Are You Confident of the Diagnosis?

What you should be alert for in the history

A personal or family history of multiple facial and mucosal papules coupled with breast or thyroid carcinoma strongly suggests Cowden syndrome.

Characteristic findings on physical examination

Cowden syndrome features multiple facial, acral and mucosal papules, as well as mucosal and especially genital pigmented macules. The facial lesions often appear verrucous while the lip and mucosal lesions are smooth and usually white. The acral papules are generally flat-topped, while the palmoplantar lesions are small hyperkeratotic plugs (Figure 1); 99% of patients will have mucocutaneous lesions by the third decade.

Figure 1.

Small flat-topped hyperkeratotic palmoplantar plugs

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The mucosal pigmented macules were originally described on the penis (speckled penis) but also occur on the female genital, anal and oral mucosa (Figure 2). Other cutaneous findings include lipomas, hemangiomas, and vascular malformations. Systemic findings include macrocephaly, hamartomatous intestinal polyposis and virginal hypertrophy of the breasts.

Figure 2.

Oral papillomas

Diagnosis confirmation

Many other syndromes are included under the overall heading of PTEN hamartoma tumor syndrome because they all have mutations in the tumor suppressor gene phosphatase and tensin homologue (PTEN). Not surprisingly, there are overlapping features. Bannayan-Riley-Ruvalcaba syndrome itself includes several other disorders; it features macrocephaly, hamartomatous intestinal polyps, lipomas, and pigmented genital macules. Patients with Lhermitte-Duclos syndrome have macrocephaly and cerebellar dysplastic gangliocytomas. Finally rare patients with some features of Proteus synxdrome may fall into the spectrum.

Dermatopathology: The facial papules are often trichilemmomas, which are benign clear-cell follicular tumors. On many occasions multiple biopsies and sections are required to find a classic trichilemmoma; often the papules simply show dermal fibrosis or follicular remnants. There is some evidence that human papilloma virus (HPV) may play a role in the formation of some trichilemmomas, but a convincing connection between HPV and Cowden syndrome has not been established.

Larger oral or cutaneous lesions may show a peculiar pattern of fibrosis described as resembling the cut surface of an onion. They have been designated as sclerotic fibromas or storiform collagenomas. While sclerotic fibromas were initially considered pathognomonic for Cowden syndrome, similar changes are not uncommon in dermatofibromas, so the lesions are no longer considered potential syndrome markers. The smaller acral and palmoplantar keratoses show hyperkeratosis without evidence for HPV infection such as koilocytes. The lipomas and vascular lesions are not usually biopsied, but are identical to sporadic tumors of the same sort.

Serologic tests: None

Cowden syndrome is caused by mutations in PTEN. Many other disorders are also caused by mutations in PTEN and overlap clinically. Over 80% of the individuals who meet the clinical criteria for Cowden syndrome have identifiable mutations in PTEN. Some diagnostic criteria for Cowden syndrome are listed in Table I.

Table I.
Pathognomonic Criteria
Adult Lhermitte-Duclos syndrome
Mucocutaneous lesions (facial, acral, palmoplantar and oral papules)
Major Criteria
Breast cancer
Thyroid cancer
Macrocephaly (>97th percentile)
Endometrial carcinoma
Minor Criteria
Other thyroid lesions (adenomas)
Mental retardation (IQ <75)
Hamartomatous gastrointestinal polyps
Fibrocystic breast disease
Genitourinary tumors (especially renal cell carcinoma)
Genitourinary malformations
Uterine fibroids

Cowden syndrome can be diagnosed if an individual meets any of the following:

–Pathognomonic mucocutaneous lesions

–Six or more facial papules, at least three of which are trichilemmomas

–Various combinations of mucocutaneous lesions

–Two or more major criteria

–One major and three or more minor criteria

–Four or more minor criteria

–If one family member has Cowden syndrome, then the diagnostic criteria are loosened so that one major or two minor criteria suffice. If a patient has just cerebellar findings and macrocephaly, Lhermitte-Duclos syndrome is diagnosed. If additional findings are present, then Cowden syndrome is preferred.

Because of the pleomorphic aspects of Cowden syndrome and the vast spectrum of PTEN hamartoma tumor syndrome, the differential diagnostic considerations are enormous. A few of the common scenarios involving dermatologists include the following:

–The mucosal pigmented lesions may be confused with Peutz-Jeghers syndrome. The gastrointestinal polyps in Peutz-Jeghers syndrome are usually in the small intestine, quite different histologically and often symptomatic (intussusception, bleeding). Peutz-Jeghers syndrome patients do not have facial or mucocutaneous papules.

–The facial lesions look very similar to the fibrofolliculomas in Birt-Hogg-Dubé syndrome and to the angiofibromas in tuberous sclerosis and MEN1, as well as to other disorders with multiple adnexal neoplasms such as Brooke-Spiegler syndrome with trichoblastomas/trichoepitheliomas. Multiple biopsies may provide histologic clues to separate the disorders, but usually the overall clinical picture provides the answer.

–Cowden syndrome and especially Bannayan-Riley-Ruvalcaba syndrome can be confused with neurofibromatosis-1 because of the presence of café-au-lait macules and cutaneous tumors.

–The palmoplantar keratoses in Cowden syndrome can be confused with the pits in nevoid basal cell carcinoma syndrome (Gorlin syndrome); these patients also have macrocephaly so the early clinical separation is difficult unless basal cell carcinomas or other associated findings are present.

In most instances, when the entire clinical picture is reviewed, the diagnosis becomes clear. In some early cases, genetic analysis is needed to make the diagnosis.

Who is at Risk for Developing this Disease?

Cowden syndrome is a rare disease affecting less than 2000 people in the United States. Its prevalence is estimated at 1:200,000.

What is the Cause of the Disease?

Cowden syndrome is caused by mutations in PTEN andinherited in an autosdomal dominant fashion, so that children of anaffected patient have a 50% chance of inheriting the syndrome. Over 80%of individuals have identifiable mutations in this gene.

PTEN isa dual-specificity phosphatase that can dephosphorylate protein andphospholipids substrates. Its main tumor suppressor activity is tofunction as a negative regulator of the AKT pathway via PIP3. It is alsointimately involved in controlling the cell cycle and cell migrationvia the MAPK pathway and cyclin 1. There are few if any tumor suppressorgenes involved in so many different cell control pathways.

Systemic Implications and Complications

Cowden syndrome has many systemic implications, and if one includes the entire spectrum of PTEN-related tumors, the situation becomes exceedingly complex. We will only consider a few of the problems regularly seen in classic Cowden syndrome.

Macrocephaly: Found in up to 75% of patients, macrocephaly is the most common presenting feature of Cowden syndrome in childhood. It may be associated with mental retardation. The cerebrospinal fluid (CSF) pressures are normal.

Breast disease: About 70% of women with Cowden syndrome have fibrocystic breast disease; some have virginal hypertrophy of the breasts. The lifetime risk for carcinoma of the breast has been estimated between 25% to 50%; tumors are usually identified in the fifth decade but appearance in puberty has been recorded. Men are also at increased risk, but their risk is lower than that of women.

Thyroid disease: Benign thyroid disease is present in up to 75% of patients; it may range from benign multinodular goiter to adenomas. The lifetime risk for thyroid carcinoma is around 10%. Patients usually develop follicular carcinomas or on occasion papillary carcinomas. Medullary thyroid carcinoma is not a feature of Cowden syndrome. Once again, rare reports of thyroid carcinoma in adolescence exist.

Endometrial disease: Benign uterine fibroids are more common than in the general population. The risk for endometrial carcinoma is around 5% to 10%.

Cerebellar disease: Cerebellar dysplastic gangliocytoma in adults is pathognomonic of Lhermitte-Duclos syndrome and may occur in patients with otherwise typical Cowden syndrome. Presenting features are headache and cerebellar dysfunction; the tumors are generally benign but many patients suffer from the residua of the required surgery. The same tumor in children is often not associated with PTEN mutations.

Hamartomatous gastrointestinal polyposis: The relationship of PTEN hamartoma tumor syndrome and juvenile polyposis syndrome is confusing. The polyps in Cowden syndrome are hamartomatous, usually few in number and generally asymptomatic. There is not an increased risk of colon carcinoma.

Treatment Options

Table II. Treatment options for Cowden’s syndrome

Table II.
Medical Treatment Surgical Procedures Physical Modalities
None Mucocutaneous lesions may be destroyed by laser ablation, shave excision, dermabrasion or curettage and cautery. None

Optimal Therapeutic Approach for this Disease

The cutaneous management of Cowden syndrome is straight-forward. Any large or disturbing mucocutaneous papules or nodules can be excised. For the multiple smaller lesions, laser ablation with a CO2 laser (10watt, spot size 2mm, continuous mode) or erbium:YAG laser (4 to 5J/cm2) may produce temporary improvement but recurrence is almost inevitable. Older ablative methods such as dermabrasion or curettage and cautery carry a much greater risk of scarring. The pigmented genital lesions are best left untreated to avoid scarring (Table II).

The systemic malignancies are treated just like the corresponding sporadic tumors. The breast, thyroid and endometrial carcinomas require surgery and then often some consolidation therapy. An intestinal polyp that is symptomatic (usually bleeding) can be excised.

The cerebellar dysplastic gangliocytomas must be excised. There is no treatment for the macrocephaly.

Patient Management

Patients in whom the diagnosis is suspected should be offered genetic testing and counseling. If the diagnosis is confirmed, the family members at risk should also be tested and counseled. The majority of the patients represent new mutations. Cowden syndrome is so protean and underdiagnosed that no reliable estimate is available for the percentage of patients with one affected parent, but it ranges from 10% to 50%. If Cowden syndrome is suspected, family investigation is always worthwhile. Prenatal genetic analysis is possible if a specific mutation has been identified in one parent.

Annual dermatologic examination is recommended. Furthermore, in evaluating patients at risk, dermatologic examination and dermatopathologic studies are often a quick and cost-effective way of confirming the diagnosis.

Detailed recommendations are available for monitoring the patients with the goal of detecting the systemic malignancies as soon as possible:

Breast carcinoma:

–Monthly self-examination starting at age 18.

–Annual breast examination starting at age 25 or 5 to 10 years before the earliest breast cancer diagnosis in the family.

–Annual mammography and breast MRI at age 30 to 35 or 5 to 10 years before the earliest breast cancer diagnosis in the family.

–Consideration of bilateral prophylactic mastectomy, especially in women with virginal hypertrophy of the breasts, which makes detecting tumors more difficult.

–Men should also perform monthly self-examination of the breasts.

Thyroid carcinoma:

–Baseline thyroid ultrasonography at age 18 or 5 years before the earliest thyroid cancer diagnosis in the family.

–Thereafter either annual clinical examination or annual imaging, depending on baseline results.

Endometrial carcinoma:

–Pre-menopause: Annual blind suction biopsies starting at 35 to 40 years or 5 years before the earliest endometrial carcinoma diagnosis in the family.

–Post-menopause: Annual transvaginal ultrasonography and biopsy of suspicious areas.

Gastrointestinal polyps:

–Baseline colonoscopy after 50 years, unless symptomatic earlier. Then routine follow-up.

Renal carcinoma:

–Annual urinalysis with cytospin

Unusual Clinical Scenarios to Consider in Patient Management

The dermatologist may be involved because the patient has mucocutaneous lesions suspicious of Cowden syndrome but histologic examination has failed to reveal trichilemmomas or sclerotic fibromas. Remember that neither is specific and that multiple biopsies are needed.

The monitoring must always be adjusted for the peculiarities of the family, if a pedigree is available. One must look harder and earlier for tumors that have been encountered in relatives, especially those appearing at an early age. Cowden syndrome and the PTEN hamartoma tumor syndrome are so pleomorphic that it is best to assume that any complaint might be related to PTEN until proven otherwise.

What is the Evidence?

Eng , C. “PTEN hamartoma tumor syndrome. Gene Reviews”. (Detailed regularly updated website.)

Eng , C. “Will the real Cowden syndrome please stand up: revised diagnostic criteria”. J Med Genetic . vol. 37. 2000. pp. 828-30. (Basis for current diagnostic criteria.)

Gorlin , RJ, Cohen, MM, Condon , LM, Burke , BA. “Bannayan-Riley-Ruvalcaba syndrome”. Am J Med Genet . vol. 44. 1992. pp. 307-14. (Classic paper combining at least three older syndromes under one name.)

Gustafson , S, Zbuk , KM, Scacheri , C, Eng , C. “Cowden syndrome”. Semin Oncol . vol. 34. 2007. pp. 428-34. (Good review on oncologic problems.)

Hobert , JA, Eng , C. “PTEN hamartoma tumor syndrome: an overview”. Genet Med . vol. 11. 2009. pp. 687-94. (Current review of the vast spectrum of PTEN-related disorders; more compact than the website.)

Pilarski , R. “Cowden syndrome: a critical review of the clinical literature”. J Genet Couns . vol. 18. 2009. pp. 13-27. (Extensive clinical review.)

Starink , TM, van der Veen , JP, Arwet F,de Waal , LP, De Lange , GG, Gille , JJ. “The Cowden syndrome: a clinical and genetic study in 21 patients”. Clin Genet . vol. 29. 1986. pp. 222-33. (Classic paper by clinical dermatologist studying several large pedigrees.)