Revision del carcinoma anaplasico de tiroides, la neoplasia tiroidea de peor pronostico y sin tratamiento efectivo conocido.

1. +
Carcinoma anaplásico (indiferenciado) de tiroides
Revisión de la bibliografía.
Ma. Mónica García Falcone

2. +
Clasificación WHO
 Variante escamosa
 Variante sarcomatoide
 Variante células
pequeñas
 Variante células
gigantes
 Tumores de células
oncocíticas (Hurthle)*

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Definición
 Carcinoma anaplásico: tumor indiferenciado de
alto grado.
 Carcinoma de células Hurthle (oncocíticas):
neoplasia folicular en la que el 75% de las células
foliculares tienen rasgos oncocíticos y no hay
indicios de tiroiditis.
 Malignidad por infiltración de la cápsula o embolias
angiolinfáticas.

4. +
Clínica, Epidemiología, Px y Ttr
 Masa cervical de rápido crecimiento, que infiltra
estructuras aledañas y provoca cambios en la voz,
disfagia y disnea.
 Edad media 65 años, > mujeres
 1-2% de Tx tiroideos; 40% de las muertes por ca.
de tiroides.
 Supervivencia media 6 meses; < 10% vivos a los 2
años.
 Resistente a todos los ttr.!
 Sinonimia: carcinoma indiferenciado, carcinosarcoma,
carcinoma sarcomatoide.

5. +
-50% tenían bocio multinodular.,
-20% carcinoma diferenciado y
-20% carcinoma diferenciado
concurrente.
Previamente…
Los reportes de caso informan entre un 9-90%
de asociación entre carcinoma anaplássico y un
carcinoma diferenciado tiroideo.

6. +
 Se estudiaron genes supresores tumorales de carcinomas
diferenciados y anaplásicos coexistentes.
 La mayoría de los tumores estudiados tenían mutaciones en
los mismos alelos a pesar de corresponder a dos sectores
morfológicos diferentes, y los carcinomas indiferenciados
agregaban más mutationes.
Fisiopatología: transformación anaplásica por “progresión
molecular y des diferenciación genética” de un carcinoma
papilar, folicular o de células de Hurthle.

7. +
Macroscopía
 Tumores grandes, solidos, con áreas de necrosis y
hemorragia que infiltran estructuras periféricas.
 El tumor presenta varios patrones/componentes:
 Células gigantes pleomórficas tipo osteoclastos con
septos formados por TC celular, puede tener senos
vasculares cavernosos semejantes a los quistes óseos
aneurismáticos,
 Células ahusadas semejantes al sarcoma,
 Células escamosas relativamente indiferenciadas pero
con ocasionales focos de queratinización.
 Células pequeñas** descartar linfoma y variantes de ca. medular!
Microscopía

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Microscopía (2)

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IHQ y Dx diferenciales
 Variante escamosa:
 Carcinoma metastásico de pulmón, esófago y vía área superior.
 HC + áreas de carcinoma tiroideo diferenciado.
 Variante celulas ahusadas (especialmente cuando es
paucicelular):
 Sarcomas como fibrosarcoma, leiomiosarcoma, histicitoma fibroso
maligno, angiosarcoma y hemangiopericitoma.
 Carcinoma medular, linfoma.
 Tiroiditis de Riedel’s.

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BRAF mutations in anaplastic thyroid
carcinoma: implications for tumor origin,
diagnosis and treatment
Shahnaz Begum1 ,
* , Eli Rosenbaum2 ,
* , Rui Henrique3
, Yoram Cohen3
, David Sidransky1 ,2 , 3
and William H Westra1 , 2 , 3
1
Department of Pathology; 2
Department of Oncology and 3
Department of Otolaryngology, Head and Neck
Surgery (Division of Head and Neck Cancer Research), The Johns Hopkins Medical Institutions, Baltimore,
MD, USA
Anaplastic thyroid carcinoma is a highly aggressive neoplasm. Affected patients typically present with
advanced disease where there is little hope for cure using conventional therapeutic modalities. Understanding
the genetic alterations underlying the development of anaplastic thyroid carcinoma, such as mutational
activation of BRAF, could help clarify its relationship with well-differentiated forms of thyroid carcinoma (ie
follicular and papillary carcinoma) and could help select patients most likely to benefit from novel therapeutic
strategies targeting BRAF. We tested 16 anaplastic thyroid carcinomas for the thymine (T)- adenine (A)
missense mutation at nucleotide 1796 in the BRAF gene using a newly developed assay that employs a novel
primer extension method (Mutectors
assay). Seven of these anaplastic thyroid carcinomas arose in association
with a well-differentiated thyroid carcinoma, and these were also evaluated. The 1796T- A mutation was
detected in eight (50%) of the anaplastic thyroid carcinomas, in four of five (80%) associated papillary thyroid
carcinomas, and in zero of two (0%) associated follicular carcinomas. In all seven cases where anaplastic
thyroid carcinoma arose in association with a well-differentiated thyroid carcinoma, BRAF status in the two
components was concordant. Like papillary thyroid carcinoma, a significant percentage of anaplastic thyroid
carcinomas also harbor BRAF mutations. Indeed, when papillary thyroid carcinoma and anaplastic thyroid
carcinoma occur together, they consistently share the same BRAF profile, supporting the notion that many
anaplastic thyroid carcinomas actually represent progressive malignant degeneration of a pre-existing well-
differentiated thyroid carcinoma. The high frequency of BRAF mutations in a tumor that is generally regarded as
uniformly fatal justifies evaluation of the potential benefits of anti-BRAF therapy for patients with anaplastic
thyroid carcinoma.
Modern Pathology (2004) 17, 1359–1363, advance online publication, 11 June 2004; doi:10.1038/modpathol.3800198
Keywords: thyroid cancer; oncogene; tyrosine kinase; mitogen activated protein kinase
M o d e rn P a th o lo g y (2 0 0 4 ) 1 7 , 1 3 5 9 – 1 3 6 3
& 2 0 0 4 U S C A P, In c A ll righ ts reser ved 0 8 9 3 -3 9 5 2 /0 4 $ 3 0 .0 0
w w w .m o d e rn p a th o lo g y .o rg
BRAF mutations in anaplastic thyroid
carcinoma: implications for tumor origin,
diagnosis and treatment
Shahnaz Begum1 ,
* , Eli Rosenbaum2 ,
* , Rui Henrique3
, Yoram Cohen3
, David Sidransky1 ,2 , 3
and William H Westra1 ,2 , 3
1
Department of Pathology; 2
Department of Oncology and 3
Department of Otolaryngology, Head and Neck
Surgery (Division of Head and Neck Cancer Research), The Johns Hopkins Medical Institutions, Baltimore,
MD, USA
Anaplastic thyroid carcinoma is a highly aggressive neoplasm. Affected patients typically present with
advanced disease where there is little hope for cure using conventional therapeutic modalities. Understanding
the genetic alterations underlying the development of anaplastic thyroid carcinoma, such as mutational
activation of BRAF, could help clarify its relationship with well-differentiated forms of thyroid carcinoma (ie
follicular and papillary carcinoma) and could help select patients most likely to benefit from novel therapeutic
strategies targeting BRAF. We tested 16 anaplastic thyroid carcinomas for the thymine (T)- adenine (A)
missense mutation at nucleotide 1796 in the BRAF gene using a newly developed assay that employs a novel
primer extension method (Mutectors
assay). Seven of these anaplastic thyroid carcinomas arose in association
with a well-differentiated thyroid carcinoma, and these were also evaluated. The 1796T- A mutation was
detected in eight (50%) of the anaplastic thyroid carcinomas, in four of five (80%) associated papillary thyroid
carcinomas, and in zero of two (0%) associated follicular carcinomas. In all seven cases where anaplastic
thyroid carcinoma arose in association with a well-differentiated thyroid carcinoma, BRAF status in the two
components was concordant. Like papillary thyroid carcinoma, a significant percentage of anaplastic thyroid
carcinomas also harbor BRAF mutations. Indeed, when papillary thyroid carcinoma and anaplastic thyroid
carcinoma occur together, they consistently share the same BRAF profile, supporting the notion that many
anaplastic thyroid carcinomas actually represent progressive malignant degeneration of a pre-existing well-
differentiated thyroid carcinoma. The high frequency of BRAF mutations in a tumor that is generally regarded as
uniformly fatal justifies evaluation of the potential benefits of anti-BRAF therapy for patients with anaplastic
thyroid carcinoma.
Modern Pathology (2004) 17, 1359–1363, advance online publication, 11 June 2004; doi:10.1038/modpathol.3800198
Keywords: thyroid cancer; oncogene; tyrosine kinase; mitogen activated protein kinase
M o d e rn P a th o lo g y (2 0 0 4 ) 1 7 , 1 3 5 9 – 1 3 6 3
& 2 0 0 4 U S C A P, In c A ll righ ts reserved 0 8 9 3 -3 9 5 2 /0 4 $ 3 0 .0 0
w w w .m o d e rn p a th o lo g y .o rg
 El gen BRAF codifica una proteína que actúa en la vía
MAP kinasa, y la mutación activadora de BRAF activa
esta vía intracelular, generando un efecto promitótico y
carcinogénico.
 BRAF mutado en la mayoría de los carcinomas papilares, y
uniformemente ausente en carcinomas foliculares.
 10% carcinomas anaplásicos presentan la mutación.

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12. +
Bibliografía consultada
 Hunt JL1,Tometsko M, LiVolsi VA, Swalsky P, Finkelstein SD,
Barnes EL. Molecular evidence of anaplastic
transformation in coexisting well-differentiated and
anaplastic carcinomas of the thyroid. Am J Surg Pathol.
2003 Dec;27(12):1559-64.
 Shahnaz Begum1,*, Eli Rosenbaum2,*, Rui Henrique3,Yoram
Cohen3, David Sidransky1,2,3 and William H Westra. BRAF
mutations in anaplastic thyroid carcinoma: implications
for tumor origin, diagnosis and treatment. Modern
Pathology (2004) 17, 1359–1363.