Cowden Disease (Multiple Hamartoma Syndrome) Workup

Updated: May 14, 2018
  • Author: Katherine H Fiala, MD; Chief Editor: William D James, MD  more...
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Laboratory Studies

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.


Imaging Studies

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]


Other Tests

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.


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 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.