Ci a ion: Nooijen, L.E.; Banales, J.M.;
de Boe , M.T.; B aconi, C.; Folse aas,
T.; Fo ne , A.; Holowko, W.;
Hoogwa e , F.J.H.; Klümpen, H.-J.;
G oo Koe kamp, B.; e al. Impac o
Posi i e Lymph Nodes and Resec ion
Ma gin S a us on he O e all
Su i al o Pa ien s wi h Resec ed
Pe ihila Cholangioca cinoma: The
ENSCCA Regis y. Cance s 2022,14,
2389. h ps://doi.o g/10.3390/
cance s14102389
Academic Edi o : Da id Wong
Recei ed: 25 Ma ch 2022
Accep ed: 10 May 2022
Published: 12 May 2022
Publishe ’s No e: MDPI s ays neu al
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Copy igh : © 2022 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
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A ibu ion (CC BY) license (h ps://
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4.0/).
cance s
A icle
Impac o Posi i e Lymph Nodes and Resec ion Ma gin S a us
on he O e all Su i al o Pa ien s wi h Resec ed Pe ihila
Cholangioca cinoma: The ENSCCA Regis y
Lynn E. Nooijen 1,2 , Jesus M. Banales 3,4,5,6, Ma ieke T. de Boe 7, Chia a B aconi 8, T ine Folse aas 9,
Alejand o Fo ne 10 , Waclaw Holowko 11 , F ede ik J. H. Hoogwa e 7, Heinz-Jose Klümpen 2,12 ,
Bas G oo Koe kamp 13, Angela Lama ca 14 , Adelaida La Cas a 15, Flo a López-López 16,
Lau a Izquie do-Sánchez 3, Alexande Schei e 17 , Ki s en U pa el 17, Ru ge -Jan Swijnenbu g 2,18,
Gee Kazemie 1,2 and Jo is I. E dmann 2,18,* on behal o he ENSCCA G oup
1Depa men o Su ge y, Ams e dam UMC—Loca ion V ije Uni e si ei Ams e dam,
1081 HV Ams e dam, The Ne he lands; l.e.nooijen@ams e damumc.nl (L.E.N.);
[email p o ec ed] (G.K.)
2Cance Cen e Ams e dam, Cance T ea men and Quali y o Li e, 1081 HV Ams e dam, The Ne he lands;
[email p o ec ed] (H.-J.K.); .j.swijnenbu g@ams e damumc.nl (R.-J.S.)
3Depa men o Li e and Gas oin es inal Diseases, Biodonos ia Heal h Resea ch Ins i u e,
Donos ia Uni e si y Hospi al, Uni e si y o he Basque Coun y (UPV/EHU), 20014 San Sebas ián, Spain;
[email p o ec ed] (J.M.B.); [email p o ec ed]g (L.I.-S.)
4
Na ional Ins i u e o he S udy o Li e and Gas oin es inal Diseases, CIBERehd, “Ins i u o de Salud Ca los
III” (ISCIII), 28029 Mad id, Spain
5
Depa men o Biochemis y and Gene ics, School o Sciences, Uni e si y o Na a a, 31080 Pamplona, Spain
6Ike basque, Basque Founda ion o Science, 48009 Bilbao, Spain
7
Sec ion o HPB Su ge y & Li e T ansplan a ion, Depa men o Su ge y, Uni e si y Medical Cen e G oningen,
Uni e si y o G oningen, 9713 GZ G oningen, The Ne he lands; [email p o ec ed] (M.T.d.B.);
[email p o ec ed] (F.J.H.H.)
8The Royal Ma sden NHS T us , London SW3 6JJ, UK; [email p o ec ed]
9No wegian PSC Resea ch Cen e and Sec ion o Gas oen e ology, Depa men o T ansplan a ion Medicine,
Di ision o Su ge y, In lamma o y Medicine and T ansplan a ion, Oslo Uni e si y Hospi al Rikshospi ale ,
0372 Oslo, No way; [email p o ec ed]
10 BCLC G oup, Li e Uni , Hospi al Clinic Ba celona, IDIBAPS, CIBEREHD, Uni e si y Ba celona,
08036 Ba celona, Spain; [email p o ec ed]
11
Depa men o Gene al, T ansplan and Li e Su ge y, Medical Uni e si y o Wa saw, 02-091 Wa saw, Poland;
[email p o ec ed]
12 Depa men o Medical Oncology, Ams e dam UMC—Loca ion Uni e si y o Ams e dam,
1105 AZ Ams e dam, The Ne he lands
13 Depa men o Su ge y, E asmus MC Cance Ins i u e, 3015 GD Ro e dam, The Ne he lands;
[email p o ec ed]
14 Depa men o Medical Oncology, The Ch is ie NHS Founda ion T us , Wilmslow Road,
Manches e M20 4BX, UK; [email p o ec ed]
15 Depa men o Medical Oncology, Biodonos ia Heal h Resea ch Ins i u e, Donos ia Uni e si y Hospi al,
Uni e si y o he Basque Coun y (UPV/EHU), 20014 San Sebas ián, Spain;
[email p o ec ed]
16 Depa men o Medical Oncology, Hospi al Uni e si a io 12 de Oc ub e, 28041 Mad id, Spain;
[email p o ec ed]
17 Ins i u e o Pa hology, Uni e si y o Regensbu g, 93053 Regensbu g, Ge many;
alexande [email p o ec ed]egensbu g.de (A.S.); [email p o ec ed]egensbu g.de (K.U.)
18 Depa men o Su ge y, Ams e dam UMC—Loca ion Uni e si y o Ams e dam,
1105 AZ Ams e dam, The Ne he lands
*Co espondence: j.i.e dmann@ams e damumc.nl; Tel.: +31-(0)-20-5627624
Simple Summa y:
Lymph node me as asis and posi i e esec ion ma gins ha e been epo ed o
be majo de e minan s o o e all su i al (OS) and poo ecu ence- ee su i al (RFS) o pa ien s
a e esec ion o pe ihila cholangioca cinoma (pCCA). The aim o cu en s udy was o assess
he p ognos ic alue o posi i e lymph nodes and esec ion ma gin s a us on OS. We ound a
majo nega i e e ec o posi i e lymph nodes on su i al and ecu ence, which, su p isingly, was
Cance s 2022,14, 2389. h ps://doi.o g/10.3390/cance s14102389 h ps://www.mdpi.com/jou nal/cance s
Cance s 2022,14, 2389 2 o 13
independen o ma gin s a us. ECOG pe o mance s a us, posi i e lymph nodes, and he g ade o
umo di e en ia ion we e ound as he main independen indica o s o oncological ou come. This
sugges s ha umo biology and pe o mance s a us ha e a highe impac on su i al han ex ended
o adical su ge y.
Abs ac :
Backg ound: Lymph node me as asis and posi i e esec ion ma gins ha e been epo ed o
be majo de e minan s o o e all su i al (OS) and poo ecu ence- ee su i al (RFS) o pa ien s
who unde wen esec ion o pe ihila cholangioca cinoma (pCCA). Howe e , he p ognos ic alue
o posi i e lymph nodes independen ly om esec ion ma gin s a us on OS has no been e alua ed.
Me hods: F om he Eu opean Cholangioca cinoma (ENSCCA) egis y, pa ien s who unde wen
esec ion o pCCA be ween 1994 and 2021 we e included in his e ospec i e coho s udy. The
p ima y ou come was OS s a i ied o esec ion ma gin and lymph node s a us. The seconda y
ou come was ecu ence- ee su i al. Resul s: A o al o 325 pa ien s om 11 di e en cen e s and six
Eu opean coun ies we e included. O hese, 194 (59.7%) pa ien s had nega i e esec ion ma gins. In 113
(34.8%) pa ien s, posi i e lymph nodes we e ound. Lymph node s a us, his ological g ade, and ECOG
pe o mance s a us we e independen p ognos ic ac o s o su i al. The median OS o N0R0, N0R1,
N+R0, and N+R1 was 38, 30, 18, and 12 mon hs, espec i ely (p< 0.001). Conclusion: These da a indica e
ha in he p esence o posi i e egional lymph nodes, esec ion ma gin s a us does no de e mine OS
o RFS in pa ien s wi h pCCA. Achie ing nega i e ma gins in pa ien s wi h posi i e nodes should no
come a he expense o mo e ex ensi e su ge y and associa ed highe mo ali y.
Keywo ds:
pe ihila cholangioca cinoma; lymph nodes; esec ion ma gin; o e all su i al;
ecu ence- ee su i al
1. In oduc ion
Radical su gical esec ion is s ill he only ea men wi h a chance o long- e m su i al
o pa ien s wi h pe ihila cholangioca cinoma (pCCA). Radical (R0) esec ion a es ange
om 60 o 90%, which is associa ed wi h a 5-yea o e all su i al (OS) up o 60%, while a
ma gin posi i e (R1) esec ion is associa ed wi h a 5-yea OS o less han 20% [
1
–
5
]. On he
o he hand, he p ognosis o pa ien s wi h esec ed pCCA is also signi ican ly de e mined
by he p esence o lymph node me as ases [1,6,7].
A explo a ion, abou 35% o pa ien s ha e loco- egional posi i e lymph nodes, which
is associa ed wi h a 5-yea OS o less han 20% e sus 55% in case o nega i e lymph
nodes [
1
,
6
,
7
]. Du ing esec ion, he e ie al o a low numbe o less han ou lymph
nodes has been epo ed o nega i ely in luence su i al, possibly due o he unde s aging
o un esec ed posi i e nodes [
8
]. In addi ion, a ecen sys ema ic e iew ound ha an
ex ended lymphadenec omy does no lead o a su i al bene i [9].
Ne e heless, a high numbe o in ol ed lymph nodes has been epo ed o be a ma-
jo de e minan o OS and an indica o o poo ecu ence- ee su i al (RFS) [
8
,
10
,
11
].
Bue ne e al.
concluded ha he ac ual su i al bene i o esec ion in pa ien s wi h posi-
i e lymph nodes is sho e han se en mon hs and should be weighed agains conside able
pos ope a i e mo bidi y and mo ali y [12].
The upda ed AJCC guidelines (8 h edi ion, 2017) dis inguish be ween he numbe
(
n≤3
o n> 3) ins ead o he loca ion o egional posi i e lymph nodes [
13
,
14
]. Se e al
s udies in es iga ed he alue o his new s aging sys em and ound a sligh ly imp o ed
p ognos ic p edic abili y, implying ha he amoun o in ol ed lymph nodes is mo e
p edic i e o su i al ou come han hei loca ion [15–17].
In clinical p ac ice, su geons a e o en con on ed wi h one o mo e posi i e lymph
nodes a ozen sec ion analysis in a pa ien unde going su gical explo a ion wi h he
in en ion o unde go an o en imes majo hepa obilia y esec ion. The echnical easibili y
o a po en ial ma gin- ee esec ion and concomi an mo bidi y and mo ali y should
be e alua ed in he ligh o po en ial oncological ou comes. Un il now, he ela ionship
Cance s 2022,14, 2389 3 o 13
be ween posi i e lymph nodes and esec ion ma gins and hei independen in luence on
OS emained unclea , making he ques ion o whe he pa ien s wi h posi i e lymph nodes
bene i om ex ended esec ions o ob ain nega i e ma gins ha d o answe . The e o e,
we pe o med a e ospec i e coho s udy, in coope a ion wi h he ENSCCA Regis y, o
de e mine he impac o posi i e lymph nodes and esec ion ma gin s a us on he OS o
pa ien s a e esec ed pCCA.
2. Ma e ials and Me hods
2.1. ENSCCA Regis y
The ENSCCA egis y, endo sed by he Eu opean Ne wo k o he S udy o Cholan-
gioca cinoma (ENSCCA), is an in e na ional, mul icen e , and obse a ional e ospec i e
and p ospec i e s udy including pa ien s wi h his ologically o adiologically p o en
cholangioca cinoma (in ahepa ic, pe ihila , and dis al cholangioca cinoma). This egis y
includes se e al di e en a iables ega ding su gical and oncological ou comes. The
ENSCCA egis y p o ocol was app o ed by he E hic Commi ee o Euskadi, Spain (Code:
PI2016137) and he E hic Commi ee o he Ams e dam UMC (loca ion AMC), he Ne he -
lands (W20_050), as coo dina ing Cen e s. Addi ionally, each pa icipa ing cen e ob ained
local e hical app o al (o equi alen ).
2.2. Included Pa ien s
F om he ENSCCA egis y, pa ien s wi h pCCA who unde wen su ge y including
diagnos ic lapa oscopy, explo a i e lapa o omy, li e ansplan a ion, o li e esec ion
we e iden i ied. Only pa ien s om cen e s ha had egis e ed a minimum o 10 pa ien s
unde going esec ion o pCCA we e included. This was in o de o secu e cen e s wi h
expe ise in ea ing pa ien s wi h pCCA o inclusion. Eligible cen e s we e asked o
comple e po en ially missing key a iables (e.g., esec ion ma gin, lymph node s a us, and
las da e o ollow-up) o o check disc epan a iables. Fo he analysis, only pa ien s who
ecei ed cu a i e-in en esec ion we e included.
2.3. Ou comes
The p ima y ou come was o assess he impac o he esec ion ma gin and lymph
node s a us on OS. The seconda y ou come was he impac o esec ion ma gin and lymph
node s a us on ecu ence- ee su i al (RFS).
2.4. S a is ical Analysis
Desc ip i e s a is ics we e used o summa ize he da a. Fo con inuous a iables
wi h no mal dis ibu ion, he da a we e p esen ed as mean
±
s anda d de ia ion (SD)
and o non-no mal dis ibu ions, as median and in e qua ile ange (IQR). Compa isons
be ween he g oups (N0 and N+) we e analyzed using chi-squa e es s o p opo ions,
Mann–Whi ney
U o medians, and unpai ed - es s o means. The OS was de ined as
he ime (in mon hs) a e su ge y o dea h o las ollow-up, and he median OS was
es ima ed using he Kaplan–Meie me hod. The RFS was de ined as he ime (in mon hs)
a e su ge y o ecu ence o las medical isi . Su i al cu es we e compa ed using he
log- ank es . The e e sed Kaplan–Meie -based me hod was used o calcula e median
ollow-up. Uni a iable and mul i a iable logis ic eg ession we e used o examine he
ela ionship be ween he p esence o posi i e lymph nodes as a dependen a iable and
he possible p edic o s as independen a iables. The e o e, he ollowing ac o s we e
included: age, ECOG, and umo size > 2.5 cm. Fac o s wi h p- alues < 0.2 a uni a i-
able analysis we e included in he mul i a iable analysis. The independen p edic o s o
su i al de e mined p io o conduc ing he s udy (i.e., age, ECOG, umo size > 2.5 cm,
ca bohyd a e an igen 19.9 (CA19.9), lymph node s a us (AJCC 8 h), ma gin s a us, and
umo
di e en ia ion [8,11])
we e analyzed using uni- and mul i a iable Cox eg ession
analysis. In addi ion, he independen p edic o s o ecu ence, also de e mined p io
o conduc ing he s udy ( umo size > 2.5 cm, T s a us (AJCC 8 h), lymph node s a us
Cance s 2022,14, 2389 4 o 13
(AJCC 8 h), esec ion ma gin, and umo di e en ia ion) we e analyzed using uni- and
mul i a iable Cox eg ession analysis [
10
,
18
]. Fac o s wi h p- alues < 0.1 a uni a iable
analysis we e included in he mul i a iable analysis. A wo-sided p- alue o < 0.05 was
conside ed o indica e s a is ical signi icance. The da a we e analyzed using IBM SPSS
s a is ics, e sion 25.0 (IBM Co p, A monk, NY, USA). Su i al cu es we e displayed
using G aphPad P ism 8.
3. Resul s
3.1. Baseline Cha ac e is ics
A o al o 1126 pa ien s wi h pCCA we e ex ac ed om he egis y; om hese,
618 (55%) pa ien s unde wen any ype o su ge y. Fo y-one pa ien s we e excluded as
hese we e om cen e s ha egis e ed ewe han en pa ien s. Thi y-nine pa ien s we e
excluded because o missing in o ma ion. F om his da ase , pa ien s unde going pallia i e
esec ion (n= 103), unde going li e ansplan a ion (n= 15), who had R2 esidual disease
(n= 12), unknown esidual disease (n= 7), unknown lymph node s a us (n= 4), who
had no esec ion (n= 60), o he diagnosis (n= 3), o we e double in he egis y (n= 9)
we e excluded, lea ing a o al o 325 pa ien s om 11 di e en cen e s in six coun ies. A
lowcha is p esen ed in Figu e 1.
Cance s 2022, 14, x FOR PEER REVIEW 4 o 14
ca bohyd a e an igen 19.9 (CA19.9), lymph node s a us (AJCC 8 h), ma gin s a us, and
umo di e en ia ion [8,11]) we e analyzed using uni- and mul i a iable Cox eg ession
analysis. In addi ion, he independen p edic o s o ecu ence, also de e mined p io o
conduc ing he s udy ( umo size > 2.5 cm, T s a us (AJCC 8 h), lymph node s a us (AJCC
8 h), esec ion ma gin, and umo di e en ia ion) we e analyzed using uni- and
mul i a iable Cox eg ession analysis [10,18]. Fac o s wi h p- alues < 0.1 a uni a iable
analysis we e included in he mul i a iable analysis. A wo-sided p- alue o < 0.05 was
conside ed o indica e s a is ical signi icance. The da a we e analyzed using IBM SPSS
s a is ics, e sion 25.0 (IBM Co p, A monk, NY, USA). Su i al cu es we e displayed
using G aphPad P ism 8.
3. Resul s
3.1. Baseline Cha ac e is ics
A o al o 1126 pa ien s wi h pCCA we e ex ac ed om he egis y; om hese, 618
(55%) pa ien s unde wen any ype o su ge y. Fo y-one pa ien s we e excluded as hese
we e om cen e s ha egis e ed ewe han en pa ien s. Thi y-nine pa ien s we e
excluded because o missing in o ma ion. F om his da ase , pa ien s unde going
pallia i e esec ion (n = 103), unde going li e ansplan a ion (n = 15), who had R2
esidual disease (n = 12), unknown esidual disease (n = 7), unknown lymph node s a us
(n = 4), who had no esec ion (n = 60), o he diagnosis (n = 3), o we e double in he egis y
(n = 9) we e excluded, lea ing a o al o 325 pa ien s om 11 di e en cen e s in six
coun ies. A lowcha is p esen ed in Figu e 1.
Figu e 1. Flow diag am o included pa ien s.
Figu e 1. Flow diag am o included pa ien s.
A o al o 206 ou o he 325 pa ien s (63.4%) we e male and he median age a su ge y
was 64 (58–71) yea s. The median Bismu h–Co le e classi ica ion was IIIb (20.6%). The
median p eope a i e umo size was 2.5 (1.9–3.7) cm. Neoadju an he apy, consis ing o
adio he apy 5 ×5 Gy, was adminis e ed o 26 (8.0%) pa ien s.
Cance s 2022,14, 2389 5 o 13
Ou o he 325 pa ien s, 194 (59.7%) had unde gone an R0 esec ion. In 113 (34.8%)
pa ien s, posi i e lymph nodes we e ound. In he la e g oup, he median numbe o
e ie ed lymph nodes was 5 (IQR: 3–7) and he median numbe o posi i e lymph nodes
was 2 (IQR: 1–3), as shown in Table 1. When selec ed o esec ion ma gin and lymph node
s a us, he ollowing g oups we e o med: 138 pa ien s wi h N0R0, 74 pa ien s wi h N0R1,
56 pa ien s wi h N+R0, and 57 pa ien s wi h N+R1. Following he AJCC 8 h edi ion, N2
disease was ound in 20 (17.7%) pa ien s and N1 in 93 (82.3%) pa ien s. The loca ion o he
lymph nodes was only men ioned in 14 pa ien s (12.4%); he e o e, we we e no able o
include he loca ion o speci ic lymph node s a ions in he analysis.
Table 1.
Baseline and pos ope a i e cha ac e is ics acco ding o esec ion ma gin and lymph node s a us.
To al N0 N+ p-Value
Pa ien s n= 325 n= 212 n= 113
Age a su ge y (median) 64 (58–71) 67 (58.3–72.0) 63 (57–69) 0.028
Male (%) 206 (63.4%) 135 (63.7%) 71 (62.8%) 0.880
ECOG pe o mance s a us 0.901
0 143 (44.0%) 96 (45.3%) 47 (41.6%)
1 81 (24.9%) 51 (24.1%) 30 (26.5%)
2 17 (5.2%) 12 (5.7%) 5 (4.4%)
3 4 (1.2%) 3 (1.4%) 1 (0.9%)
unknown 80 (24.6%) 50 (23.6%) 30 (26.5%)
Bismu h–Co le e 0.931
I 18 (5.5%) 11 (5.2%) 7 (6.2%)
II 20 (6.2%) 14 (6.6%) 6 (5.3%)
IIIa 40 (12.3%) 26 (12.3%) 14 (12.4%)
IIIb 67 (20.6%) 47 (22.2%) 20 (17.7%)
IV 49 (15.1%) 31 (14.6%) 18 (15.9%)
Unknown 131 (40.3%) 83 (39.2%) 48 (42.5%)
CA19.9 67 (11–313) 57 (10–252) 174 (13–604) 0.070
Bili ubin 12 (2–116) 12 (2–131) 13 (3–106) 0.706
P eope a i e umo size (cm) (median) (N = 221) 2.5 (1.9–3.7) 2.3 (1.7–3.6) 2.8 (2.1–4.0) 0.022
Neoadju an he apy ±26 (8.0%) 17 (14.8%) 9 (16.4%) 0.789
Size and ex en (T) 0.011
T1 20 (6.2%) 18 (8.5%) 2 (1.8%)
T2a 80 (24.8%) 59 (28.0%) 21 (18.8%)
T2b 93 (28.8%) 60 (28.4%) 33 (29.5%)
T3 92 (28.5%) 50 (23.7%) 42 (37.5%)
T4 31 (9.6%) 18 (8.5%) 13 (11.6%)
Tx 7 (2.2%) 6 (2.8%) 1 (0.9%)
Regional lymph nodes (N #) -
N0 212 (65.2%) 212 (100%) 0
N1 93 (28.6%) 0 93 (82.3%)
N2 20 (6.2%) 0 20 (17.7%)
To al numbe o esec ed lymph nodes (median) 4 (2–7) 4 (2–6) 5 (3–7) 0.024
Numbe o posi i e lymph nodes (median) (n= 103) 2 (1–3) - 2 (1–3) -
Resec ion ma gin 0.007
R0 194 (59.7%) 138 (65.1%) 56 (49.6%)
R1 131 (40.3%) 74 (34.9%) 57 (50.4%)
Di e en ia ion g ade 0.550
G ade 1: well di e en ia ed 40 (12.3%) 29 (13.7%) 11 (9.7%)
G ade 2: mode a ely di e en ia ed 150 (46.2%) 93 (43.9%) 57 (50.4%)
G ade 3: poo ly di e en ia ed 62 (19.1%) 43 (20.3%) 19 (16.8%)
No a ailable 73 (22.5%) 47 (22.2%) 26 (23.0%)
Adju an he apy 59 (18.2%) 34 (17.3%) 23 (23.1%) 0.213
Recu ence * 151 (46.5%) 89 (42.0%) 62 (54.9%) 0.003
Loca ion o ecu ence 0.990
Cance s 2022,14, 2389 6 o 13
Table 1. Con .
To al N0 N+ p-Value
Local ecu ence 54 (35.8%) 31 (34.8%) 23 (37.1%)
Li e 31 (20.5%) 18 (20.2%) 13 (21.0%)
Dis an 63 (41.7%) 38 (42.7%) 25 (40.3%)
Unknown 3 (2.0%) 2 (2.2%) 1 (1.6%)
90-day mo ali y 70 (21.5%) 44 (20.8%) 26 (23.0%) 0.638
p- alues based on comple e case analysis unless unknown is displayed. * Censo ed a 5-yea ollow-up.
# Acco ding o AJCC 8 h edi ion. ±Radio he apy 5 ×5 Gy.
3.2. N+ e sus N0
When compa ing he included pa ien s o lymph node s a us, he age a su ge y, size
and ex en o he umo , numbe o esec ed lymph nodes, esec ion ma gin, and ecu ence
we e signi ican ly di e en (Table 1). Pa ien s wi h posi i e lymph nodes we e app oxi-
ma ely ou yea s younge and p esen ed wi h a highe umo (T) s age. In hese pa ien s, a
highe median numbe o lymph nodes we e dissec ed in con as o lymph node-nega i e
pa ien s (N+: 5 s. N0: 4). The R1 esec ion ma gin (N+: 50.4% s.
N0: 34.9%
) and highe u-
mo ecu ence a e we e associa ed wi h N+ s a us (
N+: 54.9%
s.
N0: 42.0%
). On uni a i-
able logis ic eg ession analyses, age (OR: 0.98 (95%
CI 0.96–1.00
)) and
umo size > 2.5 cm
(OR: 1.62 (95% CI 0.92–2.85)) we e independen ly associa ed wi h posi i e lymph nodes.
Howe e , on mul i a iable logis ic eg ession analysis, hese ac o s we e no independen ly
associa ed wi h posi i e lymph nodes (Table S1).
3.3. O e all Su i al
Ou o he 325 pa ien s, 114 pa ien s we e ali e and 211 had died a inal ollow-up. The
median ollow-up o pa ien s ali e a las medical isi was 59 mon hs (95% CI 57.6–60.4).
Ou o he 325 pa ien s, 59 (18%) pa ien s ecei ed adju an (chemo) he apy. This conce ned
chemo he apy in 52 (16%) pa ien s, chemo– adio he apy in ou (1%), and adio he apy in
one (0.3%) pa ien . Fo wo pa ien s, his was unknown.
The median and 5-yea OS o he whole g oup was 26 mon hs (95% CI 21.0–31.0)
and 29%, espec i ely. The median and 5-yea OS di ided o lymph node s a us we e 34
mon hs (95% CI 27.9–40.1) and 36% o N0 pa ien s, and 15 mon hs (95% CI 10.6–19.4) and
18% o N+ pa ien s (p< 0.001; Figu e 2a). The median and 5-yea OS di ided o esec ion
ma gin was 31 mon hs (95% CI 23.0–39.0) and 34% o R0 disease, and 21 mon hs (95% CI
14.9–27.2) and 23% o R1 disease (p< 0.05; Figu e 2b). Including bo h esec ion ma gin
and lymph node s a us (N0R0, N0R1, N+R0 and N+R1), he median and 5-yea OS we e 38
mon hs (95% CI 28.0–48.0) and 36%, 30 mon hs (95% CI 19.8–40.2) and 36%, 18 mon hs (95%
CI 10.7–25.3) and 30%, and 12 mon hs (95% CI 7.7–16.3) and 8%, espec i ely (
p< 0.001
,
Figu e 2c). The compa ison pe s a us was as ollows: N0R0 s. N+R0: p= 0.064, N0R1 s.
N+R1: p< 0.001, N+R0 s. N+R1: p= 0.061, N0R0 s. N0R1: p= 0.61.
The p ognos ic ac o s o OS we e analyzed using a uni- and mul i a iable Cox
eg ession analysis. On uni a iable analysis, ECOG pe o mance s a us, lymph node s a us,
esec ion ma gin, and umo di e en ia ion g ade we e nega i ely associa ed wi h OS
(
p< 0.1
). A e mul i a iable Cox eg ession analysis, ECOG pe o mance s a us (ECOG 2:
HR 2.95 (95% CI 1.55–5.63)), posi i e lymph nodes (N1: HR 1.92 (95% CI 1.29–2.85)), and
umo di e en ia ion (poo ly di e en ia ed: HR 1.80 (95% CI 1.14–2.84)) we e iden i ied as
independen p ognos ic ac o s o OS (p< 0.05; Table 2).
Cance s 2022,14, 2389 7 o 13
Cance s 2022, 14, x FOR PEER REVIEW 7 o 14
Figu e 2.
(
a
): Kaplan–Meie cu e o o e all su i al and lymph node-nega i e (N0) and lymph
node-posi i e (N+) pa ien s. Only he i s 5 yea s a e displayed. Median OS was 34 mon hs
(95% CI 27.9–40.1) o he N0 e sus 15 mon hs (95% CI 10.6–19.4) o he N1 pa ien s (p< 0.001).
(b): Kaplan–Meie
cu e o o e all su i al o esec ion ma gin-nega i e (R0) and esec ion ma gin-
posi i e (R1) pa ien s. Only he i s 5 yea s a e displayed. Median OS was 31 mon hs (95% CI
23.0–39.0) o R0 e sus 21 mon hs (95% CI 14.9–27.2) o R1 pa ien s (p= 0.037). (
c
): Kaplan–Meie
cu e o o e all su i al o N0R0, N0R1, N+R0, and N+R1 pa ien s. Only he i s 5 yea s a e
displayed. Median OS was 38 mon hs (95% CI 28.0–48.0) o N0R0, 30 mon hs (95% CI 19.8–40.2)
o N0R1, 18 mon hs (95% CI 10.7–25.3) o N+R0, and 12 mon hs (95% CI 7.7–16.3) o he N+R1
pa ien s (p< 0.001). N0R0 s. N+R0: p= 0.064, N0R1 s. N+R1: p< 0.001, N+R0 s. N+R1: p= 0.061,
N0R0 s. N0R1: p= 0.61.
Cance s 2022,14, 2389 8 o 13
Table 2. Uni- and mul i a iable Cox eg ession analysis o o e all su i al.
Uni a iable Analysis Mul i a iable Analysis
HR (95% CI) p-Value $HR (95% CI) p-Value #
Age a su ge y 1.01 (0.99–1.02) 0.287
ECOG pe o mance s a us
ECOG 0 Re e ence Re e ence
ECOG 1 1.21 (0.84–1.74) 0.297 1.41 (0.92–2.15) 0.114
ECOG 2 1.80 (1.01–3.20) 0.045 2.95 (1.55–5.63) 0.001
ECOG 3 3.39 (1.23–9.36) 0.018 2.73 (0.84–8.87) 0.096
Tumo size > 2.5 cm 1.07 (0.75–1.52) 0.705
CA19.9 > 37 1.02 (0.62–1.69) 0.932
Lymph node s a us (N) *
N0 Re e ence Re e ence
N1 1.72 (1.27–2.33) 0.001 1.92 (1.29–2.85) 0.001
N2 1.97 (1.15–3.39) 0.014 1.21 (0.55–2.63) 0.640
Resec ion ma gin (R)
R0 Re e ence Re e ence
R1 1.34 (1.01–1.78) 0.042 1.14 (0.78–1.67) 0.501
Tumo di e en ia ion
Well di e en ia ed (G1) 0.67 (0.41–1.07) 0.094 0.69 (0.41–1.17) 0.168
Mode a ely di e en ia ed (G2)
Re e ence Re e ence
Poo ly di e en ia ed (G3) 2.39 (1.41–4.04) 0.013 1.80 (1.14–2.84) 0.011
* Acco ding o AJCC 8 h edi ion, $p< 0.100, #p< 0.05, p- alues based on comple e case analysis.
3.4. Recu ence
Du ing ollow-up, 156 (48%) pa ien s de eloped ecu ence. The ecu ence s a us
a inal ollow-up was unknown o 52 (16%) pa ien s. Recu ence occu ed mos o en
dis an om he p ima y umo si e (n= 63, 41.7%), being mos ly ound in he pe i oneum
(
n= 28, 49.1%
; Table 1). F om he pa ien s who had ecu ence, 32 (21%) pa ien s ecei ed
and 120 (77%) pa ien s did no ecei e adju an (chemo) he apy. Fo ou pa ien s, his
was unknown.
The o e all median ecu ence- ee su i al was 23 mon hs (95% CI 19.2–26.8). The
ecu ence- ee su i al di ided o esec ion ma gin and lymph node s a us (N0R0, N0R1,
N+R0, and N+R1) was 27 mon hs (95% CI 20.4–33.6), 33 mon hs (95% CI 19.5–46.5),
14 mon hs (95% CI 7.4–20.6), and 11 mon hs (95% CI 5.7–16.3), espec i ely (p< 0.001;
Figu e 3). The compa ison pe s a us was: N0R0 s. N+R0: p= 0.151, N0R1 s. N+R1:
p< 0.001, N+R0 s. N+R1: p= 0.109, N0R0 s. N0R1: p= 0.331.
The p ognos ic ac o s o ecu ence- ee su i al we e also analyzed using a uni-
and mul i a iable Cox eg ession analysis. On uni a iable analysis, lymph node s a us, T
s age (AJCC 8 h), and umo di e en ia ion we e nega i ely associa ed wi h OS (p< 0.1).
A e mul i a iable Cox eg ession analysis, posi i e lymph nodes (N1: HR 2.62 (95% CI
1.68–4.08)) and umo di e en ia ion (poo ly di e en ia ed: HR 1.65 (95% CI 1.05–2.58))
we e iden i ied as independen p ognos ic ac o s o ecu ence (p< 0.05; Table 3).
Table 3. Uni- and mul i a iable Cox eg ession analysis o ecu ence- ee su i al.
Uni a iable Analysis Mul i a iable Analysis
HR (95% CI) p-Value $HR (95% CI) p-Value #
Tumo size > 2.5 cm 1.25 (0.82–1.90) 0.303
T s a us (T)
T1 1.12 (0.56–2.23) 0.754 1.60 (0.61–4.20) 0.336
T2a 0.53 (0.34–0.84) 0.007 0.60 (0.36–1.01) 0.056
T2b 1.12 (0.73–1.73) 0.594 1.27 (0.76–2.12) 0.367
T3 Re e ence Re e ence
T4 1.01 (0.54–1.86) 0.988 1.04 (0.52–2.11) 0.908
Cance s 2022,14, 2389 9 o 13
Table 3. Con .
Uni a iable Analysis Mul i a iable Analysis
HR (95% CI) p-Value $HR (95% CI) p-Value #
Lymph node s a us (N) *
N0 Re e ence Re e ence
N1 1.72 (1.20–2.47) 0.003 2.62 (1.68–4.08) <0.001
N2 1.86 (0.99–3.50) 0.055 1.249 (0.70–3.17) 0.303
Resec ion ma gin (R)
R0 Re e ence
R1 0.99 (0.71–1.38) 0.940
Tumo di e en ia ion
Well di e en ia ed (G1) 0.98 (0.57–1.70) 0.946 0.98 (0.57–1.70) 0.416
Mode a ely di e en ia ed (G2) Re e ence Re e ence
Poo ly di e en ia ed (G3) 1.65 (1.05–2.58) 0.029 1.65 (1.05–2.58) 0.001
* Acco ding o AJCC 8 h, $p< 0.100, #p< 0.05, p- alues based on comple e case analysis.
Cance s 2022, 14, x FOR PEER REVIEW 9 o 14
N0R1, N+R0, and N+R1) was 27 mon hs (95% CI 20.4–33.6), 33 mon hs (95% CI 19.5–46.5),
14 mon hs (95% CI 7.4–20.6), and 11 mon hs (95% CI 5.7–16.3), espec i ely (p < 0.001;
Figu e 3). The compa ison pe s a us was: N0R0 s. N+R0: p = 0.151, N0R1 s. N+R1: p <
0.001, N+R0 s. N+R1: p = 0.109, N0R0 s. N0R1: p = 0.331.
Figu e 3. Es ima ed cumula i e ecu ence p obabili y o N0R0, N0R1, N+R0, and N+R1 pa ien s.
Only he i s 5 yea s a e displayed. The median ecu ence- ee su i al was 27 mon hs (95% CI
20.4–33.6) o N0R0, 33 mon hs (95% CI 19.5–46.5) o N0R1, 14 mon hs (95% CI 7.4–20.6) o N+R0,
and 11 mon hs (95% CI 5.7–16.3) o he N+R1 pa ien s (p < 0.001). N0R0 s. N+R0: p = 0.151, N0R1
s. N+R1: p < 0.001, N+R0 s. N+R1: p = 0.109., N0R0 s. N0R1: p = 0.331.
The p ognos ic ac o s o ecu ence- ee su i al we e also analyzed using a uni-
and mul i a iable Cox eg ession analysis. On uni a iable analysis, lymph node s a us, T
s age (AJCC 8 h), and umo di e en ia ion we e nega i ely associa ed wi h OS (p < 0.1).
A e mul i a iable Cox eg ession analysis, posi i e lymph nodes (N1: HR 2.62 (95% CI
1.68–4.08)) and umo di e en ia ion (poo ly di e en ia ed: HR 1.65 (95% CI 1.05–2.58))
we e iden i ied as independen p ognos ic ac o s o ecu ence (p < 0.05; Table 3.
Table 3. Uni- and mul i a iable Cox eg ession analysis o ecu ence- ee su i al.
Uni a iable Analysis Mul i a iable Analysis
HR (95% CI)
p
-Value
$
HR (95% CI)
p
-Value
#
Tumo size > 2.5 cm 1.25 (0.82–1.90) 0.303
T s a us (T)
T1 1.12 (0.56–2.23) 0.754 1.60 (0.61–4.20) 0.336
T2a 0.53 (0.34–0.84) 0.007 0.60 (0.36–1.01) 0.056
T2b 1.12 (0.73–1.73) 0.594 1.27 (0.76–2.12) 0.367
T3 Re e ence Re e ence
T4 1.01 (0.54–1.86) 0.988 1.04 (0.52–2.11) 0.908
Lymph node s a us (N) *
N0 Re e ence Re e ence
N1 1.72 (1.20–2.47) 0.003 2.62 (1.68–4.08) <0.001
N2 1.86 (0.99–3.50) 0.055 1.249 (0.70–3.17) 0.303
Resec ion ma gin (R)
R0 Re e ence
R1 0.99 (0.71–1.38) 0.940
Tumo di e en ia ion
Figu e 3.
Es ima ed cumula i e ecu ence p obabili y o N0R0, N0R1, N+R0, and N+R1 pa ien s.
Only he i s 5 yea s a e displayed. The median ecu ence- ee su i al was 27 mon hs (95% CI
20.4–33.6) o N0R0, 33 mon hs (95% CI 19.5–46.5) o N0R1, 14 mon hs (95% CI 7.4–20.6) o N+R0,
and 11 mon hs (95% CI 5.7–16.3) o he N+R1 pa ien s (p< 0.001). N0R0 s. N+R0: p= 0.151, N0R1
s. N+R1: p< 0.001, N+R0 s. N+R1: p= 0.109, N0R0 s. N0R1: p= 0.331.
4. Discussion
This s udy shows ha o pa ien s who unde go a esec ion o pCCA, posi i e lymph
nodes ha e a majo nega i e e ec on ecu ence and su i al. Su p isingly, his was
independen o esec ion ma gin s a us. In addi ion, ECOG pe o mance s a us, posi i e
lymph nodes, and he g ade o umo di e en ia ion we e ound as he main indepen-
den indica o s o oncological ou come. These indings sugges ha umo biology and
pe o mance s a us ha e a highe impac on su i al han ex ended o adical su ge y.
Se e al s udies desc ibe he ou comes o pa ien s wi h esec ed pCCA. Howe e , mos
o hese s udies a e single-cen e o single-coun y s udies and o en only include small
numbe s o pa ien s. The p esen analysis is he i s s udy om he ENSCCA egis y
add essing esec ed pCCA. The egis y ep esen s a la ge coho , wi h pa ien s om
mul iple expe cen e s ac oss Eu ope.
P e ious s udies epo ed compa able di e ences be ween he su i al a es o pa-
ien s wi h and wi hou lymph node in ol emen [
4
,
6
,
19
]. Fo pa ien s wi h locally ad-
anced disease who do no unde go esec ion, median OS a es o 12 mon hs a e epo ed.
Wi h he OS o N+ be ween 12 and 18 mon hs and he mo ali y a e o 23% ound in his
