Prognosis for GIST. Table 1. Antibodies, dilutions and sources in the present study. Pretreatment. Source*. Microwave. Clone. Poly. Qbend10. 1A4. Poly. Dilution.
〃"Jα伽Oncoﾉ2002,32仰347-351
HelpfulParameterforMalignantPotentialofGastrointestinalStromal Tumors(GIST) X i a o j u a n W a n g ' , I c h i r o M o r P , W e i h u a T a n g i , H i r o t o s h i U t s u n o m i y a ^ , M i s a N a k a m u r a ^ , Y a s u s h i N a k a m u r a ^ G e n y i n g Z h o u * a n d K a k u d o K e n n i c h P ^DepartmentofPathology,WakayamaMedicalUniversity,WakayamaCity,Japanand^DepartmentofPathology SchoolofMedicine,ShandongUniversity,Jinan,China ReceivedOctober15,2001;acceptedMay30,2002
Background:Althoughaseriesofhistopathologicalcriteriahavebeensuggested,thepredictionofthemalignantpotentialofgastrointestinalstromaltumors(GIST)isstilldi什icult.The o l d e r l i t e r a t u r e c a l l e d a l l g a s t r o i n t e s t i n a l s t r o m a l t u m o r s s m o o t h m u s c l e t u m o r s o r m i x e d G I S T withtruesmoothmuscletumors.ReportsonGISTincludinghomogeneouscaseswererare. Methods:Weexamined73casesofGIST,whichwereimmunohistochemicallypositivefor c-kitand/orCD34,andmainlyfocusedonthecorrelationbetweenmitoticcountandtheother c l i n i c o p a t h o l o g i c a l f e a t u r e s t o e s t a b l i s h a n y h e l p f u l a n d r e p r o d u c i b l e p a r a m e t e r s t o i n d i c a t e t h e m a l i g n a n t p o t e n t i a l a n d t o b e u s e d p r a c t i c a l l y a n d o b j e c t i v e l y i n t h e r o u t i n e h i s t o p a t h o l o g i c a l diagnosisofGIST. R e s u l t s : T h e r e s u l t s s h o w e d t h a t t h e r e w a s a s t a t i s t i c a l l y s i g n i f i c a n t d i 什 e r e n c e i n m i t o t i c c o u n l betweenbenignandmalignantgroups.Otherproposedparameters,suchashighcellularity, tumorsize≧5cm,stomachandintestinallocation,hemorrhage,necrosis,p53expressionand Ki-67labelingindex>10%,werefrequentlyobservedintumorswithmitoticfigure.Three patientswithonemitoticfigurein50HPFdiedfrommetastasisorrecurrenceofthetumors. Conclusions:Ki-67indexandcellularityshouldbeusedaspredictorsforthemalignantpotentialofGIST.Whenothermorphologicalfeaturesappearbenign,mitoticcountmightalsobea h e l p f u l p r a c t i c a l f a c t o r i n t h e p r e d i c t i o n o f t h e m a l i g n a n t p o t e n t i a l o f G I S T . Keywo此なgas"℃加趣""αﾉs"℃〃α〃"〃o応一αﾉimentarytrαα−""oticco""/一p'りg"“な−伽αﾉ靭7α耐 p o t e n t i a ノ
INTRODUCTION
Gastrointestinalstromaltumors(GIST)arethemostcommon
non-epithelialtypeoftumoramongthosearising廿omthe g a s t r o i n t e s t i n a l t r a c t ・ T h e h i s t o l o g i c a l o r i g i n o f t h i s t u m o r h a s r e c e n t l y b e e n s u g g e s t e d t o b e t h e i n t e r s t i t i a l c e l l s o f C a j a l ( 1 ) b e c a u s e o f i t s e x p r e s s i o n o f c k i t a n d / o r C D 3 4 . A s e r i e s o f h i s t o p a t h o l o g i c a l c r i t e r i a h a v e b e e n r e p o r t e d t o p r e d i c t t h e m a l i g n a n t p o t e n t i a l o f t h e s e t u m o r s b u t t h e i r c o n c l u s i o n s v a r i e d . I t w a s r e p o r t e d t h a t t h e p r o g n o s i s o f t h e G I S T c o r r e l a t e d w e l l w i t h m i t o t i c c o u n t , t u m o r s i z e , t u m o r c e l l u l a r i t y , t u m o r n e c r o s i s , a n a t o m i c a l l o c a t i o n , i n v a s i v e g r o w t h ( 2 7 ) a n d e x p r e s s i o n ofKi-67(8-12)andPCNAindex(13).However,diagnosis a n d p r e d i c t i o n o f t h e m a l i g n a n t p o t e n t i a l o f G I S T i s s t i l l d i f f i c u l t . O n t h e o t h e r h a n d , t h e o l d e r l i t e r a t u r e c a l l e d a l l s t r o m a l
F o r r e p r i n t s a n d a l l c o r r e s p o n d e n c e : X i a o j u a n W a n g , D e p a r t m e n t o f
P a t h o l o g y , W a k a y a m a M e d i c a l U n i v e r s i t y , 8 1 1 1 K i m i i d e r a , W a k a y a m a C i t 6 4 1 0 0 1 2 , J a p a n . E m a i l : w a n g x j @ m a i l . w a k a y a m a m e d . a c . j p
tumorssmoothmuscletumorsormixedGISTwithtrue
smoothmuscletumors,becausethelatteroftenoccurinthe
e s o p h a g u s a n d s h o w c l e a r e r b i o l o g i c a l b e h a v i o r ・ T h e s t u d y o f homogeneousgroupsoftrueGISThasthereforebeenadvocated(14).Theaimofthisstudywastoestablishanyhelpful a n d r e p r o d u c i b l e p a r a m e t e r s t o i n d i c a t e m a l i g n a n t p o t e n t i a l a n d t o b e u s e d p r a c t i c a l l y a n d o b j e c t i v e l y i n t h e h i s t o p a t h o l o g icaldiagnosisofGIST.Weexamined73casesofGIST immunohistochemicallypositiveforc-kitand/orCD34and
m a i n l y f o c u s e d o n t h e c o r r e l a t i o n b e t w e e n m i t o t i c c o u n t a n d o t h e r p r o p o s e d c l i n i c o p a t h o l o g i c a l f e a t u r e s . T h o s e c a s e s n e g a tiveforc-kitorCD34wereexcludedfromthestudy. PATIENTSANDMETHODS
S e v e n t y t h r e e c o n s e c u t i v e c a s e s o f G I S T w e r e s e l e c t e d f r o m 106casesoftumorspreviouslydiagnosedasleiomyoma. leiomyoblastomaandleiomyosarcomafromthefilesofthe D e p a r t m e n t o f P a t h o l o g y , S h a n d o n g U n i v e r s i t y , C h i n a , i n t h e 30-yearperiodfrom1969to1999,basedonimmunohisto◎2002FoundationforPromotionofCancerResearch
348PﾉognosisforGIST
T a b i c 1 . A n t i b o d i e s , d i l u t i o n s a n d s o u r c e s i n t l i c p r e s e n t s t u d ，
c k i t
PretreatnientDilution
Poly
Microwave
('1)34
QbendlO
Microwave
SMA
IA4
None
S-IOO
P o l y
None
Ki-67
M肥-1
None
P53
D07
Microwave
︵Ｕ Ｕ︿ ︿Ｕ Ｕ︿ ︿Ｕ Ｕ Ｏ５０︿
Clone
２ ２４．−３戸３．４ ●●■■■■①●●号●■ ！ １１１１！
Antibodv
Source*
* 1 , I m mu n o B i o c h e m i c a l L aboratories,I'ujioka,Japan;2,Novoc astra,Newcastle,UK;3,SigmaChemical,StLouis,MO,USA;4,DAKO,Kyoto,Japan; 5.Immunotech.Marseilles,France.
chemicalsludiesonc-kilandCD34.AMspecimenswerefrom
patientswhounderwentcompletelysurgicalexcisionwithoul r e c o r d o f p o s i t i v e m a r g i n . A l l o f t h e s e s u r g i c a l s p e c i m e n s w e r e routinelyHxedinformalinandembeddedinparaffin.Atleast 4-5paraffinblockswereavailableineachcaseforstudy. C l i n i c a l i n f o r m a t i o n i n c l u d i n g l u m o r s i z e w a s o b t a i n e d f r o m surgicalandpathologicalrecords.Tumorsthatdeveloped recurrenceormetastasiswerejudgedasmalignant,including t h o s e w h i c h i n d u c e d d e a t h o f t h e p a t i e n t . T u m o r s w i t h p e r i p h eralinvasivegrowthmicroscopicallywerealsodiagnosedas malignant.Theothercaseswithouttheaboveevidenceof m a l i g n a n c y w e r e c l a s s i f i e d a s b e n i g n i n t h i s s t u d y , a l t h o u g h therewasstillaslightchanceofmalignancyinthebenign group.
N o m i t o s i s g r o u p , l o w m i t o s i s g r o u p a n d h i g h m i t o s i s g r o u p weredefineddependingonmitoticnumbersasdescribedprev i o u s l y ( 4 , 5 , 1 3 , 1 4 ) . B r i e O y , 1 0 h i g h p o w e r f i e l d s i n o n e g r o u p wereobservedtofindthemitoticfigureathighcellularity fields;atotaloi"fivegroups(50high-powerfields)were observedineachcase.No-mitosiscasesvirtuallyshowedno mitosis,i.e､0/50HPF,low-mitosiscasesshowed1-4mitotic
figuresin50HPFandhigh-mitosiscasesshowed>5mitolic f i g u r e s i n 5 0 H P F . S i m u l t a n e o u s l y , ( I ) h i s t o l o g i c a l p a t t e r n : l e i o myoma-liketype,Schwannoma-liketype,leiomyoblastomal i k e t y p e a n d m i x e d t y p e ; ( 2 ) c e l l u l a r i t y : l o w ( 1 ) , i n t e r m e d i a t e ( I I ) a n d h i g h ( I I I ) ; ( 3 ) t u m o r n e c r o s i s : p r e s e n c e o r a b s e n c e ; a n d (4)tumorhemorrhage:presenceorabsence,werealsoinvcstigatedineachcase. Astandardlabeledslreptavidin-biolin(LSAB)methodof immunohistochemistrywasused.Thedilution,sourcesand pretreatmentofanfibodiesaresummarizedinTableI.Positive
a n d n e g a t i v e c o n t r o l s w e r e u s e d p r o p e r l y . Forp53,theresultswereclassifiedintothreegroups(no s t a i n i n g f o r n e g a t i v e , d i s t i n c d y s t a i n e d c e l l s < 5 0 % f o r o n e p l u s p o s i f i v e a n d > 5 0 % f o r t w o p l u s p o s i f i v e ) . F o r K i 6 7 i n d e x , t h e r e s u l t s w e r e c l a s s i f i e d i n t o t w o g r o u p s ( d i s t i n c t l y s t a i n e d c e l l s 10%foranothergroup). Time-independentcontinuousvariableswereevaluated usingStudent's/-testandthechi-squaredtestwasusedfor categoricaldata.TheFstatisticwastestedtoestimatethecor-
Figure1.(a)No-mitoticgroup.Thetumorismainlycomposedofspindle c e l l s , w i t h l o w c e l l u l a r i t y a n d f e w m i t o t i c f i g u r e s , ( b ) L o w m i t o t i c g r o u p . T h e t u m o r i s c o m p o s e d o f s p i n d l e c e i l s a n d s h o r t r o d c e l l s , w i t h m o d e r a t e c e l l u l a r i t y . M i t o t i c f i g u r e s a r e s e e n o c c a s i o n a l l y ( 1 4 / I 0 H P I ' ) . ( c ) l l i g h m i t o s i s g r o u p . T h e t u m o r i s m a i n l y c o m p o s e d o f s h o r t r o d c e l l s a n d i r r e g u l a r c e l l s w i t h h i g h c e l l u l a r i t y . M i t o l i c f i e u r e i s e a s i e r t o f i n d ( > 5 / 1 0 H P F ) .
relationbetweenmitosisandtheotherparameters.Survival a n a l y s i s w a s d o n e w i t h t h e S t a l V i e w J 5 ・ 0 s t a l i s t i c a l s o f t w a r e
p a c k a g e ( S A S I n s t i t u t e , G a r y , N C ) . F o r u n i v a r i a t e a n a l y s i s o f lime-dependentvariables,theKaplan-Meiermethodandthe l o g r a n k t e s t w e r e u s e d t o d e t e r m i n e s i g n i f i c a n t p r o g n o s l i こ f a c t o r s . I n m u l t i v a r i a t e a n a l y s i s , a C o x p r o p o r t i o n a l h a z a r d s
〃"Jα肋Oncoﾉ2002;32(9)34S
T a b l e 2 ･ C l i n i c a l , h i s t o c h e m i c a l , i m m u n o h i s t o c h e m i c a l a n d f o l l o w u p r e s u l t s i n t h e s t u d y Benign(=38)Malignant(n=35)Pvalue Age(years)
48.9
51.8
NS
Male:female
19:19
23:12
NS
5．31
9.20
O・O001
12:16:7:2
1:18:15:1
Evsothers,P=0.0015
H i s t o l o g i c a l p a t t e r n ( L e h o t h e r s ]
30:8
Low-mitosis(1-4/10HPF)
12/38
H i g h m i t o s i s ( > 5 / 1 0 H P F )
2/38
N e c r o s i s ( + : )
15:23
Hemorrhage
14:24
Ki-67
14:24
p53
13:25
Alive:dead*
18:0
︽’一二一全一Ｅ一一口一︾｜匡一■一︾︹一一”一一一一︽叩︾
21:17 24/38
●■且一︽Ｕ戸、︺今、︾句、︾○○匂〃〃。■且■■且■Ⅱ且
C e l l u l a r i t y ( l o w : m i d + h i g h ) No-mitosis(0/1OHPF)
駄９ ２０ Ｂ１ 創１ 刀２ 証２ ＆２ 動２ 銑５ ２ ２
Meantumorsize(cm' L o c a t i o n ( E : S : S I : L I )
SIvsothers,P=0.039S NS 0.0168
