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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.
2
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
3
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
4
metodología adecuada en la interpretación de los resultados permite obviar la mayoría de los problemas en las diferentes situaciones.
5
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
7
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
8
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
9
(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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