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    • Surgical Pathology Criteria

    Cowden Disease

    Definition

    • Autosomal dominant multisystem disorder characterized by a variety of hamartomas and an increased incidence of carcinomas

    Alternate/Historical Names

    • Cowden syndrome
    • Multiple hamartomas syndrome
    • PTEN hamartomatous tumor syndrome (see below)

    Diagnostic Criteria

    • Autosomal dominant
      • About half of cases appear to be de novo mutations
    • See the National Comprehensive Cancer Network Genetics/High Risk Panel guidelines for application of the following findings to diagnosis
    • Hamartomatous lesions in a variety of sites
      • Mucocutaneous lesions are most commonly observed
        • Facial trichilemmomas
        • Palmar and plantar keratoses
          • Acanthosis
          • Dense orthokeratosis
          • Prominent granular layer
        • Facial papillomatous papules
        • Mucosal fibromas
          • Predominantly oral
          • Dense fibrous core
          • Variable Acanthosis and keratoses
        • Sclerotic “plywood” fibromas
          • Fascicles of hyalinized collagen separated by stromal mucin
          • It is unclear how many of the facial papules and oral fibromas are of this type
      • Breast hyalinized hamartomatous masses
        • Intra- and extra-lobular sclerosis
        • May become completely hyalinized
        • Frequently multiple
        • May be diffuse
      • Gastrointestinal tract hamartomatous polyps
      • Central nervous system
        • Adult Lhermitte-Duclos disease
    • Neoplasms
      • Breast carcinoma
        • In situ and invasive
        • Usually ductal
        • Frequently involves sclerotic hamartomatous areas
        • 25-50% lifetime risk
      • Thyroid
        • Carcinoma
          • Follicular more frequent than papillary
          • Approximately 10% lifetime risk
        • Hyalinizing trabecular lesion (adenoma)
        • Adenomatous goiter – very common
        • Follicular adenomas – very common
      • Uterus
        • Endometrial carcinoma (probable)
          • Risk probably 5-10%
        • Leiomyomas
      • Rarely observed
        • Lipomas
        • Renal cell carcinoma
        • Melanoma
        • Urothelial carcinoma
    • Other
      • Hashimoto thyroiditis
      • Macrocephaly
      • Mental retardation
      • Genitourinary system malformations
      • Esophageal glycogenic acanthosis
    • PTEN Hamartomatous Tumor syndrome (PHTS) is the proposed name for a unified syndrome including Cowden Disease and Bannayan-Ruvalcaba-Riley syndrome (BRRS)
      • BRRS is a pediatric disorder characterized by macrocephaly, developmental retardation and penile pigmented macules
        • Among the many abnormalities, the following are of most relevance to surgical pathologists:
          • Subcutaneous lipomas and angiolipomas
          • Lymphangiomyomas and hemangiomas
          • Angiokeratomas
          • Pigmented macules of glans penis
          • Intestinal hamartomatous polyps
          • Hashimoto thyroiditis
        • Increased GI cancer risk has not been demonstrated
      • Both are associated with mutations of PTEN at 10q23.31
      • Proteus syndrome and proteus-like syndrome are included by some in PHTS
        • Congenital malformations, hemihytrophy, hamartomas, epidermal nevi, hyperostosis

    Robert V Rouse MD
    Department of Pathology
    Stanford University School of Medicine
    Stanford CA 94305-5342

    Original posting : 12/27/09, 11/12/11

    Supplemental studies

    Immunohistology

    • Sclerotic fibromas are CD34 positive

    Genetic studies

    • Mutations in PTEN at 10q23.31 identifiable in 80%

    Differential Diagnosis

    Juvenile Polyposis Cowden Disease
    No associated mucocutaneous lesions Most have facial mucocutaneous lesions
    No association with breast hamartomas or carcinomas Frequent breast hamartomas and carcinomas
    No association with thyroid carcinomas Frequent thyroid carcinomas
    PTEN mutations not seen PTEN mutations in 80%
    Ganglion cells not seen in GI polyps Ganglion cells may be present in GI polyps
    The gastrointestinal polyps are otherwise largely indistinguishable

     

    Cowden Disease Peutz-Jeghers Syndrome
    Most have facial and oral papillomas, fibromas and skin tumors Perioral mucocutaneous hyperpigmentation
    Smooth muscle not a part of polyps Prominent arborizing smooth muscle bundles in GI polyps
    Lacks pseudoinvasion May have displaced mucosa with pseudoinvasion of underlying muscularis propria
    PTEN mutations in 80% STK11 mutations in 30-70%

     

    Cronkhite-Canada Syndrome Cowden Disease
    Hair, nail, skin pigmentation changes present Most have facial mucocutaneous lesions, see description
    No association with breast hamartomas or carcinomas Frequent breast hamartomas and carcinomas
    No association with thyroid carcinomas Frequent thyroid carcinomas
    PTEN mutations not seen PTEN mutations in 80%
    Not familial Autosomal dominant (half are new mutations without family history)
    The gastrointestinal polyps are largely indistinguishable

     

    Cowden Disease Hereditary Mixed Polyposis Syndrome
    Most cases present in childhood Mean age at presentation 41 years
    Usually 50-200 polyps Usually 1-15 polyps, rarely >50
    Adenomas infrequent Adenomas common
    Most have facial mucocutaneous lesions, see description No associated mucocutaneous lesions
    Frequent breast hamartomas and carcinomas No association with breast hamartomas or carcinomas
    Frequent thyroid carcinomas No association with thyroid carcinomas
    The polyps in some cases are indistinguishable

     

    Gastric Hyperplastic Polyp Cowden Disease
    No association with similar polyps in the colorectum Many cases involve the colorectum
    No associated mucocutaneous lesions Most have facial and oral papillomas, fibromas and skin tumors
    No association with breast hamartomas or carcinomas Frequent breast hamartomas and carcinomas
    No association with thyroid carcinomas Frequent thyroid carcinomas
    PTEN mutations not seen PTEN mutations in 80%
    Not familial Autosomal dominant (half are new mutations without family history)
    Gastric hyperplastic polyps are indistinguishable from the polyps of Cowden disease

     

    Mucosal Prolapse / Cloacogenic Polyp Cowden Disease, Colorectal Polyp
    Surface erosions with granulation tissue frequent Surface erosions infrequent
    Irregular glands with scattered dilation Prominent, regularly dilated glands
    Smooth muscle extension into lamina propria of polyps No smooth muscle in lamina propria of polyps
    Restricted to rectum (rarely in sigmoid)

    May involve any part of colorectum
    No associated lesions Most have facial and oral papillomas, fibromas and skin tumors, see description LINK
    No genetic abnormality PTEN mutations in 80%

    Bibliography

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    • Hemmings CT. Thyroid pathology in four patients with Cowden's disease. Pathology. 2003 Aug;35(4):311-4.
    • The National Comprehensive Cancer Network (NCCN) Genetics/High Risk Panel http://www.nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf
    • Brownstein MH, Mehregan AH, Bikowski JB, Lupulescu A, Patterson JC. The dermatopathology of Cowden's syndrome. Br J Dermatol. 1979 Jun;100(6):667-73.
    • Starink TM, Meijer CJ, Brownstein MH. The cutaneous pathology of Cowden's disease: new findings. J Cutan Pathol. 1985 Apr;12(2):83-93.
    • Hanft VN, Shea CR, McNutt NS, Pullitzer D, Horenstein MG, Prieto VG. Expression of CD34 in sclerotic ("plywood") fibromas. Am J Dermatopathol. 2000 Feb;22(1):17-21.
    • Porter S, Cawson R, Scully C, Eveson J. Multiple hamartoma syndrome presenting with oral lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996 Sep;82(3):295-301.
    • Calva D, Howe JR. Hamartomatous polyposis syndromes. Surg Clin North Am. 2008 Aug;88(4):779-817.
    • Chen HM, Fang JY. Genetics of the hamartomatous polyposis syndromes: a molecular review. Int J Colorectal Dis. 2009 Aug;24(8):865-74.
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