 risk of women developing breast cancer
  • Radiologist - Annual mammography at age 30 years or at 5 years younger than the youngest age of a person in the family with a diagnosis of breast cancer

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Systemic therapy may temporarily control some of the cutaneous lesions of CD. Topical treatment usually is unsatisfactory.

Drug Category: Retinoids

Partially effective in treating cutaneous lesions.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• 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 CD 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).

Complications

• CD is associated with increased risk of breast and thyroid malignancies. Other cancers have been reported in CD, although the magnitude of the risk for those malignancies is not known. The following cancers have been reported:
• • Breast cancer in 20-36% of female patients and in 2 cases in male patients
  • Thyroid cancer 7% of patients (men more than women)
  • Colon cancer (2 cases)
  • Lung
  • Uterus (endometrial)
  • Acute myelogenous leukemia
  • Transitional cell carcinoma of the bladder
  • Cervical carcinoma
  • Non-Hodgkin lymphoma
  • Osteosarcoma

Prognosis

• At least 40% of CD patients have a minimum of 1 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. Many of the cancers are curable if detected early. Close follow-up care of these patients is necessary.

Patient Education

• 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.
• For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see eMedicine's patient education article Thyroid Problems.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize the association of multiple trichilemmomas or sclerotic fibromas with CD. A biopsy report with either diagnosis suggests further physical examination and, probably, further biopsies should be done. Once diagnosed, alert patients to their increased risk for specific cancers and the need for at least annual examinations by a physician.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Tok Celebi J, Chen FF, Zhang H, et al. Identification of PTEN mutations in five families with Bannayan-Zonana syndrome. Exp Dermatol. Apr 1999;8(2):134-9. [Medline].
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• Van Calenbergh F, Vantomme N, Flamen P, et al. Lhermitte-Duclos disease: 11C-methionine positron emission tomography data in 4 patients. Surg Neurol. Mar 2006;65(3):293-6; discussion 296-7. [Medline].
• Waite KA, Eng C. BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels. Hum Mol Genet. Mar 15 2003;12(6):679-84. [Medline].
• Walton BJ, Morain WD, Baughman RD, et al. Cowden''s disease: a further indication for prophylactic mastectomy. Surgery. Jan 1986;99(1):82-6. [Medline].
• Woodhouse J, Ferguson MM. Multiple hyperechoic testicular lesions are a common finding on ultrasound in Cowden disease and represent lipomatosis of the testis. Br J Radiol. Oct 2006;79(946):801-3. [Medline].
• Yen BC, Kahn H, Schiller AL, et al. Multiple hamartoma syndrome with osteosarcoma. Arch Pathol Lab Med. Dec 1993;117(12):1252-4. [Medline].
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Article Last Updated: Feb 16, 2007