Principales causas de falsos positivos en los resultados

de marcadores tumorales en suero

Revisin (2013)
Sociedad Espaola de Bioqumica Clnica y Patologa Molecular

Comit Cientfico

Comisin de Marcadores Biolgicos del Cncer

R. Molina, X. Filella, J. Trap, J. M. Aug, A. Barco, F. Caizares, A. Colomer, A. Fernndez, M. J. Gaspar,
A. Martnez-Peinado, L. Prez Surez, M. Snchez, J. M. Escudero
Rafael Molina, rmolina@clinic.ub.es

INTRODUCCIN
El marcador tumoral (MT) incluye un amplio espectro de molculas, con caractersticas muy variables, producidas o inducidas
por la clula neoplsica que reflejan su crecimiento y/o actividad
y que permiten conocer la presencia, la evolucin o la respuesta
teraputica de un tumor maligno (1-4). Esta definicin no indica que
los MTs sean especficos del cncer, ya que la mayora de ellos son
sintetizados y liberados tambin por las clulas normales, por ello se
detectan en sangre y es necesario establecer valores de referencia. Las
diversas patologas benignas que afectan a los tejidos productores
de los MTs, tambin pueden provocar los incrementos sricos de
estos MTs, dando lugar a falsos positivos. La valoracin diferencial
entre la causa de incremento de un MT, benigna o maligna, es un
problema frecuente en la prctica asistencial.

OBJETIVO Y CAMPO DE APLICACIN

El objetivo principal de este documento es mostrar las principales
causas de falsos positivos de los principales MTs empleados en la
prctica diaria asistencial, as como explicar los principales criterios
empleados en el diagnstico diferencial del incremento srico de un
MT, estableciendo si el origen es neoplsico o no.

PRINCIPALES CAUSAS DE FALSOS

POSITIVOS
En la Tabla I se muestran las principales situaciones fisiolgicas
o patolgicas de falsos positivos descritos con los principales MT
subdividido en funcin del MTs, e indicando los intervalos de referencia, los falsos positivos segn la intensidad de dicho incremento
y las principales indicaciones diagnsticas del MT. La Comisin de
Marcadores Biolgicos del Cncer ha establecido como incremento
leve a aquellos niveles sricos del MT que estn por encima del lmite

superior del intervalo de referencia, pero no suelen superar el doble de

dicho lmite. Se considera un incremento moderado cuando el valor
del MT se encuentra entre 2 y 5 veces el lmite superior del intervalo
de referencia. Por ltimo, se considera un incremento importante a
aquel que suele ser superior a aproximadamente 5 veces el lmite superior del intervalo de referencia y que son similares a los que pueden
detectarse en el caso de una neoplasia avanzada.
Al realizar una bsqueda bibliogrfica de los falsos positivos de MTs,
los resultados obtenidos son abrumadores (ver Tabla I), y las causas que
los provocan son mltiples. La lectura de dicha informacin es una
fuente de incertidumbre diagnstica para aquellos profesionales
que trabajan con MTs, ya que parecen tan inespecficos que parece
imposible evitar errores de interpretacin. No obstante, esta primera
interpretacin no se corresponde con la realidad, porque muchas de
estas publicaciones hablan a propsito 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 prctico es el CA 19.9, un MT con
mltiples causas de falsos positivos, incluyendo una publicacin
que indica incrementos en un paciente por consumo de grandes
cantidades de t (5). Este es un caso puntual, quizs asociado a
otras causas de incremento, ya que en los pases con un importante consumo de t, como Gran Bretaa, 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
patologa no neoplsica, detect falsas elevaciones de CA 19.9 en
un 18% de los pacientes, siendo las hepatopatas 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 segn la patologa que evaluemos.
Por ejemplo, la especificidad fue superior al 99% empleando 300
U/mL en los casos sin hepatopata, 500 U/mL en los pacientes con
hepatopata sin ictericia y 1000 U/mL en los casos con ictericia.
Otros autores hablan de importantes incrementos en otras patologas benignas como los derrames. En el artculo de Molina y

Documentos de la SEQC - diciembre 2013 29

cols. (6) se demuestra que tan slo el 8,9% de las patologas no

heptico-renales o pancreticas incrementan el CA 19.9, siendo
> 100 U/mL tan slo 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 slo
un nmero reducido de casos o no valorar las causas conocidas de
incremento que pueden existir de manera simultnea en un enfermo.

RECOMENDACIONES
La inespecificidad de los MTs plantea el importante problema de
discriminar ante una elevacin, el origen benigno o maligno de la
misma. Hay 4 criterios (Criterios de Barcelona) que sern de ayuda
para distinguir y valorar correctamente los resultados de los MTs (1):
1) Los niveles sricos del MT. Los niveles sricos de la mayora
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 inferiores 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 patologa maligna. El nivel sugestivo de la presencia de una neoplasia vara segn el MT, si bien en
general, cuando supera los valores y patologas benignas incluidas en
incrementos importantes, sugiere con elevada probabilidad cncer.
2) Descartar la patologa benigna. Ante un incremento de un
MT hay que descartar la existencia de determinadas patologas
benignas que puedan incrementarlo, variables segn el MT y que
podran asociarse a dos grandes grupos: las alteraciones de los tejidos productores o en su catabolismo (Tabla I). La mayora de los
MTs son catabolizados a nivel heptico y excretados por va renal.
Las alteraciones de estos rganos producirn un menor catabolismo
y/o eliminacin e indirectamente provocarn su acumulacin y
valores superiores al lmite de referencia. La mayora de los MTs

tienen incrementos moderados (de 2 a 4 veces el lmite superior

del intervalo de referencia) en los pacientes con cirrosis heptica o
insuficiencia renal: CEA, CA 125, ProGRP, CYFRA 21-1, etc. En
los pacientes con insuficiencia renal, algunos MTs pueden alcanzar
unas concentraciones sricas similares a las halladas en una patologa
neoplsica 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 plasmtica (15-20 das para la mayora 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
sricos no se modifican o tienen una tendencia a descender, la causa
habr que buscarla en otra patologa no neoplsica.
4) Interferencias tcnicas. Este aspecto adquiere cada vez ms
relevancia. Las razones pueden ser debidas a la falta de especificidad
del anticuerpo, a las reacciones cruzadas con otras molculas o a la
presencia de anticuerpos heterfilos. Adems hay que considerar
que los resultados de un MT obtenidos por un mtodo comercial no
siempre son comparables con otro, pudiendo haber discrepancias
notables, sobretodo con el CA 19.9.

CONCLUSIONES
Los falsos positivos en la interpretacin de los resultados de los MTs
es una causa frecuente de problemas, interpretaciones inadecuadas,
ansiedad, nerviosismo y realizacin de pruebas o consultas mdicas
innecesarias. El conocimiento de las causas de dichos falsos positivos
y una metodologa adecuada en la interpretacin de los resultados permite obviar la mayora de los problemas en las diferentes situaciones.

Tabla I. Principales caractersticas de los Marcadores Tumorales sricos ms empleados (1-13)

Marcador
tumoral

AFP
(6, 9, 15-32)

b HCG (15, 19,

22, 33-41)

b 2 M (42-48)

Caracteristicas

Glicoprotena con
gran homologa a
la albmina

Fraccin de
la Hormona
gonadotrofina
corinica humana
Cadena ligera de
los antgenos de
histocompatibilidad
tipo I

Valores de
referencia*

<10 ng/mL
(adultos)

Leves

Enfermedades
autoinmunes

Falsos positivos
Moderados

Enfermedades
hepatobiliares

Importantes
Embarazo,
neonatos.
Hepatopatas de
diversa ndole
(< 100 ng/mL),
tirosinemia
hereditaria
Ataxiatelangiectasia

Indicaciones
Carcinoma
hepatocelular
y tumores
germinales de
testculo (no
seminomas) u
ovario. Cancer
gstrico

<2 U/mL

Enfermedades
autoinmunes.
Consumo de
marihuana

Insuficiencia renal

Gestacin

Tumores
trofoblsticos
y neoplasias
germinales de
testculo (no
seminomas)y
ovario

2,3 mg/L

Hepatopatas
crnicas, lesiones
cerebrales,
infecciones

Enfermedades
autoinmunes

Insuficiencia renal

Mieloma, linfomas

30 Documentos de la SEQC - diciembre 2013

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

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

Mucinas
identificadas
por distintos
anticuerpos
monoclonales
frente al mismo
eptopo

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

Glicolpido
que incluye el
determinante del
grupo sanguneo
Lewis a

<35 U/mL

<37 U/mL

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

Mucina
identificada
por anticuerpos
monoclonales

<35 U/mL

Calcitonina

Hormona
protica (3,6
Kd) sintetizada
por las clulas
parafoliculares del
tiroides

Varones
<15 pg/mL
Mujeres
<7 pg/mL

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

Cromogranina A
(105-146)

Familia de
glicoprotenas

Glicoprotena
cida de 49 Kd,
perteneciente a las
graninas, presente
en los grnulos
cromafines
de las clulas
neuroendocrinas

<5 ng/mL

<100 ng/mL

CYFRA 21-1 (6-9,

97-99, 147-150)

Fragmento de la
citoqueratina 19

<3,3 ng/mL

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

Porcin externa de
la Oncoprotena
HER-2/neu

< 15 U/mL

Tratamiento con
factor estimulante
de colonias de
granulocitos.
Espordicos
en patologa
infecciosa
pulmnar,
enfermedades
autoinmunes,
quistes ovricos (<
100 U/mL)

Insuficiencia renal,
hepatopatas < 100
U/mL

Anemias
megaloblsticas
(dficit Vit B12)

Carcinomas de
mama y ovario.
Incrementos en
NCICP y linfomas

Patologa benigna
pulmnar

Patologa
gastrointestinal,
endometriosis,
quistes ovricos,
hepatopatas,
insuficiencia renal
(< 400 U/mL)

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

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

Hepatopatas,
insuficiencia renal
(< 300 U/mL).
Gestacin (lquido
amnitico).

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

Carcinomas
ovricos,
pulmnares y de
endometrio

Pico ovulatorio,
menstruacin,
infecciones
pulmnares, EPOC
(< 100 U/mL).
Sndrome
nefrtico,
patologa
ginecolgica:
quistes, miomas
endometriosis (<
200 U/mL)

Cncer medular
tiroides. Cncer de
pulmn, Sndrome
Zollinger-Ellison
5% fumadores
, mltiples
patologas
benignas
(< 15 ng/mL),

Mltiples
patologas,
agudas y crnicas.
Hipertensin

Mltiples
patologas agudas
o crnicas,
derrames (< 7ng/
mL)
Insuficiencia
renal, patologa
ginecolgica o
mamaria (<20 ng/
mL)

Neoplasias
epiteliales,
especialmente
digestivas,
medular tiroides,
mama, pulmn

Hepatopatas,
insuficiencia renal,
colitis ulcerosa,
Crohn
(< 25 ng/mL)
Neumonias,
sepsis, procesos
agudos (<500 ng/
mL). Cardiopatas
(miocardiopatas,
Insuficiencia
cardaca),
gastritis atrfica,
gastritis crnicas.
Adenomas
hipofisarios,
hiperparatiroidismo
primario
Patologa cutnea
sistmica (pnfigo,
psoriasis)
hepatopatas (< 15
ng/mL)
Hepatopatas (< 30
ng/mL)

Insuficiencia renal.
Tratamiento con
inhibidores bomba
protones. Gastritis
atrfica

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

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

Neoplasias
epiteliales,
Mesotelioma,
algunos linfomas y
sarcomas
Cncer de
mama. Discretos
incrementos en
prstata, pulmn

Documentos de la SEQC - diciembre 2013 31

HE4 (157-161)

Proteasa
epididimal

< 150 pmol/L

5 HIAA (133-141,
162-167)

Metabolito de la
serotonina

1-5 mg/24 horas.

MIA (168-169)

Melanoma
inhibitory activity

<11 U/mL

NSE (6-9, 17-18,

97-99, 131, 133,
170-178)

Dmero
(Gamma,Gamma)
de la enolasa

< 25ng/mL

PLAP (6, 9, 179180)

Isoenzima
termoestable de la
fosfatasa alcalina

> 100 U/L

ProGRP (6-9, 149,

181-185)

Propptido
liberador de la
Gastrina

<50 pg/mL

PSA (6, 9, 17-18,

186-208)

Glicoprotena con
actividad proteasa
(Kalicrena 3)

SCC (6-9, 17-18,

83, 85, 97-99,
209-222)

Subfraccin
glicoproteca
del antgeno T 4
(serin-proteasa)

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

CA 72.4 (6, 13, 1718, 64, 232, 236)

Protena acdica
nuclear dimrica
(BB) fijadora de
calcio
Glicoprotena
identificada
por anticuerpos
monoclonales
(B72.3, cc49)

Hepatopatas (<
200 pmol/L)

Derrames (< 450

pmol/L)

Insuficiencia renal

Factores
alimenticios:
caf, alcohol,
pia, frutos secos,
pltanos
Hepatopatas,
insuficiencia renal
Hepatopatas,
neumopatas

Insuficiencia renal

Tumores
carcinoides,
feocromocitoma

Hemorragias
cerebrales
Isquemia cerebral,
Hemlisis

Fumadores

Melanoma
maligno
Carcinoma
microctico de
pulmn, tumor
carcinoide,
neuroblastomas,
tumor de Wilms.
Seminoma
testicular,
carcinoma de
ovario
Carcinoma
microctico de
pulmn, tumor
carcinoide,
neuroblastomas,
tumor de Wilms.

Hepatopata (< 100

pg/mL)

Insuficiencia renal
(< 350 pg/mL)

Hiperplasia
prosttica
(especialmente con
retencin),

Prostatitis aguda

Cncer de prstata

<2,5 ng/mL

5-10 %
enfemedades
pulmnares o
hepticas
(< 4
ng/mL)

Insuficiencia renal,
pnfigo, psoriasis,
eczemas

Carcinoma
escamoso

< 0,2 ng/mL

Hepatopata,
patologa
autoinmune.

Insuficiencia
renal, Lesiones
cerebrales con
necrosis

Melanoma
maligno

<6 U/mL

Discreto
incremento en
procesos agudos,
EPOC.

Tratamientos
con AINES,
corticoides u
omeprazol

Carcinoma
digestivo, ovrico
y pulmonar

< 4 ng/mL

Patologas crnicas
(<80 pg/mL)

Ovario,
Adenocarcinomas
de endometrio,
pulmn

Manipulacin
prosttica

Tiroglobulina
(237-240)

Hormona
glicoproteca
sintetizada por las
clulas foliculares
del tiroides

< 60 ng/mL
(<1 ng/mL en
tiroidectoma)

Gestante (ltimo
trimestre),
tiroiditis subaguda,
adenoma txico
tiroideo, sndrome
de Goitier

TPA (1, 6, 50, 97,

241, 242)

Fragmentos de la
citoqueratina 8,
18 y 19

< 75 U/mL

Moderados
incrementos en
procesos agudos

TPS (1, 6, 50, 97,

241-242)

Fragmentos de la
citoqueratina 18

< 75 U/mL

Discretos
incrementos en
procesos agudos

Neoplasia folicular
y papilar de
tiroides
Hepatopata,
Insuficiencia renal,
enfermedades
infecciosas
Hepatopata ,
insuficiencia renal,
enfermedades
infecciosas

Neoplasias
epiteliales
Neoplasias
epiteliales

* Niveles normales empleados con mayor frecuencia.

ABREVIATURAS: AFP: alfa-fetoprotena; b2 M: Beta 2 microglobulina; b HCG: Fraccin b de la hormona gonadotropina corinica humana; CEA:
Antgeno carcinoembrionario; CA 19.9: Antgeno carbohidrato 19.9; CA 125: Antgeno carbohidrato 125; 5 HIAA: cido 5 hidroxiindol actico; MCA:
Antgeno asociado al carcinoma de mama; MT: Marcador tumoral; MIA: Melanoma inhibitory activity; NSE: Enolasa neuronal especfica; PLAP: Fosfatasa
alcalina termoestable; PSA: Antgeno prosttico especfico; SCC: Antgeno asociado a los carcinomas escamosos; S-100: Protena S-100; TPA: Antgeno
polipeptdico tisular; TPS: Antgeno polipeptdico tisular especfico.

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

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