lunes, 22 de agosto de 2016

Neuroblastoma: Tratamiento (PDQ®)—Versión para profesionales de salud - National Cancer Institute

Neuroblastoma: Tratamiento (PDQ®)—Versión para profesionales de salud - National Cancer Institute





National Cancer Institute

Neuroblastoma: Tratamiento (PDQ®)–Versión para profesionales de salud



SECCIONES

Información general sobre el neuroblastoma

Afortunadamente para los niños y adolescentes el cáncer es poco frecuente, aunque la incidencia general de cáncer infantil ha aumentado paulatinamente desde 1975.[1] Por lo general, los niños y adolescentes con cáncer se derivan a centros médicos que cuentan con un equipo multidisciplinario de especialistas con experiencia en el tratamiento de los cánceres que se presentan en la niñez y la adolescencia. Este enfoque multidisciplinario incorpora la pericia de los siguientes profesionales de la salud y otros profesionales para asegurar que los niños reciban tratamiento, cuidados médicos de apoyo y rehabilitación que permitan una supervivencia y calidad de vida óptimas:
  • Médico de atención primaria.
  • Cirujano pediatra.
  • Radiooncólogos.
  • Especialistas en oncología o hematología pediátrica.
  • Especialistas en rehabilitación.
  • Especialistas en enfermería infantil.
  • Trabajadores sociales.
  • Ludoterapeutas.
(Para obtener información específica sobre los cuidados médicos de apoyo para niños y adolescentes con cáncer, consultar los sumarios del PDQ sobre Cuidados médicos de apoyo).
La American Academy of Pediatrics ha establecido pautas para los centros de oncología infantil y su función en el tratamiento de los pacientes pediátricos con cáncer.[2] En estos centros de oncología infantil se dispone de ensayos clínicos para la mayoría de los tipos de cáncer que se presentan en niños y adolescentes, y se ofrece la oportunidad de participar a la mayoría de los pacientes y familiares. Los ensayos clínicos para adolescentes y niños con cáncer por lo general se diseñan con el fin de comparar un tratamiento presuntamente mejor con el tratamiento que se acepta en el presente como estándar. La mayoría de los avances logrados en la identificación de tratamientos curativos para los cánceres infantiles fueron a través de ensayos clínicos. Para mayor información sobre ensayos clínicos en curso, consultar el portal de Internet del NCI.
Se han logrado mejoras notables en la supervivencia de niños y adolescentes con cáncer.[3] Entre 1975 y 2010, la mortalidad infantil por cáncer disminuyó en más de 50%.[1,3,4] La tasa de supervivencia a 5 años para el neuroblastoma aumentó durante el mismo período de 86 a 95% en niños menores de 1 año y de 34 a 68% en niños de 1 a 14 años.[1] Los niños y adolescentes que sobreviven al cáncer necesitan un seguimiento muy cuidadoso, ya que los efectos secundarios del tratamiento del cáncer pueden persistir o presentarse meses o años después de este. Para obtener información específica sobre la incidencia, el tipo y la vigilancia de los efectos tardíos en los niños y adolescentes sobrevivientes de cáncer, consultar el sumario del PDQ sobre Efectos tardíos del tratamiento anticanceroso en la niñez.

Incidencia

El neuroblastoma es el tumor sólido extracraneal más común en la infancia. Cada año se diagnostican más de 650 casos en América del Norte.[5,6] La prevalencia es de casi 1 caso por 7.000 nacidos vivos; la incidencia es cerca de 10,54 casos por millón en niños menores de 15 años. Aproximadamente 37% de los casos se diagnostican en lactantes y 90% corresponden a niños menores de 5 años en el momento del diagnóstico, con una mediana de edad en ese momento de 19 meses.[7]
Aunque no existe una variación étnica en la incidencia, hay diferencias étnicas en la biología del tumor: los estadounidenses de origen africano presentan más probabilidades de tener una enfermedad de riesgo alto y un desenlace mortal.[8,9]
Estudios de población sobre exámenes de detección en niños con neuroblastoma, mostraron que la regresión espontánea del neuroblastoma sin detección clínica en el primer año de vida es por lo menos tan frecuente como la del neuroblastoma que se identifica clínicamente.[10-12]

Características anatómicas

El neuroblastoma se origina en la médula suprarrenal o en sitios paraespinales donde hay presencia de tejido del sistema nervioso simpático.
AMPLIAREl dibujo muestra las partes del cuerpo donde se puede encontrar un neuroblastoma, como el tejido nervioso paravertebral y las glándulas suprarrenales. También se ven la espina vertebral, y los riñones derecho e izquierdo.
Figura 1. El neuroblastoma se puede encontrar en las glándulas suprarrenales y el tejido nervioso paravertebral desde el cuello hasta la pelvis.

Factores de riesgo

Se sabe muy poco sobre las circunstancias que predisponen a la presentación de un neuroblastoma. No se ha podido establecer de manera definitiva que esto se relacione con las exposiciones de los padres.
La eliminación en la línea germinal en los locus 1p36 o 11q14-23 se relaciona con el neuroblastoma y las mismas eliminaciones se encuentran de forma somática en neuroblastomas esporádicos.[13,14]
Alrededor de 1 a 2% de los pacientes de neuroblastoma tienen antecedentes familiares de este. Estos niños son más jóvenes en promedio (9 meses en el momento del diagnóstico); alrededor de 20% presentan neuroblastomas primarios multifocales. La causa primaria del neuroblastoma familiar es una mutación en la línea germinal en el gen ALK.[15] El neuroblastoma familiar se relaciona pocas veces con el síndrome de hipoventilación central congénita (síndrome de Ondina) cuya causa es la mutación de la línea germinal del gen PHOX2B.[16]

Características biológicas y moleculares

Subtipos biológicos

Sobre la base de factores biológicos y una mejor comprensión de la evolución molecular de las células de la cresta neural que dan origen al neuroblastoma, los tumores neuroblásticos se clasifican en los tres tipos biológicos siguientes:
  • Tipo 1: se caracteriza por ganancias y pérdidas de cromosomas completos. Expresa el receptor de neurotrofina TrkA, es hiperdiploide y tiende a revertirse de forma espontánea.[17,18]
  • Tipo 2A: se caracteriza por las alteraciones en el número de copias en porciones cromosómicas. El tipo 2A expresa el receptor de neurotrofina TrkB y su ligando, ganó una copia adicional del cromosoma 17q, perdió la heterocigocidad de 14q o 11q y es genómicamente inestable.[17,18]
  • Tipo 2B: por lo general, tiene el gen MYCN amplificado y una ganancia del cromosoma 17q, pérdida del cromosoma 1p, y expresión del receptor de neurotrofina TrkB y su ligando.[17,18]
Estos cambios genéticos específicos se pueden combinar con factores clínicos tradicionales, como la edad del paciente y el estadio del tumor, para refinar las clases de riesgo de neuroblastoma.
Los niños cuyos tumores perdieron una copia del 11q cuentan con una mayor edad en el momento del diagnóstico y sus tumores contienen más cambios segmentarios en el número de copias del gen, en comparación con aquellos niños cuyos tumores muestran una amplificación del MYCN.[19,20] Más aún, los cambios cromosómicos segmentarios que no se identificaron en el momento del diagnóstico se pueden localizar en los neuroblastomas en el momento de una recaída. Esto indica que un avance tumoral importante en el aspecto clínico se relaciona con la acumulación de alteraciones cromosómicas segmentarias.[21]

Características moleculares

Aproximadamente 6 a 10% de los neuroblastomas esporádicos portan mutaciones somáticas activantes de ALK y de 3 a 4% adicionales presentan una frecuencia alta de amplificación del gen ALK. Las mutaciones resultan en una fosforilación constitutiva delALK, que conduce a la desregulación de la señalización celular y a una proliferación descontrolada de los neuroblastos mutantes del ALK. Por lo tanto, la inhibición de la cinasaALK es un objetivo potencial para el tratamiento del neuroblastoma, sobre todo en niños cuyos tumores albergan una mutación del ALK o una amplificación del gen ALK.[22]
En los estudios de vinculación del genoma completo en niños con neuroblastoma se encontraron polimorfismos de un solo nucleótido (PSN) relacionados con una modesta susceptibilidad a presentar un neuroblastoma de riesgo alto.[23,24] Otros PSN se relacionan con una susceptibilidad a presentar neuroblastoma de riesgo bajo.[24] Los PSN vinculados a la etnia predicen una incidencia más alta de neuroblastoma y un desenlace más precario.[25]
En estudios genómicos grandes se encontraron menos mutaciones recidivantes en pacientes de neuroblastoma que incluyen ALK (9,2%), PTPN11 (2,9%), ATRX (2,5%; 7,1% de eliminaciones focales), MYCN (1,7%) y NRAS (0,8%).[19,21,26,27] ATRX está comprometido con la mutación genética sinónima o imperceptible, epigenético y la longitud de telómeros. La mutación de ATRX sin amplificación de MYCN se relaciona con la edad al momento del diagnóstico en adolescentes y adultos jóvenes con neuroblastoma metastásico.[28] No resulta claro si la mutación ATRX es un factor pronóstico de riesgo independiente.
Aunque la mayoría de los neuroblastomas al principio son sensibles a la quimioterapia, muchos presentan recidiva local o en sitios de metástasis. Los análisis genéticos modernos, entre estos, la secuenciación hologenómica exhaustiva de los neuroblastomas primarios y recidivantes del mismo paciente, indican múltiples mutaciones nuevas y una evolución clonal compleja de subclones prexistentes insignificantes. Las mutaciones nuevas más comunes se encontraron en la vía RAS-MAPK.[29,30]

Exámenes de detección del neuroblastoma

La documentación vigente no respalda los exámenes de detección del neuroblastoma. Los exámenes de detección a las 3 semanas, 6 meses o 1 año no produjeron una reducción de la incidencia de neuroblastomas en estadio avanzado con características biológicas desfavorables en niños de más edad, ni disminuyó la cantidad de defunciones por neuroblastoma en lactantes sometidos a detección a cualquier edad.[11,12] No se han observado que los exámenes de detección en lactantes con neuroblastoma en estas edades, presenten beneficios para la salud pública. (Para mayor información, consultar el sumario del PDQ sobre Exámenes de detección del neuroblastoma).
Pruebas (en contra de los exámenes de detección del neuroblastoma):
  1. En un estudio poblacional grande realizado en América del Norte, en el cual se sometió a exámenes de detección a la mayoría de los lactantes de Quebec a las 3 semanas y a los 6 meses de edad, se observó que dichos exámenes pueden identificar muchos neuroblastomas con características favorables [10,11] que nunca se hubieran identificado clínicamente, aparentemente debido a la regresión espontánea de los tumores.
  2. En otro estudio de niños sometidos a exámenes de detección al año de edad, se observan resultados similares.[12]

Presentación clínica

La presentación más común del neuroblastoma es una masa abdominal. Los signos y síntomas más frecuentes de un neuroblastoma se deben a la masa tumoral y las metástasis. Como los siguientes:
  • Proptosis y equimosis periorbital: son comunes en pacientes de riesgo alto y surgen de una metástasis retrobulbar.
  • Distensión abdominal: se puede presentar con compromiso respiratorio debido a metástasis hepáticas masivas.
  • Dolor óseo: se presenta vinculado con la enfermedad metastásica.
  • Pancitopenia: puede ser consecuencia de una metástasis masiva en la médula ósea.
  • Fiebre, hipertensión y anemia: en ocasiones, se encuentran en pacientes sin metástasis.
  • Parálisis: debido a que se originan en los ganglios paraespinales, los neuroblastomas pueden invadir los agujeros neurales y comprimir la médula espinal de modo extradural. Se administra tratamiento inmediato para la compresión sintomática de la médula espinal. (Para mayor información, consultar la sección de este sumario sobreTratamiento de la compresión de la médula espinal).
  • Diarrea acuosa: con escasa frecuencia, los niños pueden sufrir de diarrea acuosa grave debida a que el tumor segrega péptidos intestinales vasoactivos o presentar enteropatía con pérdida de proteína con linfangiectasia intestinal.[31] También se puede presentar segregación de péptidos intestinales vasoactivos después del tratamiento quimioterapéutico; la resección del tumor también reduce la segregación de péptidos intestinales vasoactivos.[32]
  • Presencia del síndrome de Horner: puede obedecer a un neuroblastoma en el ganglio estrellado; los niños con síndrome de Horner sin causa aparente también se examinan para identificar el neuroblastoma y otros tumores.[33]
  • Nódulos subcutáneos: la metástasis subcutánea de un neuroblastoma a menudo tiene coloración azulada en la piel suprayacente y, por lo general, solo se observa en lactantes.
Las características clínicas del neuroblastoma en adolescentes son similares a las que se observan en los niños. La única excepción es que el compromiso de médula ósea se presenta con menos frecuencia en los adolescentes y hay una mayor frecuencia de metástasis en sitios poco habituales como el pulmón o el encéfalo.[34]

Síndrome opsoclono-mioclono

Los niños con neuroblastoma presentan con poca frecuencia manifestaciones neurológicas paraneoplásicas, incluso ataxia cerebelosa u opsoclono-mioclono.[35] El síndrome opsoclono-mioclono se relaciona con frecuencia con déficits neurológicos y cognitivos generalizados y permanentes, como retraso psicomotor. La disfunción neurológica es el síntoma más común, pero puede surgir mucho tiempo después de la extirpación del tumor.[36-38]
Los pacientes que presentan este síndrome a menudo presentan neuroblastomas con características biológicas favorables y es probable que sobrevivan, aunque hay informes sobre defunciones relacionadas con el tumor.[36]
El síndrome opsoclono-mioclono parece obedecer a un mecanismo inmunitario que todavía no está bien definido.[36,39] El tumor primario generalmente está infiltrado de forma difusa con linfocitos.[40]
Algunos pacientes pueden responder clínicamente a la extirpación del neuroblastoma, pero la mejoría puede ser lenta y parcial; con frecuencia es necesario tratar los síntomas. El tratamiento con la hormona adrenocorticotrópica o con corticoesteroides se considera eficaz, pero algunos pacientes no responden a los corticosteroides.[37,39] Se ha informado que varios medicamentos, la plasmaféresis, la gammaglobulina intravenosa y el rituximab han sido eficaces en algunos casos.[37,41-43] Los desenlaces neurológicos a largo plazo pueden ser superiores en los pacientes tratados con quimioterapia, posiblemente debido a sus efectos inmunodepresores.[35,41]

Diagnóstico

La evaluación diagnóstica del neuroblastoma incluye los siguientes procedimientos:
  • Exploración con metayodobenzilguanidina (mIBG).[44,45]
  • Imágenes de la masa tumoral primaria: generalmente se obtienen mediante tomografía computarizada o imaginología por resonancia magnética (IRM) con contraste. La imagen de los tumores paraespinales que comprimen y ponen en peligro la médula espinal, se obtienen mediante IRM.
  • Metabolitos de las catecolaminas en la orina: antes del tratamiento, se mide la excreción urinaria de ácido vanililmandélico (AVM) y ácido homovanílico (AHV) por mg de creatinina excretada. No es necesaria la recolección de orina durante 24 horas. Si estos marcadores están elevados, se pueden utilizar para determinar la persistencia de la enfermedad.
    Para el diagnóstico del neuroblastoma no se utilizan de forma rutinaria las catecolaminas séricas, excepto en circunstancias no habituales.
  • Biopsia: en los ensayos clínicos actuales del COG, con frecuencia se necesita obtener tejido tumoral para tener todos los datos biológicos necesarios para asignar el grupo de riego y la estratificación posterior del tratamiento. La obtención de la biopsia del tejido es un requisito absoluto para determinar la International Neuroblastoma Pathology Classification (INPC). En el esquema de asignación al grupo riesgo/tratamiento para los estudios del COG, el INPC se usa para determinar el tratamiento de pacientes con enfermedad en estadio 3 y enfermedad en estadio 4S, así como los pacientes de 18 meses o menos con enfermedad en estadio 4. Además, se necesita una cantidad significativa de células tumorales para determinar el número de copias de MYCN, el índice de ADN y la pérdida de heterocigocidad de 11q y 1p. En los pacientes mayores de 18 meses con enfermedad en estadio 4, el compromiso tumoral extenso de la médula ósea combinado con metabolitos de catecolamina elevados puede ser adecuado para el diagnóstico y la asignación del grupo de riesgo/tratamiento; sin embargo, la INPC no se puede determinar a partir de la diseminación tumoral a la médula ósea. Se puede realizar una prueba satisfactoria de amplificación de MYCN y de pérdida de heterocigocidad 1p/11q en la médula espinal comprometida si hay al menos 30 a 40% de compromiso tumoral.
    En casos poco frecuentes, el neuroblastoma se puede descubrir antes del nacimiento mediante ecografía fetal.[46] Las recomendaciones de tratamiento evolucionan en relación con la necesidad de una biopsia diagnóstica inmediata en los lactantes de 6 meses o menos con presuntos tumores de neuroblastoma que puedan desaparecer espontáneamente. La biopsia no constituyó un requisito para el ingreso de los niños ​​en un estudio del COG sobre observación expectante de las pequeñas masas suprarrenales en neonatos y se evitó someter a cirugía a 81% de ellos: se evitó que 81% se sometiera a cualquier cirugía.[47] En un ensayo clínico alemán, 25 lactantes de 3 meses o menos con posibilidad de neuroblastoma, fueron sometidos a observación por períodos de 1 a 18 meses antes de una biopsia o resección. No se observaron efectos adversos evidentes por la demora.[48]
El diagnóstico del neuroblastoma exige la participación de patólogos, familiarizados con los tumores infantiles. Algunos neuroblastomas no se pueden diferenciar morfológicamente solo por microscopía óptica convencional y tinción con hematoxilina-eosina de otros tumores infantiles de células azules redondas y pequeñas como los linfomas, los tumores neuroectodérmicos primitivos y los rabdomiosarcomas. En estos casos, pueden ser necesarios análisis inmunohistoquímicos y citogenéticos para diagnosticar un tumor específico de células azules, redondas y pequeñas.
El criterio mínimo establecido por acuerdo internacional para diagnosticar el neuroblastoma se basa en una de las características siguientes:
  1. Un diagnóstico patológico inequívoco realizado por análisis de tejido tumoral con microscopia con luz (con inmunohistología, microscopía electrónica o concentraciones elevadas de catecolaminas séricas [dopamina o norepinefrina] o de catecolaminas de metabolitos urinarios [AVM o AVA] o sin ninguno de estos procedimientos).[49]
  2. La combinación de una muestra de médula ósea por aspiración o la biopsia por trépano que contenga células tumorales inequívocas (por ejemplo sincitios o racimos de células inmunocitológicamente positivas) y concentraciones elevadas de catecolaminas séricas o de metabolitos de catecolaminas urinarios.[49]

Factores pronósticos

Entre 1975 y 2010, la tasa de supervivencia a 5 años para el neuroblastoma en los Estados Unidos aumentó de 86 a 95% en los niños menores de 1 año y aumentó de 34 a 68% en niños de 1 a 14 años.[1] La supervivencia general (SG) a 5 años de todos los lactantes y niños con neuroblastoma aumentó de 46% cuando se diagnosticaron entre 1974 y 1989 a 71% cuando se diagnosticaron entre 1999 y 2005;[50] sin embargo, este número aislado puede ser engañoso debido al pronóstico extremadamente heterogéneo fundamentado en la edad, el estadio y las características biológicas del paciente de neuroblastoma. (Para mayor información, consultar el Cuadro 1). Aproximadamente 70% de los pacientes con neuroblastoma presentan enfermedad metastásica al momento del diagnóstico.
El pronóstico de los pacientes de neuroblastoma se relaciona con los siguientes aspectos:[51-54]
Algunos de estos factores pronósticos se combinaron para crear grupos de riesgo a fin de ayudar a definir el tratamiento. (Para mayor información, consultar las secciones de este sumario sobre el International Neuroblastoma Risk Group Staging System y la Agrupación de grupo de riesgo del neuroblastoma del Children’s Oncology Group).

Edad en el momento del diagnóstico

El efecto de la edad al momento del diagnóstico en la supervivencia a 5 años es de suma importancia. Según las estadísticas del U.S. Surveillance, Epidemiology, and End Results (SEER) de 1975 a 2006, la supervivencia a 5 años estratificada por edad es la siguiente:[50]
  • Edad menor de 1 año: 90%.
  • Edad de 1 a 4 años: 68%.
  • Edad de 5 a 9 años: 52%.
  • Edad de 10 a 14 años: 66%.
Los niños de cualquier edad con neuroblastoma localizado y los lactantes de 18 meses o menos con enfermedad avanzada y características favorables tienen una alta probabilidad de supervivencia sin enfermedad (SSE) a largo plazo.[55] El pronóstico del neuroblastoma fetal y neonatal es similar al de los lactantes mayores con neuroblastoma y características biológicas similares.[56] Sin embargo, los niños de más edad con enfermedad en estadio avanzado presentan una reducción significativa de la probabilidad de cura aun con tratamiento intensivo.
En los informes de ensayos clínicos realizados en América del Norte en la década de 1990, los niños de 1 año o menos tuvieron una tasa de curación mayor de 80%, mientras que los niños mayores tuvieron una tasa de curación de 50 a 70% con el tratamiento relativamente intensivo entonces vigente.[57-60]
La supervivencia de pacientes con enfermedad en estadio 4 del International Neuroblastoma Staging System (INSS) depende, en gran medida, de la edad. Los niños menores de 18 meses en el momento del diagnóstico tienen probabilidades altas de supervivencia a largo plazo (es decir, tasa de SSE a 5 años de 50 a 80%);[61,62] el desenlace depende particularmente de la amplificación de MYCN y de la ploidía de las células tumorales. La hiperdiploidía tiene pronóstico favorable, mientras que la diploidía pronostica un fracaso prematuro del tratamiento.[58,63] Los lactantes de 18 meses o menos en el momento del diagnóstico de neuroblastoma en estadio 4 del INSS que no tienen la amplificación del gen MYCN se clasifican como de riesgo intermedio y tienen una supervivencia sin complicaciones (SSC) a 3 años de 81% y una SG de 93%.[7,64-67]
Adolescentes y adultos jóvenes
El neuroblastoma tiene un pronóstico a largo plazo más precario en un adolescente mayor de 10 años o en un adulto que en un niño, independientemente del estadio o el sitio; en muchos casos, tiene un curso más prolongado cuando se trata con dosis estándar de quimioterapia.
Aunque estos pacientes pueden presentar una evolución clínica más lenta y una poco frecuente amplificación de MYCN (9% en pacientes de 10 a 21 años de edad), los niños mayores con enfermedad avanzada tienen una tasa de supervivencia precaria. En la población de adolescentes y adultos jóvenes, es común encontrar cambios cromosómicos en múltiples segmentos y la frecuencia de la mutación en ALK es de alrededor de 16%.[68,69]
La SSC y la SG a 5 años en pacientes de 10 a 21 años de edad son de 32 y 46%, respectivamente; para la enfermedad en estadio IV, la SSC y la SG a 10 años son de 3 y 5%, respectivamente.[70] La quimioterapia y la cirugía intensivas han mostrado lograr un estado de enfermedad mínima en más de 50% de estos pacientes.[34,71,72] Otras modalidades, como la radioterapia local, el trasplante autógeno de células madre y la utilización de sustancias cuya actividad ha sido confirmada, pueden mejorar un pronóstico adverso en los adolescentes y adultos.[70-72]

Sitio del tumor primario

El sitio del tumor primario no es un factor pronóstico independiente. El neuroblastoma multifocal (tumores primarios múltiples) se presenta con poca frecuencia, por lo general en lactantes, y tiene un buen pronóstico.[73] El neuroblastoma familiar y la mutación de la línea germinal del gen ALK se deben tomar en cuenta en pacientes de neuroblastomas con tumores primarios múltiples.
Las características clínicas y biológicas difieren según el sitio. Es más probable que se presenten tumores primarios suprarrenales que tumores primarios extrasuprarrenales, y es más probable que los tumores primarios extratorácicos se relacionen con características de pronóstico precario que los tumores torácicos; entre estas, la amplificación de MYCN, aun después de controlar por edad, estadio y grado histológico. El neuroblastoma suprarrenal de sitio primario extratorácico también se relacionó con una incidencia más alta de tumores en estadio 4, anomalías cromosómicas segmentarias y concentraciones altas de lactato-deshidrogenasa (LDH) y ferritina.[74]

Características histológicas del tumor

La histología de los tumores neuroblásticos tiene un efecto significativo sobre el pronóstico y la asignación al grupo de riesgo (para mayor información consultar la sección sobre Clasificación celular de los tumores neuroblásticos y el Cuadro 4 de este sumario).
Las características histológicas que se consideran favorables desde el punto de vista pronóstico son las siguientes:
  • Diferenciación/maduración celular. Los grados más altos de maduración neuroblástica confieren un mejor pronóstico para los pacientes en estadio 4 con cambios cromosómicos segmentarios sin amplificación de MYCN. Los tumores neuroblásticos que contienen muchas células diferenciadas, llamados ganglioneuroblastomas, pueden tener una diferenciación difusa que confiere un pronóstico muy favorable o que contienen nódulos de células no diferenciadas cuya histología, junto con la amplificación de MYCN determina el pronóstico.[75,76]
  • Estroma schwanniano.
  • Neuroblastoma quístico. Alrededor del 25% de los informes de neuroblastoma diagnosticados en el feto y el recién nacido son quísticos; los neuroblastomas quísticos tienen una estadificación más baja y una incidencia más alta de biología favorable.[56]
Las características histológicas consideradas como desfavorables desde el punto de vista pronóstico son las siguientes:
  • Mitosis.
  • Cariorrexis.
En un estudio del COG de niños con neuroblastoma en estadio 1 y 2 sin amplificación deMYCN, y con características histológicas favorables, se notificó una SSC a 5 años de 90 a 94% y una SG de 99 a 100%, mientras aquellos con características histológicas desfavorables tuvieron una SSC de 80 a 86% y una SG de 89 a 93%.[77] Se encontraron resultados similares en un estudio europeo.[78-80]

Compromiso de los ganglios linfáticos regionales

Según el INSS, la presencia de cáncer en los ganglios linfáticos regionales del mismo lado del cuerpo que el tumor primario no afecta el pronóstico. Sin embargo, cuando el neuroblastoma metastásico en los ganglios linfáticos cruza la línea media y está en el lugar opuesto del cuerpo al tumor primario, el paciente se sobrestadifica (para mayor información, consultar la sección de este sumario sobre Información sobre los estadios del neuroblastoma) y se le otorga pronóstico es más precario.

Respuesta al tratamiento

La respuesta al tratamiento se ha relacionado con el resultado. Por ejemplo, en los pacientes con enfermedad de riesgo alto, la persistencia de células neuroblásticas en la médula ósea después de la administración de quimioterapia de inducción se relaciona con un pronóstico más precario, que se puede evaluar mediante técnicas sensibles a la enfermedad residual mínima.[81-83] El grado de reducción del volumen tumoral predice la respuesta en pacientes con riesgo alto, al igual que una disminución en la mitosis y un aumento de diferenciación histológica.[84,85] Del mismo modo, la persistencia de un tumor ávido de mlBG después de terminar el tratamiento de inducción anticipa un pronóstico adverso.[86]

Características biológicas

Se ha estudiado una cantidad de variables biológicas en niños con este tumor.[87]
  • Subtipo biológico: estos tipos no se utilizan para determinar el tratamiento en este momento; sin embargo, el tipo 1 tiene un pronóstico muy favorable, mientras que los tipos 2 y 3 tienen pronósticos precarios. (Para mayor información sobre los subtipos 1, 2A y 2B, consultar la sección de este sumario sobre Subtipos biológicos).
  • Amplificación de MYCN: la amplificación de MYCN (definida como mayor de 10 copias por genoma diploide) se identifica en 16 a 25% de los tumores,[88] En los pacientes en estadio 2, 3, 4 y 4S, la amplificación del gen MYCN anticipa sobremanera un pronóstico más precario, tanto en el período hacia la evolución tumoral como en la SG en casi todos los análisis multivariados de regresión de factores pronósticos. La amplificación del gen MYCN se relaciona no solo con una eliminación del cromosoma 1p, pero también con una ganancia en el brazo largo del cromosoma 17 (17q), que predice de modo independiente un pronóstico adverso.[89] En el seno de la cohorte localizada delMYCN amplificado, el estado de la ploidía pronostica aún más el desenlace.[90]
    El grado de la expresión del gen MYCN en el tumor no tiene valor pronóstico.[91] No obstante, una dependencia en general alta de la expresión genética MYCN y una expresión baja de los genes de diferenciación tardía de la neurona simpática, ambos pronostican un desenlace precario para los neuroblastomas que, de otra forma, se considera que tienen un riesgo de recidiva bajo o intermedio.[92]
  • Cambios cromosómicos segmentarios: los cambios en el número de cromosomas segmentados pronostican la recidiva en los lactantes con neuroblastoma localizado no resecable o metastásico sin amplificación del gen MYCN. Entre todos los pacientes con neuroblastoma, un número más alto de puntos de interrupción del cromosoma se correlaciona con una edad avanzada al momento del diagnóstico, estadio avanzado de la enfermedad, mayor riesgo de recaída y desenlace más precario, ya sea que se tomara en cuenta o no la amplificación de MYCN.[19,21,26,69,93][Grado de comprobación: 3iiD]
  • Cambios en un cromosoma completo: los cambios en el número de copias de cromosomas completos no pronostican recidiva y se relacionan con hiperdiploidía.
  • Mutaciones de ALK: la cinasa de linfoma anaplásico (ALK) es un tirosina-cinasa receptora de la superficie celular que se expresa en concentraciones importantes únicamente en el encéfalo embrionario o neonatal. Se identificaron mutaciones de línea germinal en el gen ALK como la causa principal del neuroblastoma hereditario. También se descubrió que las mutaciones de activación del gen ALK adquiridas en forma somática actúan como mutaciones oncoiniciadoras en el neuroblastoma. Se observan mutaciones de ALK en 8% de los pacientes de neuroblastoma que se relacionan con una supervivencia significativamente más precaria cuando se trata de un neuroblastoma de riesgo intermedio y alto. En los pacientes mayores de 10 años se observa la frecuencia más alta (11%) de mutaciones en ALK. En los grupos de neuroblastoma de riesgo alto, bajo e intermedio, la frecuencia de las anomalías en ALKes de 14, 8 y 6%, respectivamente. Se están formulando inhibidores micromoleculares de la cinasa ALK, como el crizotinib, y se los está evaluando en pacientes con neuroblastoma recidivante y resistente al tratamiento.[22] (Para más información sobre los ensayos clínicos de crizotinib, consultar la sección de este sumario sobreOpciones de tratamiento del neuroblastoma recidivante o resistente al tratamiento en evaluación clínica).
Otros factores biológicos pronósticos que se han investigado de manera intensiva incluyen la longitud del telómero, la actividad de la telomerasa y el ácido ribonucleico de la telomerasa;[94,95] el AVM urinario, el AHV y su proporción;[96] MRP;[97] el perfil del receptor GABAergic;[98] la dopamina; la expresión de CD44; la expresión del gen TrkA; y el grado de concentración sérica de la enolasa específica de las neuronas; el grado de concentración de la LDH y el grado de concentración de la ferritina sérica.[87] En la actualidad, no se utilizan estos factores para la estratificación en los ensayos clínicos.

Regresión espontánea del neuroblastoma

El fenómeno de una regresión espontánea se ha descrito bien en lactantes con neuroblastoma; en particular; en lactantes con el patrón 4S de diseminación metastásica.[99] (Para mayor información, consultar la sección de este sumario sobre Información sobre los estadios del neuroblastoma).
Por lo general, la regresión espontánea se presenta solamente en tumores con las siguientes características:[100]
  • Número de cromosomas casi triploide.
  • Sin amplificación de MYCN.
  • Sin pérdida del cromosoma 1p.
Otras características relacionadas con una regresión espontánea incluyen la ausencia de expresión de la telomerasa,[101,102] la expresión de Ha-ras,[103] y la expresión del receptor de neurotrofina de TrkA, un receptor del factor de crecimiento nervioso.[104]
Hay estudios que indicaron que algunos lactantes que parecen tener un neuroblastoma suprarrenal pequeño, de grado bajo, asintomático, identificado mediante un examen de detección o de forma casual durante un examen prenatal o una ecografía, a menudo presentan tumores que manifiestan regresión espontánea y se pueden someter a observación de manera segura sin intervención quirúrgica o diagnóstico de tejido.[105-107]
Pruebas (observación):
  1. Un estudio del COG, observó a 83 lactantes muy selectos, menores de 6 meses con masas suprarrenales en estadio 1 determinado mediante estudios de imágenes sin realización de biopsia. La intervención quirúrgica se reservó para aquellos con crecimiento o avance de la masa, o por concentraciones crecientes de metabolitos de catecolamina en la orina.[47]
    • Ochenta y uno por ciento no necesitaron una operación y todos estaban vivos a los 2 años de seguimiento (para mayor información, consultar la subsección de este sumario sobre Cirugía).
  2. En un ensayo clínico alemán, la regresión espontánea o carencia de evolución tumoral se presentó en casi la mitad de 93 lactantes asintomáticos de 12 meses o menos con tumores en estadios 1, 2, o 3 sin amplificación del MYCN.[48]
    • Todos fueron sometidos a observación luego de una biopsia, un resecado parcial o sin resecado.
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  88. Ambros PF, Ambros IM, Brodeur GM, et al.: International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Br J Cancer 100 (9): 1471-82, 2009. [PUBMED Abstract]
  89. Bown N, Cotterill S, Lastowska M, et al.: Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N Engl J Med 340 (25): 1954-61, 1999. [PUBMED Abstract]
  90. Bagatell R, Beck-Popovic M, London WB, et al.: Significance of MYCN amplification in international neuroblastoma staging system stage 1 and 2 neuroblastoma: a report from the International Neuroblastoma Risk Group database. J Clin Oncol 27 (3): 365-70, 2009. [PUBMED Abstract]
  91. Cohn SL, London WB, Huang D, et al.: MYCN expression is not prognostic of adverse outcome in advanced-stage neuroblastoma with nonamplified MYCN. J Clin Oncol 18 (21): 3604-13, 2000. [PUBMED Abstract]
  92. Fredlund E, Ringnér M, Maris JM, et al.: High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma. Proc Natl Acad Sci U S A 105 (37): 14094-9, 2008. [PUBMED Abstract]
  93. Schleiermacher G, Michon J, Ribeiro A, et al.: Segmental chromosomal alterations lead to a higher risk of relapse in infants with MYCN-non-amplified localised unresectable/disseminated neuroblastoma (a SIOPEN collaborative study). Br J Cancer 105 (12): 1940-8, 2011. [PUBMED Abstract]
  94. Poremba C, Hero B, Goertz HG, et al.: Traditional and emerging molecular markers in neuroblastoma prognosis: the good, the bad and the ugly. Klin Padiatr 213 (4): 186-90, 2001 Jul-Aug. [PUBMED Abstract]
  95. Ohali A, Avigad S, Ash S, et al.: Telomere length is a prognostic factor in neuroblastoma. Cancer 107 (6): 1391-9, 2006. [PUBMED Abstract]
  96. Strenger V, Kerbl R, Dornbusch HJ, et al.: Diagnostic and prognostic impact of urinary catecholamines in neuroblastoma patients. Pediatr Blood Cancer 48 (5): 504-9, 2007. [PUBMED Abstract]
  97. Haber M, Smith J, Bordow SB, et al.: Association of high-level MRP1 expression with poor clinical outcome in a large prospective study of primary neuroblastoma. J Clin Oncol 24 (10): 1546-53, 2006. [PUBMED Abstract]
  98. Roberts SS, Mori M, Pattee P, et al.: GABAergic system gene expression predicts clinical outcome in patients with neuroblastoma. J Clin Oncol 22 (20): 4127-34, 2004. [PUBMED Abstract]
  99. Nickerson HJ, Matthay KK, Seeger RC, et al.: Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study. J Clin Oncol 18 (3): 477-86, 2000. [PUBMED Abstract]
  100. Ambros PF, Brodeur GM: Concept of tumorigenesis and regression. In: Brodeur GM, Sawada T, Tsuchida Y: Neuroblastoma. New York, NY: Elsevier Science, 2000, pp 21-32.
  101. Hiyama E, Hiyama K, Yokoyama T, et al.: Correlating telomerase activity levels with human neuroblastoma outcomes. Nat Med 1 (3): 249-55, 1995. [PUBMED Abstract]
  102. Hiyama E, Reynolds CP: Telomerase as a biological and prognostic marker in neuroblastoma. In: Brodeur GM, Sawada T, Tsuchida Y: Neuroblastoma. New York, NY: Elsevier Science, 2000, pp 159-174.
  103. Kitanaka C, Kato K, Ijiri R, et al.: Increased Ras expression and caspase-independent neuroblastoma cell death: possible mechanism of spontaneous neuroblastoma regression. J Natl Cancer Inst 94 (5): 358-68, 2002. [PUBMED Abstract]
  104. Brodeur GM, Minturn JE, Ho R, et al.: Trk receptor expression and inhibition in neuroblastomas. Clin Cancer Res 15 (10): 3244-50, 2009. [PUBMED Abstract]
  105. Yamamoto K, Ohta S, Ito E, et al.: Marginal decrease in mortality and marked increase in incidence as a result of neuroblastoma screening at 6 months of age: cohort study in seven prefectures in Japan. J Clin Oncol 20 (5): 1209-14, 2002. [PUBMED Abstract]
  106. Okazaki T, Kohno S, Mimaya J, et al.: Neuroblastoma detected by mass screening: the Tumor Board's role in its treatment. Pediatr Surg Int 20 (1): 27-32, 2004. [PUBMED Abstract]
  107. Fritsch P, Kerbl R, Lackner H, et al.: "Wait and see" strategy in localized neuroblastoma in infants: an option not only for cases detected by mass screening. Pediatr Blood Cancer 43 (6): 679-82, 2004. [PUBMED Abstract]
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Clasificación celular de los tumores neuroblásticos








Neuroblastoma Treatment (PDQ®)—Health Professional Version - National Cancer Institute





National Cancer Institute

Neuroblastoma Treatment (PDQ®)–Health Professional Version



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General Information About Neuroblastoma

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1-3] For neuroblastoma, the 5-year survival rate increased over the same time, from 86% to 95% for children younger than 1 year and from 34% to 68% for children aged 1 to 14 years.[2] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Incidence and Epidemiology

Neuroblastoma is the most common extracranial solid tumor in childhood. More than 650 cases are diagnosed each year in North America.[4,5] The prevalence is about 1 case per 7,000 live births; the incidence is about 10.54 cases per 1 million per year in children younger than 15 years. About 37% are diagnosed as infants, and 90% are younger than 5 years at diagnosis, with a median age at diagnosis of 19 months.[6] The data on age at diagnosis show that this is a disease of infancy, with the highest rate of diagnosis in the first month of life.[4-6]
The incidence of neuroblastoma in black children is slightly lower than that in white children.[7] However, there are also racial differences in tumor biology, with African Americans more likely to have high-risk disease and fatal outcomes.[8,9]
Population-based studies of screening for infants with neuroblastoma have demonstrated that spontaneous regression of neuroblastoma without clinical detection in the first year of life is at least as prevalent as clinically detected neuroblastoma.[10-12]
Epidemiologic studies have shown that environmental or other exposures have not been unequivocally associated with increased or decreased incidence of neuroblastoma.[13]

Anatomy

Neuroblastoma originates in the adrenal medulla and paraspinal or periaortic regions where sympathetic nervous system tissue is present.
ENLARGEDrawing shows parts of the body where neuroblastoma may be found, including the paraspinal nerve tissue and the adrenal glands. Also shown are the spine and right and left kidney.
Figure 1. Neuroblastoma may be found in the adrenal glands and paraspinal nerve tissue from the neck to the pelvis.

Genetic Predisposition

Studies analyzing constitutional DNA in rare cohorts of familial neuroblastoma patients have provided insight into the complex genetic basis for tumor initiation. About 1% to 2% of patients with neuroblastoma have a family history of neuroblastoma. These children are, on average, younger (9 months at diagnosis) and have multifocal primary neuroblastoma (about 20%).
Several germline mutations have been associated with a genetic predisposition to neuroblastoma, including the following:
  • ALK gene mutation. The primary cause of familial neuroblastoma (about 75% of familial cases) is a germline mutation in the ALK (anaplastic lymphoma kinase) gene.[14] Somatic mutation in ALK is also seen in sporadic neuroblastoma. ALK is a tyrosine kinase receptor mutated in some lymphomas (refer to the Genomic and Biologic Features of Neuroblastoma section of this summary for more information).
  • PHOX2B gene mutation. Rarely, familial neuroblastoma may be associated with congenital central hypoventilation syndrome (Ondine curse), which is caused by a germline mutation of the PHOX2B gene.[15] Most PHOX2B mutations causing Ondine curse or Hirschsprung disease are polyalanine repeats and are not associated with familial neuroblastoma. However, germline loss-of-function PHOX2B mutations have been identified in rare patients with sporadic neuroblastoma and Ondine curse and/or Hirschsprung disease.[16] Aberration of PHOX2B has not been seen in patients with sporadic neuroblastoma without associated Ondine curse or Hirschsprung disease.
  • Germline deletion at the 1p36 or 11q14-23 locus. In case studies, germline deletion at the 1p36 or 11q14-23 locus has been associated with familial neuroblastoma, and the same deletions are found somatically in sporadic neuroblastoma.[17,18]
Sporadic neuroblastoma may also show a germline contribution, either with modest effect sizes for common polymorphic alleles or with greater effect sizes for rare pathogenic variants. As an example of the latter, rare germline variants of BARD1 have been identified in children with high-risk neuroblastoma.[19]
Genome-wide association studies have identified several common genomic variables (single nucleotide polymorphisms [SNPs]) with modest effect size that are associated with neuroblastoma. A subset of these SNPs is associated with susceptibility to high-risk neuroblastoma, including variants related to the following:
  • BARD1 (chromosome 2q35).[20]
  • LMO1 (chromosome 11p15).[21]
  • LIN28B (chromosome 6q16).[22]
  • HACE1 (chromosome 6q16).[22]
  • CASC15/NBAT-1 (chromosome 6p22).[23,24]
Other SNPs are associated with susceptibility to low-risk neuroblastoma.[25] One example that illustrates a mechanism by which SNPs may contribute to neuroblastoma risk is the polymorphism in the first intron of the oncogene LMO1 that forms a GATA transcription factor–binding site in an enhancer.[21,26] This risk allele is associated with high expression of LMO1 in aggressive neuroblastoma. LMO1 protein is necessary for growth of neuroblastoma in vitro and enhances growth of neuroblastoma cell lines with low LMO1expression.

Genomic and Biologic Features of Neuroblastoma

Neuroblastoma can be subdivided into a biologically defined subset that has a very favorable prognosis (i.e., low-risk neuroblastoma) and another group that has a guarded prognosis (i.e., high-risk neuroblastoma). While neuroblastoma in infants with tumors that have favorable biology is highly curable, only 50% of children with high-risk neuroblastoma are alive at 5 years from diagnosis, at best.
Low-risk neuroblastoma is usually found in children younger than 18 months with limited extent of disease; the tumor has changes, usually increases, in the number of whole chromosomes in the neuroblastoma cell. Low-risk tumors are hyperdiploid when examined by flow cytometry.[27,28] In contrast, high-risk neuroblastoma generally occurs in children older than 18 months, is often metastatic to bone, and usually has segmental chromosome abnormalities. They are near diploid or near tetraploid by flow cytometric measurement.[27-33] High-risk tumors also show exonic mutations (refer to the Exonic mutations in neuroblastoma section of this summary for more information), but most high-risk tumors lack mutations in genes that are recurrently mutated. Compared with adult cancers, neuroblastomas show a low number of mutations per genome that affect protein sequence (10–20 per genome).[19]
Key genomic characteristics of high-risk neuroblastoma that are discussed below include the following:
  • Segmental chromosomal aberrations, including MYCN gene amplification.
  • Low rates of exonic mutations, with activating mutations in ALK being the most common recurring alteration.
  • Genomic alterations that promote telomere lengthening.
Segmental chromosomal aberrations (including MYCN gene amplification)
Segmental chromosomal aberrations, found most frequently in 1p, 1q, 3p, 11q, 14q, and 17p (and MYCN amplification), are best detected by comparative genomic hybridization and are seen in almost all high-risk and/or stage 4 neuroblastomas.[29-33] Among all patients with neuroblastoma, a higher number of chromosome breakpoints correlated with the following, whether or not MYCN amplification was considered:
In a study of unresectable primary neuroblastomas without metastases in children older than 12 months, segmental chromosomal aberrations were found in most, and older children were more likely to have them and to have more of them per tumor cell. In children aged 12 to 18 months, the presence of segmental chromosomal aberrations had a significant effect on event-free survival (EFS) but not on overall survival (OS). However, in children older than 18 months, there was a significant difference in OS in children with segmental chromosomal aberrations versus children without segmental chromosomal aberrations (67% vs. 100%), regardless of the histologic prognosis.[33]
Segmental chromosomal aberrations are also predictive of recurrence in infants with localized unresectable or metastatic neuroblastoma without MYCN gene amplification.[27,28]
MYCN amplification (defined as more than 10 copies per diploid genome) is one of the most common segmental chromosomal aberrations, detected in 16% to 25% of tumors.[34] For high-risk neuroblastoma, 40% to 50% of cases show MYCN amplification.[35] In all stages of disease, amplification of the MYCN gene strongly predicts a poorer prognosis in both time to tumor progression and OS in almost all multivariate regression analyses of prognostic factors.[27,28] Within the localized MYCN-amplified cohort, ploidy status may further predict outcome.[36] However, patients with hyperdiploid tumors with any segmental chromosomal aberrations do relatively poorly.[29]
Most unfavorable clinical and pathobiological features are associated, to some degree, with MYCN amplification; in a multivariable logistic regression analysis of 7,102 International Neuroblastoma Risk Group patients, pooled segmental chromosomal aberrations and gain of 17q were the only poor prognostic features not associated withMYCN amplification. However, segmental chromosomal aberrations at 11q are almost mutually exclusive of MYCN amplification.
Exonic mutations in neuroblastoma
Multiple reports have documented that a minority of high-risk neuroblastomas have a small number of low-incidence, recurrently mutated genes. The most commonly mutated gene is ALK, which is mutated in approximately 10% of patients (see below). Other genes with even lower frequencies of mutation include ATRX, PTPN11, ARID1A, and ARID1B.[37-43] As shown in Figure 2, most neuroblastoma cases lack mutations in genes that are altered in a recurrent manner.
ENLARGEChart showing the landscape of genetic variation in neuroblastoma.
Figure 2. Data tracks (rows) facilitate the comparison of clinical and genomic data across cases with neuroblastoma (columns). The data sources and sequencing technology used were whole-exome sequencing (WES) from whole-genome amplification (WGA) (light purple), WES from native DNA (dark purple), Illumina WGS (green), and Complete Genomics WGS (yellow). Striped blocks indicate cases analyzed using two approaches. The clinical variables included were gender (male, blue; female, pink) and age (brown spectrum). Copy number alterations indicates ploidy measured by flow cytometry (with hyperdiploid meaning DNA index >1) and clinically relevant copy number alterations derived from sequence data. Significantly mutated genes are those with statistically significant mutation counts given the background mutation rate, gene size, and expression in neuroblastoma. Germline indicates genes with significant numbers of germline ClinVar variants or loss-of-function cancer gene variants in our cohort. DNA repair indicates genes that may be associated with an increased mutation frequency in two apparently hypermutated tumors. Predicted effects of somatic mutations are color coded according to the legend. Reprinted by permission from Macmillan Publishers Ltd: Nature Genetics (Pugh TJ, Morozova O, Attiyeh EF, et al.: The genetic landscape of high-risk neuroblastoma. Nat Genet 45 (3): 279-84, 2013), copyright (2013).
ALK, the exonic mutation found most commonly in neuroblastoma, is a cell surface receptor tyrosine kinase, expressed at significant levels only in developing embryonic and neonatal brains. Germline mutations in ALK have been identified as the major cause of hereditary neuroblastoma. Somatically acquired ALK-activating mutations are also found as oncogenic drivers in neuroblastoma.[42]
The presence of an ALK mutation correlates with significantly poorer survival in high-risk and intermediate-risk neuroblastoma patients. ALK mutation was examined in 1,596 diagnostic neuroblastoma samples.[42] ALK tyrosine kinase domain mutations occurred in 8% of samples—at three hot spots and 13 minor sites—and correlated significantly with poorer survival in patients with high-risk and intermediate-risk neuroblastoma. ALKmutations were found in 10.9% of MYCN-amplified tumors versus 7.2% of those withoutMYCN amplification. ALK mutations occurred at the highest frequency (11%) in patients older than 10 years.[42] The frequency of ALK aberrations was 14% in the high-risk neuroblastoma group, 6% in the intermediate-risk neuroblastoma group, and 8% in the low-risk neuroblastoma group.
Small-molecule ALK kinase inhibitors such as crizotinib are being developed and tested in patients with recurrent and refractory neuroblastoma.[42] (Refer to the Treatment Options Under Clinical Evaluation for Recurrent or Refractory Neuroblastoma section in the PDQ summary on Neuroblastoma Treatment for more information about crizotinib clinical trials.)
Genomic evolution of exonic mutations
There are limited data regarding the genomic evolution of exonic mutations from diagnosis to relapse for neuroblastoma. Whole-genome sequencing was applied to 23 paired diagnostic and relapsed neuroblastomas to define somatic genetic alterations associated with relapse,[44] while a second study evaluated 16 paired diagnostic and relapsed specimens.[45] Both studies identified an increased number of mutations in the relapsed samples compared with the samples at diagnosis.
  • The first study found increased incidence of mutations in genes associated with RAS-MAPK signaling at relapse than at diagnosis, with 15 of 23 relapse samples containing somatic mutations in genes involved in this pathway and each mutation consistent with pathway activation.[44]
    In addition, three relapse samples showed structural alterations involving MAPK pathway genes consistent with pathway activation, so aberrations in this pathway were detected in 18 of 23 relapse samples (78%). Aberrations were found in ALK (n = 10), NF1(n = 2), and one each in NRAS, KRAS, HRAS, BRAF, PTPN11, and FGFR1. Even with deep sequencing, 7 of the 18 alterations were not detectable in the primary tumor, highlighting the evolution of mutation presumably leading to relapse and the importance of genomic evaluations of tissues obtained at relapse.
  • In the second study, ALK mutations were not observed in either diagnostic or relapse specimens, but relapse-specific recurrent single-nucleotide variants were observed in 11 genes, including the putative CHD5 neuroblastoma tumor suppressor gene located at chromosome 1p36.[45]
Genomic alterations promoting telomere lengthening
Lengthening of telomeres, the tips of chromosomes, promotes cell survival. Telomeres otherwise shorten with each cell replication, resulting eventually in the lack of a cell’s ability to replicate. Low-risk neuroblastomas have little telomere lengthening activity. Aberrant genetic mechanisms for telomere lengthening have been identified for high-risk neuroblastoma.[37,38,46] Thus far, the following three mechanisms, which appear to be mutually exclusive, have been described:
  • Chromosomal rearrangements involving a chromosomal region at 5p15.33 proximal to the TERT gene, which encodes the catalytic unit of telomerase, occur in approximately 25% of high-risk neuroblastoma cases and are mutually exclusive with MYCNamplifications and ATRX mutations.[37,38] The rearrangements induce transcriptional upregulation of TERT by juxtaposing the TERT coding sequence with strong enhancer elements.
  • Another mechanism promoting TERT overexpression is MYCN amplification,[47] which is associated with approximately 40% to 50% of high-risk neuroblastomas.
  • The ATRX mutation or deletion is found in 10% to 20% of high-risk neuroblastomas, almost exclusively in older children,[39] and is associated with telomere lengthening by a different mechanism, termed alternative lengthening of telomeres.[39,46]
Additional biological factors associated with prognosis
MYC and MYCN expression
Immunostaining for MYC and MYCN proteins on 357 undifferentiated/poorly differentiated neuroblastomas has demonstrated that elevated MYC/MYCN protein expression is prognostically significant.[48] Sixty-eight tumors highly expressed MYCN protein, and 81 were MYCN amplified. Thirty-nine tumors expressed MYC highly and were mutually exclusive of high MYCN expression. Segmental chromosomal aberrations were not examined in this study, except for MYCN amplification.[48]
  • Patients with favorable-histology (FH) tumors without high MYC/MYCN expression had favorable survival (3-year EFS, 89.7% ± 5.5%; 3-year OS, 97% ± 3.2%).
  • Patients with undifferentiated or poorly differentiated histology tumors without MYC/MYCN expression had a 3-year EFS rate of 63.1% ± 13.6% and a 3-year OS rate of 83.5% ± 9.4%.
  • Three-year EFS rates in patients with MYCN amplification, high MYCN expression, and high MYC expression were 48.1% ± 11.5%, 46.2% ± 12%, and 43.4% ± 23.1%, respectively, and OS rates were 65.8% ± 11.1%, 63.2% ± 12.1%, and 63.5% ± 19.2%, respectively.
  • Further, when high expression of MYC and MYCN proteins were analyzed with other prognostic factors, including MYC/MYCN gene amplification, high MYC and MYCN protein expression was independent of other prognostic markers.
Most neuroblastomas with MYCN amplification in the International Neuroblastoma Pathology Classification system have unfavorable histology, but about 7% have FH. Of those with MYCN amplification and FH, most do not express MYCN, despite the gene being amplified, and have a more favorable prognosis than those that express MYCN.[49] Segmental chromosomal aberration at 11q is almost mutually exclusive of MYCNamplification.
Neurotrophin receptor kinases
Expression of neurotrophin receptor kinases and their ligands vary between high-risk and low-risk tumors. TrkA is found on low-risk tumors, and absence of its ligand NGF is postulated to lead to spontaneous tumor regression. In contrast, TrkB is found in high-risk tumors that also express its ligand, BDNF, which promotes neuroblastoma cell growth and survival.[50]

Neuroblastoma Screening

Current data do not support neuroblastoma screening. Screening at the ages of 3 weeks, 6 months, or 1 year did not lead to reduction in the incidence of advanced-stage neuroblastoma with unfavorable biological characteristics in older children, nor did it reduce overall mortality from neuroblastoma.[11,12] No public health benefits have been shown from screening infants for neuroblastoma at these ages. (Refer to the PDQ summary on Neuroblastoma Screening for more information.)
Evidence (against neuroblastoma screening):
  1. A large population-based North American study, in which most infants in Quebec were screened at the ages of 3 weeks and 6 months, has shown that screening detects many neuroblastomas with favorable characteristics [10,11] that would never have been detected clinically, apparently because of spontaneous regression of the tumors.
  2. Another study of infants screened at the age of 1 year shows similar results.[12]

Clinical Presentation

The most common presentation of neuroblastoma is an abdominal mass. The most frequent signs and symptoms of neuroblastoma are caused by tumor mass and metastases. They include the following:
  • Proptosis and periorbital ecchymosis: Common in high-risk patients and arise from retrobulbar metastasis.
  • Abdominal distention: May occur with respiratory compromise in infants due to massive liver metastases.
  • Bone pain: Occurs in association with metastatic disease.
  • Pancytopenia: May result from extensive bone marrow metastasis.
  • Fever, hypertension, and anemia: Occasionally found in patients without metastasis.
  • Paralysis: Neuroblastoma originating in paraspinal ganglia may invade through neural foramina and compress the spinal cord extradurally. Immediate treatment is given for symptomatic spinal cord compression. (Refer to the Treatment of Spinal Cord Compression section of this summary for more information.)
  • Watery diarrhea: On rare occasions, children may have severe, watery diarrhea caused by the secretion of vasoactive intestinal peptide by the tumor, or they may have protein-losing enteropathy with intestinal lymphangiectasia.[51] Vasoactive intestinal peptide secretion may also occur upon chemotherapeutic treatment, and tumor resection reduces vasoactive intestinal peptide secretion.[52]
  • Presence of Horner syndrome: Horner syndrome is characterized by miosis, ptosis, and anhidrosis. It may be caused by neuroblastoma in the stellate ganglion, and children with Horner syndrome without other apparent cause are also examined for neuroblastoma and other tumors.[53]
  • Subcutaneous skin nodules: Neuroblastoma subcutaneous metastases often have bluish discoloration of the overlying skin and is usually seen only in infants.
The clinical characteristics of neuroblastoma in adolescents are similar to those observed in children. The only exception is that bone marrow involvement occurs less frequently in adolescents, and there is a greater frequency of metastases in unusual sites such as lung or brain.[54]

Opsoclonus/myoclonus syndrome

Paraneoplastic neurologic findings, including cerebellar ataxia or opsoclonus/myoclonus, occur rarely in children with neuroblastoma.[55] Opsoclonus/myoclonus syndrome can be associated with pervasive and permanent neurologic and cognitive deficits, including psychomotor retardation. Neurologic dysfunction is most often a presenting symptom but may arise long after removal of the tumor.[56-58]
Patients who present with opsoclonus/myoclonus syndrome often have neuroblastomas with favorable biological features and are likely to survive, though tumor-related deaths have been reported.[56]
The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully defined.[56,59] The primary tumor is typically diffusely infiltrated with lymphocytes.[60]
Some patients may respond neurologically to removal of the neuroblastoma, but improvement may be slow and partial; symptomatic treatment is often necessary. Adrenocorticotropic hormone or corticosteroid treatment can be effective, but some patients do not respond to corticosteroids.[57,59] Other therapy with various drugs, plasmapheresis, intravenous gamma globulin, and rituximab have been reported to be effective in selected cases.[57,61-63] The long-term neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.[55,61]

Diagnosis

Diagnostic evaluation of neuroblastoma includes the following:
  • Tumor imaging: Imaging of the primary tumor mass is generally accomplished by computed tomography or magnetic resonance imaging (MRI) with contrast. Paraspinal tumors that might threaten spinal cord compression are imaged using MRI. Metaiodobenzylguanidine (mIBG) scanning may also be used.[64,65]
  • Urine catecholamine metabolites: Urinary excretion of the catecholamine metabolites vanillylmandelic acid (VMA) and homovanillic acid (HVA) per milligram of excreted creatinine is measured before therapy. Collection of urine for 24 hours is not needed. If elevated, these markers can be used to determine the persistence of disease.
    Serum catecholamines are not routinely used in the diagnosis of neuroblastoma except in unusual circumstances.
  • Biopsy: Tumor tissue is often needed to obtain all the biological data required for risk-group assignment and subsequent treatment stratification in current Children’s Oncology Group (COG) clinical trials. There is an absolute requirement for tissue biopsy to determine the International Neuroblastoma Pathology Classification (INPC). In the risk/treatment group assignment schema for COG studies, INPC has been used to determine treatment for patients with stage 3 disease, patients with stage 4S disease, and patients aged 18 months or younger with stage 4 disease. Additionally, a significant number of tumor cells are needed to determine MYCN copy number, DNA index, and the presence of segmental chromosomal aberrations.
    For patients older than 18 months with stage 4 disease, bone marrow with extensive tumor involvement combined with elevated catecholamine metabolites may be adequate for diagnosis and assigning risk/treatment group; however, INPC cannot be determined from tumor metastatic to bone marrow. Testing for MYCN amplification may be successfully performed on involved bone marrow if there is at least 30% tumor involvement.
    In rare cases, neuroblastoma may be discovered prenatally by fetal ultrasonography.[66] Management recommendations are evolving with regard to the need for immediate diagnostic biopsy in infants aged 6 months and younger with suspected neuroblastoma tumors that are likely to spontaneously regress. In a COG study of expectant observation of small adrenal masses in neonates, biopsy was not required for infants; 81% of patients avoided undergoing any surgery at all.[67] In a German clinical trial, 25 infants aged 3 months and younger with presumed localized neuroblastoma were observed without biopsy for periods of 1 to 18 months before biopsy or resection. There were no apparent ill effects from the delay.[68]
The diagnosis of neuroblastoma requires the involvement of pathologists who are familiar with childhood tumors. Some neuroblastomas cannot be differentiated morphologically, via conventional light microscopy with hematoxylin and eosin staining alone, from other small round blue cell tumors of childhood, such as lymphomas, primitive neuroectodermal tumors, and rhabdomyosarcomas. In such cases, immunohistochemical and cytogenetic analysis may be needed to diagnose a specific small round blue cell tumor.
The minimum criterion for a diagnosis of neuroblastoma, as established by international agreement, is that diagnosis must be based on one of the following:
  1. An unequivocal pathologic diagnosis made from tumor tissue by light microscopy (with or without immunohistology or electron microscopy).[69]
  2. The combination of bone marrow aspirate or trephine biopsy containing unequivocal tumor cells (e.g., syncytia or immunocytologically positive clumps of cells) andincreased levels of urinary catecholamine metabolites.[69]

Prognostic Factors

Between 1975 and 2010, the 5-year survival rate for neuroblastoma in the United States increased from 86% to 95% for children younger than 1 year and increased from 34% to 68% for children aged 1 to 14 years.[2] The 5-year OS for all infants and children with neuroblastoma has increased from 46% when diagnosed between 1974 and 1989, to 71% when diagnosed between 1999 and 2005.[70] This single statistic can be misleading because of the extremely heterogeneous prognosis based on the neuroblastoma patient's age, stage, and biology. However, studies demonstrate a significant improvement in survival for high-risk patients diagnosed and treated between 2000 and 2010 compared with those diagnosed from 1990 to 1999.[71] (Refer to Table 1 for more information.)
The prognosis for patients with neuroblastoma is related to the following:[72-75]
Some of these prognostic factors have been combined to create risk groups to help define treatment. (Refer to the International Neuroblastoma Risk Group Staging System section and the Children’s Oncology Group Neuroblastoma Risk Grouping section of this summary for more information.)

Age at diagnosis

The effect of age at diagnosis on 5-year survival is profound. According to the 1975 to 2006 U.S. Surveillance, Epidemiology, and End Results (SEER) statistics, the 5-year survival stratified by age is as follows:[70]
  • Age younger than 1 year – 90%.
  • Age 1 to 4 years – 68%.
  • Age 5 to 9 years – 52%.
  • Age 10 to 14 years – 66%.
Children of any age with localized neuroblastoma and infants aged 18 months and younger with advanced disease and favorable disease characteristics have a high likelihood of long-term, disease-free survival (DFS).[76] The prognosis for fetal and neonatal neuroblastoma is similar to that for older infants with neuroblastoma and similar biological features.[77] Older children with advanced-stage disease, however, have a significantly decreased chance for cure, despite intensive therapy.
The effect of patient age on prognosis is strongly influenced by clinical and pathobiological factors, as evidenced by the following:
  • Since 2000, nonrandomized studies of low-risk and intermediate-risk patients have demonstrated that patient age has no effect on outcome of International Neuroblastoma Staging System (INSS) stage 1 or 2A disease. However, stage 2B patients younger than 18 months had a 5-year OS of 99% ± 1% versus 90% ± 4% for children aged 18 months and older.[78]
  • In the COG intermediate-risk study A3961 (NCT00003093) that included only MYCN non-amplified tumors, infants with INSS stage 3 tumors were compared with children with INSS stage 3 favorable-histology tumors. When INSS stage 3 infants with any histology were compared with stage 3 children with favorable histology, only EFS rates, not OS rates, were significantly different (3-year EFS, 95% ± 2 % vs. 87% ± 3 %; OS, 98% ± 1% vs. 99% ± 1%).[79]
In North American clinical trials reported in the 1990s, infants aged 1 year and younger had a cure rate higher than 80%, while older children had a cure rate of 50% to 70% with then-current, relatively intensive therapy.[80-83]
Survival of patients with INSS stage 4 disease is strongly dependent on age. Children younger than 18 months at diagnosis have a good chance of long-term survival (i.e., a 5-year DFS rate of 50%–80%),[84,85] with outcome particularly dependent on MYCN status, tumor cell ploidy, and the pattern of chromosomal aberrations (numerical chromosomal aberrations and segmental chromosomal aberrations). Hyperdiploidy and numerical chromosomal aberrations confer a favorable prognosis while diploidy and segmental chromosomal aberrations are associated with early treatment failure.[81,86] Infants aged 18 months and younger at diagnosis with INSS stage 4 neuroblastoma who do not haveMYCN gene amplification are categorized as intermediate risk and have a 3-year EFS of 81% and OS of 93%.[6,79,87-89] Infants younger than 12 months with INSS stage 4 disease andMYCN amplification are categorized as high risk and have a 3-year EFS of 10%.[87]
Adolescents and young adults
Neuroblastoma has a worse long-term prognosis in adolescents older than 10 years or adults, regardless of stage or site. The disease is more indolent in older patients than in children.
Although adolescent and young adult patients have infrequent MYCN amplification (9% in patients aged 10–21 years), older children with advanced disease have a poor rate of survival. Tumors from the adolescent and young adult population commonly have segmental chromosomal aberrations, and ALK and ATRX mutations are much more frequent.[19,33,90]
The 5-year EFS rate is 32% for patients between the ages of 10 years and 21 years and the OS rate is 46%; for stage 4 disease, the 10-year EFS rate is 3% and the and OS rate is 5%.[91] Aggressive chemotherapy and surgery have been shown to achieve a minimal disease state in more than 50% of these patients.[54,92,93] Other modalities, such as local radiation therapy, autologous stem cell transplant, and the use of agents with confirmed activity, may improve the poor prognosis for adolescents and adults.[91-93]

Site of primary tumor

Clinical and biological features of neuroblastoma differ by primary tumor site. In a study of data on 8,389 patients entered in clinical trials and compiled by the International Risk Group Project, the following results were observed:[94]
  • Adrenal primary tumors were more likely than tumors originating in other sites to be associated with unfavorable prognostic features, including MYCN amplification, even after researchers controlled for age, stage, and histologic grade. Adrenal neuroblastomas were also associated with a higher incidence of stage 4 tumors, segmental chromosomal aberrations, diploidy, unfavorable INPC histology, age younger than 18 months, and elevated levels of lactate dehydrogenase (LDH) and ferritin. The relative risk of MYCN amplification compared with adrenal tumors was 0.7 in abdominal nonadrenal tumors and about 0.1 in nonabdominal paraspinal tumors.
  • Thoracic tumors were compared with nonthoracic tumors; after researchers controlled for age, stage, and histologic grade, results showed thoracic tumor patients had fewer deaths and recurrences (HR, 0.79; 95% confidence interval [CI], 0.67–0.92) and thoracic tumors had a lower incidence of MYCN amplification (adjusted OR, 0.20; 95% CI, 0.11–0.39).
Multifocal (multiple primaries) neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis.[95] Familial neuroblastoma and germline ALK gene mutation should be considered in patients with multiple primary neuroblastomas.

Tumor histology

Neuroblastoma tumor histology has a significant impact on prognosis and risk group assignment (refer to the Cellular Classification of Neuroblastic Tumors section and Table 4of this summary for more information).
Histologic characteristics considered prognostically favorable include the following:
  • Cellular differentiation/maturation. Higher degrees of neuroblastic maturation confer improved prognosis for stage 4 patients with segmental chromosome changes withoutMYCN amplification. Neuroblastoma tumors containing many differentiating cells, termed ganglioneuroblastoma, can have diffuse differentiation conferring a very favorable prognosis or can have nodules of undifferentiated cells whose histology, along with MYCN status, determine prognosis.[96,97]
  • Schwannian stroma.
  • Cystic neuroblastoma. About 25% of reported neuroblastomas diagnosed in the fetus and neonate are cystic; cystic neuroblastomas have lower stages and a higher incidence of favorable biology.[77]
High mitosis/karyorrhexis index is considered a prognostically unfavorable histologic characteristic, but its prognostic ability is age dependent.[98,99]
In a COG study (P9641 [NCT00003119]), 87% of 915 children with stage 1 and stage 2 neuroblastoma without MYCN amplification were treated with initial surgery and observation. Patients (13%) who had or were at risk of developing symptomatic disease, or who had less than 50% tumor resection at diagnosis, or who had unresectable progressive disease after surgery alone, were treated with chemotherapy and surgery. Those with favorable histologic features reported a 5-year EFS of 90% to 94% and OS of 99% to 100%, while those with unfavorable histology had an EFS of 80% to 86% and an OS of 89% to 93%.[78]

Regional lymph node involvement

According to the INSS, the presence of cancer in the regional lymph nodes on the same side of the body as the primary tumor has no effect on prognosis. However, when lymph nodes with metastatic neuroblastoma cross the midline and are on the opposite sides of the body from the primary tumor, the patient is upstaged (refer to the Stage Information for Neuroblastoma section of this summary for more information), and a poorer prognosis is conferred. In the COG P9641 (NCT00003119) low-risk study, stage 2b patients (those with tumor-containing lymph nodes on the same side of the body cavity as the tumor, but not on the opposite side of the cavity), but not stage 1 or 2a patients, had a poorer outcome with unfavorable histology (86% ± 5% vs. 99% ± 1%). The poorer outcome was predominantly in patients older than 18 months.[78]

Response to treatment

Response to treatment has been associated with outcome. In patients with high-risk disease, the persistence of neuroblastoma cells in bone marrow after induction chemotherapy, for example, is associated with a poor prognosis, which may be assessed by sensitive minimal residual disease techniques.[100-102] Similarly, the persistence of mIBG-avid tumor measured as Curie score (refer to the Curie score and SIOPEN score section of this summary for more information about Curie scoring) in two or more sites after completion of induction therapy predicts a poor prognosis.[103] A decrease in mitosis and an increase in histologic differentiation of the primary tumor are also prognostic.[104]
The accuracy of prognostication based on decrease in primary tumor size is less clear. In a study conducted by seven large international centers, 229 high-risk patients were treated in a variety of ways, including surgical removal of the primary tumor, radiation to the tumor bed, and, in most cases, antiGD2 antibody–enhanced immunotherapy. Primary tumor response was measured in three ways: as 30% or greater reduction in the longest dimension, 50% or greater reduction in tumor volume, or 65% or greater reduction in tumor volume (calculated from three tumor dimensions, a conventional radiologic technique). The measurements were performed at diagnosis and after induction chemotherapy before primary tumor resection. None of the methods of measuring primary tumor response were predictive of outcome.[105]

Spontaneous Regression of Neuroblastoma

The phenomenon of spontaneous regression has been well described in infants with neuroblastoma, especially in infants with the 4S pattern of metastatic spread.[106] (Refer to the Stage Information for Neuroblastoma section of this summary for more information.)
Spontaneous regression generally occurs only in tumors with the following features:[107]
  • Near triploid number of chromosomes.
  • No MYCN amplification.
  • No loss of chromosome 1p.
Additional features associated with spontaneous regression include the lack of telomerase expression,[108,109] the expression of Ha-ras,[110] and the expression of the neurotrophin receptor TrkA, a nerve growth factor receptor.[111]
Studies have suggested that selected infants who appear to have asymptomatic, small, low-stage adrenal neuroblastoma detected by screening or during prenatal or incidental ultrasound examination often have tumors that spontaneously regress and may be observed safely without surgical intervention or tissue diagnosis.[112-114]
Evidence (observation [spontaneous regression]):
  1. In a COG study, 83 highly selected infants younger than 6 months with stage 1 small adrenal masses as defined by imaging studies were observed without biopsy. Surgical intervention was reserved for those with growth or progression of the mass or increasing concentrations of urinary catecholamine metabolites.[67]
    • Eighty-one percent were spared surgery, and all were alive after 2 years of follow-up (refer to the Surgery subsection of this summary for more information).
  2. In a German clinical trial, spontaneous regression and/or lack of progression occurred in 44 of 93 asymptomatic infants aged 12 months or younger with stage 1, 2, or 3 tumors without MYCN amplification. All were observed after biopsy and partial or no resection.[68] In some cases, regression did not occur until more than 1 year after diagnosis.
  3. In neuroblastoma screening trials in Quebec and Germany, the incidence of neuroblastoma was twice that reported without screening, suggesting that many neuroblastomas are never noted and spontaneously regress.[10-12]
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Cellular Classification of Neuroblastic Tumors
  • Updated: August 19, 2016
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