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PRINCIPALES CAUSAS DE FALSOS POSITIVOS EN LOS RESULTADOS DE MARCADORES TUMORALES EN SUERO.

Sociedad Española de Bioquímica Clínica y Patología Molecular. Comisión de Marcadores Biológicos del Cáncer

Rafael Molina, Xavier Filella, Jaume Trape, Jose M. Augé, Antonio Barco, Francisco Cañizares, Anna Colomer, Antonio Fernandez, Maria J.

Gaspar, Antonio Martinez-Peinado, Luis Pérez Suárez, Marta Sánchez, Jose M. Escudero,

Correspondencia: Rafael Molina, rmolina@clinicub.es

INTRODUCCION

El marcador tumoral (MT) incluye un amplio espectro de moléculas, 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 MT 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 MT, también pueden provocar los incrementos séricos de estos MT, 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 MT, e indicando los intervalos de referencia, 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 superior del intervalo de referencia y que son similares a los que pueden

detectarse en el caso de una neoplasia avanzada.

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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 MT, 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 (1-241). Este es un caso puntual, quizás asociado a otras causas de incremento, ya que en los países con un importante consumo

de té, como Gran Bretaña, China o India no lo han descrito. Molina y cols. (62) 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 patologías benignas como los derrames. En el artículo de Molina y cols. (62) 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 MT 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 MT (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 mayor 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 inferiores a 20-25 ng/mL pueden detectarse en numerosas enfermedades benignas, pero niveles

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superiores a dicho valor indican con elevada probabilidad la existencia de una patología maligna. El nivel sugestivo 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 tejidos 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 MT). 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

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metodología adecuada en la interpretación de los resultados permite obviar la mayoría de los problemas en las diferentes situaciones.

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

Marcador tumoral Caracteristicas

Valores

de

referencia

*

Falsos positivos

Indicaciones

Leves Moderados Importantes

AFP

(7, 13-30, 62)

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

hereditaria

Ataxia-telangiectasia

Carcinoma hepatocelular y

tumores germinales de

testículo (no seminomas) u

ovario. Cancer gástrico

HCG

(7,13,17-20, 31-37)

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

6

2 M

(38-46)

Cadena ligera de

los antígenos de

histocompatibilidad

tipo I

2,3 mg/L

Hepatopatías crónicas,

lesiones cerebrales,

infecciones

Enfermedades autoinmunes Insuficiencia renal Mieloma, linfomas

CA 15.3

(MCA, CA

549, B27-29)

(7,12,15-16,47-

56,62)

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

(7-9,11,15-16,57-

73,81)

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

(7-9, 15-16, 62, 74-

Mucina identificada

por anticuerpos

monoclonales

<35 U/mL

Pico ovulatorio, menstruación,

infecciones pulmónares,

EPOC (< 100 U/mL).

Hepatopatías, insuficiencia renal

(< 300 U/mL). Gestación (líquido

amniótico).

Retenciones

líquidas: derrames

serosos, en especial

Carcinomas ováricos,

pulmónares y de endometrio

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94) Síndrome nefrótico, patología

ginecológica: quistes, miomas

endometriosis (< 200 U/mL)

con infecciones o

tumores (<1.000

U/mL)

Calcitonina

Hormona protéica

(3,6 Kd) sintetizada

por las células

parafoliculares del

tiroides

Varones

<15 pg/mL

Mujeres

<7 pg/mL

Cáncer medular tiroides.

Cáncer de pulmón,

Síndrome Zollinger-Ellison

CEA

(7-9,11-12,15-16,

49,62,84,95-103)

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

(104-145)

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

(7-9,62,81,96-

Fragmento de la

citoqueratina 19

<3,3

ng/mL

Múltiples patologías agudas o

crónicas, derrames (<

Patología cutánea sistémica

(pénfigo, psoriasis) hepatopatías Cirrosis hepática,

Neoplasias epiteliales,

Mesotelioma, algunos

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98,146-149) 7ng/mL) (< 15 ng/mL) insuficiencia renal

(<20 ng/mL)

linfomas y sarcomas

HER-2/neu

(7,150-155)

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

(156-160) Proteasa epididimal

< 150

pmol/L Hepatopatías (< 200 pmol/L)

Derrames (< 450 pmol/L)

Insuficiencia renal Ovario, Adenocarcinomas

de endometrio, pulmón

5 HIAA

(132,138-139, 161-

166)

Metabolito de la

serotonina

1-5 mg/24

horas.

Factores alimenticios: café,

alcohol, piña, frutos secos,

plátanos

Tumores carcinoides,

feocromocitoma

MIA

(167-168)

Melanoma

inhibitory activity <11 U/mL Hepatopatías, insuficiencia renal Melanoma maligno

NSE

(7-9,15-16, 62, 96,

98,132, 169-177)

Dímero

(Gamma,Gamma)

de la enolasa

< 25ng/mL Hepatopatías, neumopatías Insuficiencia renal

Hemorragias

cerebrales

Isquemia cerebral,

Hemólisis

Carcinoma microcítico de

pulmón, tumor carcinoide,

neuroblastomas, tumor de

Wilms.

PLAP

(7,178-179)

Isoenzima

termoestable de la

fosfatasa alcalina

> 100 U/L Fumadores Seminoma testicular,

carcinoma de ovario

ProGRP Propéptido <50 pg/mL Patologías crónicas Hepatopatía (< 100 pg/mL) Insuficiencia renal Carcinoma microcítico de

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(7-9,148,180-184) liberador de la

Gastrina

(<80 pg/mL) (< 350 pg/mL) pulmón, tumor carcinoide,

neuroblastomas, tumor de

Wilms.

PSA

(7,15-16,187-208)

Glicoproteína con

actividad proteasa

(Kalicreína 3)

< 4 ng/mL

Manipulación prostática

Hiperplasia prostática

(especialmente con retención), Prostatitis aguda Cáncer de próstata

SCC

(7-9,15-16,62,82,

84, 96-98,209-222)

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

(174-175,177,223-

231)

Proteína acídica

nuclear dimérica

(BB) fijadora de

calcio

< 0,2

ng/mL

Hepatopatía, patología

autoinmune.

Insuficiencia renal,

Lesiones cerebrales

con necrosis

Melanoma maligno

CA 72.4

(11,15-16,62-63,

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 pulmónar

Tiroglobulina

(237-240)

Hormona

glicoproteíca

sintetizada por las

células foliculares

< 60

ng/mL

(<1 ng/mL

en

Gestante (último trimestre),

tiroiditis subaguda, adenoma

tóxico tiroideo, síndrome de

Goitier

Neoplasia folicular y papilar

de tiroides

10

del tiroides tiroidectom

ía)

TPA

(7,96,241-242)

Fragmentos de la

citoqueratina 8, 18

y 19

< 75 U/mL Moderados incrementos en

procesos agudos

Hepatopatía,

Insuficiencia renal,

enfermedades

infecciosas

Neoplasias epiteliales

TPS

(7,96,241-242)

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; 2 M: Beta 2 microglobuina; HCG: Fracción de la hormona gonadotrofina coriónica; 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 polipetídico tisular; TPS: Antígeno polipeptídico tisular específico.

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