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Cowden Syndrome. Important Aspects That Should Be Known by Pathologists

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Cowden Syndrome. Important Aspects That Should Be Known by Pathologists Cowden Syndrome. Important aspects that should be known by pathologists Xavier Matias-Guiu, Hospital Universitari Arnau de Vilanova de Lleida, University of Lleida, IRBLLEIDA COWDEN SYNDROME (PTEN-hamartoma tumor syndrome) • Autosomal dominant. • Germline mutations in PTEN (10q23), (80%). • Cutaneous lesions (trichilemmomas, acral keratosis, papillomatosis). • Internal lesions (breast and thyroid cancer, fibrocystic disease, goiter, gastrointestinal polyps, lipomas, genitourinary lesions, Gangliocytoma) COWDEN SYNDROME (PTEN-hamartoma tumor syndrome) • Germline genetic variants were found in SDHB and SDHD genes in a cohort of patients with CS or CS-like phenotype COWDEN SYNDROME (PTEN-hamartoma tumor syndrome) • Germline hypermethylation (epimutation) of the promoter region of KLLN in patients with CS or CS-like phenotype COWDEN SYNDROME VARIANTS • Bannayan-Riley-Ruvalcaba Sd (congenital, childhood, delayed motor and intellectual development, macrocephaly, lipomatosis, hemangiomas, penile macules) • Proteus Syndrome (children, with tumors of skin and bone asymmetrical growths, vessel malformations) (AKT-1) • Proteus-like syndrome PTEN/MMAC-1 • 10q23 • 403 aa • lipid phosphatase • Cowden Sd • malignant tumors (endometrium, breast, thyroid, SNC, prostate) ATP P PIP 2 Dephosphorylation PTEN PI3K Phosphorylation ADP PIP 3 AKT-P Cell Proliferation and Survival PTEN Adapatado de Data et al., 1999 FIBROMA ESCLEROTICO (Fibroma Hipocelular; Colagenoma estoriforme) • Circunscrito • No encapsulado • Escasamente celular • Fibras colagenas homogeneas, gruesas y eosinofílicas • Patron laminar con hendiduras artefactuales • Síndrome de Cowden COWDEN SYNDROME. TAKE HOME MESSAGES SKIN LESIONS Spectrum of lesions includes:Trichilemomas, acral keratosis, mucous papillomatosis, Palmo-plantar keratosis Also café au lait spots and lipomas Storiform collagenoma is regarded as very specific of CD COWDEN SYNDROME. TAKE HOME MESSAGES ARTERIOVENOUS MALFORMATIONS AND HEMANGIOMAS Hemangiomas occurr in 22 – 35% of children in comparison with 5 – 10% in general population. Typically multifocal, intramuscular, and intracranial. PTEN plays a role in regulating VEGF COWDEN SYNDROME. SOFT TISSUE HAMARTOMAS Intramuscular, but also facial and subcutaneous Infiltrative Small arteriovenous fustulae with dilated veins Prominent adipous component, and myxoid fibrous tissue and lymphoid follicles, hypertrophic nerves Kurek KC, PTEN hamartoma of soft tissue: a distinctive lesion in PTEN syndromes. Am J Surg Pathology 2012 36:671-687 COWDEN SYNDROME. TAKE HOME MESSAGES CENTRAL NERVOUS SYSTEM LESIONS Lhermitte-Duclos Sd- Dysplastic gangliocytoma of the cerebellum COWDEN SYNDROME. TAKE HOME MESSAGES GASTROINTESTINAL HAMARTOMAS Polyps in different locations: more frequent in colon Hamartomatous polyps, but also other types. COWDEN SYNDROME (associated malignant tumors) • Breast cancer • Thyroid cancer • Endometrial Carcinoma • Other (melanoma, renal cell carcinoma, colon cancer) COWDEN SYNDROME. BREAST LESIONS Spectrum of lesions includes cystic disease, breast carcinoma. Risk of breast cancer is 25-50%, compared with 12% in general population Occasionally bilateral, ocassionally in males No differences in pathological features in comparison with general population COWDEN SYNDROME. THYROID LESIONS Risk of thyroid cancer in CS patients is 3-10%, compared to a lifetime risk of less than 1% in the general population Spectrum of lesions includes: Follicular adenoma and carcinoma, Papillary carcinoma, Lymphocytic thyroiditis, C- cell hyperplasia Frequency of follicular carcinoma higher that for papillary carcinoma. Multiple adenomatous nodules (MAN) are regarded as very specific of CD: Multiple nodules, yellow-tan, well circumscribed, unencapsulated. THYROG Barletta JA: Immunohistochemical staining of thyroidectomy specimen for PTEN can aid in the identification of patients with Cowden Syndrome Am J Surg Pathol 2011 35:1505-11 COWDEN SYNDROME. TAKE HOME MESSAGES ENDOMETRIAL LESIONS Spectrum of lesions includes endometrial hyperplasia and endometrial carcinoma. COWDEN SYNDROME. MELANOMA Insufficient data to support association MUTACIONES DE PTEN EN MELANOMA • Estudios cariotípicos en melanomas han demostrado translocaciones y delecciones en el cromosoma 10q (30-50%) • Estudios de pérdida de heterocigosidad en 10q en melanoma sugieren que PTEN es un gen supresor de tumores en melanoma • En melanomas la mayoria de mutaciones estan en metástasis • En línias celulares de melanoma – 57% tienen mutaciones de PTEN – 2ª mutación más frecuente después de CDKN2A MMES, Clark IV, Breslow 0,91mm, BGC - N T COWDEN SYNDROME. COLON CANCER Insufficient data to support association COWDEN SYNDROME. RENAL CELL CARCINOMA Insufficient data to support association COWDEN SYNDROME. TAKE HOME MESSAGES CAN WE LEARN SOMETHING FROM ANIMAL MODELS PTEN -/- LETHAL PTEN +/- MULTIPLE CANCERS PTEN -/- LETHAL PTEN +/- MULTIPLE CANCERS MODELLING ENDOMETRIAL CARCINOMA IN VIVO PTEN conditional knock-out mice TAM TAM ER:CRE ER:CRE ER:CRE Actin promoter CRE-ER X loxP PTEN loxP Deletion of both PTEN copies (PTEN-/-) PTEN IHC 21 days after Tamoxifen Corn Oil injection Cowden Syndrome. Important aspects that should be known by pathologists Xavier Matias-Guiu, Hospital Universitari Arnau de Vilanova de Lleida, University of Lleida, IRBLLEIDA.
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