lunes, 15 de agosto de 2016

Tratamiento del linfoma no Hodgkin infantil (PDQ®)—Versión para profesionales de salud - National Cancer Institute

Tratamiento del linfoma no Hodgkin infantil (PDQ®)—Versión para profesionales de salud - National Cancer Institute







Instituto Nacional Del Cáncer

Linfoma no Hodgkin infantil: Tratamiento (PDQ®)–Versión para profesionales de salud





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Información general sobre el linfoma no Hodgkin infantil

Afortunadamente el cáncer es poco frecuente en los niños y adolescentes, aunque la incidencia general de cáncer en la niñez ha estado aumentando lentamente desde 1975.[1] Los niños y adolescentes con cáncer se deben derivar a centros médicos que cuenten con un equipo multidisciplinario de especialistas en cáncer con experiencia en el tratamiento de los cánceres que se presentan en la niñez y la adolescencia. Este abordaje de equipo multidisciplinario incorpora la pericia de los siguientes profesionales de atención de la salud y otros para asegurar que los niños reciban el tratamiento, los cuidados de apoyo y la rehabilitación que les permita alcanzar una supervivencia y calidad de vida óptimas:
  • Médicos de atención primaria.
  • Cirujanos pediatras.
  • Radioncólogos.
  • Oncólogos o hematólogos pediatras.
  • Especialistas en rehabilitación.
  • Enfermeros especializados en pediatría.
  • Trabajadores sociales.
  • Ludoterapeutas infantiles.
  • Psicólogos.
(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 estableció pautas para los centros de oncología pediátrica y su función en el tratamiento de los pacientes con cáncer infantil.[2] En estos centros de oncología pediátrica, se llevan a cabo ensayos clínicos para casi todos los tipos de cáncer que se presentan en niños y adolescentes, y a la mayoría de los pacientes o familiares se les ofrece la oportunidad de participar en estos ensayos. En general, los ensayos clínicos para niños y adolescentes con cáncer se diseñan para comparar el tratamiento reconocido en la actualidad como la mejor terapia disponible (tratamiento estándar) con otro potencialmente mejor. La mayor parte del progreso alcanzado en la identificación de tratamientos curativos para los cánceres infantiles se logró a través de ensayos clínicos. Para mayor información sobre ensayos clínicos en curso, consultar elportal de Internet del NCI.
Se han logrado mejoras notables en la supervivencia de niños y adolescentes con cáncer.[1] Entre 1975 y 2010, la mortalidad por cáncer infantil disminuyó en más de 50%.[1] Para el linfoma no Hodgkin (LNH), la tasa de supervivencia a 5 años aumentó durante el mismo período de 45 a 87% en los niños menores de 15 años y de 48 a 82% en los adolescentes de 15 a 19 años.[1] Los niños y adolescentes sobrevivientes de cáncer necesitan un seguimiento minucioso porque los efectos secundarios del tratamiento de cáncer pueden persistir o presentarse meses o años después del tratamiento. (Para obtener información específica sobre la incidencia, el tipo y la vigilancia de los efectos tardíos en niños y adolescentes sobrevivientes de cáncer, consultar el sumario del PDQ sobre Efectos tardíos del tratamiento anticanceroso en la niñez).
La inmensa mayoría de los casos de LNH en niños y adolescentes se clasifica en tres categorías de acuerdo con el inmunofenotipo, las características de biología molecular y el resultado clínico del tratamiento:
  1. Linfoma no Hodgkin de células B maduras (linfoma o leucemia de Burkitt o similar al tipo Burkitt, linfoma difuso de células B grandes y linfoma mediastínico primario de células B).
  2. Linfoma linfoblástico.
  3. Linfoma anaplásico de células grandes.
Otros tipos infrecuentes de LNH infantil son los siguientes:

Incidencia

El linfoma (linfoma de Hodgkin y LNH) es la tercera neoplasia maligna infantil más común y, en los países de ingresos altos el LNH representa aproximadamente 7% de los de cánceres en niños menores de 20 años.[3,4]
Los siguientes factores afectan la incidencia de LNH en niños y adolescentes:[3]
  • Localización geográfica: en los Estados Unidos, cada año se diagnostican unos 800 casos nuevos de LNH. La incidencia es de aproximadamente 10 casos por millón de personas por año.
    En el África subsahariana, la incidencia alta de linfoma o leucemia de Burkitt causados por el virus de Epstein-Barr (VEB) es entre 10 a 20 veces mayor, y como resultado la incidencia de LNH es mucho más alta.[5]
  • Edad: aunque no hay una edad máxima definida, el LNH infantil se presenta con mayor frecuencia en la segunda década de la vida, y es muy poco común en niños menores de 3 años.[3] El LNH es muy escaso en los lactantes (1% en los ensayos Berlín-Frankfurt-Münster [BFM] de 1986 a 2002).[6] La incidencia total de LNH está aumentando debido a un incremento ligero en la incidencia en jóvenes de 15 a 19 años; sin embargo, la incidencia de LNH en niños menores de 15 años ha permanecido constante en las últimas décadas.[3]
  • Raza: la incidencia de LNH es más alta en blancos que en estadounidenses de piel negra y el linfoma o leucemia de Burkitt es más frecuente en blancos no hispanos (3,2 casos/millón años-persona) que en blancos hispanos (2,0 casos/millón años-persona).[7]
  • Sexo: el LNH infantil es más común en varones que en mujeres, con excepción del linfoma mediastínico primario de células B cuya incidencia es casi igual en varones que en mujeres.[3,8] En una revisión de los datos del Surveillance, Epidemiology, And End Results (SEER) sobre los casos de linfoma o leucemia de Burkitt diagnosticados en los Estados Unidos entre 1992 y 2008, se describieron 2,5 casos/millón años-persona; más casos en varones que en mujeres (3,9:1,1).[3] La incidencia de linfoma difuso de células B grandes aumenta con la edad, tanto en varones como mujeres. La incidencia de linfoma linfoblástico permanece relativamente constante en todas las edades, tanto en varones como mujeres.[3]
  • Características histológicas: la incidencia y distribución por edad por tipo histológico específico de LNH de acuerdo con el sexo se describen en el Cuadro 1.
Cuadro 1. Incidencia y distribución por edad de tipos específicos de linfoma no Hodgkina
 Incidencia de LNH por millón años-persona
 VaronesMujeres
LACG = linfoma anaplásico de células grandes; LDCBG = linfoma difuso de células B grandes; LNH = linfoma no Hodgkin.
aAdaptado de Percy et al.[3]
bEn adolescentes mayores, se están empezando a encontrar características histológicas de malignidad baja y alta (que se ven más comúnmente en pacientes adultos).
Edad (años)<55–910-1415-19<55-910-1415-19
Burkitt3,266,12,80,81,10,81,2
Linfoblástico1,62,22,82,20,91,00,70,9
LDCBG0,51,22,56,10,60,71,44,9
Otro (principalmente LACG)2,33,34,37,8b1,51,62,83,4b

Epidemiología

Se han publicado relativamente pocos datos sobre la epidemiología del LNH infantil. Sin embargo, se conocen los factores de riesgo siguientes:
  • Virus de Epstein-Barr: el VEB se relaciona con la mayoría de los casos de LNH que se observan en la población con inmunodeficiencia.[3] Casi todos los casos de linfoma o leucemia de Burkitt se relacionan con VEB en África endémica; no obstante, se detectará VEB en el tejido tumoral de aproximadamente 15% de los casos en Europa o los Estados Unidos.[9]
  • Inmunodeficiencia: la inmunodeficiencia, tanto congénita como adquirida (infección por el virus de la inmunodeficiencia humana [VIH] o inmunodeficiencia posterior a un trasplante), aumenta el riesgo de LNH.[3,4]
  • Neoplasia previa: el LNH que se presenta como una neoplasia maligna secundaria es poco frecuente en el ámbito pediátrico. En una revisión retrospectiva del German Childhood Cancer Registry se identificaron 2.968 niños con diagnósticos nuevos de cáncer, de los cuales 11 (0,3%) se diagnosticaron posteriormente con LNH como una neoplasia secundaria antes de los 19 años.[10] En esta pequeña cohorte, el desenlace fue similar al de aquellos pacientes con LNH nuevo tratados con terapia estándar.[10]

Características anatómicas

A diferencia de los adultos con LNH que casi siempre presentan enfermedad ganglionar, es típico que los niños tengan enfermedad extraganglionar con compromiso del mediastino, el abdomen o la cabeza y el cuello, así como de la médula ósea o el sistema nervioso central.[4] Por ejemplo, en los países desarrollados, el linfoma o la leucemia de Burkitt se presenta en el abdomen (aproximadamente 60% de los casos), y entre 15% a 20% de los casos surgen en la cabeza y el cuello.[11,12] Esta incidencia alta de enfermedad extraganglionar justifica el uso del sistema de estadificación de Murphy en el LNH infantil, y no el sistema de estadificación de Ann Arbor.

Evaluación diagnóstica

Se utilizan las siguientes pruebas y procedimientos en el diagnóstico del LNH infantil:
  • Antecedentes y examen físico.
  • Examen anatomopatológico de las células tumorales.
    • Inmunofenotipado mediante inmunohistoquímica o citometría de flujo.
    • Análisis de citogenética o hibridación fluorescente in situ (HFIS).
  • Aspiración y biopsia de la médula ósea.
  • Punción lumbar.
  • Imágenes de cuerpo completo (por ejemplo, tomografía computarizada, tomografía por emisión de positrones y resonancia magnética).
  • Electrólitos séricos, ácido úrico, nitrógeno ureico sanguíneo (NUS) y creatinina.
  • Pruebas funcionales hepáticas.

Pronóstico y factores pronósticos del linfoma no Hodgkin infantil

En los países de ingresos altos, más del 80% de los niños y adolescentes con LNH sobrevivirán por lo menos 5 años gracias a los tratamientos actuales, aunque los desenlaces varían en función de varios factores, como el estadio clínico y las características histológicas.[13]
Los factores pronósticos del LNH infantil son los siguientes:

Reacción al tratamiento

La reacción al tratamiento en el linfoma infantil es uno de los marcadores de pronóstico más importantes. Independientemente de las características histológicas, el LNH infantil resistente al tratamiento de primera elección tiene un pronóstico muy precario.[14-16]
  • Linfoma o leucemia de Burkitt: uno de los factores pronósticos más importantes es la reacción al tratamiento de profase inicial; quienes reaccionan mal al tratamiento (es decir, <20% de resolución de la enfermedad) tienen una supervivencia sin complicaciones (SSC) de 30%.[17,18] También se observó que la incapacidad para lograr una remisión completa tras los primeros ciclos de inducción afecta en forma desfavorable la supervivencia en el linfoma o la leucemia de Burkitt.[17,18]
  • Linfoma linfoblástico: en los estudios BFM 90-95, se encontró que la presencia de masa mediastínica residual en el día 33 o al final de la inducción no se relacionó con disminución en la supervivencia, pero el tratamiento se reforzó en todos los pacientes con una disminución menor de 70% al final de la inducción.[19]
Se han propuesto criterios internacionales de reacción al tratamiento para el LNH infantil, y estos necesitan una evaluación prospectiva. No obstante, la utilidad clínica de estos criterios nuevos está en investigación.[20]
En contraste con la leucemia aguda, en el LNH infantil todavía es incierta la importancia pronóstica de la presencia de enfermedad residual mínima (ERM) después del inicio del tratamiento y se necesita investigación adicional.
  • Linfoma o leucemia de Burkitt: en un estudio se describió un desenlace precario para pacientes con linfoma o leucemia de Burkitt que tenían ERM detectable después de la quimioterapia de inducción;[21] pero la ERM al final de la inducción no tuvo un valor pronóstico en 32 pacientes de LNH de células B con EDM, posiblemente, por el número bajo de recaídas.[22]
  • Linfoma linfoblástico de células T: en un estudio pequeño, entre 10 pacientes, el único paciente con recaída fue el que presentó una ERM mensurable al final de la inducción.[23]
  • Linfoma anaplásico de células grandes: en un análisis retrospectivo de un estudio europeo colaborativo, se observó que los pacientes sin ERM después de la inducción presentaron un riesgo de recaída de aproximadamente 20% y una tasa de supervivencia general (SG) de aproximadamente 90%. Por el contrario, los pacientes con ERM tuvieron un riesgo de recaída de 81% y una tasa de SG de 65% (P < 0,001). La presencia de ERM se relaciona de forma significativa con los subtipos histológicos poco comunes que tienen componentes de células pequeñas o linfohistiocíticos.[24][Grado de comprobación: 2A]

Estadio en el momento del diagnóstico y enfermedad con diseminación mínima

En general, los pacientes con enfermedad en estadio bajo (es decir, tumor único extrabdominal o extratorácico o tumor intrabdominal extirpado en su totalidad) tienen un pronóstico excelente (tasa de supervivencia a 5 años de aproximadamente 90%), sin importar las características histológicas.[17,19,25-28] Además de esto, el desenlace según el estadio clínico no difiere de manera significativa, siempre y cuando se administre el tratamiento correcto, excepto en los pacientes en estadio IV con enfermedad en el SNC.
En muchos estudios se observó que un sustituto de la carga tumoral (es decir, concentraciones elevadas de lactato-deshidrogenasa [LDH]) tienen valor pronóstico.[17,26,29,30]
Por lo general, la EDM se define como la afección submicroscópica de la médula ósea en el momento del diagnóstico. Usualmente, la EDM se detecta mediante métodos sensibles como citometría de flujo o reacción en cadena de la polimerasa con transcripción inversa (RT-PCR). Se considera que los pacientes cuya médula ósea presenta compromiso morfológico con más de 5% de células de linfoma tienen una enfermedad en estadio IV.
  • Linfoma o leucemia de Burkitt: todavía no se ha definido la función de la EDM. En un estudio se indicó que la EDM permite pronosticar el desenlace,[31] mientras que en otro estudio se indicó lo contrario.[22]
  • Linfoma linfoblástico de células T: en un estudio del Children's Oncology Group (COG) se describió una SSC a 2 años de 91% en pacientes cuyo grado de EDM medido por citometría de flujo era menor de 1%, en comparación con 68% si el grado de EDM era mayor de 1%, y 52% si el grado de EDM era de 5%, o mayor.[32]
  • Linfoma anaplásico de células grandes: en un análisis retrospectivo de subgrupos de niños con linfoma anaplásico de células grandes, se encontró que en el momento del diagnóstico 57% de los pacientes tenía EDM detectada mediante RT-PCR del gen NPM-ALK y que esto se relacionaba con el estadio clínico.[33] La presencia de EDM se relacionó con una incidencia acumulada de recaída de 46% en comparación con 15% en los pacientes sin afección en la médula ósea.[33] Los pacientes con EDM que lograron un estado sin ERM antes del segundo ciclo de tratamiento, presentaron una SSC intermedia (69%) en comparación con los pacientes sin EDM (82%) y aquellos cuyo estado era positivo para EDM y ERM (19%).[33]
    La presencia de EDM se relacionó de manera significativa con los subtipos histológicos poco comunes que contienen componentes de células pequeñas o linfohistiocíticos.[33]

Sitios de la enfermedad en el momento del diagnóstico

En el LNH infantil, algunos sitios de enfermedad parece que tienen un valor pronóstico, entre ellos, los siguientes:
  • Médula ósea y sistema nervioso central: por lo general, los pacientes que al momento del diagnóstico presentan compromiso leucémico (>25% de blastos en la médula ósea) o en el SNC necesitan un tratamiento más intensivo.[18,19,34] Aunque estos tratamientos intensivos han mejorado los desenlaces, los pacientes que presentan enfermedad en el SNC siguen teniendo el peor pronóstico.[18,19,34,35] Los pacientes con linfoma o leucemia de células B maduras con compromiso del SNC en el cuadro clínico inicial tienen una SSC a 3 años de cerca de 70%, mientras que aquellos que solo tienen compromiso de la médula ósea presentan una SSC a 3 años de 90%.[18,26,30] Parece que lo que más afecta el desenlace es la combinación del compromiso del SNC y la médula ósea.[18]
  • Mediastino: al contrario de los adultos, el compromiso mediastínico en los niños y adolescentes con LNH no linfoblástico conlleva un desenlace más precario.[13,17,26,30] Se reportó una SSC a 3 años de entre 50 a 70% en series de niños y adultos jóvenes con linfoma mediastínico primario de células B.[26,29,30,36] No obstante, se logró una SSC de casi 90% en un estudio reciente del NCI en el que se usó el protocolo de dosis ajustadas (DA)-EPOCH (etopósido, prednisona, vincristina y doxorrubicina) con rituximab.[37]
  • Vísceras: en un estudio retrospectivo del European Intergroup for Childhood NHL (EICNHL) con pacientes de linfoma anaplásico de células grandes se encontró un grupo de riesgo alto definido por el compromiso mediastínico, cutáneo o visceral.[38] En el análisis de un estudio posterior del EICNHL en el que se usaron factores de riesgo biológico, se encontró que las características de riesgo clínico no eran significativas.[39] En el ensayo CCG-5941 de pacientes con linfoma anaplásico de células grandes, no se logró corroborar estos factores clínicos de riesgo y solo el compromiso de la médula ósea predijo una supervivencia sin evolución (SSA) más corta.[40][Grado de comprobación: 2A]
  • Huesos: aunque en los estudios anteriores se pensó que era un sitio de pronóstico precario, los pacientes con LNH que surge en los huesos presentan un pronóstico excelente, independientemente de las características histológicas.[41,42]
  • Testículos: el compromiso de los testículos no afecta el pronóstico.[19,25,43]
  • Cabeza y cuello: en el caso del LNH de células B maduras, la SG es comparable a la observada en los pacientes con tumores primarios en otros sitios. Los tumores primarios de cabeza y cuello se relacionan con tasas más altas de diseminación y enfermedad en el SNC, así como con tasas más bajas de concentraciones de LDH que duplican el umbral de normalidad. El LNH infantil ubicado en la cabeza o el cuello no se relaciona con una SG más precaria.[12]
  • Piel: las implicaciones pronósticas del compromiso cutáneo se limitan al linfoma anaplásico de células grandes y dependen de si la enfermedad está localizada en la piel. El linfoma anaplásico de células grandes circunscrito a la piel que no expresa ALKpresenta un pronóstico excelente. No obstante, en estudios del EICNHL y el COG se observó que el compromiso cutáneo del linfoma anaplásico de células grandes sistémico no tiene un valor pronóstico positivo.[39,40]

Características biológicas del tumor

  • Linfoma de células B maduras: en comparación con los tratamientos en adultos, en el ámbito de la pediatría se han usado regímenes Burkitt más intensivos en el tratamiento tanto del linfoma o la leucemia de Burkitt, como de las neoplasias con características histológicas de células B grandes, sin que esto implique diferencias de los desenlaces según las características histológicas.[13,17,26,27,30] La excepción es el linfoma mediastínico primario de células B, que presenta un desenlace más precario con estos regímenes.[13,17,26,29,30,36]
    En los pacientes con linfoma o leucemia de Burkitt infantil, las anomalías citogenéticas secundarias, excepto los reordenamientos de c-myc, se relacionan con un resultado más precario,[44,45] y las anomalías citogenéticas como la ganancia de 7q o la deleción de 13q parece que determinan un desenlace más precario con el protocolo de quimioterapia FAB 96.[45,46] El desenlace parece que es peor en pacientes pediátricos con linfoma difuso de células B grandes y reordenamiento cromosómico de MYC(8q24).[45]
    Se encontró que un subgrupo de casos pediátricos de linfoma difuso de células B grandes tiene una traslocación que yuxtapone el oncogén IRF4 junto a uno de los locus de inmunoglobulina, y se le ha relacionado con un pronóstico favorable en comparación con los casos de linfoma difuso de células B grandes que no presentan esta característica.[47]
  • Linfoma linfoblástico de células T: en pacientes pediátricos con linfoma linfoblástico de células T, el grupo BFM informó que se observó pérdida de la heterocigosis del cromosoma 6q en 12% de los pacientes (25 de 217) y que esto se relacionó con un pronóstico desfavorable (probabilidad de SSC [pSSC], 27% vs. 86%, P <0,0001).[48,49] Se observaron mutaciones NOTCH1 en 60% de los pacientes (70 de 116) que se relacionaron con pronóstico favorable (pSSC, 84% vs. 66%; P = 0,021). Las mutacionesNOTCH1 fueron muy escasas en los pacientes con pérdida de la heterocigosis en 6q16.[48]
  • Linfoma anaplásico de células grandes: en adultos, la enfermedad que no expresa ALK conlleva un desenlace más precario; sin embargo, en niños no se ha mostrado una diferencia en los desenlaces de la enfermedad que expresa ALK o que no lo expresa.[50-52] En una serie de 375 niños y adolescentes con linfoma anaplásico de células grandes sistémico que expresa ALK, se observó que 32% de los pacientes tenía un componente de células pequeñas o linfohistiocítico que estaba relacionado de forma significativa con un riesgo más alto de ineficacia del tratamiento en el análisis multivariante controlado por las características clínicas.[53]
    En el estudio COG-ANHL0131 (NCT00059839), a pesar de las diferentes pautas quimioterapéuticas de base, se presentó un aumento significativo en el riesgo de ineficacia del tratamiento en la variante de células pequeñas del linfoma anaplásico de células grandes, así como en otras variantes según las características histológicas.[52]

Edad

El LNH es muy escaso en los lactantes (1% en los ensayos BFM de 1986 a 2002).[6] En una revisión retrospectiva, el desenlace para los lactantes fue más precario en comparación con los pacientes de más edad con LNH.[6]
Se informó que los adolescentes presentan desenlaces más precarios en comparación con los niños más jóvenes.[11,13,54,55] Los efectos adversos de la edad parece que son más notables en los adolescentes con linfoma difuso de células B grandes, y en menor medida para aquellos con linfoma linfoblástico de células T, comparados con los niños más jóvenes que presentan los mismos diagnósticos.[13,55] Por el contrario, en los pacientes con linfoma o leucemia de Burkitt o similar al tipo Burkitt del ensayo clínico FAB LMB 96 (COG-C5961), la edad de los adolescentes (≥15 años) no fue un factor de riesgo independiente de un desenlace más precario.[30]

Reacción inmunitaria contra el tumor

Una reacción inmunitaria contra la proteína ALK (es decir, valores de anticuerpos anti-ALK ) parece que se relaciona con un estadio clínico más bajo y que predice la probabilidad de recaída pero no la SG.[56] En un estudio del EICNHL, en el que se combinó la concentración de anticuerpos anti-ALK con la EDM, se mostró que los pacientes con un diagnóstico nuevo de linfoma anaplásico de células grandes podrían clasificarse de forma fiable en tres grupos de riesgo (bajo, intermedio y el resto de los pacientes) con SSA de 28, 68 y 93%, respectivamente (P < 0,0001).[39]
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  9. Gutiérrez MI, Bhatia K, Barriga F, et al.: Molecular epidemiology of Burkitt's lymphoma from South America: differences in breakpoint location and Epstein-Barr virus association from tumors in other world regions. Blood 79 (12): 3261-6, 1992. [PUBMED Abstract]
  10. Landmann E, Oschlies I, Zimmermann M, et al.: Secondary non-Hodgkin lymphoma (NHL) in children and adolescents after childhood cancer other than NHL. Br J Haematol 143 (3): 387-94, 2008. [PUBMED Abstract]
  11. Patte C, Auperin A, Michon J, et al.: The Société Française d'Oncologie Pédiatrique LMB89 protocol: highly effective multiagent chemotherapy tailored to the tumor burden and initial response in 561 unselected children with B-cell lymphomas and L3 leukemia. Blood 97 (11): 3370-9, 2001. [PUBMED Abstract]
  12. Lervat C, Auperin A, Patte C, et al.: Head and neck presentations of B-NHL and B-AL in children/adolescents: experience of the LMB89 study. Pediatr Blood Cancer 61 (3): 473-8, 2014. [PUBMED Abstract]
  13. Burkhardt B, Zimmermann M, Oschlies I, et al.: The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol 131 (1): 39-49, 2005. [PUBMED Abstract]
  14. Attarbaschi A, Dworzak M, Steiner M, et al.: Outcome of children with primary resistant or relapsed non-Hodgkin lymphoma and mature B-cell leukemia after intensive first-line treatment: a population-based analysis of the Austrian Cooperative Study Group. Pediatr Blood Cancer 44 (1): 70-6, 2005. [PUBMED Abstract]
  15. Kobrinsky NL, Sposto R, Shah NR, et al.: Outcomes of treatment of children and adolescents with recurrent non-Hodgkin's lymphoma and Hodgkin's disease with dexamethasone, etoposide, cisplatin, cytarabine, and l-asparaginase, maintenance chemotherapy, and transplantation: Children's Cancer Group Study CCG-5912. J Clin Oncol 19 (9): 2390-6, 2001. [PUBMED Abstract]
  16. Harris RE, Termuhlen AM, Smith LM, et al.: Autologous peripheral blood stem cell transplantation in children with refractory or relapsed lymphoma: results of Children's Oncology Group study A5962. Biol Blood Marrow Transplant 17 (2): 249-58, 2011. [PUBMED Abstract]
  17. Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007. [PUBMED Abstract]
  18. Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007. [PUBMED Abstract]
  19. Reiter A, Schrappe M, Ludwig WD, et al.: Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood 95 (2): 416-21, 2000. [PUBMED Abstract]
  20. Sandlund JT, Guillerman RP, Perkins SL, et al.: International Pediatric Non-Hodgkin Lymphoma Response Criteria. J Clin Oncol 33 (18): 2106-11, 2015. [PUBMED Abstract]
  21. Mussolin L, Pillon M, Conter V, et al.: Prognostic role of minimal residual disease in mature B-cell acute lymphoblastic leukemia of childhood. J Clin Oncol 25 (33): 5254-61, 2007. [PUBMED Abstract]
  22. Shiramizu B, Goldman S, Kusao I, et al.: Minimal disease assessment in the treatment of children and adolescents with intermediate-risk (Stage III/IV) B-cell non-Hodgkin lymphoma: a children's oncology group report. Br J Haematol 153 (6): 758-63, 2011. [PUBMED Abstract]
  23. Stark B, Avigad S, Luria D, et al.: Bone marrow minimal disseminated disease (MDD) and minimal residual disease (MRD) in childhood T-cell lymphoblastic lymphoma stage III, detected by flow cytometry (FC) and real-time quantitative polymerase chain reaction (RQ-PCR). Pediatr Blood Cancer 52 (1): 20-5, 2009. [PUBMED Abstract]
  24. Damm-Welk C, Mussolin L, Zimmermann M, et al.: Early assessment of minimal residual disease identifies patients at very high relapse risk in NPM-ALK-positive anaplastic large-cell lymphoma. Blood 123 (3): 334-7, 2014. [PUBMED Abstract]
  25. Link MP, Shuster JJ, Donaldson SS, et al.: Treatment of children and young adults with early-stage non-Hodgkin's lymphoma. N Engl J Med 337 (18): 1259-66, 1997. [PUBMED Abstract]
  26. Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005. [PUBMED Abstract]
  27. Gerrard M, Cairo MS, Weston C, et al.: Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Br J Haematol 141 (6): 840-7, 2008. [PUBMED Abstract]
  28. Seidemann K, Tiemann M, Schrappe M, et al.: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 97 (12): 3699-706, 2001. [PUBMED Abstract]
  29. Reiter A, Schrappe M, Tiemann M, et al.: Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 94 (10): 3294-306, 1999. [PUBMED Abstract]
  30. Cairo MS, Sposto R, Gerrard M, et al.: Advanced stage, increased lactate dehydrogenase, and primary site, but not adolescent age (≥ 15 years), are associated with an increased risk of treatment failure in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB LMB 96 study. J Clin Oncol 30 (4): 387-93, 2012. [PUBMED Abstract]
  31. Mussolin L, Pillon M, d'Amore ES, et al.: Minimal disseminated disease in high-risk Burkitt's lymphoma identifies patients with different prognosis. J Clin Oncol 29 (13): 1779-84, 2011. [PUBMED Abstract]
  32. Coustan-Smith E, Sandlund JT, Perkins SL, et al.: Minimal disseminated disease in childhood T-cell lymphoblastic lymphoma: a report from the children's oncology group. J Clin Oncol 27 (21): 3533-9, 2009. [PUBMED Abstract]
  33. Damm-Welk C, Busch K, Burkhardt B, et al.: Prognostic significance of circulating tumor cells in bone marrow or peripheral blood as detected by qualitative and quantitative PCR in pediatric NPM-ALK-positive anaplastic large-cell lymphoma. Blood 110 (2): 670-7, 2007. [PUBMED Abstract]
  34. Salzburg J, Burkhardt B, Zimmermann M, et al.: Prevalence, clinical pattern, and outcome of CNS involvement in childhood and adolescent non-Hodgkin's lymphoma differ by non-Hodgkin's lymphoma subtype: a Berlin-Frankfurt-Munster Group Report. J Clin Oncol 25 (25): 3915-22, 2007. [PUBMED Abstract]
  35. Williams D, Mori T, Reiter A, et al.: Central nervous system involvement in anaplastic large cell lymphoma in childhood: results from a multicentre European and Japanese study. Pediatr Blood Cancer 60 (10): E118-21, 2013. [PUBMED Abstract]
  36. Gerrard M, Waxman IM, Sposto R, et al.: Outcome and pathologic classification of children and adolescents with mediastinal large B-cell lymphoma treated with FAB/LMB96 mature B-NHL therapy. Blood 121 (2): 278-85, 2013. [PUBMED Abstract]
  37. Dunleavy K, Pittaluga S, Maeda LS, et al.: Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 368 (15): 1408-16, 2013. [PUBMED Abstract]
  38. Le Deley MC, Reiter A, Williams D, et al.: Prognostic factors in childhood anaplastic large cell lymphoma: results of a large European intergroup study. Blood 111 (3): 1560-6, 2008. [PUBMED Abstract]
  39. Mussolin L, Damm-Welk C, Pillon M, et al.: Use of minimal disseminated disease and immunity to NPM-ALK antigen to stratify ALK-positive ALCL patients with different prognosis. Leukemia 27 (2): 416-22, 2013. [PUBMED Abstract]
  40. Lowe EJ, Sposto R, Perkins SL, et al.: Intensive chemotherapy for systemic anaplastic large cell lymphoma in children and adolescents: final results of Children's Cancer Group Study 5941. Pediatr Blood Cancer 52 (3): 335-9, 2009. [PUBMED Abstract]
  41. Lones MA, Perkins SL, Sposto R, et al.: Non-Hodgkin's lymphoma arising in bone in children and adolescents is associated with an excellent outcome: a Children's Cancer Group report. J Clin Oncol 20 (9): 2293-301, 2002. [PUBMED Abstract]
  42. Zhao XF, Young KH, Frank D, et al.: Pediatric primary bone lymphoma-diffuse large B-cell lymphoma: morphologic and immunohistochemical characteristics of 10 cases. Am J Clin Pathol 127 (1): 47-54, 2007. [PUBMED Abstract]
  43. Dalle JH, Mechinaud F, Michon J, et al.: Testicular disease in childhood B-cell non-Hodgkin's lymphoma: the French Society of Pediatric Oncology experience. J Clin Oncol 19 (9): 2397-403, 2001. [PUBMED Abstract]
  44. Onciu M, Schlette E, Zhou Y, et al.: Secondary chromosomal abnormalities predict outcome in pediatric and adult high-stage Burkitt lymphoma. Cancer 107 (5): 1084-92, 2006. [PUBMED Abstract]
  45. Poirel HA, Cairo MS, Heerema NA, et al.: Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Leukemia 23 (2): 323-31, 2009. [PUBMED Abstract]
  46. Nelson M, Perkins SL, Dave BJ, et al.: An increased frequency of 13q deletions detected by fluorescence in situ hybridization and its impact on survival in children and adolescents with Burkitt lymphoma: results from the Children's Oncology Group study CCG-5961. Br J Haematol 148 (4): 600-10, 2010. [PUBMED Abstract]
  47. Salaverria I, Philipp C, Oschlies I, et al.: Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults. Blood 118 (1): 139-47, 2011. [PUBMED Abstract]
  48. Bonn BR, Rohde M, Zimmermann M, et al.: Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence. Blood 121 (16): 3153-60, 2013. [PUBMED Abstract]
  49. Burkhardt B, Moericke A, Klapper W, et al.: Pediatric precursor T lymphoblastic leukemia and lymphoblastic lymphoma: Differences in the common regions with loss of heterozygosity at chromosome 6q and their prognostic impact. Leuk Lymphoma 49 (3): 451-61, 2008. [PUBMED Abstract]
  50. Stein H, Foss HD, Dürkop H, et al.: CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood 96 (12): 3681-95, 2000. [PUBMED Abstract]
  51. Brugières L, Le Deley MC, Rosolen A, et al.: Impact of the methotrexate administration dose on the need for intrathecal treatment in children and adolescents with anaplastic large-cell lymphoma: results of a randomized trial of the EICNHL Group. J Clin Oncol 27 (6): 897-903, 2009. [PUBMED Abstract]
  52. Alexander S, Kraveka JM, Weitzman S, et al.: Advanced stage anaplastic large cell lymphoma in children and adolescents: results of ANHL0131, a randomized phase III trial of APO versus a modified regimen with vinblastine: a report from the children's oncology group. Pediatr Blood Cancer 61 (12): 2236-42, 2014. [PUBMED Abstract]
  53. Lamant L, McCarthy K, d'Amore E, et al.: Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study. J Clin Oncol 29 (35): 4669-76, 2011. [PUBMED Abstract]
  54. Cairo MS, Sposto R, Perkins SL, et al.: Burkitt's and Burkitt-like lymphoma in children and adolescents: a review of the Children's Cancer Group experience. Br J Haematol 120 (4): 660-70, 2003. [PUBMED Abstract]
  55. Burkhardt B, Oschlies I, Klapper W, et al.: Non-Hodgkin's lymphoma in adolescents: experiences in 378 adolescent NHL patients treated according to pediatric NHL-BFM protocols. Leukemia 25 (1): 153-60, 2011. [PUBMED Abstract]
  56. Ait-Tahar K, Damm-Welk C, Burkhardt B, et al.: Correlation of the autoantibody response to the ALK oncoantigen in pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with tumor dissemination and relapse risk. Blood 115 (16): 3314-9, 2010. [PUBMED Abstract]
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Clasificación del linfoma no Hodgkin infantil según las características histopatológicas y moleculares
  • Actualización: 6 de julio de 2016












Childhood Non-Hodgkin Lymphoma Treatment (PDQ®)—Health Professional Version - National Cancer Institute







National Cancer Institute

Childhood Non-Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version

SECTIONS







General Information About Childhood Non-Hodgkin Lymphoma (NHL)

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
  • Primary care physicians.
  • Pediatric surgical surgeons.
  • Radiation oncologists.
  • Pediatric medical oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
  • Child life professionals.
  • Psychologists.
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of children with cancer have been outlined by the American Academy of Pediatrics.[2] At these pediatric cancer centers, clinical trials are available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare therapy that is accepted as the best currently available therapy (standard therapy) with potentially better therapy. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
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] For non-Hodgkin lymphoma (NHL), the 5-year survival rate has increased over the same time period from 45% to 87% in children younger than 15 years and from 48% to 82% for adolescents aged 15 to 19 years.[1] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on the 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.)
On the basis of immunophenotype, molecular biology, and clinical response to treatment, the vast majority of NHL cases occurring in childhood and adolescence fall into three categories:
  1. Mature B-cell NHL (Burkitt and Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma).
  2. Lymphoblastic lymphoma.
  3. Anaplastic large cell lymphoma.
Other rare types of pediatric NHL include the following:

Incidence

Lymphoma (Hodgkin lymphoma and NHL) is the third most common childhood malignancy, and NHL accounts for approximately 7% of cancers in children younger than 20 years in high-income countries.[3,4]
The following factors affect the incidence of NHL in children and adolescents:[3]
  • Geographic location: In the United States, about 800 new cases of NHL are diagnosed each year. The incidence is approximately ten cases per 1 million people per year.
    In sub-Saharan Africa, the high incidence of Epstein-Barr virus (EBV)-induced Burkitt lymphoma/leukemia is tenfold to twentyfold higher, resulting in a much higher incidence of NHL.[5]
  • Age: Although there is no sharp age peak, childhood NHL occurs most commonly in the second decade of life, and occurs infrequently in children younger than 3 years.[3] NHL in infants is very rare (1% in Berlin-Frankfurt-Münster [BFM] trials from 1986 to 2002).[6] The incidence of NHL is increasing overall because of a slight increase in the incidence for those aged 15 to 19 years; however, the incidence of NHL in children younger than 15 years has remained constant over the past several decades.[3]
  • Race: The incidence of NHL is higher in whites than in African Americans, and Burkitt lymphoma/leukemia is more frequent in non-Hispanic whites (3.2 cases/million person-years) than in Hispanic whites (2.0 cases/million person-years).[7]
  • Gender: Childhood NHL is more common in males than in females, with the exception of primary mediastinal B-cell lymphoma, in which the incidence is almost the same in males and females.[3,8] A review of Surveillance, Epidemiology, and End Results (SEER) data revealed that 2.5 cases per 1 million person-years of Burkitt lymphoma/leukemia were diagnosed in the United States between 1992 and 2008, with more cases in males than in females (3.9:1.1).[3] The incidence of diffuse large B-cell lymphoma increases with age in both males and females. The incidence of lymphoblastic lymphoma remains relatively constant across ages for both males and females.[3]
  • Histology: The incidence and age distribution of histologic type of NHL according to gender is described in Table 1.
Table 1. Incidence and Age Distribution of Specific Types of NHLa
 Incidence of NHL per Million Person-Years
 MalesFemales
ALCL = anaplastic large cell lymphoma; DLBCL = diffuse large B-cell lymphoma; NHL = non-Hodgkin lymphoma.
aAdapted from Percy et al.[3]
bIn older adolescents, indolent and aggressive histologies (more commonly seen in adult patients) are beginning to be found.
Age (y)<55–910–1415–19<55–910–1415–19
Burkitt3.266.12.80.81.10.81.2
Lymphoblastic1.62.22.82.20.91.00.70.9
DLBCL0.51.22.56.10.60.71.44.9
Other (mostly ALCL)2.33.34.37.8b1.51.62.83.4b

Epidemiology

Relatively little data have been published on the epidemiology of childhood NHL. However, known risk factors include the following:
  • EBV: EBV is associated with most cases of NHL seen in the immunodeficient population.[3] Almost all Burkitt lymphoma/leukemia is associated with EBV in endemic Africa; however, approximately 15% of cases in Europe or the United States will have EBV detectable in the tumor tissue.[9]
  • Immunodeficiency: Immunodeficiency, both congenital and acquired (human immunodeficiency virus infection [HIV] or posttransplant immunodeficiency), increases the risk of NHL.[3,4]
  • Previous neoplasm: NHL presenting as a subsequent neoplasm is rare in pediatrics. A retrospective review of the German Childhood Cancer Registry identified 2,968 children who were newly diagnosed with cancer, 11 of whom (0.3%) were later diagnosed with NHL as a subsequent neoplasm before the age of 19 years.[10] In this small cohort, outcome was similar to patients with de novo NHL when treated with standard therapy.[10]

Anatomy

Unlike adults with NHL who most often present with nodal disease, children typically have extranodal disease involving the mediastinum, abdomen, and/or head and neck, as well as marrow or CNS.[4] For example, in developed countries, Burkitt lymphoma/leukemia occurs in the abdomen (approximately 60% of cases), with 15% to 20% of cases arising in the head and neck.[11,12] This high incidence of extranodal disease substantiates use of the Murphy staging system for pediatric NHL, as opposed to the Ann Arbor staging system.

Diagnostic Evaluation

The following tests and procedures are used to diagnose childhood NHL:
  • History and physical exam.
  • Pathologic examination of tumor cells.
    • Immunophenotyping by immunohistochemistry and/or flow cytometry.
    • Cytogenetics and/or fluorescence in situ hybridization (FISH).
  • Bone marrow biopsy and aspiration.
  • Lumbar puncture.
  • Total-body imaging (e.g., computed tomography scan, positron emission tomography, and magnetic resonance imaging).
  • Serum electrolytes, uric acid, blood urea nitrogen (BUN), and creatinine.
  • Liver function tests.

Prognosis and Prognostic Factors for Childhood NHL

In high-income countries and with current treatments, more than 80% of children and adolescents with NHL will survive at least 5 years, although outcome is variable depending on a number of factors, including clinical stage and histology.[13]
Prognostic factors for childhood NHL include the following:

Response to therapy

Response to therapy in pediatric lymphoma is one of the most important prognostic markers. Regardless of histology, pediatric NHL that is refractory to first-line therapy has a very poor prognosis.[14-16]
  • Burkitt lymphoma/leukemia: One of the most important predictive factors is response to the initial prophase treatment; poor responders (i.e., <20% resolution of disease) had an event-free survival (EFS) of 30%.[17,18] Failure to achieve a complete remission after the initial induction courses has also been shown to adversely affect survival in Burkitt lymphoma/leukemia.[17,18]
  • Lymphoblastic lymphoma: The presence of a residual mediastinal mass at day 33 or at the end of induction was not found to be associated with a decreased survival in the BFM 90-95 studies, but all patients with less than 70% reduction at end induction had therapy intensified.[19]
International pediatric NHL response criteria have been proposed and require prospective evaluation. However, the clinical utility of these new criteria are under investigation.[20]
As opposed to acute leukemia, the prognostic value of minimal residual disease (MRD) following initiation of the therapy in pediatric NHL remains uncertain and requires further investigation.
  • Burkitt lymphoma/leukemia: One study suggests inferior outcome for patients with Burkitt lymphoma/leukemia that had detectable MRD after induction chemotherapy,[21] but a positive MRD at end induction was not prognostic in B-cell NHL in 32 MDD-positive patients, possibly because of the low number of relapses.[22]
  • T-lymphoblastic lymphoma: In a small study, one of ten patients had measurable MRD at end induction and this was the only patient who relapsed.[23]
  • Anaplastic large cell lymphoma: A retrospective analysis of a collaborative European study showed that after induction, MRD-negative patients had a relapse risk of approximately 20% and an overall survival (OS) rate of approximately 90%. By contrast, MRD-positive patients had a relapse risk of 81% and an OS rate of 65% (P < .001). The presence of MRD is significantly associated with uncommon histologic subtypes containing small cell and/or lymphohistiocytic components.[24][Level of evidence: 2A]

Stage at diagnosis/minimal disseminated disease (MDD)

In general, patients with low-stage disease (i.e., single extra-abdominal/extrathoracic tumor or totally resected intra-abdominal tumor) have an excellent prognosis (a 5-year survival rate of approximately 90%), regardless of histology.[17,19,25-28] Apart from this, the outcome by clinical stage, if the correct therapy is given, does not differ significantly, except for stage IV patients with CNS disease.
A surrogate for tumor burden (i.e., elevated levels of lactate dehydrogenase [LDH]) has been shown to be prognostic in many studies.[17,26,29,30]
MDD is generally defined as submicroscopic bone marrow involvement that is present at diagnosis. MDD is generally detected by sensitive methods such as flow cytometry or reverse transcription–polymerase chain reaction (RT-PCR). Patients with morphologically involved bone marrow with more than 5% lymphoma cells are considered to have stage IV disease.
  • Burkitt lymphoma/leukemia: The role of MDD remains to be defined. One study suggests MDD to be predictive of outcome,[31] while another study does not.[22]
  • T-lymphoblastic lymphoma: A Children's Oncology Group (COG) study demonstrated the 2-year EFS for patients who had an MDD level by flow cytometry of less than 1% was 91% compared with 68% if the MDD level was more than 1%, and 52% if the MDD was 5% and greater.[32]
  • Anaplastic large cell lymphoma: In a retrospective subset analysis of children with anaplastic large cell lymphoma, MDD detected by RT-PCR for the NPM-ALK gene, could be found in 57% of patients at diagnosis and correlated with clinical stage.[33] The presence of MDD was associated with a 46% cumulative incidence of relapse compared with a 15% cumulative incidence of relapse in patients with no marrow involvement.[33] Patients with MDD who achieved MRD negative status before their second course of therapy had an intermediate EFS (69%) compared with MDD-negative patients (82%) and compared with patients with both MDD and positive MRD status (19%).[33]
    The presence of MDD is significantly associated with uncommon histologic subtypes containing small cell and/or lymphohistiocytic components.[33]

Sites of disease at diagnosis

In pediatric NHL, some sites of disease appear to have prognostic value, including the following:
  • Bone marrow and CNS: In general, patients with leukemic involvement (>25% blasts in marrow) or CNS involvement at diagnosis require more intensive therapy.[18,19,34] Although these intensive therapies have improved outcome, patients who present with CNS disease continue to have the worst outcome.[18,19,34,35] Patients with mature B-cell lymphoma/leukemia with CNS disease at presentation have a 3-year EFS of around 70%, while those with marrow involvement alone have a 3-year EFS of 90%.[18,26,30] The combination of CNS involvement and marrow disease appears to impact outcome the most.[18]
  • Mediastinum: As opposed to adults, mediastinal involvement in children and adolescents with nonlymphoblastic NHL results in an inferior outcome.[13,17,26,30] In children and young adults with primary mediastinal B-cell lymphoma, series have reported a 3-year EFS of 50% to 70%.[26,29,30,36] However, a recent study from the NCI that utilized the dose-adjusted (DA)-EPOCH protocol (etoposide, prednisone, vincristine, and doxorubicin) with rituximab achieved an EFS close to 90%.[37]
  • Viscera: In anaplastic large cell lymphoma, a retrospective study by the European Intergroup for Childhood NHL (EICNHL) found a high-risk group of patients defined by involvement of mediastinum, skin, or viscera.[38] In a subsequent study analysis from EICNHL utilizing biologic risk factors, the clinical risk features were not found to be significant.[39] In the CCG-5941 study for anaplastic large cell lymphoma patients, these clinical risk factors could not be confirmed and only bone marrow involvement predicted inferior progression-free survival (PFS).[40][Level of evidence: 2A]
  • Bone: Although previously thought to be a poor prognostic site, patients with NHL arising in bone have an excellent prognosis, regardless of histology.[41,42]
  • Testicle: Testicular involvement does not affect prognosis.[19,25,43]
  • Head and Neck: For mature B-cell NHL, OS is comparable to that observed for patients with primary tumors at other sites. Head and neck primary tumors are associated with higher rates of disseminated and CNS disease and lower rates of LDH levels that were more than twofold above the upper limit of normal. Childhood NHL of the head and neck site was not associated with inferior OS.[12]
  • Skin: The prognostic implication of skin involvement is limited to anaplastic large cell lymphoma and depends on whether the disease is localized to skin. ALK-negative, skin-limited anaplastic large cell lymphoma appears to have an excellent prognosis. However, studies from EICNHL and the COG have demonstrated that skin involvement in systemic anaplastic large cell lymphoma does not appear to have positive prognostic value.[39,40]

Tumor biology

  • Mature B-cell lymphoma: Compared with treatments for adults, aggressive Burkittregimens in pediatrics have been used to treat both Burkitt lymphoma/leukemia and large B-cell histologies, resulting in no difference in outcome based on histology.[13,17,26,27,30] The exception is primary mediastinal B-cell lymphoma, which has had an inferior outcome with these regimens.[13,17,26,29,30,36]
    For pediatric Burkitt lymphoma/leukemia patients, secondary cytogenetic abnormalities, other than c-myc rearrangement, are associated with an inferior outcome,[44,45] and cytogenetic abnormalities involving gain of 7q or deletion of 13q appeared to have an inferior outcome on the FAB 96 chemotherapy protocol.[45,46] For pediatric patients with diffuse large B-cell lymphoma and chromosomal rearrangement at MYC (8q24), outcome appears to be worse.[45]
    A subset of pediatric diffuse large B-cell lymphoma cases were found to have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci and has been associated with favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this finding.[47]
  • T-lymphoblastic lymphoma: For pediatric patients with T-cell lymphoblastic lymphoma, the BFM group reported that loss of heterozygosity at chromosome 6q was observed in 12% of patients (25 of 217) and was associated with unfavorable prognosis (probability of EFS [pEFS], 27% vs. 86%, P <.0001).[48,49] NOTCH1 mutations were seen in 60% of patients (70 of 116) and were associated with favorable prognosis (pEFS, 84% vs. 66%; P = .021). NOTCH1 mutations were rarely seen in patients with loss of heterozygosity in 6q16.[48]
  • Anaplastic large cell lymphoma: In adults, ALK-negative disease has an inferior outcome; however, in children, the difference in outcome between ALK-positive and ALK-negative disease has not been demonstrated.[50-52] In a series of 375 children and adolescents with systemic ALK-positive anaplastic large cell lymphoma, the presence of a small cell or lymphohistiocytic component was observed in 32% of patients and was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics.[53]
    In the COG-ANHL0131 (NCT00059839) study, despite a different chemotherapy backbone, the small cell variant of anaplastic large cell lymphoma, as well as other histologic variants, had a significantly increased risk for failure.[52]

Age

NHL in infants is rare (1% in BFM trials from 1986 to 2002).[6] In this retrospective review, the outcome for infants was inferior compared with the outcome for older patients with NHL.[6]
Adolescents have been reported to have inferior outcome compared with younger children.[11,13,54,55] This adverse effect of age appears to be most pronounced for adolescents with diffuse large B-cell lymphoma, and to a lesser degree T-cell lymphoblastic lymphoma, compared with younger children with these diagnoses.[13,55] On the other hand, for patients with Burkitt and Burkitt-like lymphoma/leukemia on the FAB LMB 96 (COG-C5961) clinical trial, adolescent age (≥15 years) was not an independent risk factor for inferior outcome.[30]

Immune response to tumor

An immune response against the ALK protein (i.e., anti-ALK antibody titer) appeared to correlate with lower clinical stage and predicted relapse risk but not OS.[56] A study by the EICNHL, which combined the level of anti-ALK antibody with MDD, demonstrated that newly diagnosed anaplastic large cell lymphoma patients could be reliably stratified into three risk groups (low, intermediate, and all remaining patients), with a PFS of 28%, 68% and 93%, respectively (P < .0001).[39]
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Histopathologic and Molecular Classification of Childhood NHL
  • Updated: August 11, 2016
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