Exp ession o P-glycop o ein and Me allo hionein
in Gas oin es inal S omal Tumo and Leiomyosa comas.
Clinical Implica ions
So ia PÉREZ-GUTIÉRREZ,1Rica do GONZÁLEZ-CÁMPORA,2Joaquín AMÉRIGO-NAVARRO,3
An onio BEATO-MORENO,4Ma ía SÁNCHEZ-LEÓN,2Ma ía Jesús PAREJA MEGÍA,2
Juan An onio VIRIZUELA-ECHABURU,5An onio LÓPEZ-BELTRÁN6
1Pa hology Se ice, Juan Ramón Jiménez Hospi al, Huel a; 2Depa men o Pa hology, Vi gen Maca ena Uni e si y
Hospi al and Uni e si y o Se ille Medical School, Se ille; 3Pa hology Se ice, Hospi al To ecá denas, Alme ía;
4Depa men o S a is ic and Ope a ions Resea ch, Uni e si y o Se ille, Se ille; 5Oncology Se ice,
Vi gen Maca ena Uni e si y Hospi al, Se ille; 6Depa men o Pa hology, Reina So ia Uni e si y Hospi al
and Có doba Uni e si y Medical School, Có doba, Spain
ARTICLE
© 2007 A ányi Lajos Founda ion
PATHOLOGY ONCOLOGY RESEARCH Vol 13, No 3, 2007
A icle is a ailable online a h p://www.webio.hu/po /2007/13/3/0203
In oduc ion
Gas oin es inal s omal umo s (GIST) a e neoplasms
o igina ing om in e s i ial cells o Cajal (ICC) o hei
p ecu so ,9and accoun o 1-3% o malignancies in he
Recei ed: Oc 17, 2006; accep ed: July 10, 2007
Co espondence: P o . Rica do GONZÁLEZ-CÁMPORA, Depa -
men o Pa hology, Vi gen Maca ena Uni e si y Hospi al, A da, D .
Fed iani s/n, 41009 Se ille, Spain. Tel: 34 955008556, Fax: 34
954371284, e-mail: [email p o ec ed]
We in es iga ed he exp ession o P-glycop o ein
(P-GP) and me allo hionein (MT) in a se ies o 92
GIST and 14 gas oin es inal leiomyosa comas (GI-
LMS) wi h he pu pose o expand ou knowledge
on he biological bases o GIST chemo- esis ance
and o asce ain hei signi icance in pa ien s’ p og-
nosis. P-GP exp ession was mo e equen in GIST
han in GI-LMS (83.7% s. 21.4%, p<0.001), wi h no
di e ence be ween low- and high- isk GIST
(p=1.000) o low- and high-g ade GI-LMS (p=0.538).
P-GP exp ession was un ela ed o ana omic loca-
ion (gas ic s. in es inal) in GIST (39/45 s. 35/43,
p=0.770) and in GI-LMS (0/2 s. 2/6, p=1.000). MT
exp ession was non-signi ican ly highe in GI-LMS
han in GIST (35.7% s. 14.1%, p=0.060), wi h no
di e ence be ween low- and high- isk GIST
(p=1.000) o low- and high-g ade GI-LMS (p=1.000).
MT exp ession was un ela ed o he ana omic loca-
ion (gas ic s. in es inal) in GIST (7/45 s. 6/43)
and GI-LMS (0/2 s. 1/6) (p=1.000 and p=0.1000,
espec i ely). O e all umo -speci ic su i al (p<
0.001) and disease- ee su i al (p<0.001) we e di -
e en in GIST as compa ed wi h GI-LMS, and he
numbe o e en s was highe in GI-LMS. When he
su i al analysis ook in o conside a ion P-GP o
MT exp ession, he o e all su i al in GIST was
in luenced by he exp ession o MT (p=0.021) bu
no by ha o P-GP (p=0.638). Howe e , in GI-LMS,
P-GP exp ession in luenced disease- ee su i al
(p=0.050); in addi ion, i is impo an o ecognize
he limi ed alue o hese esul s because o he low
numbe o cases in ol ed in he s udy. Di e en ial
exp ession o P-GP and MT migh explain he
known a iabili y in esponse o sys emic
chemo he apy in hese umo s. De ec ion o P-GP
and MT seems o add ce ain p ognos ic alue in
GIST (MT) o GI-LMS (P-GP).
(Pa hology Oncology
Resea ch Vol 13, No 3, 203–208)
Key wo ds: gas oin es inal s omal umo s, GIST, leiomyosa comas, P-glycop o ein, me allo hionein
gas oin es inal ac (GI).1Un il 1998, when Hi o a e al10
and Kindblom e al13 demons a ed ha GIST a e a special
g oup o GI mesenchymal umo s cha ac e ized by CD117
exp ession and equen KIT mu a ion, mos o hese neo-
plasms we e conside ed leiomyosa comas (LMS), we e
ea ed wi h chemo he apy and had low esponse a e.
This chemo- esponse con as ed wi h hose epo ed in
LMS in o he loca ions whe e he esponse a e was sig-
ni ican ly highe .3The biological bases o chemo-sensi i -
i y o hese neoplasms emain unce ain, bu i is well
known ha an h acyclines and cispla in, d ugs used in
ad anced LMS and GIST, a e he subs a e o mul i-d ug
esis ance (MDR) p o eins15 and me allo hionein (MT),12
espec i ely.
On he o he hand, since he in oduc ion o he apeu ic
a ge ing wi h y osine kinase inhibi o ima inib (Glee ec,
No a is Pha ma AG, Basel, Swi ze land) o GIST ea -
men ,11 special e o has been made o sepa a e his umo s
om hei mimic y, and specially om LMS, which has
e y low- o-null esponse o ima inib,14 which is in i o
also a subs a e o MDR.7
Ou pu pose is o es ablish whe he o no he exp es-
sion o he MDR p o eins, pa icula ly P-glycop o ein (P-
GP) and me allo hionein (MT) may co ela e o he
pa ien s’ ou come and i addi ionally migh assis o
explain he obse ed di e ences in esponse o sys emic
chemo he apy in a se ies o GIST and gas oin es inal
LMS (GI-LMS).
Ma e ial and me hods
Pa ien s
The s udy g oup included 106 pa ien s wi h GIST (n=92)
o GI-LMS (n=14) e ie ed om 3 hospi als in Sou he n
Spain. Pa ien s’ ollow-up was a ailable in 77 cases (64
GIST and 12 GI-LMS) and was calcula ed as he numbe
o mon hs om he da e o he su gical p ocedu e o he
las isi o dea h. The o e all umo -speci ic su i al was
de ined as he ime be ween diagnosis and he pa ien ’s
dea h. The disease- ee su i al was de ined as he ime
be ween he diagnosis and he i s elapse o he appea -
ance o me as ases. Cance - ela ed dea h was de ined as
ha caused by he umo .
Pa hology
GIST umo s we e g ouped in o wo p ognos ic ca e-
go ies esul ing om g ouping he ou ca ego ies o igi-
nally p oposed by Fle che e al5wi h he addi ion o an
“o e ly malignan g oup”:16 low (65: 3 e y low isk, 42
low isk, 20 in e medium isk) and high (27: 26 high isk,
1 o e ly malignan wi h me as asis). LMS20 we e g aded
as low (n=8) and high (n= 6). In o de o de e mine i he
exp ession o P-GP o MT in GI-LMS is egion-depen-
den , an addi ional g oup o 26 non-GI LMS om he
u e us (12), e ope i oneum (8), skin and so issues (6)
was e alua ed. Addi ional immunohis ochemical ma ke s
(CD117, CD34, smoo h muscle ac in, desmin and S-100)
we e included o con i m pa hologic diagnosis in GIST
and LMS.
A ailable hema oxylin and eosin s ained slides we e e-
assessed by h ee pa hologis s (SGP, RGC, ALB) blind o
he clinical s a us. Fo immunohis ochemis y, a ep e-
sen a i e pa a in block om each umo , selec ed based
on he amoun o umo p esen , was se ially cu a 4 µm
hick, depa a inized in xylene, ehyd a ed in g aded
e hanol and washed o 5 min wi h phospha e-bu e ed
saline. Fo an igen e ie al, he sec ions we e boiled
imme sed in 10 mM ci a e bu e (pH 6.0). To a oid non-
speci ic CD117 immunos aining, we ollowed he manu-
ac u e ecommenda ions and he p ocedu e included
wi h Ta ge Re ie al Solu ion (S1699, Dako, Glos up,
Denma k). Endogenous pe oxidase was blocked by incu-
ba ion o he slides o 30 minu es wi h 3% hyd ogen pe -
oxide in me hanol. Sec ions we e hen incuba ed wi h he
p ima y mouse monoclonal an ibodies a oom empe a-
u e (Table 1).
Immunohis ochemis y was pe o med using he high-
ly sensi i e polyme -based sys em (EnVision, Dako) 30
min a oom empe a u e wi h diaminobenzidine ch o-
mogen subs a e solu ion (0.6 mg/ml in T is-bu e ed
saline, pH 7.6, wi h 12 ml 30% hyd ogen pe oxide). Sec-
ions we e coun e s ained wi h Maye ’s hema oxylin,
dehyd a ed and moun ed ollowing s anda d p ocedu e.
Th ee pa hologis s (SGP, RGC, ALB) independen ly
e alua ed all immunos ainings in a blinded ashion. The
ollowing s aining pa e ns we e conside ed: CD117,
cy oplasmic and/o memb ane; CD34, memb ane;
smoo h muscle ac in and desmin, cy oplasmic; S-100,
cy oplasmic and nuclea ; P-GP, memb ane and some-
imes also cy oplasmic; MT, cy oplasmic and nuclea .
Cases wi h less han 10% posi i e cells we e conside ed
nega i e.
204 PÉREZ-GUTIÉRREZ e al
PATHOLOGY ONCOLOGY RESEARCH
Table 1. P ima y an ibodies used in he assessmen o GIST and GI-LMS
P ima y an ibodies Clone Wo king dilu ion Sou ce Con ols
CD117 (c-ki ) 104D2 1:50 Dako mas cells
CD34 AM236-5M p edilu ed Biogenex endo helial cells
Smoo h muscle ac in 1A4 p edilu ed Dako muscle laye om in es inal wall
Desmin D33 p edilu ed Dako muscle laye om in es inal wall
S-100 p o ein AM058-5M p edilu ed Biogenex Schwann cells om no mal in es inal wall
Me allo hionein E9 1:200 Dako mamma y gland
P170/P-glycop o ein C494 p edilu ed LabVision Co co ical ad enal gland
MDR Ab-5
S a is ical analysis
Bi a ia e analysis o compa e
p ognos ic ca ego ies and he
exp ession o P-GP and MT
we e unde aken by Fishe es
and chi-squa e analysis. Uni a i-
a e su i al analysis o P-GP
and MT exp essions was con-
duc ed using Kaplan-Meie
me hod and di e ences among
g oups we e es ed by log- ank
es . All s a is ical analyses we e
pe o med using he SPSS o
Windows So wa e (SPSS Inc,
Chicago, IL, USA). A p- alue o
less han 0.05 was conside ed as
signi ican .
Resul s
Table 2 shows ele an com-
pa a i e da a on GIST and GI-
LMS cases included in his s udy.
Plasma memb ane and some-
imes cy oplasmic exp ession o
P-GP was obse ed in GIST
(83.7%) and GI-LMS (21.4%)
(p<0.001) (Fig. 1a,b). No di e -
ences we e ound be ween low-
and high- isk GIST (p=1.000) o
low- and high-g ade GI-LMS
(p=0.538). In he same way, P-
GP exp ession was un ela ed o
ana omic loca ion (gas ic s.
in es inal) in GIST (39/45 s.
35/43, p=0.770), in bo h low-
(p=0.447) and high- isk g oups
(p=0.355), and in GI-LMS (0/2
s. 2/7, p=1.000).
MT was de ec ed in sca e ed
umo cells in he cy oplasm and
occasionally in he nucleus (Fig. 1c,d) in GI-LMS (35.7%)
and GIST (14.1%) (p=0.060). No di e ences we e
obse ed be ween low- and high- isk GIST (p=1.000) o
low- and high-g ade GI-LMS (p=1.000). No associa ion
was ound be ween MT exp ession and ana omical loca-
ion (gas ic s. in es inal) in GIST (7/45 s. 6/43) o GI-
LMS (0/2 s.1/6) (bo h p=1.000). Simul aneous P-GP and
MT exp ession was obse ed in 11/92 GIST and 1/14 GI-
LMS cases (p=1.000).
O e all umo -speci ic su i al and disease- ee su -
i al we e di e en in GIST as compa ed wi h GI-LMS
(bo h p<0.001); he numbe o e en s was highe in GI-
LMS (Table 3). When he s udy was es ic ed o high-
isk GIST and all GI-LMS, no signi ican di e ences
we e obse ed in o e all o disease- ee su i al
(p=0.081 and p=0.373, espec i ely). When he su i al
analysis ook in o conside a ion P-GP o MT exp ession,
he o e all su i al in GIST was in luenced by he
exp ession o MT (p=0.021) bu no by P-GP (p=0.638).
On he o he hand, P-GP exp ession signi ican ly in lu-
enced disease- ee su i al in GI-LMS (p=0.050) (Table
3); howe e , i is impo an o ecognize he limi ed alue
o hese esul s because o he low numbe o cases
in ol ed in he s udy. No di e ences we e obse ed
205
P-glycop o ein and Me allo hionein in GIST and Leiomyosa comas
Vol 13, No 3, 2007
Table 2. Clinical, pa hological da a and ma ke exp ession in 92 cases o GIST as
compa ed wi h 14 GI-LMS cases
GIST (n=92) GI-LMS (n=14)
Age (yea s)
Mean 61.44 70.83
Median 64.00 74.50
Sex
Male 49 (53.3%) 4 (28.6%)
Female 43 (46.7%) 10 (71.4%)
Loca ion
S omach 45 (48.9%) 2 (14.3%)
Small bowel 38 (41.3%) 5 (35.7%)
La ge bowel 5 (5.4%) 2 (14.3%)
Mesen e y-omen um 4 (4.3%) 5 (35.7%)
Size (cm)
Mean 6.85 8.28
Median 5.00 9.00
Cell ype
Spindle 66 (71.7%) 14 (100%)
Epi helioid 22 (23.9%) –
Mixed 4 (4.3%) –
Risk/g ade ca ego y
Low 65 (70.7%) 8 (57.1%)
High 27 (29.3%) 6 (42.9%)
Make immuno eac i i y
P-glycop o ein 77 (83.7%) 3 (21.4%)
Low- isk: 58 (89.2%) Low-g ade: 1 (12.5%)
High- isk: 19 (70.4%) High-g ade: 2 (33.3%)
Me allo hionein 13 (14.1%) 5 (35.7%)
Low- isk: 8 (12.3%) Low-g ade: 3 (37.5%)
High- isk: 5 (18.5%) High-g ade: 2 (33.3%)
Clinical ollow-up n=64 (69.5%) n=13 (86.6%)
Low- isk: 43 (67.2%) Low-g ade: 8 (61.5%)
High- isk: 21(32.8%) High-g ade: 5 (38.5%)
Mean (mon hs) 66.48 32.08
Median (mon hs) 36.00 23.50
Tumo ecu ence 10 (15.6%) 4 (33.3%)
Me as ases 8 (12.5%) 6 (50%)
Ali e wi h disease 11 (17.2%) 2 (16.7%)
Ali e wi hou disease 41 (64.0%) 3 (25.0%)
Dead o disease 8 (12.5%) 7 (58.3%)
Dead o o he causes 4 (6.2%) 0 (0%)
be ween GI-LMS and non-GI
LMS o P-GP (p=0.199) o MT
exp ession (p=0.979).
Discussion
Se e al d ug esis ance p o-
eins ha e been conside ed as he
sou ce o explaining chemo-sen-
si i i y in malignan umo s.
Two o he mos ex ensi ely
s udied p o eins a e P-GP and
MT. P-GP is a ansmemb ane
p o ein, encoded by he MDR1
gene, which ac s as an e lux
anspo e sys em o a a ie y
o o ganic subs ances, including
cy o oxic d ugs, like an h acy-
clines, Vinca alkaloids and
epipodophyllo oxins.15 MT is a
low-molecula -weigh cys ein-
ich enzyme ha binds di alen
206 PÉREZ-GUTIÉRREZ e al
PATHOLOGY ONCOLOGY RESEARCH
Table 3. O e all and disease- ee su i al o pa ien s wi h GIST and GI-LMS
acco ding o P-glycop o ein and me allo hionein exp ession
O e all Disease- ee
su i al p- alue su i al p- alue
GIST P-glycop o ein P-glycop o ein
– + – +
1/12 7/52 p=0.638 4/12 15/52 p=0.692
Me allo hionein Me allo hionein
– + – +
5/56 3/8 p=0.021 16/56 3/8 p=0.571
GI-LMS P-glycop o ein P-glycop o ein
– + – +
7/10 0/2 p=0.066 8/10 1/2 p=0.050
Me allo hionein Me allo hionein
– + – +
3/7 4/5 p=0.258 4/7 5/5 p=0.210
GIST s.
GI-LMS 8/64 s.7/12 p<0.001 19/64 s. 9/12 p<0.001
Da a a e p esen ed as numbe o e en s / case numbe in he g oups wi h nega i e o
posi i e exp ession o he ma ke s
Figu e 1. Gas oin es inal s omal umo . Posi i e immuno eac ion o P-GP, 20x (a) and MT, 40x (b). Gas oin es inal leiomyosa -
coma. Posi i e immuno eac ion o P-GP, 40x (c) and MT, 20x (d)
ab
cd
me al ions and plays a p o ec i e ole agains an icance
d ugs, such as cispla in.4,12 I is well known ha GIST is
mo e chemo- esis an han LMS,3,14,18 bu li le is known
on he subjacen mechanism. Plaa e al18 s udied he
exp ession o P-GP, MRP1 and LRP in 29 pa ien s wi h
so issue LMS and 26 pa ien s wi h a p ima y malignan
GIST, and ound ha P-GP and MRP1 exp essions we e
signi ican ly highe in GIST han in LMS, and ha pa ien s
wi h LMS had a be e o e all su i al and a me as a ic
pa e n di e en om GIST. Mo e ecen ly, Theou e al19
in es iga ed he exp ession o MDR p o eins (P-GP,
MRP1 and BCRP) by Wes e n blo ing in 21 GIST cases,
showing P-GP and MRP1 in 86% and 62%, espec i ely,
and nega i i y o BCRP. These au ho s ound signi ican
di e ences in P-GP exp ession be ween gas ic and non-
gas ic umo s. In addi ion, hey sugges ed ha MDR p o-
eins do no impai he ini ial esponse o he umo o ima-
inib, since none o he six pa ien s ea ed wi h ima inib
was esis an .
In he p esen se ies we ha e ound simila esul s
ega ding P-GP, showing signi ican di e ences be ween
GIST and GI-LMS. On he o he hand, GI-LMS had a
wo se o e all (p<0.001) and disease- ee (p=0.001) su -
i al han GIST, bu when only high- isk GIST en e ed he
analysis, no di e ences we e ound. This inding, which
di e s om ha epo ed by Plaa e al,18 may be ela ed o
Plaa ’s selec ion c i e ia since hey included high- isk
GIST only, 68% o which exp essed c-ki . In his se ies we
could no con i m he di e en P-GP exp ession be ween
gas ic and in es inal cases, since 39/45 o gas ic and
35/43 o non-gas ic neoplasms exp essed P-GP. None o
ou pa ien s we e ea ed wi h ima inib.
MT exp ession is known as an ad e se p ognos ic ac o
in some umo s, including sa comas2bu , as a as we
know, his is he i s epo ela ing i s exp ession wi h
su i al in GIST. We ha e ound no signi ican di e ences
be ween GI-LMS (35.7%) and GIST (14.1%) (p=0.060),
bu in GIST, MT exp ession was associa ed wi h o e all
cance -speci ic su i al (p=0.021). Ou esul s in GI-LMS
ag ee wi h hose o Gaumann e al6whe e MT exp ession
in LMS was un ela ed o he pa ien s’ su i al.
We did no ind any di e ences in he P-GP and MT
exp ession be ween GI-LMS and non-GI LMS, a inding
ha may help o explain ha he lowe esponse a e o
con en ional chemo he apy, obse ed in p e ious GI-
LMS se ies,3could be ela ed o misclassi ica ion o
umo s a he han hei loca ion. None heless, chemo-
esis ance is a complex phenomenon whe e o he d ug
esis ance21 and/o an i-apop o ic mechanisms ela ed o
KIT o PDGFRA o e exp ession a e implica ed.8,17 In
GIST, ima inib esis ance seems o be ela ed o KIT o
PDGFRA mu a ions a he han o MDR p o eins sys-
ems, since some speci ic mu a ions cause a low o null
esponse.8
In conclusion, di e ences in P-GP and MT exp ession
could help o explain he obse ed esponse o sys emic
chemo he apy in GIST and LMS. Immunoexp ession o P-
GP and MT may assis in di e en ia ing GIST and GI-
LMS in selec ed cases, and seems o and ce ain p ognos-
ic alue in GIST (MT) and GI-LMS (P-GP).
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