Medscape is available in 5 Language Editions – Choose your Edition here.


Cowden Disease (Multiple Hamartoma Syndrome) Workup

  • Author: Katherine H Fiala, MD; Chief Editor: William D James, MD  more...
Updated: Feb 07, 2014

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.[25]

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.[22] 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.[26]

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.[27]

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.[19]


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.[11]

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[28] :

  • 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).[16]



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.[29]

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.

Contributor Information and Disclosures

Katherine H Fiala, MD Assistant Professor, Department of Dermatology, Scott and White Northside Clinic

Katherine H Fiala, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Christian Medical and Dental Associations

Disclosure: Nothing to disclose.


Christopher Grant Staples, MD Chief Resident, Department of Dermatology, Texas A&M University Health Science Center, Scott & White

Christopher Grant Staples, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Texas Medical Association, Society for Pediatric Dermatology, Texas Dermatological Society

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Texas Medical Association, Association of Military Dermatologists, Texas Dermatological Society

Disclosure: Nothing to disclose.

Lester F Libow, MD Dermatopathologist, South Texas Dermatopathology Laboratory

Lester F Libow, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, Texas Medical Association

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

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

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

Craig A Elmets, MD is a member of the following medical societies: American Academy of Dermatology, American Association of Immunologists, American College of Physicians, American Federation for Medical Research, Society for Investigative Dermatology

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.


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.

Disclosure: Nothing to disclose.

  1. Liaw D, Marsh DJ, Li J, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997 May. 16(1):64-7. [Medline].

  2. Lloyd KM II, Dennis M. Cowden's disease. A possible new symptoms complex with multiple system involvement. Ann Intern Med. 1963. 58:136-142.

  3. Tan MH, Mester J, Peterson C, Yang Y, Chen JL, Rybicki LA. A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. Am J Hum Genet. 2011 Jan 7. 88(1):42-56. [Medline].

  4. Pritchard CC, Smith C, Marushchak T, Koehler K, Holmes H, Raskind W. A mosaic PTEN mutation causing Cowden syndrome identified by deep sequencing. Genet Med. 2013 Dec. 15(12):1004-7. [Medline].

  5. Orloff MS, He X, Peterson C, Chen F, Chen JL, Mester JL. Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes. Am J Hum Genet. 2013 Jan 10. 92(1):76-80. [Medline].

  6. Waite KA, Eng C. BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels. Hum Mol Genet. 2003 Mar 15. 12(6):679-84. [Medline].

  7. Bennett KL, Mester J, Eng C. Germline epigenetic regulation of KILLIN in Cowden and Cowden-like syndrome. JAMA. 2010 Dec 22. 304(24):2724-31. [Medline].

  8. Yin Y, Shen WH. PTEN: a new guardian of the genome. Oncogene. 2008 Sep 18. 27(41):5443-53. [Medline].

  9. Chen H and Fang J. Genetics of the hamartomatous polyposis syndromes: a molecular review. Int J Colorectal Dis. 2009 Aug. 24(8):865-74. [Medline].

  10. Tok Celebi J, Chen FF, Zhang H, Ping XL, Tsou HC, Peacocke M. Identification of PTEN mutations in five families with Bannayan-Zonana syndrome. Exp Dermatol. 1999 Apr. 8(2):134-9. [Medline].

  11. Hobert JA, Eng C. PTEN hamartoma tumor syndrome: an overview. Genet Med. 2009 Oct. 11(10):687-94. [Medline].

  12. Schaffer JV, Kamino H, Witkiewicz A, McNiff JM, Orlow SJ. Mucocutaneous neuromas: an underrecognized manifestation of PTEN hamartoma-tumor syndrome. Arch Dermatol. 2006 May. 142(5):625-32. [Medline].

  13. Requena L, Gutierrez J, Sanchez Yus E. Multiple sclerotic fibromas of the skin. A cutaneous marker of Cowden's disease. J Cutan Pathol. 1992 Aug. 19(4):346-51. [Medline].

  14. Hall JE, Abdollahian DJ, Sinard RJ. Thyroid disease associated with cowden syndrome: A meta-analysis. Head Neck. 2012 Mar 20. [Medline].

  15. Fackenthal JD, Marsh DJ, Richardson AL, et al. Male breast cancer in Cowden syndrome patients with germline PTEN mutations. J Med Genet. 2001 Mar. 38(3):159-64. [Medline].

  16. Chen YM, Ott DJ, Wu WC, Gelfand DW. Cowden's disease: a case report and literature review. Gastrointest Radiol. 1987. 12(4):325-9. [Medline].

  17. Nishizawa A, Satoh T, Watanabe R, et al. Cowden syndrome: a novel mutation and overlooked glycogenic acanthosis in gingiva. Br J Dermatol. 2009 May. 160(5):1116-8. [Medline].

  18. Schmeler KM, Daniels MS, Brandt AC, Lu KH. Endometrial cancer in an adolescent: a possible manifestation of Cowden syndrome. Obstet Gynecol. 2009 Aug. 114(2 Pt 2):477-9. [Medline].

  19. 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. 2006 Oct. 79(946):801-3. [Medline].

  20. Yen BC, Kahn H, Schiller AL, Klein MJ, Phelps RG, Lebwohl MG. Multiple hamartoma syndrome with osteosarcoma. Arch Pathol Lab Med. 1993 Dec. 117(12):1252-4. [Medline].

  21. Walsh S, Carter M, Tubridy N, McDermott EW. Lhermitte-Duclos and Cowden diseases: breast cancer as an unusual initial presentation of these overlapping conditions. BMJ Case Rep. 2011 Oct 20. 2011:[Medline].

  22. Lok C, Viseux V, Avril MF, et al. Brain magnetic resonance imaging in patients with Cowden syndrome. Medicine (Baltimore). 2005 Mar. 84(2):129-36. [Medline].

  23. Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst. 2013 Nov 6. 105(21):1607-16. [Medline].

  24. Loffeld A, McLellan NJ, Cole T, Payne SJ, Fricker D, Moss C. Epidermal naevus in Proteus syndrome showing loss of heterozygosity for an inherited PTEN mutation. Br J Dermatol. 2006 Jun. 154(6):1194-8. [Medline].

  25. Milas M, Mester J, Metzger R, Shin J, Mitchell J, Berber E. Should patients with Cowden syndrome undergo prophylactic thyroidectomy?. Surgery. 2012 Dec. 152(6):1201-10. [Medline].

  26. Van Calenbergh F, Vantomme N, Flamen P, et al. Lhermitte-Duclos disease: 11C-methionine positron emission tomography data in 4 patients. Surg Neurol. 2006 Mar. 65(3):293-6; discussion 296-7. [Medline].

  27. Bosserhoff AK, Grussendorf-Conen EI, Rubben A, et al. Multiple colon carcinomas in a patient with Cowden syndrome. Int J Mol Med. 2006 Oct. 18(4):643-7. [Medline].

  28. Pilarski R. Cowden syndrome: a critical review of the clinical literature. J Genet Couns. 2009 Feb. 18(1):13-27. [Medline].

  29. O'Hare AM, Cooper PH, Parlette HL 3rd. Trichilemmomal carcinoma in a patient with Cowden's disease (multiple hamartoma syndrome). J Am Acad Dermatol. 1997 Jun. 36(6 Pt 1):1021-3. [Medline].

  30. Cnudde F, Boulard F, Muller P, Chevallier J, Teron-Abou B. [Cowden disease: treatment with acitretine]. Ann Dermatol Venereol. 1996. 123(11):739-41. [Medline].

  31. Walton BJ, Morain WD, Baughman RD, Jordan A, Crichlow RW. Cowden's disease: a further indication for prophylactic mastectomy. Surgery. 1986 Jan. 99(1):82-6. [Medline].

  32. Squarize CH, Castilho RM, Gutkind JS. Chemoprevention and treatment of experimental Cowden's disease by mTOR inhibition with rapamycin. Cancer Res. 2008 Sep 1. 68(17):7066-72. [Medline].

  33. Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012 Jan 15. 18(2):400-7. [Medline].

  34. Diggelmann HR, Van Daele DJ, O'Dorisio TM, Hoffman HT. Insular thyroid carcinoma in a patient with Cowden syndrome. Laryngoscope. 2010 Mar. 120(3):454-7. [Medline].

  35. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet. 2008 Nov. 16(11):1289-300. [Medline].

A patient with trichilemmoma papules on the face.
Multiple benign oral fibromas.
Multiple trichilemmomas in patient with Cowden disease.
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.