Implicación de las características clínico-patológicas, radiológicas y marcadores moleculares en el tratamiento de la acromegalia

Resumen

1. Introducción o motivación de la tesis La acromegalia se debe a la producción excesiva de hormona del crecimiento (GH), generalmente por un adenoma hipofisario. El tratamiento primario de elección es el quirúrgico, con unos índices de remisión del 80-90% en pacientes con microadenomas y del 50% en los macroadenomas. Sin embargo, la disponibilidad de fármacos para el tratamiento de la acromegalia como los análogos de somatostatina (SSA) y, en menor medida, los agonistas dopaminérgicos (DA), ha modificado la secuencia terapéutica en algunos casos. Los SSA (octreótida, lanreótida y pasireótida) inhiben la secreción de GH mediante la unión a receptores específicos de la somatostatina (SRIF). En particular, los SSA de primera generación, octreótida y lanreótida, se unen preferentemente a receptores SST2; mientras que el SSA de segunda generación, pasireótida, se une a varios receptores y con mayor afinidad a SST5. Por su parte, los DA se unen fundamentalmente al receptor de dopamina tipo-2 (DR2). Aunque se ha demostrado que estos fármacos son capaces de reducir los niveles de GH y aliviar algunos síntomas, su eficacia no es generalizada y un porcentaje de los pacientes presentan baja o nula respuesta de partida, o una pérdida de la misma, probablemente asociada a unos bajos niveles de expresión de receptores de SST y dopamina en el adenoma somatotropo. Por desgracia, hasta el momento actual, no hay descrito ningún parámetro clínico, bioquímico, anatomopatológico, inmunohistoquímico ni molecular a nivel tumoral que nos permita predecir con seguridad la eficacia del tratamiento médico pre-quirúrgico y/o la curación de la acromegalia en los enfermos tratados con cirugía, siendo necesario el seguimiento de por vida en todos los casos. 2.Contenido de la investigación El objetivo de este estudio es determinar la posible relación entre las características clínico-patológicas de los pacientes al diagnóstico de la acromegalia y la expresión de distintos receptores moleculares a nivel tumoral. El segundo objetivo de nuestro estudio es analizar si existe una relación entre la señal en T2 en la Resonancia Magnética Nuclear (RMN) del adenoma y las características clínico-patológicas de los pacientes al diagnóstico de la acromegalia y/o con la expresión génica de distintos receptores a nivel tumoral, para así poder anticipar cuál podría ser el tratamiento más eficiente en la terapia prequirúrgica del paciente. Así mismo, como último objetivo se pretendió evaluar la posible capacidad de la expresión de receptores para predecir la curación o recidiva de la acromegalia. Para ello se diseñó un estudio observacional retrospectivo, en el que se incluyeron 22 pacientes con acromegalia diagnosticados en el servicio de Endocrinología y Nutrición del Hospital Universitario Reina Sofía que se intervinieron quirúrgicamente, y en los que se realizó el estudio molecular del tumor en el Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC) y el Departamento de Biología Celular de la Universidad de Córdoba. Los resultados demuestran que: 1) No existen diferencias en cuanto a la curación quirúrgica o el control bioquímico, entre aquellos que recibieron tratamiento con SSA antes de la cirugía, y los que no lo recibieron. 2) Los niveles de expresión de los receptores en el adenoma no se correlacionaron con las medidas de IGF-1 o de GH sérica después de la SOG. 3) Los adenomas con crecimiento extraselar y concretamente aquellos con crecimiento supraselar tienen mayor expresión de SST3, por lo que pasireótida podría ser una alternativa terapéutica. También expresan más DR4, por lo que probablemente sea interesante el estudio de este receptor como diana para el tratamiento de estos pacientes. A su vez, tienen mayor expresión de SST3 y mayor expresión de Ki67. Concretamente aquellos con crecimiento supraselar tienen mayor expresión de SST3, DR4 y DR5 que aquellos sin crecimiento supraselar. Los adenomas con invasión de senos cavernosos también expresan más DR5 que aquellos sin invasión. 4) Los niveles de colesterol total basal, y los de LDL-c se correlacionan de forma directa con SST2, lo que sugiere que los pacientes con hipercolesterolemia se podrían beneficiar mejor del tratamiento con octreótida o lanreótida. 5) Los niveles de cortisol plasmático se relacionan de forma directa con la expresión de SST2, SST3, SST5 y DR2L. 6) Existe una correlación inversa entre la edad al diagnóstico y la talla y entre la edad al diagnóstico y los niveles de GH plasmáticos. 7) Los adenomas hiperintensos en T2 tendían a ser más grandes, sobre todo en el diámetro inferoposteiror (DIP) y a ser más invasivos, pues tenían un índice de Knosp mayor. Además, los adenomas hiperintensos en T2 tendían a tener niveles más altos de IGF-1 y un nadir menor de GH tras SOG, y mayor expresión de DR5 y Ki67 que aquellos isointensos. 8) La expresión de DR5 se correlaciona de forma directa con los diámetros DAP y DIP, y también existe una correlación directa entre el índice de Knosp y la expresión de DR5 y de SST3. Además, el índice de proliferación Ki67 se correlacionó de forma directa con la expresión de DR5, SST2 y SST3. 9) Los adenomas con mayores niveles de expresión del DR2T muestran una correlación con un mejor control bioquímico de los pacientes. 3.Conclusión - Existe una correlación entre parámetros clínicos pre-quirúrgico y la expresión de ciertos receptores de somatostatina y dopamina en la pieza tumoral de los pacientes con acromegalia. Estos datos iniciales sugieren la posibilidad de que determinados parámetros clínicos pudieran predecir el patrón molecular de los adenomas somatotropos, lo que, a su vez, ayudaría a seleccionar tratamientos médicos pre-quirúrgicos más dirigidos y posiblemente eficaces. - Los pacientes controlados bioquímicamente después de la cirugía presentaban una mayor expresión de receptores DR2 que los que no estaban controlados. Este hecho es plausible, debido a que la respuesta a octeótrida es mejor en aquellos adenomas que expresan niveles altos de DR2. - Los adenomas hipofisarios productores de GH hiperintensos en T2 son más grandes y tienden a ser más agresivos, tanto por la invasión de zonas adyacentes, como por la expresión de marcadores moleculares (mayor expresión de DR5 y Ki67), y por tanto tienen mayores niveles de IGF-1. Un estudio de imagen exhaustivo prequirúrgico puede ayudar a elegir el tratamiento idóneo antes de la cirugía. 4. Bibliografía 1. 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