Cáncer-Principales Causas de Falsos Positivos en Los Resultados de Marcadores Tumorales en Suero...

Documentos de la SEQC - diciembre 2013 • 29

Principales causas de falsos positivos en los resultados de marcadores tumorales en suero

Revisión (2013)

Sociedad Española de Bioquímica Clínica y Patología MolecularComité CientíficoComisión de Marcadores Biológicos del Cáncer

R. Molina, X. Filella, J. Trapé, J. M. Augé, A. Barco, F. Cañizares, A. Colomer, A. Fernández, M. J. Gaspar, A. Martínez-Peinado, L. Pérez Suárez, M. Sánchez, J. M. Escudero

Rafael Molina, [email protected]

INTRODUCCIÓN

El marcador tumoral (MT) incluye un amplio espectro de mo-léculas, con características muy variables, producidas o inducidas por la célula neoplásica que reflejan su crecimiento y/o actividad y que permiten conocer la presencia, la evolución o la respuesta terapéutica de un tumor maligno (1-4). Esta definición no indica que los MTs sean específicos del cáncer, ya que la mayoría de ellos son sintetizados y liberados también por las células normales, por ello se detectan en sangre y es necesario establecer valores de referencia. Las diversas patologías benignas que afectan a los tejidos productores de los MTs, también pueden provocar los incrementos séricos de estos MTs, dando lugar a falsos positivos. La valoración diferencial entre la causa de incremento de un MT, benigna o maligna, es un problema frecuente en la práctica asistencial.

OBJETIVO Y CAMPO DE APLICACIÓN

El objetivo principal de este documento es mostrar las principales causas de falsos positivos de los principales MTs empleados en la práctica diaria asistencial, así como explicar los principales criterios empleados en el diagnóstico diferencial del incremento sérico de un MT, estableciendo si el origen es neoplásico o no.

PRINCIPALES CAUSAS DE FALSOS POSITIVOS

En la Tabla I se muestran las principales situaciones fisiológicas o patológicas de falsos positivos descritos con los principales MT subdividido en función del MTs, e indicando los intervalos de refe-rencia, los falsos positivos según la intensidad de dicho incremento y las principales indicaciones diagnósticas del MT. La Comisión de Marcadores Biológicos del Cáncer ha establecido como incremento leve a aquellos niveles séricos del MT que están por encima del límite

superior del intervalo de referencia, pero no suelen superar el doble de dicho límite. Se considera un incremento moderado cuando el valor del MT se encuentra entre 2 y 5 veces el límite superior del intervalo de referencia. Por último, se considera un incremento importante a aquel que suele ser superior a aproximadamente 5 veces el límite su-perior del intervalo de referencia y que son similares a los que pueden detectarse en el caso de una neoplasia avanzada.

Al realizar una búsqueda bibliográfica de los falsos positivos de MTs, los resultados obtenidos son abrumadores (ver Tabla I), y las causas que los provocan son múltiples. La lectura de dicha información es una fuente de incertidumbre diagnóstica para aquellos profesionales que trabajan con MTs, ya que parecen tan inespecíficos que parece imposible evitar errores de interpretación. No obstante, esta primera interpretación no se corresponde con la realidad, porque muchas de estas publicaciones hablan a propósito de un caso o no tienen en cuenta la posibilidad de que existan enfermedades intercurrentes, algunas de ellas conocidas como causa de falsos positivos de un determinado MT. Un ejemplo práctico es el CA 19.9, un MT con múltiples causas de falsos positivos, incluyendo una publicación que indica incrementos en un paciente por consumo de grandes cantidades de té (5). Este es un caso puntual, quizás asociado a otras causas de incremento, ya que en los países con un impor-tante consumo de té, como Gran Bretaña, China o India no lo han descrito. Molina y cols. (6) en un estudio reciente de pacientes no seleccionados ingresados en el Hospital Clinic de Barcelona con patología no neoplásica, detectó falsas elevaciones de CA 19.9 en un 18% de los pacientes, siendo las hepatopatías y la insuficiencia renal las principales causas de falsos positivos (p<0,0001). Para evitar falsas interpretaciones y no perder sensibilidad, se sugiere emplear distintos valores de referencia según la patología que evaluemos. Por ejemplo, la especificidad fue superior al 99% empleando 300 U/mL en los casos sin hepatopatía, 500 U/mL en los pacientes con hepatopatía sin ictericia y 1000 U/mL en los casos con ictericia.

Otros autores hablan de importantes incrementos en otras pa-tologías benignas como los derrames. En el artículo de Molina y

30 • Documentos de la SEQC - diciembre 2013

cols. (6) se demuestra que tan sólo el 8,9% de las patologías no hepático-renales o pancreáticas incrementan el CA 19.9, siendo > 100 U/mL tan sólo el 1,1% de los casos. En resumen, la Tabla I debe valorarse con cautela, reflejando las publicaciones sobre el tema, pero muchas de ellas deben ser cuestionadas al incluir sólo un número reducido de casos o no valorar las causas conocidas de incremento que pueden existir de manera simultánea en un enfermo.

RECOMENDACIONES

La inespecificidad de los MTs plantea el importante problema de discriminar ante una elevación, el origen benigno o maligno de la misma. Hay 4 criterios (Criterios de Barcelona) que serán de ayuda para distinguir y valorar correctamente los resultados de los MTs (1):

1) Los niveles séricos del MT. Los niveles séricos de la mayoría de los MTs, que se observan en ausencia de una neoplasia, suelen ser moderados. Cuanto mayores sean las concentraciones de un MT detectadas en un paciente, mayores son las probabilidades de tratarse de un tumor maligno. Por ejemplo, niveles de CEA inferio-res a 20-25 ng/mL pueden detectarse en numerosas enfermedades benignas, pero niveles superiores a dicho valor indican con elevada probabilidad la existencia de una patología maligna. El nivel suges-tivo de la presencia de una neoplasia varía según el MT, si bien en general, cuando supera los valores y patologías benignas incluidas en incrementos importantes, sugiere con elevada probabilidad cáncer.

2) Descartar la patología benigna. Ante un incremento de un MT hay que descartar la existencia de determinadas patologías benignas que puedan incrementarlo, variables según el MT y que podrían asociarse a dos grandes grupos: las alteraciones de los te-jidos productores o en su catabolismo (Tabla I). La mayoría de los MTs son catabolizados a nivel hepático y excretados por vía renal. Las alteraciones de estos órganos producirán un menor catabolismo y/o eliminación e indirectamente provocarán su acumulación y valores superiores al límite de referencia. La mayoría de los MTs

tienen incrementos moderados (de 2 a 4 veces el límite superior del intervalo de referencia) en los pacientes con cirrosis hepática o insuficiencia renal: CEA, CA 125, ProGRP, CYFRA 21-1, etc. En los pacientes con insuficiencia renal, algunos MTs pueden alcanzar unas concentraciones séricas similares a las halladas en una patología neoplásica y por ello no pueden utilizarse en estos pacientes, como en el caso del SCC, S-100 o el HE4. En la Tabla I se muestran las principales causas de falsos positivos, y su intensidad.

3) Estudio secuencial del MT. El hallazgo de unos niveles elevados de cualquier MT, de forma aislada, tiene un valor limitado. Cuando existen dudas respecto a un resultado, deben realizarse dos o tres mediciones seriadas, con un intervalo de tiempo entre ellas superior al de su vida media plasmática (15-20 días para la mayoría de los MTs). Si las cifras del MT tienen un incremento continuo (>50%) a lo largo del tiempo (por encima del nivel elevado del rango de referencia), se puede afirmar que con elevada probabilidad es de origen tumoral, ya que reflejan el crecimiento del tumor. Por el contrario, si los niveles séricos no se modifican o tienen una tendencia a descender, la causa habrá que buscarla en otra patología no neoplásica.

4) Interferencias técnicas. Este aspecto adquiere cada vez más relevancia. Las razones pueden ser debidas a la falta de especificidad del anticuerpo, a las reacciones cruzadas con otras moléculas o a la presencia de anticuerpos heterófilos. Además hay que considerar que los resultados de un MT obtenidos por un método comercial no siempre son comparables con otro, pudiendo haber discrepancias notables, sobretodo con el CA 19.9.

CONCLUSIONES

Los falsos positivos en la interpretación de los resultados de los MTs es una causa frecuente de problemas, interpretaciones inadecuadas, ansiedad, nerviosismo y realización de pruebas o consultas médicas innecesarias. El conocimiento de las causas de dichos falsos positivos y una metodología adecuada en la interpretación de los resultados per-mite obviar la mayoría de los problemas en las diferentes situaciones.

Marcador tumoral Caracteristicas Valores de

referencia*Falsos positivos

IndicacionesLeves Moderados Importantes

AFP (6, 9, 15-32)

Glicoproteína con gran homología a la albúmina

<10 ng/mL (adultos)

Enfermedades autoinmunes

Enfermedades hepatobiliares

Embarazo, neonatos.Hepatopatías de diversa índole (< 100 ng/mL), tirosinemia hereditariaAtaxia-telangiectasia

Carcinoma hepatocelular y tumores germinales de testículo (no seminomas) u ovario. Cancer gástrico

b HCG (15, 19, 22, 33-41)

Fracción β de la Hormona gonadotrofina coriónica humana

<2 U/mL

Enfermedades autoinmunes. Consumo de marihuana

Insuficiencia renal Gestación

Tumores trofoblásticos y neoplasias germinales de testículo (no seminomas)y ovario

b 2 M (42-48)

Cadena ligera de los antígenos de histocompatibilidad tipo I 2,3 mg/L

Hepatopatías crónicas, lesiones cerebrales, infecciones

Enfermedades autoinmunes Insuficiencia renal Mieloma, linfomas

Tabla I. Principales características de los Marcadores Tumorales séricos más empleados (1-13)



CA 15.3 (MCA, CA 549, B27-29) (6, 9, 14, 17, 18, 49-58)

Mucinas identificadas por distintos anticuerpos monoclonales frente al mismo epítopo

<35 U/mL

Tratamiento con factor estimulante de colonias de granulocitos. Esporádicos en patología infecciosa pulmónar, enfermedades autoinmunes, quistes ováricos (< 100 U/mL)

Insuficiencia renal, hepatopatías < 100 U/mL

Anemias megaloblásticas (déficit Vit B12)

Carcinomas de mama y ovario. Incrementos en NCICP y linfomas

CA 19.9 (6-9, 13, 15, 17, 18, 58-74)

Glicolípido que incluye el determinante del grupo sanguíneo Lewis a

<37 U/mL Patología benigna pulmónar

Patología gastrointestinal, endometriosis, quistes ováricos, hepatopatías, insuficiencia renal (< 400 U/mL)

Pancreatitis, Colestasis,(<1.000 U/mL)quistes mucinosos o bronquiectasias (<500 U/mL)

Neoplasias digestivas, en especial páncreas, carcinomas mucinosos e indiferenciados de ovario

CA 125 (6-9, 15, 17, 18, 74-95)

Mucina identificada por anticuerpos monoclonales

<35 U/mL

Pico ovulatorio, menstruación, infecciones pulmónares, EPOC (< 100 U/mL).Síndrome nefrótico, patología ginecológica: quistes, miomas endometriosis (< 200 U/mL)

Hepatopatías, insuficiencia renal (< 300 U/mL). Gestación (líquido amniótico).

Retenciones líquidas: derrames serosos, en especial con infecciones o tumores (<1.000 U/mL)

Carcinomas ováricos, pulmónares y de endometrio

Calcitonina

Hormona protéica (3,6 Kd) sintetizada por las células parafoliculares del tiroides

Varones<15 pg/mLMujeres<7 pg/mL

Cáncer medular tiroides. Cáncer de pulmón, Síndrome Zollinger-Ellison

CEA (6-9, 13-15, 17-18,49-51, 82, 95-104)

Familia de glicoproteínas <5 ng/mL

5% fumadores , múltiples patologías benignas (< 15 ng/mL),

Hepatopatías, insuficiencia renal, colitis ulcerosa, Crohn (< 25 ng/mL)

Neoplasias epiteliales, especialmente digestivas, medular tiroides, mama, pulmón…

Cromogranina A (105-146)

Glicoproteína ácida de 49 Kd, perteneciente a las graninas, presente en los gránulos cromafines de las células neuroendocrinas

<100 ng/mL

Múltiples patologías, agudas y crónicas. Hipertensión

Neumonias, sepsis, procesos agudos (<500 ng/mL). Cardiopatías (miocardiopatías, Insuficiencia cardíaca), gastritis atrófica, gastritis crónicas. Adenomas hipofisarios, hiperparatiroidismo primario

Insuficiencia renal. Tratamiento con inhibidores bomba protones. Gastritis atrófica

Tumores neuroendocrinos (carcinoides, feocromocitomas, neuroblastomas, ganglioneuromas). Incrementos moderados en otras neoplasias

CYFRA 21-1 (6-9, 97-99, 147-150)

Fragmento de la citoqueratina 19 <3,3 ng/mL

Múltiples patologías agudas o crónicas, derrames (< 7ng/mL)

Patología cutánea sistémica (pénfigo, psoriasis) hepatopatías (< 15 ng/mL)

Cirrosis hepática,insuficiencia renal (<20 ng/mL)

Neoplasias epiteliales, Mesotelioma, algunos linfomas y sarcomas

HER-2/neu (6, 151-156)

Porción externa de la Oncoproteína HER-2/neu

< 15 U/mL

Insuficiencia renal, patología ginecológica o mamaria (<20 ng/mL)

Hepatopatías (< 30 ng/mL)

Cáncer de mama. Discretos incrementos en próstata, pulmón


HE4 (157-161) Proteasa epididimal < 150 pmol/L Hepatopatías (<

200 pmol/L)

Derrames (< 450 pmol/L) Insuficiencia renal

Ovario, Adenocarcinomas de endometrio, pulmón

5 HIAA (133-141, 162-167)

Metabolito de la serotonina 1-5 mg/24 horas.

Factores alimenticios: café, alcohol, piña, frutos secos, plátanos

Tumores carcinoides, feocromocitoma

MIA (168-169) Melanoma inhibitory activity <11 U/mL Hepatopatías,

insuficiencia renalMelanoma maligno

NSE (6-9, 17-18, 97-99, 131, 133, 170-178)

Dímero (Gamma,Gamma) de la enolasa

< 25ng/mL Hepatopatías, neumopatías Insuficiencia renal

Hemorragias cerebralesIsquemia cerebral, Hemólisis

Carcinoma microcítico de pulmón, tumor carcinoide, neuroblastomas, tumor de Wilms.

PLAP (6, 9, 179-180)

Isoenzima termoestable de la fosfatasa alcalina

> 100 U/L Fumadores

Seminoma testicular, carcinoma de ovario

ProGRP (6-9, 149, 181-185)

Propéptido liberador de la Gastrina

<50 pg/mL Patologías crónicas (<80 pg/mL)

Hepatopatía (< 100 pg/mL)

Insuficiencia renal (< 350 pg/mL)

Carcinoma microcítico de pulmón, tumor carcinoide, neuroblastomas, tumor de Wilms.

PSA (6, 9, 17-18, 186-208)

Glicoproteína con actividad proteasa (Kalicreína 3)

< 4 ng/mLManipulación prostática

Hiperplasia prostática (especialmente con retención),

Prostatitis aguda Cáncer de próstata

SCC (6-9, 17-18, 83, 85, 97-99, 209-222)

Subfracción glicoproteíca del antígeno T 4 (serin-proteasa)

<2,5 ng/mL

5-10 % enfemedades pulmónares o hepáticas (< 4 ng/mL)

Insuficiencia renal, pénfigo, psoriasis, eczemas

Carcinoma escamoso

S-100 (175-178, 223-231)

Proteína acídica nuclear dimérica (BB) fijadora de calcio

< 0,2 ng/mLHepatopatía, patología autoinmune.

Insuficiencia renal, Lesiones cerebrales con necrosis

Melanoma maligno

CA 72.4 (6, 13, 17-18, 64, 232, 236)

Glicoproteína identificada por anticuerpos monoclonales (B72.3, cc49)

<6 U/mL

Discreto incremento en procesos agudos, EPOC.

Tratamientos con AINES, corticoides u omeprazol

Carcinoma digestivo, ovárico y pulmonar

Tiroglobulina (237-240)

Hormona glicoproteíca sintetizada por las células foliculares del tiroides

< 60 ng/mL(<1 ng/mL en tiroidectomía)

Gestante (último trimestre), tiroiditis subaguda, adenoma tóxico tiroideo, síndrome de Goitier

Neoplasia folicular y papilar de tiroides

TPA (1, 6, 50, 97, 241, 242)

Fragmentos de la citoqueratina 8, 18 y 19

< 75 U/mLModerados incrementos en procesos agudos

Hepatopatía, Insuficiencia renal, enfermedades infecciosas

Neoplasias epiteliales

TPS (1, 6, 50, 97, 241-242)

Fragmentos de la citoqueratina 18 < 75 U/mL

Discretos incrementos en procesos agudos

Hepatopatía , insuficiencia renal, enfermedades infecciosas

Neoplasias epiteliales

* Niveles normales empleados con mayor frecuencia.ABREVIATURAS: AFP: alfa-fetoproteína; b2 M: Beta 2 microglobulina; b HCG: Fracción b de la hormona gonadotropina coriónica humana; CEA: Antígeno carcinoembrionario; CA 19.9: Antígeno carbohidrato 19.9; CA 125: Antígeno carbohidrato 125; 5 HIAA: Ácido 5 hidroxiindol acético; MCA: Antígeno asociado al carcinoma de mama; MT: Marcador tumoral; MIA: Melanoma inhibitory activity; NSE: Enolasa neuronal específica; PLAP: Fosfatasa alcalina termoestable; PSA: Antígeno prostático específico; SCC: Antígeno asociado a los carcinomas escamosos; S-100: Proteína S-100; TPA: Antígeno polipeptídico tisular; TPS: Antígeno polipeptídico tisular específico.



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