Background

Cowden syndrome (CS) is a autosomal dominant inherited syndrome. These patients are characterized by multiple hamartomas occurring in the skin, breast, thyroid, gastrointestinal tract, endometrium, and brain. Patients do have an increased risk of experiencing malignant tumors with the most common ones are breast, endometrial, and thyroid cancer.

OUTLINE

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	Multiple hamartoma syndrome

DISEASE ASSOCIATIONS	CHARACTERIZATION
Bannayan-Zonnana syndrome	Some cases show overlap with macrocephaly, intestinal polyps, and lipomas, and mulitple trichilemmomas are found in both diseases Genetic basis of these two diseases is identical.
INVERTED FOLLICULAR KERATOSES
Multiple inverted follicular keratoses as a presenting sign of Cowden's syndrome: case report with human papillomavirus studies. Ruhoy SM, Thomas D, Nuovo GJ. Department of Pathology, Sunrise Hospital and Medical Center, USA.	J Am Acad Dermatol. 2004 Sep;51(3):411-5. Abstract quote Inverted follicular keratosis is characterized by a squamous epithelial expansion of the infundibular portion of the hair follicle in an exophytic and endophytic pattern. The lesion is often associated with squamous eddies similar to an irritated keratosis and may have a superficial papillomatous architecture. The lesion most often arises as a solitary nodule on the face of middle age to elderly individuals. Inverted follicular keratosis has been described as a distinct entity by some while others believe that it is related to trichilemmomas and/or verruca vulgares. The cutaneous pathology of Cowden's syndrome is characterized by multiple trichilemmomas. We present a woman who fulfills the clinical criteria for Cowden's syndrome and who initially presented with multiple inverted follicular keratoses. Also, in situ hybridization studies performed on the patient's keratoses do not reveal evidence of human papillomavirus infection.
Lhermitte-Duclos disease	Cancer 1992;70:869-76 Dysplastic gangliocytoma of the cerebellum

PATHOGENESIS

CHARACTERIZATION

Identification of a PTEN mutation in a family with Cowden syndrome and Bannayan-Zonana syndrome

J Am Acad Dermatol 2001;44:183-7 Single kindred with individuals manifesting both CS and BZS phenotypes (CS/BZS overlap family) Novel mutation in PTEN by DNA sequencing. The PTEN gene (phosphatase and tensin homolog deleted from chromosome 10) has been identified as the susceptibility gene for CS and BZS Also known as MMAC1 (mutated in multiple advanced cancers) or TEP1 (TGF-regulated and e pithelial cell-enriched p hosphatase), is a tumor suppressor gene located on chromosome 10q23.28-30 It has 9 exons that encode a protein of 403 amino acids. The presence of individuals with CS and BZS within the same family, and moreover the identification of identical PTEN gene mutations in these individuals, suggest that these two syndromes represent different phenotypic expressions of one disease

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
General
VARIANTS
BRAIN	38% of CS patients have macrocephaly
BREAST	Fibrocystic breast disease Fibroadenomas Carcinoma (30% to 50% of female patients)
ENDOMETRIUM	Endometrial carcinoma
GI	Intestinal polyposis
SKIN	Manifest by the late teens to twenties Present in 99% of patients with CS These most common mucocutaneous findings are: Trichilemmomas Oral papillomatoses Acral and palmoplantar keratoses.
TESTICLE
Testicular lipomatosis in Cowden's syndrome. Woodhouse JB, Delahunt B, English SF, Fraser HH, Ferguson MM. 1Department of Urology, Christchurch Hospital, Christchurch, New Zealand.	Mod Pathol. 2005 Sep;18(9):1151-6. Abstract quote   Cowden's syndrome is either familial or sporadic and is associated with the predominantly postpubertal development of a variety of cutaneous, stromal and visceral neoplasms. The syndrome is associated with mutations of the PTEN gene and is closely related to Bannayan's syndrome in which macrocephaly and benign tumors, especially lipomas and hemangiomas are pathognomic. In PTEN knockout mice testicular tumors have been reported and for this reason we felt it prudent to examine the testes of our patients with genetically proven Cowden's syndrome. Seven of eight patients who underwent testicular ultrasound were found to have diffuse bilateral hyperechoic lesions. Four patients consented to testicular biopsy and on histological examination multiple foci of adipocytes were found within the testicular interstitium, with no evidence of dysplasia or preclinical malignancy. Immunohistochemical assessment of adipocytes suggested a stromal derivation without evidence of metaplasia from Leydig cells. In one case there was focal atrophy of seminiferous tubules, while in two others there was nodular periorchitis of the tunica albuginea. Biochemical evaluation of testicular function (luteinizing hormone, follicle-stimulating hormone, testosterone, sex hormone binding globulin and free androgen index), prostate-specific antigen and testicular tumor markers were normal, while seminal fluid analysis showed only minor abnormalities. The high incidence of testicular lipomatosis in our adult subjects suggests this to be an important diagnostic criterion for Cowden's syndrome.
THYROID	Thyroid adenomas, goiter Carcinoma (3% to 10% of all CS patients)

 

HISTOPATHOLOGICAL VARIANTS	CHARACTERIZATION
SKIN
SCLEROTIC FIBROMA
Pleomorphic sclerotic fibroma: a case report and literature review. Chen TM, Purohit SK, Wang AR. Departments of Pathology and Laboratory Medicine (A.R.W.) and Surgery (S.K.P.), Tulane University Health Sciences Center, New Orleans, Louisiana; and Baylor College of Medicine, Houston, TX, U.S.A. (T.M.C.).	Am J Dermatopathol 2002 Feb;24(1):54-8 Abstract quote Pleomorphic sclerotic fibroma is a benign neoplasm exhibiting features of sclerotic fibroma and pleomorphic fibroma. We report another such case. The tumor presented as a firm, 0.5-cm, flesh-colored papule on the forehead of a 72-year-old white man for an unknown duration. Histologic examination revealed a neoplasm in which the superficial portion showed features of a pleomorphic fibroma, the deeper portion showed features of a sclerotic fibroma, and a transitional area was present in between. We propose that pleomorphic fibroma, sclerotic fibroma, and pleomorphic sclerotic fibroma form a spectrum. Pleomorphic sclerotic fibroma may be used as a broad diagnostic term to encompass the spectrum.

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Hum Pathol 1998;29:47-53.
J Am Acad Dermatol 2001;44:183-7
Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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Last Updated September 30, 2005

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