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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
        • Typically small, sessile colonic polyps
        • Lamina propria inflamed, frequent follicles, but rarely eroded
          • Fibrotic with smooth muscle proliferation
        • Mucous retention cysts not prominent
        • Frequently contain ganglion cells with or without neural proliferatiiion
      • 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 and last update: 12/27/09, 1/31/16

    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%
    GI polyps exophytic, cystic, eroded GI polyps sessile, few cysts, not eroded
    Ganglion cells not seen in GI polyps Ganglion cells may be present in GI polyps
    The gastrointestinal polyps in some cases may be largely indistinguishable

     

    Cowden Disease Peutz-Jeghers Syndrome
    Most have facial and oral papillomas, fibromas and skin tumors Perioral mucocutaneous hyperpigmentation
    Sessile, smooth muscle not prominent Polypoid with 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 Rare in stomach, most 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 may be indistinguishable from the polyps of Cowden disease

     

    Mucosal Prolapse / Cloacogenic Polyp Cowden Disease, Colorectal Polyp
    Surface erosions with granulation tissue frequent Surface erosions infrequent
    Polypoid Sessile
    Prominent smooth muscle extension into lamina propria of polyps Smooth muscle in lamina propria usually not promiinent
    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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    • Shaco-Levy R, Jasperson KW, Martin K, Samadder NJ, Burt RW, Ying J, Bronner MP. Morphologic characterization of hamartomatous gastrointestinal polyps in Cowden syndrome, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. Hum Pathol. 2016 Mar;49:39-48. doi: 10.1016/j.humpath.2015.10.002. Epub 2015 Oct 31. PubMed PMID: 26826408.
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