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CIN 2: crónica de una muerte anunciada.

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Ponente: Javier Cortés Bordoy. Coordinador del Grupo Español sobre vacuna VPH. Palma de Mallorca.

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CIN 2: crónica de una muerte anunciada.

  1. 1. CIN2 La Crónica de una Muerte Anunciada Javier Cortés Palma de Mallorca JC14 He recibido becas de viaje y honorarios por asesorías de Genómica, Qiagen y Roche
  2. 2. CIN2 La Crónica de una Muerte Anunciada JC14
  3. 3. CIN2 La Crónica de una Muerte Anunciada JC14 CIN2: Reality or Myth? Anna Barbara Moscicki CS 3-3 EUROGIN 2013, Firenze
  4. 4. El problema no es el TENEMOS UN PROBLEMA: ACUDAMOS A LOS PENSADORES El problema no es el problema. El problema es tu actitud ante el problema. JC14
  5. 5. ¿COMO AFRONTAMOS LOS PROBLEMAS QUE TENEMOS? JC14
  6. 6. Fu YS, Reagan JW, Richart RM, Stock R.: Definition of cervical cancer precursors. Grundmann E., Eds. Cancer of the Uterine Cervix. Stuttgart; Gustav Fischer Verlag, 1985 Richart RM.: Natural History of Cervical Intraepithelial Neoplasia Clin Obstet Gynecol 1967; 10:748-84 DISPLASIA LEVE DISPLASIA MODERADA DISPLASIA SEVERA CARCINOMA IN SITU CIN1 CIN2 CIN3 HE AQUÍ EL PROBLEMA JC14
  7. 7. La dimensión española del problema Nº DE CASOS ANUALES CIN1 40.500 CIN2 26.200CIN2 26.200 CIN3 28.400 En España nos gastamos al año 147.284.211 € en tratar el CIN Castellsagué X.: JLGTD 2009; 13:38-45 Estimación ICO. Cortesía Xavier Bosch JC14
  8. 8. LAS CLAVES DEL PROBLEMA • La reproducibilidad inter/intraobservador de un diagnóstico de CIN2 no supera• La reproducibilidad inter/intraobservador de un diagnóstico de CIN2 no supera el 50% • 1 de cada 3 CIN2 regresan sin tratamiento en un período de 12 meses especialmente en mujeres < 24 años • 1 de cada 3 CIN2 progresan a CIN3 Dalla Palma P.: The reproducibility of CIN diagnoses among different pathologists: data from histology reviews from a multicenter randomized study. Am J Clin Pathol 2009;132:125-32. Guedes AC.: Short-term outcome of cervical intraepithelial neoplasia grade 2: considerations for management strategies and reproducibility of diagnosis. Anticancer Res 2010;30:2319-23. JC14
  9. 9. LAS TASAS DE PROGRESIÓN / REGRESIÓN CIN2 CIN1 30% CIN2: Reality or Myth? Anna Barbara Moscicki CS 3-3 EUROGIN 2013, Firenze 1997 mujeres de 35 - 45 años seguidas 6 años CIN3 30% JC14 1997 mujeres de 35 - 45 años seguidas 6 años Evolución de los CIN2: 56% Normal 24% CIN1 4% CIN2 16% CIN3+ Wang SM.: Int J Gynecol Cancer 2013;23:716-23.
  10. 10. ¿EXISTE EL CIN2? ¿Es el CIN2 un CIN1 sobre-diagnosticado? ¿Es el CIN2 un CIN3 infra-diagnosticado? JC14 Necesitamos ser objetivos en nuestro diagnóstico, porque la repercusión en el procedimiento clínico derivado es muy importante
  11. 11. • Alrededor de un 60-80% de las lesiones de CIN1 se resuelven espontáneamente sin necesidad de tratamiento: sólo un 5- 10% progresan a CIN3. • Recomendación – Co-test a los 12 meses (preferible). – Colposcopia y citología a los 12 meses (aceptable) OBSERVAR LOS CIN1 – Con CIN1 persistente por al menos 2 años (biopsia requerida) se aceptan dos posibles conductas: • Seguimiento anual mediante co-test • Tratamiento de la lesión Guía Española de Prevención Secundaria del Cáncer de Cuello de Útero. En Prensa. JC14
  12. 12. • El Dr. George Herbert "Herb" Green (1916–2001) dirigió un ensayo de seguimiento de carcinomas in situ de cérvix no tratados, sin consentimiento de las pacientes, entre 1966 y 1974 en el National Women’s Hospital de Auckland, New Zealand. • El sostenía que el CIS no era una lesión preneoplásica y que por tanto no necesitaba ser tratado TRATAR LOS CIN3 tanto no necesitaba ser tratado • La aparición de un substancial número de cánceres invasores en la cohorte motivó una investigación – la Cartwright Inquiry - que determinó la ilegalidad no ética del ensayo y sentó las bases de la necesidad de tratar el CIS McCredie MR, Sharples KJ, Paul C, Baranyai J, Medley G, Jones RW, Skegg DC.: Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol 2008;9:425-34 JC14
  13. 13. ¿QUE HACEMOS CON EL CIN2? No podemos resolver los problemas pensando de la misma manera que cuando los creamos JC14
  14. 14. Una referencia olvidada del pionero • Datos recientes demuestran de forma consistente que el HPV es etiológicamente necesario para que se desarrolle un cáncer de cérvix. Richart RM.: A modified terminology for cervical intraepithelial neoplasia. Obstet Gynecol 1990;75:131-3. cáncer de cérvix. • Sugerimos que la terminología de las lesiones precancerosas de cérvix VPH-relacionadas sea modificada a dos términos, mejor que a tres. • Esta nueva terminología, CIN de bajo grado con cambios VPH y CIN de alto grado, se adaptaría mejor a los requerimientos del cuidado clínico y a las evidencias de la ciencia básica. JC14
  15. 15. UNA PROPUESTA RECIENTE EN ESTA LÍNEA El College of American Pathologists y la American Society for Colposcopy and Cervical Pathology, en colaboración con otras 35 organizaciones convocaron una conferencia de consenso llamada ”Lower Anogenital Squamous Terminology (LAST) Project” Las conclusiones de este proyecto incluyen el uso de una terminología en dos bloques para describir la histología de las lesiones asociadas al VPH en toda el área genital, vulva, vagina, cervix, pene, periano y ano: “bajo grado” Waxman AG.: Revised terminology for cervical histopathology and its implications for management of high-grade squamous intraepithelial lesions of the cervix Obstet Gynecol 2012;120:1465-71 toda el área genital, vulva, vagina, cervix, pene, periano y ano: “bajo grado” y “alto grado”, similar a la que recomienda el Sistema Bethesda para los resultados citológicos JC14
  16. 16. Los Criterios Histológicos LSIL Proliferación de células escamosas o metaplásicas con características nucleares anormales. Hay poca maduración/diferenciación del citoplasma en el tercio inferior del epitelio: comienza en el tercio medio y es relativamente HSIL Proliferación de células escamosas o metaplásicas con características nucleares anormales. Hay poca o nula maduración/diferenciación del citoplasma en los tercios medio y superficial del epitelio.del epitelio: comienza en el tercio medio y es relativamente normal en el tercio superior. Las figuras mitóticas están presentes solo en la parte inferior del epitelio. Presencia de koilocitosis. superficial del epitelio. Las figuras mitóticas se pueden encontrar en la parte media y/o superficial del epitelio. Darragh TM and Members of LAST Project Work Groups. The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis. 2012;16:205-42. JC14
  17. 17. LA PROPUESTA LAST Nuno T, Garcia F.: The Lower Anogenital Squamous Terminology Project and its implications for clinical care. Obstet Gynecol Clin North Am. 2013;40:225-33 La inmunotinción tisular para p16INK4a es recomendada para clasificar adecuadamente las lesiones. Waxman AG.: Revised terminology for cervical histopathology and its implications for management of high-grade squamous intraepithelial lesions of the cervix Obstet Gynecol 2012;120:1465-71 JC14
  18. 18. Un recordatorio bastante esquemático • El oncogen E7 del VPH inactiva el genRB, que regula el ciclo celular a través de la producción de pRb: la célula, liberada de su control principal de replicación, entra en un proceso incontrolado de multiplicación. • El oncogen E6 del VPH destruye la p53, proteina producida por un gen supresor tumoral que detecta los daños genéticos y si no puede reparalos induce la apoptosis celular: la célula dañada nopuede reparalos induce la apoptosis celular: la célula dañada no se repara y no entra en apoptosis. • P16INK4a es una proteina codificada por el gen supresor tumoral CDKN2A, localizado en el cromosoma 9. Regula la producción de pRb. • La p16INK4a trata de activar el gen Rb degradado para intentar frenar el proceso y se sobrexpresa. JC14
  19. 19. El valor predictivo negativo para CIN2+ de la expresión de p16INK4a en histologías de CIN1 es del 96%, lo que sugiere un papel decisivo de esta valoración en el manejo de este tipo de lesiones Hariri J.: Int J Gynecol Pathol 2007; 26: 223 - 8 P16INK4a en el procedimiento diagnóstico del CIN • Liao GD.: p16INK4A immunohistochemical staining and predictive value for progression of cervical intraepithelial neoplasia grade 1: A prospective study in China. Int J Cancer 2014;134:1715-24 • Pacchiarotti A.: Prognostic value of p16-INK4A protein in women with negative or CIN1 histology result: a follow-up study. Int J Cancer 2014;134:897-904. JC14
  20. 20. Facilita el diagnostico diferencial entre los simuladores de lesion cervical (metaplasia escamosa inmadura, paraqueratosis, atrofia e inflamacion) y las verdaderas lesiones P16INK4a en el procedimiento diagnóstico del CIN verdaderas lesiones intraepiteliales de alto grado A) Negativo en una mucosa exocervical atrófica B) Positivo focal (NEGATIVO) en un epitelio escamoso exocervical con paraqueratosis C) Positividad difusa y basal en una lesión de bajo grado D) Positividad difusa y basal en una lesión de alto grado . Tomado de Torres FJ.: Rev Esp Patol 2012;45:86-95 JC14
  21. 21. PARA LLEVAR A CASA…Y ACTUAR EN CONSECUENCIA • Adoptar la clasificación LAST para las lesiones intraepiteliales de tracto genital inferior – Bajo y Alto Grado • Despedir con todos los honores a Ralph Richart y sus• Despedir con todos los honores a Ralph Richart y sus CIN 1-2-3 • Dejar de especular y usar la p16INK4a para la filiación adecuada histológica de las lesiones intraepiteliales • Ir a celebrarlo JC14
  22. 22. JC14
  23. 23. http://www.eurogin.com/ MUCHAS GRACIAS Javier Cortés cortes@ocea.es JC14

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