Cowden Syndrome. Important aspects that should be known by

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)
P
ATP
PIP2
Dephosphorylation
PTEN
PI3K
Phosphorylation
ADP
PIP3
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, Ccell 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
Actin promoter
CRE-ER
ER:CRE
ER:CRE
X
loxP
PTEN
Deletion of both PTEN copies (PTEN-/-)
PTEN IHC
Corn Oil
21 days after Tamoxifen
injection
loxP
Cowden Syndrome. Important
aspects that should be known
by pathologists
Xavier Matias-Guiu,
Hospital Universitari Arnau de
Vilanova de Lleida, University of
Lleida, IRBLLEIDA