Eu . J. Gynaecol. Oncol. - ISSN: 0392-2936
XLI, n. 6, 2020
doi: 10.31083/j.ejgo.2020.06.2191
©2020 Baquedano Maina e al.
Published by IMR P ess.
This is an open access a icle unde he CC BY 4.0 license
(h ps://c ea i ecommons.o g/licenses/by/4.0/).
Sho Communica ion
HE4 in endome iod and non- endome ioid sub ype o
endome ial cance does no mean he same
Lau a Baquedano Maina 1, And ea Espiau Rome a1, Plu io Jesús Co onado Ma ín2
1Depa men o Obs e ics and Gynecology, Miguel Se e Uni e si y Hospi al, Pº Isabel la Ca ólica 1-3, 50009, Za agoza, Spain
2Women’s Heal h Ins i u e, Hospi al Clinico San Ca los, IdISSC, Complu ense Uni e si y o Mad id, C/P o Ma ín Lagos s/n, 28040, Mad id,
Spain
Summa y
Objec i e: To s udy he associa ion be ween he p eope a i e alue o se um HE4 ma ke and poo his ological p ognos ic ac o s
depending on he sub ype o endome ial cance (EC): endome ioid and non-endome ioid umo s. Me hods: P ospec i e and mul icen e
coho s udy including pa ien s wi h EC in Miguel Se e Uni e si y Hospi al o Za agoza (Spain) and Hospi al Clínico San Ca los
o Mad id (Spain) om Janua y 2017 o Ma ch 2020. P eope a i e se um le els o HE4 we e analyzed by clinical and pa hological
cha ac e is ics. Resul s: O e all, 190 pa ien s we e included. O hem, 158 we e sub ype I o EC and 32 we e sub ype II umo s. In
endome ioid EC, a s a is ically signi ican associa ion was ound be ween he p eope a i e HE4 alue and umo size (p<0.001),
deep myome ial in asion (p= 0.001), lympho ascula space in asion (LVSI) (p= 0.002), ce ical (p= 0.001), adnexal (p= 0.023),
is hmus (p<0.001) and pa ame ial in ol emen (p= 0.012), lymph node me as asis (p= 0.025) and FIGO s age (p<0.001). On he
con a y, no his ological ac o s showed s a is ical associa ion excep LVSI (p= 0.025) in he non-endome ioid sub ype. Conclusions:
The p eope a i e alue o HE4 is ela ed di e en ly wi h se e al es ablished p ognos ic ac o s o EC acco ding o he his ological ype
o umo . These esul s could be ele an in o de o s anda dize a p ognos ic alue o HE4 in EC.
Key wo ds: HE4; Endome ioid endome ial cance ; Se ous endome ial cance ; Clea cells endome ial cance .
In oduc ion
Endome ial cance (EC) is he mos common gyneco-
logical malignancy in de eloped coun ies and i s incidence
is inc easing yea -by-yea [1].
The endome ioid sub ype, also known as sub ype I, is
he mos common and is he bes p ognos ic sub ype, as i is
usually diagnosed a an ea ly s age, low g ade and wi h su-
pe icial myome ial in asion. The non-endome ioid sub-
ype, o sub ype II, includes especially u e ine se ous can-
ce (USC) and clea -cell ca cinoma (CCC). These sub ypes
show a mo e agg essi e de elopmen and hey a e associ-
a ed wi h a highe isk o ecu ence, and despi e i s low
p e alence, hey accoun o he majo i y o dea hs ela ed
o u e ine cance [2, 3].
HE4 is a ecen applica ion umo ma ke , desc ibed by
i s ime in 1991 by Ki chho e al. whose u ili y has
been demons a ed in he diagnosis and moni o ing o o a -
ian cance wi h he Risk o O a ian Malignancy Algo i hm
(ROMA) [4]. Howe e , he e is inc easing e idence o i s
possible applica ion in EC. Cu en ly, he e is no consensus
on he possible applica ion o HE4 as a p eope a i e ma ke
o EC. Howe e , he e seems o be a co ela ion be ween
EC p ognos ic ac o s and p eope a i e HE4 le els [5].
The aim o he p esen s udy is o explo e i he HE4
ma ke is ela ed o his ological p ognos ic ac o s o EC
by his ologic sub ype.
Me hods
We conduc ed a p ospec i e and mul icen e s udy in a
coho o pa ien s diagnosed o EC a wo medical cen e s in
Spain: “Hospi al Uni e si a io Miguel Se e ” in Za agoza
and “Hospi al Clínico San Ca los” in Mad id, om Janua y
1s , 2017 o Ma ch 1s , 2020. In bo h Cen e s EC is man-
aged ollowing he same clinical guidelines and p o ocols.
In he pe iod unde e iew, 208 pa ien s diagnosed and
ea ed o EC had a p eope a i e de e mina ion in se um o
HE4. Blood samples we e collec ed wi hin 2 weeks be o e
planned su ge y. Se um was s o ed a -80 ◦C un il analysis
in ou ine clinical labo a o y o bo h hospi als. This s udy
used he se um HE4 elec ochemiluminiscen ki s Cobas
e411 (Roche Diagnos ics®). Women wi h pleu al e u-
sion, hepa ic ailu e o enal insu iciency we e excluded
due o possible in e e ence wi h HE4 alues. Pa ien s
diagnosed wi h o he his ological sub ypes, synch onic o
me ach onous umo s o who had ecei ed neoadju an
ea men s we e also excluded.
In all cases, HE4 was assessed in se um p eope a i ely.
All pa ien s unde wen hys e ec omy and salpingoopho ec-
omy. Pel ic, o pel ic and pa a-ao ic lymphadenec omy
(LDN) was pe o med ollowing guidelines o he Span-
ish Socie y o Gynecology and Obs e ics and he Eu opean
Socie y o Gynecological Oncology [6, 7]. LDN was pe -
o med in all sub ype II cases.
1040 Lau a Baquedano Maina , And ea Espiau Rome a, Plu io Jesús Co onado Ma ín
We ca ied ou wo compa a i e g oups based on he clas-
sic cance classi ica ion: sub ype I included endome ioid
sub ype and sub ype II included USC and CCC. We s ud-
ied he possible ela ionship o he p eope a i e HE4 alue
depending on his classi ica ion.
All pos ope a i e specimens we e s udied by a leas
wo pa hologis s specialized in oncological gynecology and
when con o e sy exis ed, a hi d pa hologis e iewed he
su gical sample. Pa ien s we e classi ied acco ding o his-
ological FIGO g ade in low-mode a e g ade (G1-G2) and
high g ade (G3), and acco ding o FIGO s age in ea ly s age
(I and II) and ad anced s age (III and IV). The his o ype was
e iewed by a leas wo gynecological pa hologis s using
cu en Wo ld Heal h O ganiza ion c i e ia [8].
The p esen s udy was app o ed by he Resea ch E hics
Commi ee in A agón (CEICA), wi h he s udy e e ence
code PI16/0252. All pa ien s ga e w i en in o med con-
sen . The s udy was conduc ed in acco dance wi h appli-
cable laws and egula ions, including he e hical p inciples
con ained in he Decla a ion o Helsinki.
S a is ical analysis
Da a was collec ed in acco dance o p i acy policies.
S a is ics P ocess Social Sciences (SPSS) 22.0 o Win-
dows (Copy igh © Inc., 2013) was used o u he s a is-
ical analysis.
Fo he desc ip i e analysis he ca ego ical a iables
we e exp essed wi h hei equencies and pe cen ages. The
pa ame ic dis ibu ion o he HE4 ma ke was s udied wi h
he Kolmogo o -Smi no es . The a iables ha did no
ollow a no mal dis ibu ion we e exp essed wi h he me-
dian and in e qua ile ange (IQR) and hose ha p esen a
no mal dis ibu ion we e exp essed in mean and s anda d
de ia ion (SD).
U Mann-Whi ney es was used o he analysis o di-
cho omous quali a i e a iables, and K uskal-Wallis es o
non-dicho omous quali a i e ones. In all s a is ical es s,
p<0.05 was conside ed as he e e ence alue o signi -
icance.
Resul s
We included 190 pa ien s wi h sub ype I EC (n = 158) and
sub ype II umo s (n = 32). The mean age o women a diag-
nosis was 64.8 yea s (SD 10.4) o sub ype I and 69.1 (SD
11.6) yea s o sub ype II. The median o he p eope a i e
HE4 ma ke a iable was 72.7 pmol/L (IQR 68.6 pmol/L)
and 85.1 pmol/L (IQR 60), espec i ely, wi h no s a is ical
di e ences be ween he g oups (p= 0.340). LDN was pe -
o med in 59 pa ien s (62.7%) wi h endome ioid EC and 28
pa ien s (87.5%) wi h USC o CCC. The easons o no pe -
o ming LDN in hese cases we e ad anced age and coexis-
ence o se e e medical como bidi ies ha signi ican ly in-
c eased he su gical isk. The demog aphic and his ological
cha ac e is ics depending on he sub ype o EC a e shown
in Table 1.
We pe o med an analysis o s udy he ela ionship be-
ween HE4 p eope a i e alue and he his ological isks ac-
o s o EC. In endome ioid EC g oup, he p eope a i e
alue o HE4 ma ke was associa ed wi h all s udied his o-
logical p ognos ic ac o s, inding a s a is ically signi ican
associa ion wi h all o hem. Howe e , in sub ype II g, only
lympho ascula space in asion (LVSI) was signi ican ly as-
socia ed wi h he p eope a i e HE4 alue (p= 0.025). The
es o he s udied his ological ac o s did no show a s a-
is ically signi ican associa ion wi h he p eope a i e HE4
alue in his g oup. This da a is shown in Table 2.
Discussion
In ou sample, he p eope a i e alue o HE4 in sub ype
I o EC was co ela ed wi h all s udied his ological p ognos-
ic ac o s: a highe HE4 ma ke alue was associa ed wi h
poo his ological p ognos ic ac o s. Howe e , in sub ype
II o EC, p eope a i e HE4 alue only showed s a is ical
associa ion wi h LVSI. Thus, we hink ha he HE4 se um
le les mus be in e p e ed di e en ly o endome ioid and
non-endome ioid EC.
The classic dualis ic classi ica ion p oposed by
Bokhman in 1983 is s ill in use oday [9]. Following
his classi ica ion, he e a e wo di e en his ological
ypes o endome ial umo s, wi h di e en beha io and
p ognosis. His ological ea u es a e also di e en be ween
hem. Thus, ype II umo s can ha e an agg essi e beha io
wi hou being associa ed wi h o he his ological classic
ac o s o poo p ognosis. Con e sely, his is no he
case in sub ype I, in which his ological ac o s a e usually
co ela ed especially in well o mode a ely di e en ia ed
umo s [3, 10].
The signi icance o he HE4 ma ke in EC has been less
s udied han in o he ypes o umo s such as o a ian cance
[4, 11-13]. The e a e ew s udies ha analyze he ela ion-
ship o se um HE4 ma ke wi h his ological isk ac o s, and
hei esul s a e he e ogeneous. They do no usually ake
in o accoun he di e ences in beha io o bo h umo s e-
po ed by he dualis ic classi ica ion. To da e, his is he i s
s udy compa ing he signi icance o p eope a i e HE4 in EC
based on he his ological sub ype.
Bigno i e al. s udied he ela ionship be ween HE4 and
he clinic-pa hological ea u es in 138 pa ien s wi h EC and
ound ou ha HE4 se um le els we e signi ican ly associ-
a ed wi h se e al a iables o poo p ognosis: myome ial
in asion, LVSI, ce ical and adnexal in ol emen , lymph
node s a us and FIGO s age. The e was no di e ence in
HE4 alue be ween he endome ioid (n = 109) and non-
endome ioid sub ype (n = 29) g oups. The au ho s demon-
s a ed o he i s ime ha high HE4 p eope a i e le els
may iden i y pa ien s ha bo ing a mo e agg essi e EC phe-
no ype [14]. One yea la e , Zano i e al. eached a e y
simila conclusion, bu only 15 cases o se ous ca cinoma
and clea cells we e included in hei s udy [15]. None o
hem s udied whe he he associa ion showed be ween HE4
and his ological ac o s was di e en when he analysis was
pe o med aking in o accoun he his ological EC sub ype.
HE4 in endome iod and non- endome ioid sub ype o endome ial cance does no mean he same 1041
Table 1. — Demog aphic and his ological ea u es in endome ioid and non-endome ioid EC g oups.
Endome ioid Non-endome ioid
n (%) n (%)
Pa i y
Nullipa ous 35 (22.2) 8 (25)
<3 bi h 89 (56.3) 14 (43.7)
≥3 bi hs 34 (21.5) 10 (31.3)
A e ial hype ension 87 (55.1) 13 (40.6)
Diabe es Melli us 33 (20.9) 5 (15.6)
Menopausal s a us 139 (88) 30 (93.8)
Obesi y
BMI∗<25 63 (39.9) 12 (37.5)
BMI∗25-40 77 (48.7) 20 (62.5)
BMI∗>40 18 (11.4) 0
Tumo size <20 mm 55 (34.8) 10 (31.2)
≥20 mm 103 (65.2) 22 (68.8)
His ological g ade High g ade (G3) 23 (14.6) 32 (100)
Low g ade (G1-G2) 135 (85.4) 0
Myome ial in asion
No in asion 27 (17.1) 4 (12.5)
In asion <50 % 82 (51.9) 14 (43.8)
In asion >50% 49 (31.1) 14 (43.8)
Lymph- ascula space in asion P esence 13 (8.2) 11 (34.4)
Absence 145 (9.2) 21 (65.6)
His ological sub ype
Endome ioid 158 (100) 0
Se ous 0 27 (84.4)
Clea cell 0 5 (15.6)
FIGO s age I-II 144 (91.1) 18 (56.3)
III-IV 14 (8.9) 14 (43.7)
Lympha ic node in ol emen P esence 8 (5.3) 10 (31.2)
Absence 150 (94.7) 22 (68.8)
U e ine is hmus in ol emen P esence 19 (12) 4 (12.5)
Absence 139 (88) 28 (87.5)
Adnexal in ol emen P esence 6 (3.8) 5 (15.6)
Absence 152 (96.2) 27 (84.4)
U e ine ce ical in ol emen P esence 11 (7) 5 (15.6)
Absence 147 (93) 27 (84.4)
Pa ame ial in ol emen P esence 4 (2.5) 4 (12.5)
Absence 154 (97.5) 28 (87.5)
∗BMI (Body Mass Index).
O he subsequen s udies ha e e iewed he co ela ion
be ween HE4 and se e al his ological p ognos ic ac o s
[16-20]. One o he mos impo an is he s udy by Wang
e al. which included 258 pa ien s. A co ela ion o he
ma ke wi h his ological ac o s o poo p ognosis was ob-
se ed again. Howe e , in his no able s udy, he his ologi-
cal ype o umo s was no epo ed [16]. O he s udies in-
cluded exclusi ely endome ioid umo s showing he p og-
nos ic signi icance o HE4 alue in his g oup [17, 18].
In ou s udy, he e we e no signi ican di e ences in he
HE4 alue based on he his ological sub ype. This esul is
consis en wi h o he p e ious s udies [14, 15, 19, 21] and
implies ha i s p eope a i e absolu e alue is no an accu-
a e ool o di e en ia e he his ological ype o he umo .
These do no nega e ou inding ha he HE4 alue mus be
in e p e ed di e en ly be ween he wo classic ypes o EC.
The co ela ion be ween p eope a i e HE4 le els and he
FIGO s age has been s udied in he li e a u e. The majo i y
o s udies analyze he di e ences be ween ea ly (I-II) and
ad anced (III-IV) s ages, howe e , some au ho s make al-
e na i e compa isons [14, 16, 22]. The e o e, he esul s
when analyzing he possible associa ion be ween he HE4
ma ke and he s age a e he e ogeneous and di icul o com-
pa e.
Li e al. s udied he isk ac o s o node me as asis om
he clinicopa hological cha ac e is ics and p eope a i e lab-
o a o y esul s o 393 pa ien s su gically s aged wi h EC
[23]. The majo i y (84.2%) was sub ype I o EC. Highe
p eope a i e le els o se um HE4 (OR 4.25, 95% CI 1.65-
10.94, p= 0.003), and non-endome ioid his ology (OR
16.64, 95% CI 5.96-46.47, p<0.001) we e independen
isks ac o s o pel ic lympha ic me as asis in EC. The au-
1042 Lau a Baquedano Maina , And ea Espiau Rome a, Plu io Jesús Co onado Ma ín
Table 2. — S a is ical analysis o he ela ionship o HE4 ma ke wi h p ognos ic ac o s in endome ioid and
non-endome ioid EC g oups.
Endome ioid HE4 p alue Non-endome ioid HE4 p alue
Median (IQR)* Median (IQR)*
Tumo size <20 mm 55.5 (35.6) <0.001 57.9 (55.6) 0.096
≥20 mm 86.4 (80.6) 97.1 (96.9)
Myome ial in asion
No in asion 45.3 (16)
<0.001
81.6 (47.5)
0.508In asion <50 % 69 (50.9) 65.6 (56.8)
In asion >50% 105.3 (98.1) 95.3 (99.5)
Lymph- ascula space in asion P esence 152 (183.9) 0.002 115.4 (117.7) 0.025
Absence 68.5 (57.3) 76.1 (42.6)
FIGO s age I-II 69 (57.5) <0.001 61.3 (54.1) 0.071
III-IV 119.4 (253.4) 98 (325.2)
Lympha ic node in ol emen P esence 144.1 (296.3) 0.025 102.5 (76.3) 0.114
Absence 70 (59.6) 75.1 (50.7)
U e ine is hmus in ol emen P esence 148.3 (240) <0.001 77 (50.5) 0.345
Absence 68.5 (53.2) 130 (265.5)
Adnexal in ol emen P esence 105.9 (388.8) 0.023 88.1 (53.5) 0.749
Absence 70.6 (60.8) 75.1 (203.4)
U e ine ce ical in ol emen P esence 148.3 (287.7) 0.001 79.6 (50.6) 0.579
Absence 69.5 (56.8) 150 (117.9)
Pa ame ial in ol emen P esence 210.6 (733.2) 0.012 77 (51) 0.305
Absence 71.3 (62.6) 101.7 (243.2)
*IQR: in e qua ile ange.
ho s p oposed a cu -o poin o all cases o EC (≥132
pmol/L) wi h a high sensi i i y o he de ec ion o lym-
pha ic me as ases. Bu no dis inc ion was made based on he
his ological EC sub ype, despi e being independen ac o s
in he s a is ical analysis. As we ha e shown in ou s udy,
he p eope a i e HE4 alue does no ha e he same clinical
signi icance in sub ype I and II o EC. The e o e, we hink
ha i migh be mo e app op ia e o p opose a di e en cu -
o poin o each sub ype.
LVSI is conside ed one o he i s s eps o me as a ic
sp ead in EC, and i is an impo an p ognos ic ac o o e-
cu ence and su i al [24]. In he las Eu opean consen-
sus con e ence on EC, LVSI was ag eed o be an impo an
isk ac o ha can be u ilized o de ine new isk g oups and
guide adju an he apy use. Howe e , his is only applica-
ble o well o mode a ely di e en ia ed umo s, no o high
g ade EC [25]. A small numbe o s udies show a signi ican
associa ion be ween he p esence o LVSI and HE4 ma ke
inc ease [14, 26, 27]. Cu iously, in ou s udy i was he only
his ological ac o ela ed o HE4 in bo h ypes o umo s.
Cu en ly, his inding does no seem o ha e an impac on
clinical managemen in his subg oup, because all cases a e
high g ade umo s. Fu he s udies a e needed o in es iga e
whe he highe HE4 alue migh be use ul o di e en ia e a
mo e agg essi e subg oup wi hin ype II o EC.
Two ecen me a-analysis s udied he alue o HE4
ma ke in he diagnosis and p ognosis o EC [28, 29]. In he
i s one, 6 s udies wi h a o al o 781 pa ien s wi h EC we e
included, bu wi h a limi ed numbe o non-endome ioid
cases. The esul s sugges ed ha exp ession o HE4 was
associa ed wi h a wo se p ognosis in pa ien s wi h EC. In
he second, he au ho s sugges ed ha se um HE4 is gene -
ally an accu a e ool in EC diagnosis, bu wi h di e ences
depending on he his ological ype.
The e o e, i has been shown ha he alue o he p e-
ope a i e HE4 ma ke has an impo an p ognos ic signi i-
cance in EC. Howe e , i is no e i ied i i has he same
meaning depending on he ype o umo . Based on ou e-
sul s, we belie e ha he e a e impo an di e ences in he
associa ion o HE4 wi h well-es ablished his ological isk
ac o s o EC acco ding o he his ological ype.
Ou main limi a ion is he sample size o sub ype II, only
28 cases. This implies ha a he momen hese esul s
should be aken wi h cau ion. The au ho s assume ha pe -
haps a la ge sample in his g oup could d aw di e en con-
clusions. Mo e s udies wi h a la ge sample a e needed o
e i y hese indings and o es ablish i a di e en cu -o
poin associa ed o p ognos ic alue is necessa y depending
on he ype o umo .
Conclusions
P eope a i e alue o HE4 is ela ed di e en ly o his o-
logical p ognos ic ac o s o EC depending on he his olog-
ical ype o umo . While in endome ioid sub ype, highe
HE4 p eope a i e alue is ela ed o mul iple his ological
ac o s o poo p ognosis, in non-endome ioid sub ype, i
HE4 in endome iod and non- endome ioid sub ype o endome ial cance does no mean he same 1043
is only ela ed o LVSI. These esul s can be e y ele-
an /signi ican in o de o s anda dize hea p ognos ic alue
o HE4 in EC, which p obably is di e en depending on he
his ological sub ype. Fu he s udies wi h a la ge sample,
especially wi h mo e non-endome iod sub ype cases, a e
needed o e i y hese indings.
Au ho s’ con ibu ions
LBM has elabo a ed he esea ch p ojec . LBM and AER
ha e designed he s udy and da abase. They ha e pa ici-
pa ed on he elabo a ion o he a icle. PJCM has been e-
sponsible o supe ising he me hodology. LBM, AER and
PJCM ha e con ibu ed o da a collec ion. All au ho s con-
ibu ed o edi o ial changes in he manusc ip . All au ho s
ead and app o ed he inal manusc ip .
Acknowledgmen s
Thanks o he Depa men o Pa hological Ana omy o
he Miguel Se e Uni e si y Hospi al.
Con lic o In e es
The au ho s decla e no compe ing in e es s.
Submi ed: June 08, 2020
Accep ed: Augus 31, 2020
Published: Decembe 15, 2020
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1044 Lau a Baquedano Maina , And ea Espiau Rome a, Plu io Jesús Co onado Ma ín
Co esponding Au ho :
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Se e Uni e si y Hospi al, Pº Isabel la Ca ólica 1-3,
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