Eu . J. Gynaecol. Oncol. - ISSN: 0392-2936
XLI, n. 6, 2020
doi: 10.31083/j.ejgo.2020.06.2185
©2020 Na a o Sie a 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/).
Re iew
P ima y endome ial ca cinoma wi h signe - ing cells. A case
epo and e iew o he li e a u e
Ja ie Na a o Sie a1, And ea Espiau Rome a1, Ma a Na áez Salaza 1, Ma ía Jesús Puen e Luján1,
Bea iz Eizagui e Za za2, Lau a Baquedano Maina 1
1Depa men o Obs e ics & Gynecology o Miguel Se e Uni e si y Hospi al, 50009, Za agoza, Spain
2Depa men o Ana omic Pa hology o Miguel Se e Uni e si y Hospi al, 50009, Za agoza, Spain
Summa y
Endome ial adenoca cinoma wi h signe - ing cells is an in equen his ological ype o ca cinoma ha usually co esponds o a
me as asis o a p ima y ca cinoma o ano he o igin, mainly om he gas oin es inal ac o he b eas . Fo his eason, in iew o his
his ological inding, i is essen ial o ca y ou a ho ough e alua ion including mammog aphy, gas oscopy, colonoscopy and ho acoab-
dominopel ic CT. To da e, only six cases o p ima y endome ial ca cinoma wi h signe - ing cells ha e been epo ed in he English
li e a u e. A 73-yea -old pa ien was e e ed o he Gynecology Depa men wi h a 3-day his o y o pos menopausal bleeding. She was
diagnosed wi h p ima y endome ial adenoca cinoma wi h signe - ing cells. The ana omopa hological special ea u es o he su gical
specimen a e p esen ed, as well as he e olu ion o he pa ien , who emained asymp oma ic and ee o disease 28 mon hs a e su ge y.
A e iew o he li e a u e is pe o med, emphasizing he peculia i ies o his a e his ological sub ype. Despi e he ac ha p ima y en-
dome ial ca cinoma wi h signe - ing cells is an in equen umo , i mus be conside ed in he di e en ial diagnosis o malignan umo s
o a o esaid o igin. I is essen ial o ca y ou a co ec and an ex ensi e in es iga i e s udy as well as an immunohis ochemical analysis
o he samples ob ained o i s con i ma ion diagnosis.
Key wo ds: Endome ial adenoca cinoma; Signe - ing cells; Immunohis ochemical analysis.
In oduc ion
Endome ial adenoca cinoma wi h signe - ing cells is a
ype o ca cinoma ha owes i s peculia appea ance o he
p esence o a la ge mucin- illed acuole wi hin i s cells ha
displaces he nucleus o he pe iphe y [1]. When his in e-
quen his ological sub ype appea s in he endome ium, i
usually co esponds o a me as asis o a p ima y ca cinoma
o ano he o igin, mainly om he gas oin es inal ac o
he b eas [1].
The Wo ld Heal h O ganiza ion Classi ica ion o umo s
conside s signe - ing cell ca cinoma as a a e his ological
a ian o ce ical ca cinoma o he u e us, al hough i does
no include i among he his ological a ian s o endome ial
ca cinoma [2]. To da e, only six cases o p ima y endome-
ial ca cinoma wi h signe - ing cells ha e been published
in he English li e a u e [1, 3-6].
The objec i e o his wo k is o p esen he case o a pa-
ien diagnosed wi h p ima y endome ial ca cinoma wi h
signe - ing cells, pe o ming a e iew o he li e a u e on
his a e pa hology.
The publica ion o his case epo was app o ed by
A agon E hics Commi ee in Za agoza, Spain, and com-
plied wi h he decla a ion o Helsinki o Human Resea ch
o 1974 (las modi ied in 2000).
Case Repo
A case o a 73-yea -old pa ien , wi hou oxic habi s
(non-smoke , non-d inke o alcohol), wi h a body mass in-
dex o 32 kg/m2, hype ension and DM-2 unde going ea -
men wi h a su gical his o y o colpope ineoplas y in 2008
and endome ial polypec omy by hys e oscopy in 2011, is
p esen ed. She was e e ed o he Gynecology Depa men
in No embe 2017 due o a pos menopausal bleeding o 3
days o e olu ion wi hou o he associa ed symp oms.
Gynecological examina ion e ealed no mal ex e nal
geni als, old blood emained in he agina wi hou ac i e
bleeding, sligh ly p ominen a ophic ce ix, wi h no mal
examina ion on bimanual palpa ion. The ans aginal ul-
asound e ealed a u e us wi h mul iple myomas, wi h a
dominan 28mm in amu al myoma on he le la e al ace,
and a hickened and he e ogeneous endome ium o 35 ×
30 ×17 mm wi hou a isible subendome ial halo. An as-
pi a ion biopsy was aken wi h a pa hological diagnosis o
mucinous adenoca cinoma wi h signe - ing cells (Figu e 1).
In he immunohis ochemical s udy (IHC) i was ound: Es-
ogen Recep o s (ER) posi i e (90%), P oges e one Recep-
o s (PR) posi i e (80%), Vimen in posi i e, p16 nega i e,
Ca cinoemb yonic An igen (CEA) posi i e, Cy oke a in 7
(CK7) posi i e, Cy oke a in 20 (CK20) nega i e, GATA3
nega i e and PAX8 posi i e. The immunohis ochemical
o e exp ession o he ho monal ecep o s and imen in, in
880 Ja ie Na a o Sie a, And ea Espiau Rome a, Ma a Na áez Salaza , Ma ía Jesús Puen e Luján...
Figu e 1. — Endome ial mucosa wi h di use in il a ion by signe - ing cells. (A) Endome ial mucosa wi h di use in il a ion by signe -
ing cells. No mal endome ial gland is seen wi hin he umo . Hema oxylin-eosin (H&E) 10×. (B) Di use p oli e a ion o signe - ing
cells: basophilic, mucinous cy oplasm and nucleus ejec ed o he pe iphe y. H&E 20×.
Figu e 2. — Immunohis ochemical analysis. (A) Endome ial mucosa wi h di use in il a ion by signe - ing cells. Cy oke a in 7 + 35,
7×. (B) Signe - ing cells: mucinous cy oplasm and nucleus pushed o he pe iphe y. Cy oke a in 20-25, 4×. (C) Signe - ing cells PAX8
+ 35, 7×. (D) Signe - ing cells p oges e one ecep o s (PR) + 32×.
addi ion o he nega i i y o p16, sugges endome ial o igin
e sus endoce ical o igin. Besides, nega i i y o GATA3
and CK20 seems o ule ou a p ima y o igin in he b eas
and colon, espec i ely (Figu e 2).
Magne ic esonance imaging (MRI) e ealed an en-
dome ium occupied by a 40 ×28 ×35 mm lobula ed,
poo ly de ined and he e ogeneous mass, wi h pos -con as
enhancemen and signi ican es ic ion in he di usion se
P ima y endome ial ca cinoma wi h signe - ing cells. A case epo and e iew o he li e a u e 881
Table 1. — Published cases o Endome ial Adenoca cinoma wi h signe - ing cells: e iew o he li e a u e.
AUTOR AGE SYMPTOMS IHQ FIGO
STAGE
SURGICAL
TREATMENT
ADJUVANCE PATIENT FOLLOW-UP
Mooney e al. 1997 [3] 65 Asymp oma ic Vimen in-/BRST-2-/CEA+ - HT+DA+BPL+ -F ee o disease 6 mon hs
a e su ge yOmen ec omía
Chebib e al. 2010
[4]
51 T ousseau Synd ome +
asci es + weigh loss
CK7+/CK20-/p16-/CEA- IVB HT+DA+BPL QT (6 cycles wi h
Ca bopla in + Taxol)
Dea h o me as asic disease
6 mon hs a e su ge y
Boyd e al. 2010 [5] 46 Hea y mens ual
bleeding
ER+/CK7+/CEA+ - Sub o al HT - -
Boyd e al. 2010 [5] 59 Pos menopausal
bleeding
ER+/CK7+/CK20- - HT - -
Pusiol e al. 2014
[6]
53 Hea y mens ual
bleeding
ER-/PR-/Vimen in+/p16+/
CEA-
IB HT+DA+BPL+PL - F ee o disease 22 mon hs
a e su ge y
Akkalp e al. 2015
[1]
77 Pos menopausal
bleeding
ER+/Vimen in+/CK7+/CK20-
/CEA-
IA HT+DA+BPL RT F ee o disease 14 mon hs
a e su ge y
Case p esen ed 73 Pos menopausal
bleeding
ER+/PR+/Vimen in+/p16-
/CK7+/CK20-
/CEA+/GATA3-/PAX8+
IIIA HT+DA+BPL+PL
+Omen ec omía QT (6 cycles wi h
Ca bopla in + Taxol) + RT
F ee o disease 28 mon hs
a e su ge y
HT: Hys e ec omy, DA: Double Anexec omy, BPL: bila e al pel ic lymphadenec omy, PL: Pa ao ic lymphadenec omy, QT: chemo he apy, RT: adio he apy, CK7: Cy-
oke a in 7, CK20: Cy oke a in 20, ER: Es ogen ecep o s, PR: p oges e one ecep o s, CEA: ca cinoemb yonic an igen.
882 Ja ie Na a o Sie a, And ea Espiau Rome a, Ma a Na áez Salaza , Ma ía Jesús Puen e Luján...
quence. Besides, he mass in aded mo e han one-hal o
he myome ium, p edominan ly on he an e io side. The
ce ix appea ed no o be in aded. Tho acoabdominopel ic
CT uled ou he exis ence o lymphadenopa hy and neo-
plas ic in ol emen a a dis ance. In he p eope a i e an-
aly ical s udy umo ma ke s we e eques ed, wi h CA-125
alues o 15.77 U/ml and HE-4 o 152 pmol/L. The emain-
de o he e alua ion, which included mammog aphy, ches
X- ay, colonoscopy and gas oscopy, was no mal.
In Decembe 2017, comple e s aging su ge y o en-
dome ial cance was pe o med ia abdominal, includ-
ing pe i oneal la ages, simple o al hys e ec omy wi h bi-
la e al adnexec omy, pel ic and pa a-ao ic lymphadenec-
omy, and omen ec omy. The pa ien pos ope a i e cou se
was une en ul and she was discha ged on he i h day a e
he in e en ion.
The de ini i e pa hology diagnosis in he su gical spec-
imen, made by wo expe gynecologic oncology pa hol-
ogis s, was FIGO IIIA undi e en ia ed endome ial ade-
noca cinoma wi h signe - ing cells (pT3a (u e ine se osa
in ol emen ), pN0 (0/29)). In a mul idisciplina y umo
boa d, due o he de ini i e diagnosis and he ad anced
FIGO s age o he umo , i was decided o adminis e adju-
an ea men wi h chemo he apy (ca bopla in + pacli axel
6 cycles), ollowed by adju an ex e nal adio he apy (46
Gy di ided in 23 doses) and b achy he apy o he aginal
cu , which ended in Augus 2018.
In Ap il 2020, 28 mon hs a e su ge y, he pa ien was
asymp oma ic and wi hou e idence o ecu ence.
Discussion
Signe - ing cell adenoca cinoma is an in equen p i-
ma y umo sub ype in he endome ium. To da e, only six
cases ha e been desc ibed in he li e a u e, which a e sum-
ma ized in Table 1.
The diagnosis o his ype o adenoca cinoma is one o
exclusion, as in he p esence o signe - ing cells in an en-
dome ial umo , he i s diagnosis o ule ou is a me as a-
sis o a p ima y ca cinoma o ano he o igin, mainly om
he gas oin es inal ac o he b eas . Fo his eason, i
is essen ial o ca y ou a ho ough e alua ion o include
mammog aphy, gas oscopy, colonoscopy and ho acoab-
dominopel ic CT [1].
Likewise, in iew o his his ological inding, he IHC
analysis o he su gical specimen is essen ial and is qui e
help ul o guide us owa ds he p ima y o igin o he umo .
In his sense, i has been desc ibed ha p ima y endome ial
ca cinoma is usually posi i e o cy oke a in 7 and nega-
i e o cy oke a in 20, while me as a ic adenoca cinoma
o he colon is usually he opposi e [1, 4, 5]. Fu he mo e,
nega i i y o GATA3, a ma ke no used in he p e ious
published cases, ules ou he p ima y o igin in he b eas
because o i s high sensi i i y when he e is a p ima y u-
mo o he a o esaid o igin [7]. Mo eo e , PAX8 is a no el
umo ma ke whose posi i i y sugges s a umo o igin in
he epi helium o he Mülle ian duc s a he han a gas oin-
es inal o b eas ca cinoma [8]. In ela ion o CEA, a umo
ma ke associa ed mainly wi h umo s o he gas oin es i-
nal ac , he cases published o da e ha e no been consis-
en in hei esul s, since h ee cases we e CEA nega i e [1,
4, 6], while h ee o he s we e CEA posi i es [3, 5]. The e-
o e, his ma ke has a limi ed alue bo h o con i m o o
ule ou a gas oin es inal o igin o he p ima y umo .
On he o he hand, i is also impo an o make a di e en-
ial diagnosis be ween an endome ial o ce ical o igin o
he umo . The p esence o absence o ce ain isk ac o s,
he indings o he physical examina ion and imaging es s
and he de e mina ion o he human papilloma i us (HPV)
s a us will help es ablished he diagnosis, as well as he IHC
s udies since he posi i i y o he ho monal ecep o s and i-
men in, and he nega i i y o p16, oge he wi h he absence
o HPV in ec ion, sugges an endome ial o igin o he le-
sion [1, 4, 5], while con a y esul s a e associa ed wi h a
ce ical o igin, as published by Gio dano e al. [9]Only
he case published by Pusiol e al. [6] had nega i e ho -
monal ecep o s and posi i e p16 as well as in ec ion by
HPV geno ype 11, despi e he endome ium being i s p i-
ma y o igin.
Fu he mo e, i is impo an o bea in mind ha some-
imes we can ind signe - ing cells in he endome ium
whose o igin is no neoplas ic; his occu s occasionally du -
ing he decidualiza ion p ocess o he endome ium [10] o
eac i ely a e ce ical cau e iza ion [11].
Fou o he published cases ha e appea ed in pos -
menopausal women [1, 3, 4, 5], in which he mos desc ibed
symp om, as in he pa ien p esen ed in his wo k, has been
bleeding [1, 5] In ela ion o he o he wo cases, one had
a la e p esen a ion wi h a clinical his o y o asci es, weigh
loss, and bila e al deep ein h ombosis [4] while he o he
u ned up by chance in a sc eening cy ology [3]. In con as ,
he wo cases published in p emenopausal women p esen ed
wi h hea y mens ual bleeding o se e al mon hs o e olu-
ion [5, 6].
Rega ding he he apeu ic managemen o his in e-
quen sub ype o ca cinoma, he e is no s anda dized ea -
men p o ocol and he cases published o da e di e in he
schemes used. In ela ion o he su gical ac , he majo i y
o cases include hys e ec omy (HT) + double adnexec omy
(DA) + bila e al pel ic lymphadenec omy (BPL) in hei
schemes [1, 3, 4, 6], while in he wo cases by Boyd e al. [5]
only HT was pe o med. The FIGO s age and subsequen
disease- ee su i al o he pa ien s a e unknown. Only his
case and he one by Pusiol e al. [6] include he pe o mance
o a pa a-ao ic lymphadenec omy. Mo eo e , an omen ec-
omy has only been ca ied ou in wo cases, his case and
he one by Mooney e al. [3]. Fu he mo e, in ela ion o
adju an ea men , only wo o he cases published o da e
ecei ed i . The pa ien epo ed by Chebib e al. [4] e-
cei ed chemo he apy, while he pa ien epo ed p esen ed
by Akkalp e al. [1] was ea ed wi h adio he apy.
Despi e his g ea disc epancy in he managemen
schemes used, hese umo s end o be conside ed as high-
P ima y endome ial ca cinoma wi h signe - ing cells. A case epo and e iew o he li e a u e 883
g ade ca cinomas and wi h a high isk o ecu ence, so we
conside ha he he apeu ic a i ude should be simila o
o he high- isk endome ial ca cinomas, pe o ming com-
ple e s aging su ge y ollowed by adju an ea men wi h
chemo he apy and adio he apy [12, 13]. Only in his case
his scheme has been ollowed in i s en i e y, and due o he
good e olu ion he pa ien has had, being he one wi h he
longes isease- ee in e al o da e (28 mon hs), his scheme
could be conside ed he mos app op ia e he apeu ic man-
agemen op ion o his ype o umo .
Cu en ly, i is e y di icul o assess he long- e m p og-
nosis o his kind o neoplasia because o he ew cases de-
sc ibed in he li e a u e o da e and he sho ollow-up pe-
iod epo ed in mos o hem.
Conclusions
Despi e he ac ha p ima y endome ial ca cinoma
wi h signe - ing cells is an in equen umo , i mus be
aken in o accoun in he di e en ial diagnosis o malig-
nan umo s o he a o esaid o igin. I is essen ial o ca y
ou a co ec and ex ensi e clinical e alua ion, as well as an
immunohis ochemical analysis o he samples ob ained o
con i ma ion o he diagnosis.
E hics app o al and consen o pa icipa e
The publica ion o his case epo was app o ed
by A agon E hics Commi ee (CEICA), in ac numbe
19/2016, in Za agoza, Spain. Besides, his wo k complied
wi h he decla a ion o Helsinki o Human Resea ch o
1974 (las modi ied in 2000).
Au ho s’ con ibu ions
Ja ie Na a o Sie a and Lau a Baquedano Maina es-
ablished he suspicion o an endome ial cance in he
pa ien . Ja ie Na a o Sie a pe o med he e iew o
he li e a u e. And ea Espiau Rome a and Ma a Na áez
Salaza pe o med he s aging su ge y o endome ial can-
ce . BE ca ied ou he pa hological and immunohis ochem-
ical s udy o he samples. Ja ie Na a o Sie a, Ma ía
Jesús Puen e Luján and Lau a Baquedano Maina w o e he
manusc ip . 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
All au ho s decla e no acknowledgemen s o inancial
suppo o sponso ship.
Con lic o In e es
The au ho s decla e no compe ing in e es s.
Submi ed: July 01, 2020
Accep ed: Augus 05, 2020
Published: Decembe 15, 2020
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Co esponding Au ho :
LAURA BAQUEDANO MAINAR, M.D., Ph.D.
Hospi al Uni e si a io Miguel Se e , Obs e ics & Gy-
necology Depa men , Paseo Isabel La Ca ólica 1-3,
50009, Za agoza, Spain
e-mail: [email p o ec ed]